CADTH Reimbursement Review

Tralokinumab (Adtralza)

Sponsor: LEO Pharma Inc.

Therapeutic area: Atopic dermatitis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Introduction

Atopic dermatitis (AD) is the most common type of eczema. It is a chronic, relapsing, inflammatory skin condition characterized by severely itchy skin (pruritus) that results in red and swollen skin (rash). Lesions associated with AD may appear as fluid-filled vesicles that ooze, crack, and crust. Pruritus of the skin can cause frequent scratching and may result in lichenification (thickening of the skin) and secondary skin infections. Atopic dermatitis typically involves the skin folds behind the knees (popliteal areas) and in front of the elbows (antecubital areas). It may also appear on the face, neck, and hands. Individuals with AD have skin with impaired barrier function and reduced water-holding capacity, resulting in dry skin that requires treatment with specific bathing, cleansing, and moisturizing practices.

The goals of AD management are to prevent flares (episodes of worsening symptoms typically requiring escalation of treatment), and effectively manage flares when they occur by preventing disease progression. While there is no cure for AD, several therapeutic options are available to patients to manage the condition. The majority of patients treat AD by using general skin care methods, avoiding skin irritants, and applying topical anti-inflammatory treatments. If these common methods fail to improve AD, patients may use off-label systemic (i.e., immunosuppressant) therapy or other therapies such as phototherapy.

The most common pharmaceutical topical therapies include the use of topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs). The former act as anti-inflammatory therapies and are considered first-line treatment for AD.² The latter are steroid-free, anti-inflammatory, immunosuppressant drugs that can be used long-term. In Canada, the 2 available second-line drugs are pimecrolimus and tacrolimus. Crisaborole, a topical phosphodiesterase type 4 inhibitor, is also available in Canada, although it is not recommended by CADTH for reimbursement.^1,2 Phototherapy is another second-line therapy that is commonly used after failure of TCS, TCIs, and crisaborole.¹⁶

Systemic therapy for AD typically involves the use of antimicrobials, antihistamines, or immunomodulators.^15-17 Immunomodulatory drugs, including methotrexate, cyclosporine, mycophenolate mofetil, azathioprine (listed in order of frequency of use in Canada), can be used in patients who are not responsive to other treatments.^13,15,16 Dupilumab (Dupixent) is an interleukin (IL)-4 and IL-13 inhibitor indicated for use in adults and pediatric patients with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. CADTH recommended that dupilumab be reimbursed with conditions and it is currently reimbursed by participating drug programs for patients whose AD is inadequately controlled with topical prescription therapies and who have demonstrated failure or intolerance to an adequate trial of phototherapy (where available), methotrexate, and cyclosporine.³

Tralokinumab is indicated for the treatment of moderate to severe AD in adult patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. It is administered by subcutaneous injection into the thigh or abdomen, and the recommended dosage for adult patients is an initial dose of 600 mg (4 injections of 150 mg) followed by 300 mg (2 injections of 150 mg each) administered every other week. At the prescriber’s discretion, dosing every fourth week may be considered for some patients who achieve clear or almost-clear skin after 16 weeks of treatment. Tralokinumab can be used with or without TCS. Tralokinumab may be used with TCIs.

The objective of this review was to perform a systematic review of the beneficial and harmful effects of tralokinumab for the treatment of moderate to severe AD in adult patients (> 18 years of age) whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from clinical expert(s) consulted by CADTH for the purpose of this review.

Patient Input

CADTH received 2 patient group submissions for the review of tralokinumab for AD: 1 from the Eczema Society of Canada (ESC) and a joint submission from the Canadian Skin Patient Alliance (CSPA) and Eczéma Québec. The ESC conducted a survey and interviews regarding how AD affects quality of life, experiences with symptoms and treatments, and the patient journey. The group received more than 3,000 responses from adults living with AD as well as their caregivers and family. The CSPA and Eczéma Québec created a web-based survey, to which 26 adults (85% patients and 8% caregivers) responded. The joint submission also included information from 56 Canadians with AD and caregivers who participated in health technology assessment surveys and interviews regarding Janus kinase (JAK) inhibitor treatments.

Patients who responded to the ESC survey described itching as the most burdensome symptom, with 72% and 95% of patients with moderate and severe AD, respectively, reporting feeling itchy multiple times a day. Moreover, 44% of respondents with severe disease were itchy all the time, and more than half of the respondents described being unable to control the urge to scratch their skin, and that it could be overwhelming and uncontrollable. Flares of worsening symptoms such as extreme itching and pain frequently led to loss of sleep. For instance, 63% and 86% of patients with moderate and severe AD, respectively, reported sleep disruptions and half of respondents with severe AD had lost sleep at least 8 nights per month. In the CSPA and Eczéma Québec submission, nearly all of those with AD experienced itching (98%), skin redness (91%), repeated rashes (87%), frequent scratching (87%), cracked skin (87%), and dry and rough skin (81%).

Patients expressed interest in new therapies that could reduce those symptoms. Those with moderate or severe AD noted the importance of having a medication that provided long-term relief and improved their quality of life. Respondents also indicated that new treatments should be covered by insurance or be affordable, allow them to stop using topical therapies, and be low-maintenance and not very time-consuming. Among the CSPA and Eczéma Québec respondents, 64% reported that it was important AD treatments did not require injections, while the other 34% were indifferent or reported it was not important.

In the ESC submission, patients reported accessing tralokinumab through a clinical trial, and many reported that it had significantly alleviated their pain, itching, discomfort, and the frequency of flares. Some patients reported experiencing improvements in 4 to 6 weeks, while others noted changes took a few months. According to patients who were interviewed by the ESC, an injectable medication is generally considered to be simpler and more convenient than other skin care routines and topicals, which can be messy and painstaking to administer. Some patients raised concerns over a fear of needles but anticipated they would be able to overcome this challenge.

Clinician Input

Input From Clinical Experts Consulted by CADTH

Two clinical experts with expertise in the diagnosis and management of AD consulted by CADTH indicated that some patients with moderate to severe AD respond to the current therapies; however, there is a need for additional therapies for patients with inadequate access to phototherapy or patients who experienced side effects with systemic therapies such as methotrexate and cyclosporine A. The clinical experts also stated that tralokinumab would complement other therapies and can be added to other treatments (excluding dupilumab, as both treatments act on similar receptors) such as TCS. The clinical experts indicated a trial of an appropriate topical therapy should be considered first before considering therapies such as tralokinumab, particularly because of the cost associated with tralokinumab. The clinical experts differed on the place in therapy of tralokinumab, with 1 clinical expert indicating that tralokinumab may offer a safer and more effective treatment option compared with the off-label systemic therapies currently available. The other clinical expert disagreed with that statement due to the lack of long-term evidence of safety and the fact that trials results were not encouraging. The clinical experts indicated that patients who would be best suited for treatment with tralokinumab are those with moderate to severe AD who have not responded to an adequate trial of topical therapies and an adequate trial of phototherapy. In terms of assessing response to treatment, the clinical experts were not aware of useful predictors of a good response to tralokinumab, but suggested that a clinically meaningful response would include improvements in quality-of-life scores, itch scores, and clinical scores from an Investigator’s Global Assessment (IGA) or the Eczema Area and Severity Index (EASI). One clinical expert indicated that the treatment response should be assessed monthly early on in treatment, and every 3 to 6 months later in the course of treatment, while the other noted that the response to tralokinumab should not be assessed earlier than 16 weeks, and that responders should be assessed every 6 months. According to both clinical experts, the factors to consider for discontinuation would be a lack of efficacy and adverse effects (e.g., severe conjunctivitis unresponsive to treatment measures). The clinical experts indicated that it would be reasonable to have a dermatologist diagnose, treat, and monitor patients receiving tralokinumab. The clinical experts indicated that tralokinumab is not expected to cause a dramatic shift in the current treatment paradigm but may present an additional option in the class of biologic therapies. Dupilumab has already established a precedent in this class of therapies.

Clinician Group Input

Input from 2 individual clinicians was received for the review of tralokinumab. One clinician, a dermatologist practising in British Columbia, provided input on behalf of the Canadian Dermatology Association (CDA) and the other was a dermatologist who practises at the Origins Dermatology Centre (ODC) in Saskatchewan. One clinician advised that tralokinumab would be used in first-line settings, while the other advised that topicals should be used as first-line therapy followed by phototherapy and then systemics, including biologics. According to the clinician input, tralokinumab would be relevant to clinical practice as 2/3 of patients who are treated with dupilumab do not achieve clear skin, creating a need for additional systemic medications with different mechanisms of action. Additionally, both clinicians emphasized that there is a need for treatments to be convenient and durable for patients. One clinician noted that this issue is of particular concern for Indigenous populations living in remote areas. These patients are often hard to reach virtually and have limited access to health care, which makes it extremely difficult monitor patient safety while they are on treatment with traditional systemic immunosuppressants. The clinician emphasized that traditional immunosuppressants can lead to side effects such as worsening of infection, cytopenias, and liver damage, for which many people on reserves and remote areas may not be able to receive adequate follow-up care. Both clinicians stated that patients with moderate to severe AD who do not respond to topicals and phototherapy have a high unmet need for this drug. Additionally, 1 clinician noted that women of childbearing age also have an unmet need as most off-label systemics are teratogenic.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review processes. The following were identified as key factors that could affect the implementation of a CADTH recommendation for tralokinumab:

• Access to phototherapy may be limited in some areas of Canada. One clinical expert consulted by CADTH noted that phototherapy is typically accessible in urban areas, but access may be limited in rural areas. The expert noted that this barrier to phototherapy should be considered in the reimbursement review decision-making process.

• Could tralokinumab be initiated in patients who have failed previous treatment with a biologic drug? One clinical expert noted that it is unlikely that they would initiate tralokinumab with patients who had failed a biologic, and they would more likely prescribe JAK inhibitors instead.

• Should patients be required to have been enrolled in a previous trial of (or be ineligible for) cyclosporine, methotrexate, and phototherapy before initiating treatment with tralokinumab? One clinical expert consulted by CADTH noted that patients should follow the standard hierarchy of treatments, with biologics being the second-line treatment, and that a trial of 2 of the 4 immunomodulators (methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine) should be considered before initiating tralokinumab.

• Could the reimbursement criteria that were recommended for dupilumab (e.g., initiation and renewal criteria) be applicable to tralokinumab? One clinical expert consulted by CADTH noted that the criteria for dupilumab could be applicable for tralokinumab and could be implemented in clinical practice.

• Should patients be required to undergo an adequate trial with dupilumab before being eligible for treatment with tralokinumab? One clinical expert consulted by CADTH noted that prior therapy with dupilumab should not be required for patients to be eligible for treatment with tralokinumab. Both experts agreed that tralokinumab should not be a rescue therapy for failed previous treatment with a biologic. It would be preferable to use tralokinumab first, and if it fails, then use dupilumab or JAK inhibitors.

• On the question of whether tralokinumab should be used in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs, phototherapy, or immunosuppressants, the clinical experts disagreed. One expert would not use tralokinumab with JAK inhibitors, but was not aware of any contraindications when combining tralokinumab with immunosuppressants or phototherapy. The other expert indicated that the only practical combination would be phototherapy and tralokinumab.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

The evidence for this review was derived from a systematic literature review of pivotal and phase III studies that was supplemented with additional studies to address important gaps in the evidence from randomized controlled trials (RCTs). The systematic review included 4 double-blind phase III RCTs.

Both the ECZTRA 1 (N = 802) and ECZTRA 2 (N = 794) trials were randomized, double-blind, placebo-controlled, identically designed, 52-week trials that evaluated the efficacy and safety of tralokinumab as a monotherapy compared to placebo in adults with moderate to severe AD. The studies had 3 key phases: an initial treatment phase (0 to 16 weeks), a maintenance treatment phase (16 to 52 weeks), and a safety follow-up (52 to 66 weeks). All patients used an emollient twice daily (or more often, as needed) for at least 14 days before randomization and were to continue this treatment throughout the trial. Patients were randomized in the initial treatment phase in a 3:1 ratio to either biweekly 300 mg tralokinumab injections (following the baseline 600 mg loading dose on day 0) or to a placebo administered every 2 weeks. At week 16, patients who achieved a clinical response (defined as an IGA score of 0 or 1, or at least 75% reduction in an EASI score from baseline [EASI-75]) and who were assigned to the tralokinumab group in the initial treatment phase were re-randomized in a 2:2:1 ratio to biweekly 300 mg tralokinumab injections, tralokinumab 300 mg every 4 weeks (alternating biweekly doses of placebo and 300 mg tralokinumab injections), or placebo. The primary outcomes were the percentage of patients achieving an IGA response of 0 (clear skin) or 1 (almost-clear skin) and the percentage of patients achieving an EASI-75 score at week 16, with secondary end points addressing symptom severity on the Scoring of Atopic Dermatitis (SCORAD), itch severity (worst daily pruritus numeric rating score [NRS]), and health-related quality of life (HRQoL) measures related to AD. Of the patients enrolled in the ECZTRA 1 trial, the overall mean age at baseline was 38.8 years, and 59.1% of the trial population were men. The mean body surface area involvement with AD was 53.1%, |||||||||||||||||||||||||||||||||||||||||||||| and the duration of AD was 28.3 years. Of the patients enrolled in the ECZTRA 2 trial, the mean age at baseline was 36.7 years, and 59.6% of the total trial population were men. At baseline, the mean body surface area involvement with AD was 52.7%, |||||||||||||||||||||||||||||||||| and the mean duration of AD was 28.1 years.

The ECZTRA 3 study (N = 380) was a randomized, double-blind, placebo-controlled, 32-week trial that evaluated the efficacy and safety of tralokinumab as a combination therapy with TCS compared to placebo plus TCS in adults with moderate to severe AD. All patients were to use an emollient twice daily (or more often, as needed) for at least 14 days before randomization and were to continue this treatment throughout the trial. The trial had a 16-week initial treatment period followed by an additional 16-week continuation period. On day 0 of the initial treatment period, patients received a loading dose of 600 mg of tralokinumab or placebo. In the initial treatment period, 380 patients were randomized in a 2:1 ratio to receive subcutaneous doses of tralokinumab or placebo every second week during the 16-week initial treatment period. At baseline, all patients were instructed to initiate treatment once daily with a supplied TCS (mometasone furoate 0.1% cream) on lesional skin and continue as needed throughout the trial. Patients randomized to tralokinumab in the initial treatment period who had a clinical response (defined as an IGA score of 0 or 1, or an EASI-75 score) at week 16 were re-randomized to the continuation treatment period in a 1:1 ratio, stratified by region (Europe and North America) and IGA response at week 16 (IGA 0 or 1, or IGA > 1): tralokinumab 300 mg every 2 weeks, or tralokinumab 300 mg every 4 weeks (alternating dose administrations of tralokinumab 300 mg and placebo). The trial evaluated the percentage of patients achieving an IGA response of 0 (clear) or 1 (almost clear) (IGA 0 or 1) and the percentage of patients achieving an EASI-75 score at week 16 (primary end points). The mean age at baseline was 39.1 years. In the group receiving tralokinumab every 2 weeks plus TCS, men and women were equally distributed. In the placebo plus TCS group, there was a higher proportion of men than women (66.1% versus 33.9%, respectively). Most patients (75.8%) were White. The mean body surface area involvement with AD was 48.1%, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| and the mean duration of AD was 28.2 years.

The ECZTRA 7 study (N = 277) was a randomized, double-blind, placebo-controlled, 26-week trial that evaluated the efficacy and safety of tralokinumab as a combination therapy with TCS compared to placebo plus TCS in adults with severe AD who were not adequately controlled with or have contraindications to oral cyclosporine A. Patients were randomized in a 1:1 ratio to receive tralokinumab 300 mg plus TCS or placebo plus TCS. The randomization was stratified by prior cyclosporine A use (yes or no), country (Germany: yes or no), and baseline disease severity (IGA = 3 or 4). All patients were instructed to use a supplied TCS (mometasone furoate 0.1% cream) once daily, as needed, on lesional skin during the treatment period. Each patient received a loading dose of 600 mg of tralokinumab or placebo. At subsequent visits in the treatment period, patients received either tralokinumab 300 mg every 2 weeks or placebo every 2 weeks. The trial evaluated the percentage of patients achieving an EASI-75 score at week 16 (the primary end point). |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| There was a higher proportion of men than women (59.6% versus 40.4% patients, respectively). Most patients (98.2%) were White. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Efficacy Results

Treatment with tralokinumab elicited a statistically significant improvement in markers of AD severity, such as IGA and EASI, at 16 weeks in adults with moderate to severe AD. For participants who achieved an IGA score of 0 or 1 at week 16, the difference between tralokinumab and placebo was 8.6% in the ECZTRA 1 trial (95% confidence interval [CI], 4.1 to 13.1; P = 0.002), 11.1% in the ECZTRA 2 trial (95% CI, 5.8 to 16.4; P < 0.001), and 12.4% in the ECZTRA 3 trial (95% CI, 2.9 to 21.9; P = 0.015), all favouring tralokinumab. In the ECZTRA 7 trial, for participants who achieved an IGA score of 0 or 1 at week 16, the difference between tralokinumab and placebo was ||||||||||||||||||||||||||||||||||; however, due to the insignificant difference between tralokinumab and placebo in the reduction of worst daily pruritus NRS outcome, which was first in the testing hierarchy, statistical testing was not conducted for this outcome.

For participants who achieved an EASI-75 score at week 16, the percent difference between tralokinumab and placebo was 12.1% in the ECZTRA 1 trial l(95% CI, 6.5 to 17.7; P < 0.001), 21.6% in the ECZTRA 2 trial (95% CI, 15.8 to 27.3; P < 0.001), 20.2% in the ECZTRA 3 trial (95% CI, 9.8 to 30.6; P < 0.001), and 14.1% in the ECZTRA 7 trial (95% CI, 2.5 to 25.7; P < 0.018). These differences were statistically significantly in favour of tralokinumab in all 4 trials.

The adjusted mean change from baseline in SCORAD was statistically significantly larger in the tralokinumab group compared with the placebo group at week 16 in the ECZTRA 1, ECZTRA 2, and ECZTRA 3 trials, with differences between tralokinumab and placebo of −10.4 in the ECZTRA 1 trial (95% CI, −14.4 to −6.5; P < 0.001), −14.0 in the ECZTRA 2 trial (95% CI, −18.0 to −10.1; P < 0.001), and −10.9 in the ECZTRA 3 trial (95% CI, −15.2 to −6.6; P < 0.001). The difference between tralokinumab and placebo in the ECZTRA 7 trial was −8.6 (95% CI, −13.0 to −4.2); however, due to the insignificant difference between tralokinumab and placebo in the reduction of worst daily pruritus NRS outcome, which was first in the testing hierarchy, statistical testing was not conducted for this outcome.

The adjusted mean change from baseline in Patient-Oriented Eczema Measure (POEM) scores also favoured tralokinumab when compared to placebo at week 16, with differences between tralokinumab and placebo of −4.6 in the ECZTRA 1 trial (95% CI, −6.0 to −3.1; P < 0.001), −5.1 in the ECZTRA 2 trial (95% CI, −6.5 to −3.6; P < 0.001), −4.0 in the ECZTRA 3 trial (95% CI, −5.6 to −2.4; P < 0.001), and −3.4 in the ECZTRA 7 trial (95% CI, −5.0 to −1.8; P < 0.001). However, this outcome was exploratory and was not adjusted for multiple testing in any of the included trials.

In terms of symptom reduction, for participants who achieved an improvement of at least 4 points in the weekly average of daily pruritus NRS scores at week 16, the difference between tralokinumab and placebo was 9.7% in the ECZTRA 1 trial (95% CI, 4.4 to 15.0; P = 0.002), 15.6% in the ECZTRA 2 trial (95% CI, 10.3 to 20.9; P < 0.001), 11.3% in the ECZTRA 3 trial (95% CI, 0.9 to 21.6; P = 0.037), and 9.7% in the ECZTRA 7 trial (95% CI, −2.0 to 21.4; P = 0.106). The between-group difference was statistically significantly in favour of tralokinumab in the ECZTRA 1, ECZTRA 2, and ECZTRA 3 trial, but not in the ECZTRA 7 trial.

Participants who received tralokinumab also experienced improvements in how much eczema interfered with sleep at week 16 based on the eczema-related sleep NRS, for which the difference between groups in the adjusted mean change from baseline at week 16 was −0.7 in the ECZTRA 1 trial (95% CI, −1.2 to −0.2; P = 0.007), −1.4% in the ECZTRA 2 trial (95% CI, −1.9 to −0.9; P < 0.001), −1.3% in the ECZTRA 3 trial (95% CI, −1.8 to −0.8; P < 0.001), and −0.8% in the ECZTRA 7 trial (95% CI, −1.3 to −0.2; P = 0.005) in favour of tralokinumab. The minimal important difference (MID) has not been identified for the eczema-related sleep NRS in populations with AD; this outcome was exploratory and was not adjusted for multiple testing in any of the included trials.

Treatment with tralokinumab also elicited a statistically significant improvement in HRQoL at week 16 based on the Dermatology Life Quality Index (DLQI) measure in the ECZTRA 1, ECZTRA 2, and ECZTRA 3 trials. For instance, the between-group difference in the adjusted mean change from baseline in the DLQI was statistically significantly larger in the tralokinumab group compared with the placebo group at week 16 in the ECZTRA 1 (−2.1; 95% CI, −3.4 to −0.8; P = 0.002), ECZTRA 2 (−3.9; 95% CI, −5.2 to −2.6; P < 0.001), and ECZTRA 3 (−2.9; 95% CI, −4.3 to −1.6; P < 0.001) trials. Treatment with tralokinumab also elicited a improvement in HRQoL at week 16 based on the DLQI measure in the ECZTRA 7 trial, in which the between-group difference in the adjusted mean change in the DLQI was larger in the tralokinumab group compared with the placebo group (−1.5; 95% CI, −2.6 to −0.4); however, as this outcome was ranked after the hierarchical analysis failed and was stopped, no appropriate statistical comparisons can be made. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. No MIDs have yet been identified in populations with AD for the DLQI, Short Form (36) Health Survey (SF-36), and EQ-5D 5-Levels questionnaire (EQ-5D-5L) outcome measures; the SF-36 and EQ-5D-5L outcomes were exploratory and were not adjusted for multiple testing in any of the included trials.

Harms Results

In the ECZTRA 1 trial, adverse events (AEs) were reported in 76.4% of patients (n = 460) treated with tralokinumab and 77.0% of patients (n = 151) treated with placebo at week 16, and serious adverse events (SAEs) were reported in 3.8% of patients (n = 23) treated with tralokinumab and 4.1% of patients (n = 8) treated with placebo. Treatment-emergent AEs leading to permanent discontinuation of the study drug were reported in 3.3% of patients (n = 20) treated with tralokinumab and 4.1% of patients (n = 8) treated with placebo at week 16. At week 52, AEs were reported in 79.4% of patients (n = 54) in the tralokinumab every 2 weeks group, 69.7% of patients (n = 53) in the tralokinumab every 4 weeks group, and 71.4% of patients (n = 25) in the placebo group. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

In the ECZTRA 2 trial, AEs were reported in 61.5% of patients (n = 364) treated with tralokinumab and 66.0% of patients (n = 132) treated with placebo at week 16, while SAEs were reported in 1.7% of patients (n = 10) treated with tralokinumab and 2.5% of patients (n = 5) treated with placebo. Treatment-emergent AEs leading to permanent discontinuation of the study drug were reported in 1.5% of patients (n = 9) in the tralokinumab group and 1.5% of patients (n = 3) in the placebo group. At week 52, AEs were reported in 68.1% of patients (n = 62) in the tralokinumab every 2 weeks group, 62.9% of patients (n = 56) in the tralokinumab every 4 weeks group, and 69.6% of patients (n = 32) in the placebo group. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

In the ECZTRA 3 trial, AEs were reported in 71.4% of patients (n = 180) treated with tralokinumab every 2 weeks plus TCS and 66.7% of patients (n = 84) treated with placebo plus TCS at week 16. SAEs were reported in 0.8% of patients (n = 2) treated with tralokinumab every 2 weeks plus TCS and 3.2% of patients (n = 4) treated with placebo plus TCS. Treatment-emergent AEs leading to permanent discontinuation of the study drug were reported in 2.4% of patients (n = 6) treated with tralokinumab every 2 weeks plus TCS and 0.8% of patients (n = 1) treated with placebo plus TCS at week 16. At week 32, AEs were reported in 69.6% of patients (n = 48) in the tralokinumab every 2 weeks plus TCS group and 59.4% of patients (n = 41) in the tralokinumab every 4 weeks plus TCS group. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

In the ECZTRA 7 trial, AEs were reported in 77.5% of patients (n = 107) treated with tralokinumab every 2 weeks plus TCS and 78.8% of patients (n = 108) treated with placebo plus TCS at week 26; SAEs were reported in 0.7% of patients (n = 1) treated with tralokinumab every 2 weeks plus TCS and 3.6% patients (n = 5) treated with placebo plus TCS. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| No deaths were reported in the ECZTRA 7 trial.

Harms of special interest at week 16 included AD, which occurred in 25.9% of patients (n = 156) treated with tralokinumab and 38.3% of patients (n = 75) treated with placebo in the ECZTRA 1 trial and in 16.6% of patients (n = 98) treated with tralokinumab and 33.5% of patients (n = 67) treated with placebo in the ECZTRA 2 trial. Viral upper respiratory tract infection occurred in 23.1% of patients (n = 139) treated with tralokinumab and in 20.9% of patients (n = 41) treated with placebo in the ECZTRA 1 trial and in 8.3% of patients (n = 49) treated with tralokinumab and 18.5% of patients (n = 17) treated with placebo in the ECZTRA 2 trial. In the ECZTRA 3 and ECZTRA 7 trials, the most common AE was viral upper respiratory tract infection, which occurred in 19.4% of patients (n = 49) treated with tralokinumab plus TCS and 11.1% of patients (n = 14) treated with placebo plus TCS in the ECZTRA 3 trial and in 26.8% of patients (n = 37) treated with tralokinumab plus TCS and 25.5% of patients (n = 35) treated with placebo plus TCS in the ECZTRA 7 trial. Among notable harms at week 16, pruritus occurred in 5.3% of patients (n = 32) treated with tralokinumab and 5.1% of patients (n = 10) treated with placebo in the ECZTRA 1 trial; upper respiratory infraction occurred in 10.0% of patients (n = 59) treated with tralokinumab and 8.5% of patients (n = 17) treated with placebo in the ECZTRA 2 trial; conjunctivitis occurred in 11.1% of patients (n = 28) treated with tralokinumab plus TCS and 3.2% of patients (n = 4) treated with placebo plus TCS in the ECZTRA 3 trial; and headache occurred in 15.2% of patients (n = 21) treated with tralokinumab plus TCS and 9.5% of patients (n = 13) treated with placebo in the ECZTRA 7 trial.

Critical Appraisal

Although the analyses were appropriate and investigators accounted for multiplicity, several limitations are associated with the design of the trials. First, the ECZTRA 1, ECZTRA 2, and ECZTRA 3 trials included a 2- to 6-week washout period during which no topical corticosteroid use was allowed. As noted by Wollenberg et al.,⁸ the patient population being studied has significant disease and high levels of prior medication use. The washout period therefore may have been long enough to exacerbate AD, leading to patients being labelled as “nonresponders” early in the studies. Second, the duration of the initial treatment period (16 weeks) in ECZTRA 1, 2, and 3 may not have been sufficient. Assessments of longer-term efficacy and safety in the ECZTRA 1, 2, and 3 trials were also limited by the fact that only patients who achieved a clinical response at week 16 were eligible to be re-randomized. As a result, the estimates of the effect in the maintenance phase are uncertain, and the analyses in the maintenance phase were not powered, which signifies that the long-term efficacy and safety of tralokinumab is uncertain. Another limitation is the absence of a comparator with a similar mechanism of action (e.g., dupilumab). Within the context of the trials, the performance of tralokinumab is therefore statistically significantly superior with respect to the primary and secondary end points in comparison to placebo. However, the intervention was not compared to another biologic currently available to patients. Last, pauses in dosing or the use of rescue medication in situations where the intervention was not available due to the coronavirus 2019 (COVID-19) pandemic during the ECZTRA 7 trial may have affected the results.

In terms of external validity, the ECZTRA 3 and ECZTRA 7 trials are more reflective of real-world practice because tralokinumab was combined with TCS as the intervention. In ECZTRA 1 and ECZTRA 2, patients who used rescue medication were considered “nonresponders,” which does not align with real-world use of biologics, which, according to the clinical experts consulted by CADTH for this review, are initiated as add-on therapy to TCS for active lesions.

Indirect Comparisons

Description of Studies

CADTH summarized and appraised 2 indirect treatment comparisons (ITCs): 1 matched adjusted indirect comparison (MAIC)⁹ submitted by the sponsor and a published network meta-analysis (NMA) by the Institute for Clinical and Economic Review (ICER).¹⁰ The ICER meta-analysis¹⁰ compared tralokinumab against dupilumab (the only drug approved for use in the treatment of AD at the time of this review), upadacitinib and abrocitinib (currently under review by Health Canada and CADTH for use in the treatment of AD), and several drugs that were not listed as under review by Health Canada or CADTH at the time of this review (e.g., nemolizumab, lebrikizumab, and baricitinib). The sponsor-submitted MAIC⁹ compared ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Efficacy Results

Result from the NMA showed that tralokinumab was generally superior to placebo, while being inferior to upadacitinib (both 15 mg and 30 mg), abrocitinib 200 mg, and dupilumab 300 mg. These results were consistent when the treatments were used as monotherapy or in combination with topical therapies.

The sponsor-submitted MAIC reported that ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Harms Results

Results from the sponsor-submitted MAIC indicate that ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Critical Appraisal

Neither ITC included comments on the methods of study selection, data extraction, or quality assessment. The sponsor’s review was clearer on the methods for conducting the MAIC, referring to National Institute for Health and Care Excellence¹¹ protocols, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Conclusions regarding the long-term efficacy of tralokinumab compared to the active comparators relevant to this review cannot be drawn from the NMA, as it used results collected over a inappropriately short period of time for use in a study involving a chronic condition such as AD. There is also uncertainty due to the inherent heterogeneity across trials in the networks. The robustness of the comparative efficacy was further compromised by the lack of precision in some of the findings, and the results from the NMA must therefore be interpreted with caution.

Other Relevant Evidence

Description of Studies

One ongoing, open-label, single-arm, long-term, extension study (ECZTEND) has been summarized to provide additional evidence on the safety and efficacy of tralokinumab in patients with AD who have previously participated in clinical trials for tralokinumab (i.e., the ECZTRA 1 through 8 and TraSki trials). The ECZTEND study consists of a 2-week screening period (which is expected to overlap with the end of the parent trial for most patients), a 0.5- to 5-year treatment phase, and a 14-week follow-up beginning 2 weeks after the final dose. At the time of data cut-off, 1,174 patients were included in the ECZTEND trial. The primary outcome is safety or the number of AEs experienced during the study. The secondary outcomes apply to drug efficacy and include achieving an IGA score of 0 or 1 and an EASI-75 score at weeks 16, 56, 88, 104, 136, 152, 184, 216, and 248 during the treatment phase relative to baseline. Blinding of treatment allocation was maintained for patients who continued from a blinded parent trial and entered the open-label extension study.

Efficacy Results

Responders were defined as achieving an IGA score of 0 or 1 or an EASI-75 score. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Harms Results

Overall, 844 (71.9%) patients experienced 1 or more AEs, with the 3 most common AEs being viral upper respiratory tract infection (21.3%), dermatitis atopic (13.5%), and upper respiratory tract infection (7.1%). Other harms of special interest that were identified in CADTH’s systematic review protocol ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Nineteen patients (1.6%) withdrew due to an AE, and no deaths were reported.

Critical Appraisal

The ECZTEND trial lacked a comparator, which made it difficult to adjust for natural changes in the course of AD or the effects of potential confounders. Additionally, the open-label design may have influenced patient and clinician perceptions of improvement, which could affect the reporting of harms and efficacy measures. The number of patients screened from the parent trials was not reported, nor were the reasons for screening failures. Moreover, patients were recruited exclusively from the parent trials of tralokinumab, and only those who could tolerate the treatments were able to enrol in the ECZTEND study. No formal sample size or power calculations were performed, no control for multiplicity was described in the report, and there was no imputation of missing safety data. Most patients in the study were White (71.3%), which may be a product of the regions where the study took place (mainly Europe and North America). While the clinical experts CADTH consulted for this review were uncertain if race would bias the outcomes, this factor may limit how the results can be interpreted in the context of a broader patient population in Canada. Treatment history was not described in this report and whether the patients were treatment-naive and which medications they have had experience with (e.g., topical, systemic, or biologic) were unknown, which limits the generalizability of the results to other patients with AD and prevents comparisons with other treatments.

Conclusions

Three double-blind RCTs demonstrated that, compared with placebo, 16 weeks of treatment with tralokinumab was associated with statistically significant improvements in a range of outcomes that are important in the management of AD in adults, including overall severity of AD (EASI, IGA response, SCORAD), symptoms (pruritus NRS), and HRQoL (DLQI). These trials included the use of tralokinumab as monotherapy (ECZTRA 1 [N = 802] and ECZTRA 2 [N = 794]) and as combination therapy (ECZTRA 3 [N = 380]). The ECZTRA 7 trial, which evaluated the efficacy and safety of tralokinumab as a combination therapy with TCS compared to placebo plus TCS in adults with severe AD who are not adequately controlled with or have contraindications to oral cyclosporine A, demonstrated statistically significant improvement in EASI scores in the tralokinumab group compared to the placebo group. Tralokinumab was well-tolerated in the short term (16 weeks) and long-term (32 or 52 weeks) phase III studies. There were no direct comparisons between tralokinumab and other active AD treatments.

Results from a sponsor-submitted MAIC ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Results from the NMA conducted by ICER suggest that tralokinumab may be inferior to dupilumab in terms of most efficacy outcomes. However, the MAIC comparisons were |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. There is also uncertainty in the results from the NMA due to the inherent heterogeneity across trials in the networks. The robustness of the comparative efficacy was further compromised by the lack of precision in some of the findings, and the results from the indirect comparisons must be interpreted with caution.

Introduction

Disease Background

Atopic dermatitis is the most common type of eczema. It is a chronic, relapsing, inflammatory skin condition characterized by severely itchy skin (pruritus) that results in red and swollen skin (rash). Lesions associated with AD may appear as fluid-filled vesicles that ooze, crack, and crust. Pruritus of the skin can cause frequent scratching and may result in lichenification (thickening of the skin) and secondary skin infections. Atopic dermatitis typically involves the skin folds behind the knees (popliteal areas) and the skin folds in front of the elbows (antecubital areas). It may also appear on the face, neck, and hands. Individuals with AD have skin with impaired barrier function and reduced water-holding capacity, resulting in dry skin that requires treatment with specific bathing, cleansing, and moisturizing practices.

As a hereditary form of eczema, AD generally presents in infancy, with most cases beginning before the age of 5 years. The majority of these children will outgrow the condition by adolescence. It is common for children with AD to develop asthma and/or hay fever. This process is referred to as the “atopic march,” and AD is often the first step in the sequential development of these other atopic conditions. The clinical manifestations of AD vary with age, with infants showing AD on the extensor surfaces of the extremities, face, neck, scalp, and trunk. Children are typically affected on the flexural surfaces of the extremities, neck, wrists, and ankles, while adolescents and adults are generally affected on the flexural surfaces of the extremities and the hands and feet.

The CDA reports that the lifetime prevalence of AD approaches 17% in the Canadian population, and there is evidence to suggest that the prevalence has increased over the past 30 years. Patients often experience worsening itching symptoms throughout the night, and this may result in sleep loss, which may result in detrimental effects pertaining to school or work. Individuals with AD may also suffer from the social stigma of having a highly visible condition. Overall, these patient experiences describe a physically and mentally exhausting condition that can result in anxiety, depression, and decrease in quality of life.

The goals of AD management are to prevent flares (episodes of worsening of symptoms typically requiring escalation of treatment), and effectively manage flares when they occur by preventing progression of the disease. While there is no cure for AD, several therapeutic options are available to patients to manage the condition. The majority of patients treat AD by using general skin care methods, avoiding skin irritants, and applying topical anti-inflammatory therapy. If these common methods fail to improve AD, patients may use off-label systemic therapy (i.e., immunosuppressant therapy) or other therapies such as phototherapy.

Standards of Therapy

General Skin Care

General skin care practices for patients with AD include irritant avoidance and managing dry skin. The symptoms of AD may be reduced or prevented through the avoidance of known skin irritants or triggers.^1,3 Some common irritants include temperature, humidity, dust, pets (animal dander), smoke, and grass. Using mild detergents to wash clothing, with no bleach or fabric softener and double-rinsing, has been recommended to those with AD. Dry skin associated with AD can be countered through specific bathing, cleansing, and moisturizing practices. Baths using lukewarm water and emulsifying oil followed by the use of moisturizers are recommended. Limiting the use of soap and fragranced products may also help reduce symptoms.^1-3,14

Topical Therapy

While a number of nonpharmacological topical therapies exist for treating the symptoms of AD, the most common therapy is the use of moisturizers, which combat dry skin through hydration and the prevention of trans-epidermal water loss. Moisturizers are routinely used to provide some barrier protection for the skin from irritants or allergens and can act to soften skin, reduce itching, and minimize cracking, fissuring, and lichenification.^3,14 Moisturizers are routinely used frequently throughout the day, preferably after bathing. Moisturizers can contain a combination of emollients, humectants, and occlusive drugs. Emollients such as glycol, glyceryl stearate, and soy sterols lubricate soften, and smooth out the surface of the skin by filling the spaces with droplets. Humectants (e.g., glycerol, lactic acid, and urea) attract water and increase the skin’s water-holding capacity. Humectants sting open skin and are not useful in children with AD. Occlusive drugs (e.g., petrolatum, dimethicone, and mineral oil) provide a layer of oil on the surface of the skin to slow trans-epidermal water loss, prevent water loss though evapouration, and increase the moisture content of the skin. The choice of moisturizer depends on the area of the body and the degree of dryness of the skin.^3,14

The most common pharmaceutical topical therapies include the use of TCS and TCIs. Topical corticosteroids act as anti-inflammatory therapy and are considered to be first-line treatments for AD.² There are more than 30 different types of TCS, which can take the form of lotions, creams, oily creams, ointments, or gels and be combined with other drugs such as antibiotics.¹⁵ The potency of TCS varies. In Canada, low-potency (1%) hydrocortisone is the most commonly prescribed type of TCS for the face.³ For the body, moderate-potency triamcinolone or betamethasone valerate are most commonly prescribed. All TCS varieties are applied directly to the area of affected skin before the use of emollients, and a response is typically seen within 10 to 14 days. Side effects associated with the long-term use of TCS include striae (stretch marks), petechiae (small red and/or purple spots), telangiectasia (small, dilated blood vessels on the surface of the skin), thinning of the skin, atrophy, and acne.² Use of TCS is also recommended for children, according to the American Academy of Dermatology (AAD), with cautions regarding dosing, as children have a larger ratio of surface area to body mass and there are mixed results from various studies suggesting that systemic absorption may affect growth.

Topical calcineurin inhibitors are steroid-free, anti-inflammatory, immunosuppressant drugs that can be used long-term. In Canada, the 2 available second-line drugs are pimecrolimus and tacrolimus. Pimecrolimus 1% cream can be used for short-term and intermittent long-term therapy for mild to moderate AD and is effective in controlling pruritus.³ Topical tacrolimus is an ointment that can be used for short-term and intermittent long-term therapy of moderate to severe AD and demonstrates rapid and sustained AD symptom control.^3,15 The most common AE associated with TCIs is application site–specific burning and irritation.^2,3 Packaging for TCIs come with a black-box warning regarding lymphoma; however, long-term (10-year) surveillance studies have not found an increased risk of lymphoma over that of the general pediatric population.

Crisaborole, a topical phosphodiesterase type 4 inhibitor, is also available in Canada (although it is not recommended by CADTH for reimbursement).^1,2 The advantage of the calcineurin inhibitors and crisaborole is that both can be safely applied to the face and creases, whereas TCS that are more potent than hydrocortisone 1% are inappropriate. Other topical therapies for AD include treatments with diluted bleach baths, which can help reduce the occurrence of secondary skin infections.^3,16

Systemic Therapy

Systemic therapy for the treatment of AD typically involves the use of antimicrobials, antihistamines, or immunomodulators.^15-17 Systemic antibiotic treatment can be used to counter widespread secondary bacterial infection. Many patients encounter infection with Staphylococcus aureus, and this may cause new inflammation and exacerbate AD symptoms. The choice of systemic antibiotic drug depends upon the skin culture and sensitivity profile. Sedating antihistamines have been used in cases in which patients are not achieving adequate sleep due to itching.^1,15

Immunomodulatory drugs, including methotrexate, cyclosporine, mycophenolate mofetil, azathioprine (listed in order of frequency of use in Canada), can be used in patients who are not responsive to other treatments.^13,15,16 However, these commonly used off-label treatments are administered at the lowest dose for the shortest duration possible due to side effects.^16,17 According to the AAD, cyclosporine is an effective treatment in pediatric patients. The AAD notes that the evidence for the use of methotrexate in pediatric AD patients is limited; however, a recent 12-week study showed it to have a slower onset than low-dose cyclosporine but an increased time before relapse after discontinuation. Regarding azathioprine, the AAD noted there is evidence of efficacy in children, but recommended that its use should be reserved for recalcitrant AD, or for patients in whom AD is having a significant psychosocial impact. The AAD noted that mycophenolate mofetil was a relatively safe systemic therapy in pediatric AD patients, although its long-term (> 24 months) efficacy and safety in pediatric patients have not been studied. With respect to corticosteroids, there is a longstanding understanding that chronic use can affect growth in children. The AAD does not recommend corticosteroid use in children with AD unless they are given as part of a short-term transition to systemic immunomodulators.

Dupilumab (Dupixent) is an IL-4 and IL-13 inhibitor indicated for use in adult and pediatric patients with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. CADTH recommended that dupilumab be reimbursed with conditions, and dupilumab is currently reimbursed by the participating drug programs for patients whose AD is inadequately controlled with topical prescription therapies and who have demonstrated failure or intolerance to an adequate trial of phototherapy (where available), methotrexate, and cyclosporine.³

Other Therapy

Phototherapy is another second-line therapy that is commonly used after failure of TCS, TCIs, and crisaborole. This therapy includes several sessions and is guided by a number of factors, including patient skin type and skin cancer history.¹⁶ According to AAD guidelines, phototherapy is considered to be a safe and effective treatment for AD in children. There are no studies of the long-term consequences of phototherapy use in pediatric AD patients, although an increased risk of nonmelanoma skin cancer has been reported in children receiving psoralen plus UV A (UVA) exposure to treat psoriasis.

Drug

Tralokinumab is indicated for the treatment of moderate to severe AD in adult patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Tralokinumab can be used with TCIs. The recommended dosage of tralokinumab for adult patients is an initial dose of 600 mg (4 injections of 150 mg each) followed by 300 mg (2 injections of 150 mg each) administered every other week as subcutaneous injection. At the prescriber’s discretion, every-fourth-week dosing may be considered for some patients who achieve clear or almost-clear skin after 16 weeks of treatment. It is administered by subcutaneous injection into the thigh or abdomen. If someone other than the patient administers the injection, the upper arm can also be used. Tralokinumab is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any nonmedicinal ingredient or component of the container. This drug has not been previously reviewed by CADTH.

Tralokinumab is a fully human immunoglobin G4 monoclonal antibody that specifically binds to the type 2 cytokine IL-13 and inhibits its interaction with the IL-13 receptor alpha-1 and alpha-2 subunits (of the type II receptor). Tralokinumab restores expression of skin barrier markers decreased by IL-13 in human keratinocytes.

The sponsor’s reimbursement request is for the treatment of adult patients with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable and who had an adequate trial or are ineligible for each of the following therapies: phototherapy (where available), methotrexate, and cyclosporine.

The characteristics of tralokinumab and its most common comparators for the purpose of this review are presented in Table 5.

Stakeholder Perspectives

Summary of Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

About the Patient Group(s) and Information Gathered

CADTH received 2 patient group submissions for the review of tralokinumab for AD. One was from the ESC and the other was a joint submission from the CSPA and Eczéma Québec.

The ESC is a registered Canadian charity working to improve the lives of those living with eczema through support, education, awareness, and research. For its submission, ESC conducted a survey and interviews covering how AD affects quality of life, experiences with symptoms and treatments, and the patient journey. The group received more than 3,000 responses from adults living with AD as well as their caregivers and family.

Both the CSPA and Eczéma Québec are nonprofit organizations. The CSPA is dedicated to advocating, educating, and supporting Canadians affected by skin, hair, and nail disorders. Eczéma Québec is a patient advisory committee created as a branch of the McGill University Hospital Network Centre of Excellence for Atopic Dermatitis and consists of adult patients with AD and health care practitioners in the field of AD. The 2 organizations created a web-based survey (available from April 26 to May 16, 2021) in English and French using the Survey Monkey platform asking about experiences with AD and tralokinumab. The survey was distributed via the groups’ newsletters and social media networks in addition to being sent to the clinical trial investigators, whose contact information was requested and received from the sponsor, to be shared directly with the clinical trial participants from the investigators. Twenty-six individuals responded to the survey (14 in French and 12 in English), with 81% of responses from Québec, 15% from Ontario, and 4% from France. Patients and caregivers made up the majority of respondents (85% and 8%, respectively) and all were adults. The groups’ submission (based on information gathered between March 29 and April 23, 2021) also included information from 56 Canadians with AD along with caregivers who participated in health technology assessment surveys and interviews regarding JAK inhibitor treatments. Most of the responses were from adults but 2 children younger than 12 years of age also contributed.

Disease Experience

Patients who responded to the ESC survey described itching as the most burdensome symptom, with 72% and 95% of those with moderate and severe AD, respectively, reporting feeling itchy multiple times a day. Moreover, 44% of respondents with severe disease were itchy all the time and more than half of the group described being unable to control the urge to scratch their skin and that it could be “overwhelming and uncontrollable.” Many patients reported having scars and marks from scratching as well as cracked and blistered skin that could bleed through clothing, while others had to vacuum daily to clean dead skin from the floors. Flares of worsening symptoms such as extreme itching and pain frequently led to loss of sleep. For example, 63% and 86% of patients with moderate and severe AD, respectively, noted sleep disruptions, and half of respondents with severe AD had lost sleep at least 8 nights per month. According to 1 patient, “It was so severe that the pain would interrupt my sleep, which would lead to more inflammation and pain, which would further interrupt my sleep and my ability to heal. I was trapped in a destructive cycle.”

Of the respondents to the CSPA and Eczéma Québec survey, 62% indicated having experienced symptoms for more than 10 years, with 15% and 39% of patients reporting having moderate and severe disease, respectively. Although individuals reported being affected by AD on all parts of their body, the most common areas were the backs of hands (68%), outsides of arms and/or elbows (57%), thighs and/or legs (57%), elbow folds (55%), neck (51%), and abdomen (51%). Nearly all of those with AD experienced itching (98%), skin redness (91%), repeated rashes (87%), frequent scratching (87%), cracked skin (87%), and dry and rough skin (81%). Disrupted sleep, pain, bleeding, skin flaking and thickening, swelling, and oozing were other issues that patients faced. One patient described what it has been like living with AD: “As I grew up, my disease got worse and worse, until it got to the point where I frequently had to miss school, and had trouble sleeping at night. On days when I could attend school, I was teased because of the way my skin looked, and people stared or made comments on my appearance…. I felt as though no one understood what it was like living in my skin.” Another patient recalled, “I used to be unable to do any sport without getting a huge debilitating rash. I also wouldn’t be able to shower or go swim if I didn't have unscented lotion with me. My eczema would be considered moderate to severe growing up and I was in constant pain.” Patients reported their average level of pain to be 4.95 out of 10 and the average level of itch to be 6.44 out of 10. More than half of the patients reported that their pain was controlled or that they were not experiencing pain, whereas most indicated that their itch was poorly controlled.

The symptoms of AD contribute negatively to stress and significantly affect mental health and relationships. The ESC also emphasized that the mental health impact of having AD is “a significant aspect of the condition and is often not understood by others, nor prioritized by health care providers.” Patients reported feelings of embarrassment, anxiety, depression, poor self-esteem, low energy, and suicidal thoughts, and described the symptoms as difficult for those without AD to fully appreciate and understand. One patient stated, “People don’t understand the reality of living with eczema. It affects how you operate as a human being. Tasks as simple as bathing can be excruciating. Falling asleep can be nearly impossible.” Beyond the psychological impacts, having AD could also make bathing and handwashing painful, which affects individuals’ hygiene and in turn causes other health and social issues. The ESC noted that poor hygiene could lead to a higher risk of infection and the need for systemic antibiotics and other treatments. Nearly a third of respondents with moderate or severe AD reported missing work events, and 30% changed their careers or gave up activities as a result of the condition. These challenges are captured in the following patient quotes: “I was in such bad shape that daily tasks became almost unbearable. I couldn’t work and wasn’t able to play with my children without breaking my skin” and “You are scared to move your body — even if it’s just walking or running errands — because a little drip of sweat can irritate you severely and make you stop everything to scratch.”

Living with AD also affects caregivers and family members, who reported loss of sleep and missed days of work or school, along with feelings of helplessness, guilt, and frustration. Caregivers of those with AD expressed needing “to be mindful of their comfort level going into public… especially if they're having a bad flare-up,” while another noted that caring for their family member could affect their sleep, productivity at work, and increase their overall stress. Family members also noted how AD affected patients’ behaviours, from influencing their clothing choices and wanting to cover their skin to not going out to see friends, and how the burden of treatment routines could cause tension between a patient and their immediate caregiver.

Experiences With Currently Available Treatments

The ESC noted that topical treatments can be effective at controlling AD for some patients, but there is still a small group of individuals who live with uncontrolled moderate and severe forms of AD for whom these medications are inadequate. Lack of symptom control from trying various drugs can be frustrating for patients, and dermatologists may recommend systemic treatments such as off-label immune-suppressing medications (e.g., methotrexate and cyclosporine), oral corticosteroids (e.g., prednisone), or phototherapy. The ESC acknowledged that a biologic drug was recently approved for AD, but despite this and the previously listed nontopical treatments, challenges and limitations to current treatments still exist for many patients. For example, a patient who received prednisone indicated that “it helped with flares but there were all kinds of side effects. I gained weight and couldn’t sleep because my body was racing all the time. It is not a long-term solution.” Other patients reported that phototherapy did not offer long-term control over the AD, and that clinics may not be accessible to all individuals. A patient who had experience with both topical treatments and phototherapy stated, “My dermatologist kept prescribing me harsher and harsher creams, but my skin just kept getting worse. I tried phototherapy, but it was more than 30 minutes away and my schedule couldn’t keep up. You have to go often for it to work and I just couldn’t.” Respondents in the CSPA and Eczéma Québec submission reported experiencing financial barriers to access, such as only being able to afford treatments due to their own employer benefits or spouse’s private insurance, which may be in addition to having to pay for medications for other conditions.

Three respondents in the CSPA and Eczéma Québec surveys reported experience with dupilumab, while none had used either TCIs or cyclosporine. There was a general sentiment that most treatments were not effective at managing AD, although the most efficacious were TCIs (60% of respondents), emollient creams or ointments (47%), and phototherapy (30%).

According to a recent survey conducted by the ESC, oral corticosteroids (OCS) may be used as “rescue medication” for AD flares and as systemic treatment. However, OCS were associated with the highest safety concerns among patients and may only be used for a short period of time, and patients expressed frustration that OCS were not a solution given the chronic nature of AD. Furthermore, flares that occurred after taking OCS were described by some patients as devastating.

The trial-and-error process of testing currently available treatments and still having uncontrolled disease for years has left patients with little hope and low expectations that medications will work. Patients expressed renewed optimism that, when new treatments come out, something might finally work. The patient group submissions emphasized the need for effective treatment options that are affordable, accessible, and easy to use; can control the most significant symptoms; and offer long-term relief for patients who do not respond to current medications.

Improved Outcomes

Patients expressed interest in new therapies that could reduce symptoms such as itching, flares, redness, inflammation pain, dryness, flaking, blistering, and cracked skin. Those with moderate or severe AD noted the importance of having a medication that provides long-term relief, allowing them to sleep better, heal, and avoid new flares, complications, and secondary infections. Respondents also felt that new treatments should be covered by insurance or be affordable, allow them to stop using topical therapies, be low-maintenance and not very time-consuming, and improve their quality of life. In the CSPA and Eczéma Québec surveys, 64% indicated it was important that AD treatments not require injections, while the other 34% were indifferent or reported that it was not important. When asked about preferred modes of administration, daily oral pills were ranked the highest, followed by daily topical treatments, and injections every other week.

Respondents appeared to be willing to accept serious side effects based on the severity of their AD and previous experiences with treatments. For example, according to the input from CSPA and Eczéma Québec, 1 patient answered, “Yes and no depending on the side effects. Enough for me would be stopping the itchiness… and break outs [flares].” Another stated, “No!! I only expect to reduce the intensity of the flares, not eliminate them,” and yet another shared, “I had injections for almost a year and I would not want them again.”

Based on the input from the ESC, patients also valued being able to carry out everyday activities such as bathing, being productive at work, exercising, and not feeling the psychological burden that comes with AD. Moreover, respondents reported that they simply want to feel comfortable in their skin and maintain social relationships without being self-conscious. As 1 patient put it, “You just want a medication that works. You want to be able to sleep, to fit in with your peers, and to not feel hopeless anymore.”

Experience With the Drug Under Review

From the ESC submission, patients had accessed tralokinumab through a clinical trial and many reported that it had significantly alleviated their pain, itching, discomfort, and the frequency of flares. Some patients experienced improvements in 4 to 6 weeks while others noted changes took a few months. One patient shared, “This drug changed my life. I have not had an open wound, infection, or even a skin eruption since about the first 6 months of this trial. I have only used topical ointment a handful of times since starting tralokinumab.” According to another, “Once I started experiencing an improvement from the medication, it has relieved my eczema symptoms ever since. I scratch minimally during sleep instead of all night long. Not having any open areas on me has improved my mindset and has made my life considerably better.” Furthermore, tralokinumab has allowed patients to resume daily routines and activities they were previously unable to enjoy, such as exercising, being outdoors, bathing, swimming, and playing with their children. The improvements were clear to 1 patient who stated, “Before my trial, I was existing, now I am a contributing member of my family and society. I hope that these drugs become covered by benefits for everyone (particularly when nothing else works).”

Side effects in the form of fatigue and temporary redness and irritation at the injection site have been reported by those who received tralokinumab. Nevertheless, patients reported that they would carefully consider the risks and benefits of a new medication and many would accept potential side effects if the treatment was able to provide symptom relief. According to patients who were interviewed by the ESC, an injectable medication is simpler and more convenient in general compared with other skin care routines and topicals that can be messy and painstaking to apply. Some patients raised concerns over a fear of needles, although they indicated they would be able to overcome this challenge.

Two patient respondents in the CSPA and Eczéma Québec submission had experience with tralokinumab. When considering previous medications, 1 patient stated that they “left many gaps, were ineffective. Tralokinumab greatly improved quality of life.” Overall, both individuals appeared satisfied with the drug, as illustrated in the following quotes:

This was the first time I used an injection treatment. It is much easier and cleaner than others. It was very easy to notice a difference for me as my face was the first area to start to improve and continued to improve. I don’t have to load up on creams before I get dressed or before bed. Itchy level has decreased noticeabl[y] and has increased my night sleep. I can use a moisturizing cream daily and it works to stop the cracking skin that makes day to day life so much more comfortable.

Tralokinumab greatly improved all symptoms including flaking, itching, redness, pain, sleep interruption etc. I have not noticed any negative side effects, or problems. Great improvement in quality of life.

The benefits also extended beyond symptom relief to other aspects of their lives: “[It] made everything easier, ability to do whatever I want and wear what I want. Not have to worry about what others are thinking when they see rashes on my face. Being able to do my job without having to worry about getting dirt on my skin or having to keep cool is a great thing” and “Tralokinumab greatly improved family dynamics, as I was less ill, and in pain, and able to engage in normal day to day activities.”

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of AD.

Unmet Needs

Some patients with moderate to severe AD respond to the current therapies. However, several issues suggest a need for additional therapies. For example, there may be inadequate access to phototherapy (patients need to travel to an office 3 times a week for at least 12 weeks), there are side effects with systemic therapies such as methotrexate and cyclosporine A, and, while subcutaneous dupilumab is offered in addition to therapy, treatment is hampered by cost and limited reimbursement (as well as side effects of conjunctivitis and facial dermatitis). Last, not all patients respond to the current therapies.

Place in Therapy

Tralokinumab’s mechanism of action appears to be through IL-13 inhibition. It would therefore complement other therapies and can be added to other treatments (excluding dupilumab, as both treatments act on similar receptors). It can complement the use of TCIs or be used after trying and failing topical therapies. Although 1 of the clinical experts indicated that there are no clinical reasons why it could not be used as a first-line treatment, both experts indicated that it makes sense to trial an appropriate topical therapy first before considering therapies such as tralokinumab. One clinical expert indicated that tralokinumab may offer a safer and more effective treatment option, as compared to the off-label systemic therapies that are currently available. The other clinical expert disagreed with that statement, referring to the lack of long-term evidence of safety and their own view that the efficacy data are not impressive. Overall, tralokinumab is not expected to cause a dramatic shift in the current treatment paradigm but may present an additional therapy in the class of small-molecule and biologic therapies. Dupilumab has already established a precedent in this class of therapies.

In terms of whether or not it would be appropriate to recommend that patients try other treatments before initiating treatment with tralokinumab, the clinical experts indicated that, for economic reasons, tralokinumab should be used after failing topical therapies. However, they were not aware of a clinical reason that could prevent tralokinumab from being a first-line treatment.

Patient Population

According to the clinical experts, it would make sense to treat patients with moderate to severe AD who have not responded to adequate topical therapies and an adequate trial of phototherapy if access was not an issue. Moderate to severe AD carries significant short-term and long-term effects on quality of life; all patients with uncontrolled moderate to severe AD would therefore benefit from intervention.

Patients with AD often have comorbid allergic disease. However, there is no strong evidence that tralokinumab helps reduce asthma exacerbations. Following the precedent set by the other biologic (dupilumab) assessments, such as the EASI, NRS, and IGA, quality-of-life scores such as the DLQI can be used. Severe AD is generally not difficult to diagnose. Pre-symptomatic patients should not be treated.

Patients who have conditions other than AD would be least suitable for treatment.

Assessing Response to Treatment

The clinical experts were not aware of good predictors of a good response to tralokinumab. The same assessments used for severity (NRS, IGA, and quality-of-life scores such as the DLQI and EASI) can also be used to assess response. A clinically meaningful response would include improvements in quality of life, itch and clinical scores (IGA or EASI). The clinical experts disagreed on when the treatment response should be assessed. One expert indicated that the treatment response should be assessed monthly early on in treatment, and every 3 to 6 months later on in the course of treatment. The other clinical expert would not typically assess response to tralokinumab earlier than 16 weeks and then every 6 months.

Discontinuing Treatment

According to the clinical experts, the factors to consider for discontinuation would be lack of efficacy and/or clinical response, and adverse effects (e.g., severe conjunctivitis unresponsive to treatment measures).

Prescribing Conditions

Hospital, specialty, and community clinics are appropriate places to initiate tralokinumab. The actual administration can be carried out at home with nursing support (subcutaneous injection). It would be reasonable to have a dermatologist diagnose, treat, and monitor patients receiving tralokinumab. No companion diagnostic testing is required.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

Two individual clinician inputs were received for the review of tralokinumab. One dermatologist practising in British Columbia provided input on behalf of the CDA and the other input was provided by a dermatologist who practises at the ODC in Saskatchewan. The CDA is a national medical specialty association that represents certified Canadian dermatologists. Its mandate is to promote the development of new medicine and surgery related to skin hair and nails; provide continuing professional education and development for its members; support patient care; and educate the public on sun protection and other aspects of skin, hair, and nail health. The ODC is an independent skin health centre that provides dermatology services to the general patient population in southern Saskatchewan. Additionally, the centre provides remote dermatology clinics in northern and southern Saskatchewan in the form of virtual care and teledermatology, and in-person clinics with a particular focus on providing culturally sensitive dermatology services to Indigenous populations.

Current Treatments

The clinician from the ODC informed CADTH that, other than dupilumab, there are currently no other FDA-approved systemic medications to treat moderate to severe AD. Traditional systemic immunosuppressants methotrexate and cyclosporin A are available but are associated with safety concerns.

The clinician from the CDA stated that most patients are initially treated with emollients, topical steroids, TCIs (pimecrolimus and tacrolimus) and/or phosphodiesterase inhibitors. The most commonly used of these treatments are topical steroids, which may take up to an hour or an hour and a half per application for moderate to severe disease. Newer antihistamines such as bilastine and rupatadine may be prescribed as adjunctive therapy to minimize itching, as they have a better safety profile compared with first-generation antihistamines, which can often cause dry mouth and diminish sleep quality and work productivity. The clinician explained that these antihistamines are often effective for approximately 90% of patients. Patients with more aggressive disease that does not respond to these treatments are treated with phototherapy (e.g., narrowband and broadband UV B, UVA and psoralen plus UVA), or systemic treatments in addition to topical therapy. However, psoralen plus UVA is now less commonly used due to an increase in skin cancer rates. The only FDA-approved systemic treatment, dupilumab, is administered subcutaneously every other week. Although this treatment has a good safety profile and has helped many patients, it has only been effective for approximately a third of patients with dermatitis. It is associated with side effects such as conjunctivitis and facial dermatitis, which can result in significant morbidity and lead the patient to terminate the treatment early. Off-label immunosuppressants such as methotrexate, cyclosporine, azathioprine, and mycophenolate mofetil can be used if there are no alternatives. However, the CDA clinician noted that the side effects of these immunosuppressants currently limit their use and that there is a lack of high-quality RCTs in dermatitis to advise the use of these immunosuppressants. These immunosuppressants require frequent laboratory monitoring, which can be troublesome for patients. The most commonly used immunosuppressants are methotrexate and cyclosporine. However, cyclosporine is considered a short-term (3- to 6-month) treatment due to adverse effects such as nephrotoxicity, structural renal damage, infections, and hypertension. Methotrexate is teratogenic and may cause bone marrow suppression, hepatic toxicity, malignancies, infections, and pulmonary fibrosis. Mycophenolate mofetil is also teratogenic and associated with serious infections and malignancies. Azathioprine is mutagenic and may cause bone marrow suppression and malignancies. The clinician added that immunosuppressants have put patients at an increased risk for these adverse effects during the COVID-19 pandemic. Systemic glucocorticoids can also be used in the short term but are associated with adverse effects and are therefore not considered for long-term therapy. Rebound is also common after systemic glucocorticoids are discontinued.

Unmet Needs

Both clinicians explained that the goals of treatment are to provide long-term relief of itching and clear the skin. The clinician from the CDA noted that 2/3 of patients who are treated with dupilumab do not achieve clear skin, and there is therefore a need for additional systemic medications with different mechanisms of action. Additionally, both clinicians emphasized that there is a need for treatments to be convenient and durable for patients. The clinician from the ODC specifically voiced this concern for Indigenous populations living in remote areas. These patients are often hard to reach virtually and have limited access to health care, which makes it extremely difficult to monitor patient safety while they are being treated with traditional systemic immunosuppressants. The clinician emphasized that traditional immunosuppressants can lead to side effects, such as worsening of infection, cytopenias, and liver damage, for which many people on reserves and remote areas may not be able to receive adequate follow-up care. There is therefore a significant need for treatments that not only have an improved safety and tolerability profile but are also easier to access. Both clinicians emphasized that the ultimate goal of treatment is to improve the overall quality of life of patients and enable them to regain their ability to function adequately in society.

Clinicians were asked to specify the patient groups that have the greatest unmet need for a drug such as tralokinumab. Both clinicians stated that patients with moderate to severe AD who do not respond to topicals and phototherapy have a high unmet need for this drug. Additionally, the clinician from the CDA noted that women of childbearing age also have an unmet need, as most off-label systemics are teratogenic. The clinician from the ODC re-emphasized the significant unmet need for Indigenous populations in Canada. The clinician stated that AD is a common skin disease among Indigenous populations, a situation that is often exacerbated by health barriers and disadvantages such as poverty, communicable disease, inadequate water supply, and difficulties accessing basic skin care products. Effective access to a treatment like tralokinumab can significantly help alleviate the symptoms of AD and promote a better quality of life.

Place in Therapy

The clinician from the CDA explained that tralokinumab is a biologic that has a different mechanism of action compared to dupilumab. Dupilumab is a monoclonal antibody directed against the alpha subunit of the IL-4 receptor, which is also a component of the IL-13 receptor. Tralokinumab is a monoclonal antibody against IL-13. The clinician explained that tralokinumab will be prescribed to patients with moderate to severe AD for whom topical therapy and phototherapy has failed. It would be prescribed as the first systemic drug, as well as after other systemics, including dupilumab, have failed. Furthermore, the clinician explained that tralokinumab would likely be used in addition to the topical therapies that the patient is using. However, once the AD improves, the topicals will most likely only be applied to any resistant areas.

Similarly, the clinician from the ODC advised that, in addition to tralokinumab, topical therapy would continue to be used for the remaining dermatitis. However, the clinician advised that chronic inflammation must be attended to and it is unsafe for patients to apply topical steroids daily on wide surface areas of the body.

Clinicians were asked to indicate whether or not it would be appropriate to recommend that patients try other treatments before initiating treatment with the drug under review. Both clinicians advised that it is unsafe to recommend the use of tralokinumab after systemics such as methotrexate and cyclosporine, as there is little evidence to support their use for AD. These systemics are also associated with significant toxicity concerns, such as renal damage, if used in the long term.

In terms of sequencing of therapies, the clinician from ODC advised that tralokinumab would be used in first-line settings. The clinician from CDA advised that topicals will continue to be used as a first-line therapy, followed by phototherapy and then systemics, including biologics. Currently, no data support the use of tralokinumab in patients who have failed dupilumab. It is possible that, because the mechanisms of action of tralokinumab and dupilumab are different, tralokinumab could work in patients in whom dupilumab did not work, and vice versa. It may also be possible for patients to be prescribed tralokinumab if they have conjunctivitis as a baseline atopic comorbidity. Additionally, tralokinumab may be used before other toxic systemic drugs. However, if tralokinumab and dupilumab do not work, patients will need to try another treatment, which could include immunosuppressives after the biologics.

Patient Population

Clinicians were asked to indicate which patients would be best suited for treatment with the drug under review. The clinician from CDA responded that patients with moderate to severe AD affecting more than 10% of their body surface area who experience intense itching, and patients who have failed to respond to topical and phototherapy, are best suited for this treatment. However, the clinician cautioned that there is no evidence to indicate which subtypes of patients with moderate to severe AD will respond better. Similarly, the clinician from the ODC noted that patients with moderate to severe AD who have failed traditional immunosuppressants would be best suited for tralokinumab. Both clinicians stated that these groups of patients are easily identifiable in clinical practice.

Clinicians were asked to identify which patients would be least suited to treatment. The clinician from the CDA explained that patients with mild AD or a different disease state would be least suited for this treatment. The clinician from ODC stated that patients with contraindications to tralokinumab such as hypersensitivity would be least suited to the treatment. In addition, the data are uncertain about the use of this treatment for pregnant women and children.

Assessing Response to Treatment

Clinicians were asked if it is possible to identify those patients who are most likely to exhibit a response to treatment with the drug under review. The clinician from the CDA explained that a waterfall plot of patient responses has shown that most patients have some response to tralokinumab; however, it is unclear how nonresponders would be identified. The clinician from the ODC responded that the DLQI test can be administered easily to help identify patients who are most likely to exhibit a response. A virtual EASI and Psoriasis Area and Severity Index scores can also be used; however, they are challenging to conduct virtually.

The clinician from the CDA stated that itch NRS, body surface area, and the IGA scale are outcomes often used in clinical practice to determine whether a patient is responding to treatment. Furthermore, the clinician explained that, in clinical trials, SCORAD and the DQLI are often used in addition to the EASI; however, SCORAD is mainly a European instrument and is difficult to calculate. The clinician from the ODC also mentioned the utility of the EASI and DLQI, as well as the IGA scale and body surface area scoring.

The clinician from the ODC noted that a 4-point reduction in itching, a reduction in IGA to mild or better, and a reduction in the affected body surface area would indicate a clinically meaningful response to treatment. The clinician further noted that lichenification can take many months to resolve when patients are improving. The clinician from the CDA specified that a reduction of 50% or greater in the EASI from baseline (EASI-50) or an EASI-75 response, a 2-point drop in the IGA score, and in improvement in quality-of-life indices would be considered clinically meaningful responses.

The clinician from the CDA advised that responses to treatment should be assessed at 6-month intervals, and yearly thereafter. Many patients with moderate to severe AD do not show maximal improvements until after at least 6 months of treatment. The clinician from the ODC advised that patients should be assessed approximately every 3 months until they are relatively stable, after which they could be assessed annually, given the favourable safety profile of tralokinumab.

Discontinuing Treatment

Both clinicians noted that nonresponse to the treatment or disease progression would signal a patient to discontinue treatment. The clinician from the ODC also specified that AEs from tralokinumab would also lead to discontinuation; however, the clinician from the CDA noted that there are no major safety concerns with tralokinumab, and that injection-site reactions and conjunctivitis rarely lead to treatment discontinuation.

Prescribing Conditions

Both clinicians noted that the disease is diagnosed, treated, and monitored by a dermatologist. The clinician from the CDA also specified that allergists may also play a role in management of the disease. In terms of prescribing tralokinumab, the clinician from CDA advised that it is usually prescribed initially by an allergist or dermatologist and may be renewed by other physicians after 6 months of treatment.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 6.

Table 6: Summary of Drug Plan Input and Clinical Expert Response

AD = atopic dermatitis; CDEC = CADTH Canadian Drug Expert Committee; DMARDS = disease-modifying antirheumatic drugs; EASI = Eczema Area and Severity Index; EASI-75 = 75% reduction in Eczema Area and Severity Index from baseline; IGA = Investigator’s Global Assessment; JAK = Janus kinase; RCT = randomized controlled trial.

Clinical Evidence

The clinical evidence included in the review of tralokinumab is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of tralokinumab for the treatment of moderate to severe AD in adult patients (> 18 years of age) whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Methods

Studies selected for inclusion in the systematic review include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 7. Outcomes included in the CADTH review protocol reflect those considered to be important to patients, clinicians, and drug plans.

The systematic review protocol described in Table 7 was established before the granting of a Notice of Compliance by Health Canada.

Table 7: Inclusion Criteria for the Systematic Review

AE = adverse event; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; IGA = Investigator’s Global Assessment; NRS = numeric scale; POEM = Patient-Oriented Eczema Measure; RCT = randomized controlled trial; SAE = serious adverse event; SCORAD = Scoring Atopic Dermatitis; SF-36 = Short Form (36) Health Survey; UVA/B = UV A/B; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.¹⁷

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946—) via Ovid and Embase (1974—) via Ovid. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were tralokinumab. Clinical trials registries searched included the US National Institutes of Health’s clinicaltrials.gov, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Appendix 1 provides detailed search strategies.

The initial search was completed on May 26, 2021. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on September 22, 2021.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.¹⁸ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Appendix 1 provides more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the sponsor of the drug was contacted for information regarding unpublished studies.

Findings from the Literature

Four studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 8, Table 5 Table 9, and Table 10. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

Four pivotal studies were included in this review:

ECZTRA 1 and 2

The ECZTRA 1 (N = 802) and ECZTRA 2 (N = 794) studies were 52-week, phase III, double-blind RCTs that aimed to evaluate the efficacy of tralokinumab compared with placebo in treating moderate to severe AD. The RCTs began with a screening period of 2 to 6 weeks, during which patients were assessed for study eligibility, and systemic and topical treatments for AD were washed out. All patients were to use an emollient twice daily (or more, as needed) for at least 2 weeks before randomization and were to continue this treatment throughout the trial. Following the screening period, the study had 3 key phases: an initial treatment phase (0 to 16 weeks), a maintenance treatment phase (16 to 52 weeks), and a safety follow-up (52 to 66 weeks) (Figure 2). At the start of the initial treatment phase, patients were randomized, stratified by region (North America, Japan, and Europe) and baseline disease severity (IGA of 3 or 4), in a 3:1 ratio to 1 of the following groups: a total loading dose of 600 mg of tralokinumab on day 0 followed by 300 mg of tralokinumab every 2 weeks or a total loading dose of 600 mg of placebo on day 0 followed by 300 mg of placebo every 2 weeks. Patients who achieved a clinical response at week 16 (defined as an IGA of 0 or 1, or an EASI-75 score) and who had been randomized to tralokinumab in the initial treatment phase were re-randomized 2:2:1 to 1 of the following groups: tralokinumab every 2 weeks, alternating dose administrations of placebo and tralokinumab every 2 weeks, or placebo every 2 weeks. Patients who did not achieve a clinical response at week 16, as well as those who did not maintain an adequate clinical response during the maintenance treatment period, were transferred to open-label tralokinumab every 2 weeks, with optional use of TCS. Patients randomized to the placebo group in the initial treatment period who achieved a clinical response at week 16 (defined as an IGA of 0 or 1, or an EASI-75 score) continued to receive placebo every 2 weeks in the maintenance treatment period. Randomization was conducted using a computer-generated randomization schedule stratified by region and baseline disease severity. The trials were unblinded once all randomized patients had completed the week 52 visit. At unblinding, all efficacy, safety, pharmacokinetic, and antidrug antibody data for the randomized treatment periods were collected and all end points used to test pre-specified hypotheses were final. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| (The Other Relevant Evidence section provides details).

Figure 2: ECZTRA 1 and ECZTRA 2 Trial Design

EASI75 = 75% or greater reduction in Eczema Area and Severity Index from baseline; IGA = Independent Investigator’s Assessment; rando = randomization; TCS = topical corticosteroids; w = week.

Source: Clinical Study Reports for ECZTRA 1⁷ and 2.⁵

ECZTRA 3

The ECZTRA 3 (N = 380) study was a 46-week phase III, double-blind RCT that aimed to demonstrate that tralokinumab in combination with TCS is superior to placebo in combination with TCS in treating moderate to severe AD. The ECZTRA 3 trial began with a 2- to 6-week screening period during which patients were assessed for study eligibility, and when systemic and topical treatments for AD were washed out. During the screening period, all patients received an electronic diary to collect patient-reported outcome data from 2 weeks before randomization until week 32 (Figure 3). All patients were to use an emollient twice daily (or more, as needed) for at least 14 days before randomization and were to continue this treatment throughout the trial. Following the screening period, the RCT had 2 key phases: an initial treatment phase (0 to 16 weeks) and a continuation treatment phase (16 to 32 weeks). At the start of the initial treatment phase, patients were randomized in a 2:1 ratio into 1 of 2 groups, stratified by region (Europe and North America) and baseline disease severity (IGA = 3 or 4): a total loading dose of 600 mg of tralokinumab on day 0 followed by 300 mg of tralokinumab every 2 weeks or a total loading dose of 600 mg of placebo on day 0 followed by 300 mg of placebo every 2 weeks. From baseline, all patients were instructed to use a supplied TCS (mometasone furoate 0.1% cream; Europe: class 3 [potent], US: class 4 [mid-strength]) once daily, as needed, on lesional skin throughout the treatment periods. Patients who were randomized to tralokinumab in the initial treatment phase who had a clinical response at week 16 (defined as an IGA score of 0 or 1, or an EASI-75 score) were re-randomized into the continuation treatment period in a 1:1 ratio, stratified by region (Europe and North America) and IGA response at week 16 (IGA 0 or 1, or IGA > 1) to 1 of the following groups: tralokinumab every 2 weeks or alternating dose administrations of placebo and tralokinumab every 2 weeks. Patients randomized to placebo in the initial treatment phase who had a clinical response at week 16 continued to receive placebo every 2 weeks in the continuation treatment period by blinded treatment allocation. Patients randomized to tralokinumab or placebo in the initial treatment period who did not have a clinical response at week 16 received tralokinumab every 2 weeks in the continuation treatment period. All patients stayed on the TCS regimen during the continuation treatment phase. All patients who did not enter the ECZTEND trial continued in a 14-week off-treatment follow-up period for the assessment of safety at week 46. Randomization involved assigning patients the lowest available randomization number, and a central interactive voice response system was used to control the randomization and stratification factors.

The trial was unblinded once all randomized patients had completed the week 32 visit. At unblinding, all efficacy, safety, pharmacokinetic, and antidrug antibody data for the randomized treatment periods were collected and all end points used to test pre-specified hypotheses were final. The trial had 2 database locks: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Figure 3: ECZTRA 3 Trial Design

AD = atopic dermatitis; Q2W = every 2 weeks; Q4W = every 4 weeks; TCS = topical corticosteroids; w = week.

Source: Clinical Study Report for ECZTRA 3.⁶

ECZTRA 7

The ECZTRA 7 (N = 277) study was a 40-week phase III, double-blind RCT that aimed to demonstrate that tralokinumab in combination with TCS is superior to placebo in combination with TCS in treating severe AD in patients who are not adequately controlled with or have contraindications to oral cyclosporine A. The RCT began with a 2- to 6-week screening period during which patients were assessed for study eligibility and systemic and topical treatments for AD were washed out. During the screening period, all patients attended a screening visit 2 weeks before baseline, when they received electronic diary training and started completion of the patient-reported outcomes questionnaires in the diary (data entered into the diary were used to calculate baseline values of the patient-reported outcomes). All patients were to use an emollient twice daily (or more, as needed) for at least 14 days before randomization and were to continue this treatment throughout the trial. On lesional skin, the emollient was applied only when TCS was not applied; on TCS-untreated areas, the emollient was applied at all times. Following the screening period, patients were randomized in a 1:1 ratio to 1 of the following groups stratified by prior cyclosporine A use (yes or no), country (Germany: yes or no), and baseline disease severity (IGA = 3 or 4): a total loading dose of 600 mg of tralokinumab on day 0 followed by 300 mg of tralokinumab every 2 weeks or a total loading dose of 600 mg of placebo on day 0 followed by 300 mg of placebo every 2 weeks (Figure 4). Patients in both groups applied a thin film of a supplied TCS (mometasone furoate, 0.1% cream, Europe: class 3 [potent]) once daily to areas with active lesions as needed; lower-potency TCS or TCIs could be prescribed if needed for body areas where the supplied TCS are not advisable or for areas where continued treatment with TCS was considered unsafe. Topical therapy was discontinued when control was achieved. The safety and appropriateness of continued or repeated courses of TCS was monitored and supervised by the site staff. Patients who did not enter the ECZTEND trial after completion of the week 26 visit completed a 14-week off-treatment follow-up period for the assessment of safety. Interactive response technology was used to control randomization and stratification factors. The ECZTRA 7 trial had 1 primary outcome: the percentage of patients achieving an EASI-75 score at week 16. All staff involved in the conduct of the trial remained blinded to treatment allocation for the entire duration of the trial. This principle was applied to all investigator staff and to staff employed by the sponsor, except for sponsor staff who handled trial supply and who were directly involved in the execution of the analysis following double-blinding and unblinding. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Figure 4: ECZTRA 7 Trial Design

AD = atopic dermatitis; TCI = topical calcineurin inhibitors; TCS = topical corticosteroids; w = week.

Source: Clinical Study Report for ECZTRA 7.⁴

Populations

Inclusion and Exclusion Criteria

All RCTs included males and females 18 years of age or older, with a diagnosis of AD for at least 1 year who had inadequate response to treatment with topical medications or for whom topical medications were medically inadvisable. Inadequate response was defined as failure to achieve and maintain remission or a low disease activity state (comparable to IGA 0 = clear to 2 = mild) despite treatment with a daily regimen of TCS of medium to higher potency. Patients were required to have EASI of 12 or greater at screening and 16 or greater at baseline (with the exception of the ECZTRA 7 trial, in which where patients were required to have an EASI of at least 20 at screening and baseline), an IGA score of 3 or greater at screening and at baseline, AD involvement of at least 10% of body surface area at screening and baseline, and a worst daily pruritus NRS average score of 4 or greater during the week before baseline. Women of childbearing potential were required to use a highly effective form of birth control (confirmed by the investigator) throughout the trial and for at least for 16 weeks (5 half-lives) after last administration of treatment. Patients who had been treated with a topical phosphodiesterase type 4 inhibitor, TCS, or TCI within 2 weeks of randomization, or used systemic immunosuppressive or immunomodulating drugs, systemic corticosteroids, or 3 or more bleach baths within 4 weeks of baseline were excluded, as were those who used tanning beds or phototherapy within 6 weeks before randomization, received cell-depleting drugs within 6 months of randomization or other biologics within 5 half-lives or 12 weeks before randomization (whichever was longer).

Baseline Characteristics

Across the 4 trials, the overall mean age of patients at baseline was similar, ranging from 36.5 to 39.1 years. In the ECZTRA 1, ECZTRA 2, and ECZTRA 7 trials, more than 59% of the patients at baseline were men. The ECZTRA 3 trial had a slightly lower percentage of men at baseline (55%). The mean body surface area involvement with AD at baseline was approximately 53%, with the exception of the ECZTRA 3 trial, for which it was 48.1%. The median age of onset of AD was 3.0 (ECZTRA 1), 2.0 (ECZTRA 2), and 4.0 (ECZTRA 3); however, the median age of onset was much higher in the ECZTRA 7 trial (10.0). Compared to the ECZTRA 1, ECZTRA 2, and ECZTRA 3 trials, the ECZTRA 7 trial also had a slightly lower duration of AD (reported in years). The duration of AD was 26.2 years at baseline for the ECZTRA 7 trial, whereas the other 3 trials included patients with a duration of AD of 28 years. Greater than 99% of patients reported previous use of AD treatments across all 4 trials. The percentage of patients with severe disease (IGA = 4) was approximately 50% in all but the ECZTRA 3 trial, which included 46.3% of patients with severe AD. The details of the baseline characteristics of patients in each RCT are included in the following section.

ECZTRA 1

Of the patients enrolled in ECZTRA 1, the overall mean age at baseline was ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Patients were included from 3 regions: |||||||| of patients from North America (US), |||||||| of patients from Europe (|||||||| from Germany, |||||||| from France, and ||||| from Spain) and ||||| of patients from Asia (Japan). |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, and the ||||||||||||||||||||||||||||||. For all randomized patients, |||||||||||||||||||| (moderate disease based on IGA) and 50.7% had IGA 4 (severe disease based on IGA), with comparable percentages for the tralokinumab every 2 weeks and placebo treatment groups, respectively. A total of 99.1% of patients reported use of any previous AD treatment, which included TCS (98.0% of patients), systemic steroids (59.4% of patients), topical and systemic calcineurin inhibitors (49.9% of patients), and phototherapy (48.1% of patients). No major differences in demographic and clinical characteristics were seen between-trial groups. Table 11 provides details.

ECZTRA 2

Of the patients enrolled in the ECZTRA 2 trial, the mean age at baseline was |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Patients were included from 4 regions: |||||| of patients from North America (|||||| from Canada and |||||| from the US), |||||| of patients from Europe (|||||| from Poland, |||||| from Great Britain, |||||| from Italy, |||||| from Russia, and |||||| from Denmark), |||||| of patients from Australia, and |||||| of patients from Asia (Korea). At baseline, the ||||||||||||||||||||||||||||||||||||||||||, the ||||||||||||||||||||||||||||||||||||, and the ||||||||||||||||||||||||||||||||||||||||||||||||. For all randomized patients, |||||||||||||||||||||||| (moderate disease based on IGA) and 48.7% had IGA 4 (severe disease based on IGA), and the percentages were comparable for the tralokinumab every 2 weeks and placebo treatment groups, respectively. A total of 99.7% of all randomized patients reported use of previous AD treatment, which included TCS (98.7% of patients), systemic steroids (67.4% of patients), |||||||||||||||||||||||||||||| calcineurin inhibitors (46.5% of patients), and phototherapy (43.7% of patients). No major differences in demographic and clinical characteristics were seen between-trial groups. Table 11 provides details.

ECZTRA 3

Of the patients enrolled in the ECZTRA 3 trial, |||||||||||||||||||||||||||||||||||||||||| and 55.0% of the trial population were men. In the placebo plus TCS group, there was a higher proportion of men than women (66.1% versus 33.9% patients, respectively). Most patients were White (75.8%) and ||||||||||||||||||||||||||||||||||||||||||||||||. There was a higher proportion of White patients (80.2% versus 66.9%) and a lower proportion of Asian patients (6.7% versus 18.9%) in the tralokinumab every 2 weeks plus TCS group than in the placebo plus TCS group, respectively. In both treatment groups, the distribution of ethnicity was comparable. Approximately ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In both treatment groups, the distribution of patients between regions (North America and Europe) was comparable and the distribution of patients between countries did not differ markedly between the 2 treatment groups. At baseline, the ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. For all randomized patients, 53.2% had an IGA of 3 (moderate disease) and 46.3% had an IGA of 4 (severe disease). All patients reported previous use of AD treatments. Almost all of the patients (98.2%) had used TCS. The frequent use of TCS was in line with the target population of patients with a recent history (within 1 year before the screening visit) of inadequate response to treatment with TCS. High proportions of patients (≥ 40%) had also used systemic steroids (61.6%), ||||||||||||||||||||||||||||||||||||||||||||||||||||||, phototherapy (46.1%), and antibiotics (40.0%) in both treatment groups. In addition, previous use of cyclosporine (31.1% patients), methotrexate (15.5% patients), azathioprine (6.6% patients), and mycophenolate (3.2% patients) was also reported in both treatment groups. At baseline, previous use of methotrexate and azathioprine was less frequent in the tralokinumab every 2 weeks plus TCS group than in the placebo plus TCS group (11.5% versus 23.6% patients and 5.1% versus 9.4% patients, respectively). Table 12 provides details.

ECZTRA 7

Of the patients enrolled in the ECZTRA 7 trial, |||||||||||||||||||||||||||||||||||||||||||||||||||||| and 59.6% of the trial population were men. There was a higher proportion of men than women (59.6% versus 40.4% patients, respectively). Most patients (98.2%) were White and ||||||||||||||||||||||||||||||||||||||||||||||||. The patients were all located in Europe, mostly in Poland (27.8%). At baseline, the ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. For all randomized patients, 50.2% had IGA score of 3 (moderate disease) and 49.8% had IGA score of 4 (severe disease), and the ||||||||||||||||||||||||||||||||||||||||||||||||. All patients reported previous use of AD treatments. Almost all of the patients (99.6%) had used TCS. High proportions of patients (≥ 40%) had also used systemic steroids (68.2%), |||||||||||||||||||||||||||||||||||||||||| phototherapy (58.8%), |||||||||||||||||||||||||||||||||||||||||| in both treatment groups. In addition, previous use of cyclosporine (74.7% patients), methotrexate (17.7% patients), azathioprine (13.0% patients), and mycophenolate (2.9% patients) was also reported in both treatment groups. Table 13 provides details.

Table 11: Summary of Baseline Characteristics for the ECZTRA 1 and ECZTRA 2 Trials

BSA = body surface area; EASI = Eczema Area and Severity Index; IGA = Investigator’s Global Assessment; NA = not applicable; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; SCORAD = Scoring Atopic Dermatitis; SD = standard deviation

Source: Clinical Study Reports for ECZTRA 1⁷ and 2.⁵

Table 12: Summary of Baseline Characteristics for the ECZTRA 3 Trial

BSA = body surface area; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; SCORAD = Scoring Atopic Dermatitis; q.2.w = every 2 weeks; SD = standard deviation; TCS = topical corticosteroids.

Source: Clinical Study Report for ECZTRA 3.⁶

Table 13: Summary of Baseline Characteristics for the ECZTRA 7 Trial

BSA = body surface area; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; SCORAD = Scoring Atopic Dermatitis; q.2.w. = every 2 weeks; SD = standard deviation; TCS = topical corticosteroids.

Source: Clinical Study Report for ECZTRA 7.⁴

Interventions

ECZTRA 1 and ECZTRA 2

Following the screening period, patients were randomized 3:1 to the intervention group or placebo for 16 weeks. In the intervention group, each patient received 4 subcutaneous injections (1 mL each) of 150 mg tralokinumab for a total loading dose of 600 mg tralokinumab on day 0. At subsequent visits in the initial treatment period (week 0 to 16), each patient received 2 injections (1 mL each) of 150 mg tralokinumab every 2 weeks. Patients randomized to the placebo group received an initial loading dose of 4 mL at day 0, and then 2 mL every second week. All injections were administered subcutaneously. Patients eligible for the maintenance period (week 16 to 52) were re-randomized 2:2:1 to receive either 300 mg tralokinumab every 2 weeks, alternating administrations of 300 mg tralokinumab and 2 mL placebo every 2 weeks, or 2 mL placebo every 2 weeks.

All patients were to use an additive-free, basic, bland emollient twice daily (or more often, as needed) for at least 14 days before randomization and were to continue this treatment throughout the trial. Rescue treatment for AD could be provided to trial patients at the discretion of the investigator. For analysis of the primary end points, patients who received rescue treatment during the initial treatment phase were considered nonresponders, but they continued tralokinumab or placebo treatment if the rescue treatment consisted of topical medications only. Investigators were encouraged to try topical treatments first and escalate to systemic medications only for patients who did not respond adequately after at least 14 days. Any WHO class of TCS could be used as topical rescue treatment, although it was unclear if any restrictions were imposed on frequency or dose of topical rescue treatment. A TCI could also be used but such use should be reserved for problem areas only (e.g., face, neck, intertriginous, and genitals). Systemic rescue treatment with corticosteroids or nonsteroidal immunosuppressive drugs (e.g., cyclosporine or methotrexate) required immediate discontinuation of tralokinumab. After the treatment with these drugs was completed, tralokinumab could be resumed if deemed appropriate by the investigator and the sponsor’s medical expert, but no sooner than 5 half-lives after the last dose of the systemic rescue treatment. Investigators could prescribe concomitant medications or treatments to provide adequate supportive care as deemed necessary, except for medications considered prohibited. The following concomitant medications related to AD treatment were permitted from screening through safety follow-up: oral antibiotics, antiviral, or antifungal therapy for skin infections as appropriate, stable doses of an emollient, and oral antihistamines.

ECZTRA 3

Following the screening period, patients were randomized 2:1 into the following groups, stratified by region (Europe and North America) and baseline disease severity (IGA = 3 or 4): a total loading dose of 600 mg tralokinumab or placebo on day 0 followed by tralokinumab 300 mg every 2 weeks (2 subcutaneous injections [1.0 mL each] of 150 mg tralokinumab) or placebo every 2 weeks (2 subcutaneous injections [1.0 mL each]). From baseline, all patients were instructed to initiate treatment once daily with a supplied TCS on lesional skin and continue as needed throughout the treatment period. At week 16, patients entered the continuation treatment period that lasted until week 32. The treatment assigned depended on the treatment in the initial treatment period and on the patient’s clinical response at week 16 (IGA of 0 or 1, or EASI-75). Patients randomized to tralokinumab in the initial treatment period who had a clinical response at week 16 were re-randomized to the continuation treatment period in a 1:1 ratio, stratified by region (Europe and North America) and IGA response at week 16 (IGA of 0 or 1, or IGA > 1) to receive either tralokinumab 300 mg every 2 weeks or tralokinumab 300 mg every 4 weeks (alternating dose administrations of tralokinumab 300 mg every 2 weeks and placebo every 2 weeks). Patients randomized to placebo in the initial treatment period who had a clinical response at week 16 continued to receive placebo every 2 weeks in the continuation treatment period via blinded treatment allocation. Patients randomized to tralokinumab or placebo in the initial treatment period who did not have a clinical response at week 16 were allocated to receive tralokinumab every 2 weeks in the continuation treatment period. All patients stayed on the TCS regimen during the continuation treatment period.

Rescue treatment for AD could be provided to patients at the discretion of the investigator. Investigators were encouraged to try topical treatments first and escalate to systemic medications only for patients who did not respond adequately after at least 14 days. Patients who received systemic rescue treatment with corticosteroids or nonsteroidal immunosuppressive drugs (cyclosporine, methotrexate, mycophenolate mofetil, or azathioprine) were required to immediately discontinue tralokinumab or placebo. After treatment with these medications was completed, treatment with the tralokinumab or placebo could be resumed if deemed appropriate by the investigator and the sponsor’s medical expert, but no sooner than 5 half-lives after the last dose of systemic rescue medication. Investigators could prescribe concomitant medications or treatments to provide adequate supportive care as deemed necessary, except for medications considered prohibited. The following concomitant medications related to AD treatment were permitted from screening through safety follow-up: oral antibiotics, antiviral, or antifungal therapy for skin infections as appropriate, and oral antihistamines.

ECZTRA 7

Following the screening period, patients were randomized 1:1 to 1 of the following groups stratified by prior cyclosporine A use (yes or no), country (Germany: yes or no), and baseline disease severity (IGA = 3 or 4): tralokinumab 600 mg loading dose at day 0 followed by tralokinumab 300 mg every 2 weeks or placebo 600 mg loading dose at day 0 followed by placebo every 2 weeks. Patients in both treatment groups applied a thin film of a supplied TCS once daily to areas with active lesions as needed; lower-potency TCS or a TCI could be prescribed if needed for body areas where the supplied TCS was not advisable or for areas where continued treatment with TCS was considered unsafe. Topical therapy was discontinued when control was achieved; discontinuation should preferably be gradual. The safety and appropriateness of continued or repeated courses of TCS therapy was monitored and supervised by the site staff. Patients, except those who entered the long-term extension trial after completion of the week-26 visit (ECZTEND), completed a 14-week off-treatment follow-up period for the assessment of safety, pharmacokinetics, and antidrug antibodies.

Rescue treatment for AD could be provided to trial patients at the discretion of the investigator. Investigators were encouraged to try topical treatments first and escalate to systemic medications only for patients who did not respond adequately after at least 14 days. Patients who received systemic rescue treatment with corticosteroids or nonsteroidal immunosuppressive drugs (e.g., methotrexate, mycophenolate mofetil, or azathioprine) were required to immediately discontinue tralokinumab or placebo. After treatment with these medications was completed, treatment with tralokinumab or placebo could be resumed if deemed appropriate by the investigator, but no sooner than 5 half-lives after the last dose of systemic rescue treatment. Investigators could prescribe concomitant medications or treatments to provide adequate supportive care as deemed necessary, except for medications considered prohibited. The following concomitant medications related to AD treatment were permitted from screening through safety follow-up: oral antibiotics, antiviral, or antifungal therapy for skin infections as appropriate, and oral antihistamines.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 14. These end points are then further summarized. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 3.

In the ECZTRA 1, ECZTRA 2, and ECZTRA 3 trials, the coprimary outcomes were patients with an IGA score of 0 or 1 at week 16 and patients who had achieved an EASI-75 score at week 16. In the ECZTRA 7 trial, the primary outcome was patients who had achieved an EASI-75 score at week 16.

Investigator’s Global Assessment

The IGA score is an investigator-reported assessment used to rate AD severity. It is based on a 5-point scale ranging from 0 to 4, in which “0” indicates clear, and “4” indicates severe AD.²⁰ A decrease in score reflects improvement in signs and symptoms. The validity and reliability of the measure was determined to be adequate in patients with varying severities of AD based on a study by Bożek (2017),²¹ and reliability was also found to be adequate in a study conducted by Zhao et al. (2017),²² which compared patients with lighter and darker skin. No MID was identified in patients with AD.

Eczema Area and Severity Index

The EASI is a scale used in clinical trials to assess the severity and extent of AD.²³ In the EASI, 4 disease characteristics of AD (erythema, infiltration or papulation, excoriations, and lichenification) are assessed for severity by the investigator on a scale of “0” (absent) to “3” (severe). The scores are added up for each of the 4 body regions (head, arms, trunk, and legs). The assigned percentages of body surface area for each section of the body are 10% for head, 20% for arms, 30% for trunk, and 40% for legs respectively. Each subtotal score is multiplied by the body surface area represented by that region. In addition, the affected area of AD assessed as a percentage by each body region is converted to a score of 0 to 6, in which the area is expressed as 0 (none), 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). Each of the body area scores is multiplied by the area affected. The total EASI score therefore ranges from 0 to 72 points, with higher scores indicating worse severity of AD.²⁴ It is suggested that the severity of AD based on the EASI are categorized as follows: 0 = clear; 0.1 to 1.0 = almost clear; 1.1 to 7.0 = mild; 7.1 to 21.0 = moderate; 2l.1 to 50.0 = severe; and 50.1 to 72.0 = very severe.²⁵ The EASI-50, EASI-75, EASI-90, and EASI-100 end points indicate improvements of 50% or greater, 75% or greater, 90% or greater, and 100% improvement from baseline, respectively.

The psychometric properties of the EASI have been examined in several studies of patients with AD.^26-31 Validity of the EASI and SCORAD was adequate, with correlation coefficients ranging from 0.84 to 0.93.²⁹ Intra- and inter-rater reliability were estimated to be adequate based on correlation coefficients ranging from 0.8 to 0.9, and responsiveness was adequate in populations of children and adults with AD.²⁹ It was determined that the EASI is a validated scale and can be used reliably to assess the severity and extent of AD. Inter-rater reliability for the EASI was also assessed in a study that separated patients into 2 groups: those with lighter skin (melanin index ≤ 200; n = 11) and those with darker skin (melanin index > 200; n = 14), and was found to be adequate (intraclass correlation coefficients of 0.83 and 0.77, respectively).²² The overall MID is 6.6, based on results from 1 study that included patients with atopic eczema.³²

Scoring Atopic Dermatitis

The SCORAD tool was developed to standardize the evaluation of the extent and severity of AD.³³ It is considered a valid and reliable tool for the objective assessment of eczema clinical signs.³⁴ The instrument assesses 3 components of AD: the extent of affected body surface area (0 to 100), severity (0 to 18), and symptoms (0 to 20). The extent of AD is assessed as a percentage of each defined body area and reported as the sum of all areas. The score ranges from 0 to 100. The severity of 6 specific signs of AD (redness, swelling, oozing and/or crusting, excoriation, skin thickening and/or lichenification, and dryness) is assessed using a 4-point scale (none = 0, mild = 1, moderate = 2, and severe = 3) with a minimum score of 0 and a maximum of 18. Relevant symptoms (itch and sleeplessness) are recorded by the patient or relative on a visual analogue scale, with scores ranging from 0 (no symptoms) to 10 (worst imaginable symptom) and a maximum possible score of 20. The SCORAD total is calculated based on the 3 components, with a maximum possible total score of 103, in which a higher score indicates poorer or a more severe condition.

The SCORAD tool has been found to be valid and reliable in patients with AD, with excellent agreement with global assessments of disease severity.^23,35 Content validity has been deemed adequate, with good construct validity (Spearman R values range from 0.53 to 0.92) and internal consistency. Sensitivity to change and inter-observer reliability are also adequate; the latter with measurements of the intraclass coefficient from 0.84 to 0.99. However, intra-observer (test-retest) reliability was unclear.²³ The MID has been estimated using mean change scores of SCORAD of patients that showed a relevant improvement based on IGA, defined as an “improvement” or “decline” of at least 1 point in the Physician’s Global Assessment (PGA) and IGA. A difference of 8.7 points in SCORAD was estimated as the MID for the patients with AD.³²

Worst Pruritus Numeric Rating Score

The pruritus NRS is used to report the intensity of itches during a daily recall period. Patients rate their overall (average) and maximum intensity of itch experienced during the past 24 hours based on a scale of 0 to 10 (0 = “no itch” and 10 = “worst itch imaginable”).

The reliability of the NRS is adequate,³⁶ with pooled intraclass coefficients in a range of 0.95 to 0.97.³⁶ The NRS scores are stable over a period of time. The validity of the NRS has been shown using known-groups approaches with all results above the Cohen threshold of 0.80 for large effect sizes.³⁶ Based on a study by Simpson et al., an estimated improvement on the pruritus NRS is at least a 3- to 4-point reduction.³⁶ This estimate was calculated using anchor- and distribution-based methods and data from a phase IIb study of dupilumab used to treat patients with moderate to severe AD. Yosipovitch et al. 2019 also estimated the MID using both distribution-based methods as well as patient-reported outcome and clinician-reported outcome anchor-based methods.³⁷ The MIDs were reported to range from 2.2. to 4.2 points for clinician-reported outcome anchors (i.e., EASI and IGA) but were generally lower at 0.76 and 2.6 points for the half–standard deviation (SD) distribution–based method and patient-reported outcome anchor (i.e., pruritus categorical scale), respectively. The investigators suggested that the pruritus categorical scale may be the more appropriate anchor as it had a stronger correlation with the NRS than with the EASI or IGA.

Dermatology Life Quality Index

The DLQI is a widely used HRQoL instrument. It is a 10-item questionnaire that assesses 6 different aspects that may affect quality of life.^38,39 These aspects are symptoms and feelings, daily activities, leisure, work and school performance, personal relationships, and treatment. Each of the 10 questions is scored on a 4-point scale (0 = not at all or not relevant, 1 = a little, 2 = a lot, and 3 = very much), and the overall DLQI is calculated by summing the score of each question resulting in a numeric score between 0 and 30 (or a percentage of 30).^38,39 The higher the score, the more quality of life is impaired. The meaning of the DLQI scores on a patient’s life is as follows⁴⁰: 0 to 1 = no effect; 2 to 5 = small effect; 6 to 10 = moderate effect; 11 to 20 = very large effect; and 21 to 30 = extremely large effect.

The DLQI has previously been validated in patients with a variety of skin conditions, including eczema.^41-44 Patel et al. (2019) aimed to assess the validity, responsiveness, and floor and ceiling effects of the DLQI in a group of 340 adults with AD, and determined that the DLQI has adequate content validity and moderate convergent validity when compared to the EASI (r_S = 0.44), SCORAD (r_S = 0.55), NRS-itch (r_S = 0.59), and POEM (r_S = 0.61).⁴⁵ Convergent validity was also assessed in a 2021 study by Schwartzman et al. that included 994 adults with AD and showed similar outcomes for the EASI (r_S = 0.48), SCORAD (r_S = 0.48), NRS-itch (r_S = 0.53 worst itch and r_S = 0.49 average itch), and POEM (r_S = 0.61) instruments.⁴⁶ To assess discriminative validity, Patel et al. (2019) also determined that the DLQI has adequate discriminative validity, good internal consistency (Cronbach alpha = 0.89) and fair to moderate correlation among individual items (rho = 0.28 to 0.60). The DLQI was found to be less responsive for patients who showed either 1- or 3-point improvement and more responsive for those who showed at least 3-point worsening. A study by Holm et al. (2006) looked at 101 patients with AD (66 adults and 35 children) along with 30 healthy controls who completed the DLQI at 2 time points 6 months apart, and determined that the instrument is sensitive to differing severities of AD.⁴⁷ Last, the Patel et al. study reported no floor or ceiling effects, defined as at least 15% of patients scoring in the lowest or highest values, for the overall DLQI scores, although they could be noted for individual items.⁴⁵

A study by Basra et al. (2015) used an anchor-based approach to assess the responsiveness of the DLQI and estimate a MID.⁴⁸ A total of 192 patients with different skin conditions ranging from acute to chronic were included (50.5% with psoriasis, 21.9% with acne, 12.5% with eczema, and 15.1% other). Details regarding the disease severity of patients were not reported. Using the Global Rating of Change Questionnaire as an anchor and considering a change in score of 2 or 3 points to be a “small,” an MID of 3.3 was estimated for the DLQI.⁴⁸ There are a few limitations with the determination of the MID for the DLQI. The anchor-based approach used a subjective, global assessment of change that is subject to recall bias and not specific to AD.⁴⁸ The authors acknowledged this and noted that the use of a global assessment was reasonable because the population comprised patients with a mix of diagnosed skin conditions; however, the lack of specificity to AD is a limitation that should be taken into consideration when applied to an AD-specific population.

Hospital Anxiety and Depression Scale

The Hospital Anxiety and Depression Scale (HADS) is a widely used patient-reported questionnaire designed to identify anxiety disorders and depression in patients at nonpsychiatric medical institutions. Repeated administration also provides information about changes in a patient’s emotional state.^49-51 The HADS questionnaire contains 14 items that assess symptoms experienced in the previous week, including 7 items related to anxiety and 7 related to depression. Patients provided responses to each item based on a 4-point Likert scale. Each item is scored from 0 (the best) to 3 (the worst); a patient can therefore score between 0 and 21 for each subscale (anxiety and depression). A high score was indicative of a poor state. Scores of 11 or more on either subscale were considered to be a “definite case” of psychological morbidity, while scores of 8 to 10 represented a “probable case” and 0 to 7 “not a case.”⁵¹ One study⁵² indicated that the HADS has good construct validity when applied to adult AD patients, with no overall floor or ceiling effects. The author concluded that the HADS may be useful for the assessment of AD patients in clinical trials and practice, but added that additional research is needed to confirm the construct validity and to assess content validity and feasibility in research and clinical practice.⁵² No additional validity and MID information regarding application of the HADS to patients with AD was found in a literature search.

Patient-Oriented Eczema Measure

The POEM is a 7-item questionnaire used in clinical trials to assess disease symptoms in children and adults. Based on frequency of occurrence during the past week, the 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) are assessed using a 5-point scale. The possible scores for each question are: “0” for no days, “1” for 1 to 2 days, “2” for 3 to 4 days, “3” for 5 to 6 days, and “4” for every day. The maximum total score is 28; a high score is indicative of a poor quality of life (0 to 2 indicates clear or almost clear; 3 to 7 mild eczema; 8 to 16 moderate eczema; 17 to 24 severe eczema; and 25 to 28 very severe eczema).⁵³

The POEM has been tested and found to be adequate for validity, reliability, and responsiveness.^30,54,55 Two 2020 studies by Silverberg et al. (N = 602⁵⁶ and N = 29,157) assessed patient-reported outcomes in adults with AD. For convergent validity, Pearson (r) and Spearman (r_S) correlation coefficients generally indicated a strong correlation between the POEM and the DLQI (r = 0.62,⁵⁶ r_S = 0.59⁵⁷), NRS-itch (r = 0.58,⁵⁶ r_S = 0.45 and 0.50⁵⁷ for worst itch and average itch, respectively), and the EASI (r_S = 0.52⁵⁷), but moderate correlation with the HADS anxiety and depression subscores (r = 0.33 and 0.31,⁵⁶ respectively). The POEM also demonstrated adequate criterion validity through significant and stepwise increases with different levels of self-reported global AD severity (e.g., mild, moderate, and severe). Discriminant validity was generally adequate and the POEM showed varying ability to distinguish between mild and moderate AD (area under the curve [AUC] = 0.67⁵⁷ to 0.75,⁵⁶ poor to fair ability), mild and severe AD (AUC = 0.70⁵⁷ to 0.89,⁵⁶ fair to good ability), and moderate and severe AD (AUC = 0.52⁵⁷ to 0.73,⁵⁶ unable to fairly ability). Test-retest reliability, calculated using the intraclass correlation coefficient, was acceptable (0.86) when assessed in 189 patients.⁵⁷ Changes in scores, a measure of responsiveness, were assessed, with closer correlation evident between the POEM and the DLQI (r = 0.67) compared to the EASI (r = 0.47) and itch NRS (r = 0.48 for both worst and average itch).⁵⁷ Floor effects were noted for the overall POEM score and all individual items of the instrument for the study with 602 patients,⁵⁶ while no floor effects were noted for the study with 291 patients.⁵⁷ No ceiling effects were observed in either study.

Using data from 3 RCTs for AD treatment, Schram et al. (2012) reported an overall mean MID for the POEM to be 3.4 points (SD = 4.8), with an IGA score improvement of 1 points used as an anchor.³¹ A different study by Silverberg et al. (2020) estimated an MID of 5.0 points based on an anchor of at least a 1-point improvement for patient-reported global severity.⁵⁷ The MID was smaller (3.7) for patients who reported baseline clear-to-mild AD or greater (6.1) for those who reported moderate to severe AD.

Short Form (36) Health Survey 36 (Acute Recall)

The SF-36 is a 36-item general health status assessment. Patients were asked to answer each question by selecting 1 of 3 to 6 categorical response options. The instrument instructions do not state a specific recall period; however, a recall period is defined for most items. The acute recall version, which asks patients about the last week, was used in this trial.⁵⁸ This version of the survey (SF-36 Acute Recall) yields scores for 8 health domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health) and 2 psychometrically derived summary scores (a physical component summary and a mental component summary). Although no literature was found that assessed the SF-36 Acute Recall for validity or reliability in patients with AD, the instrument has been validated in other disease areas such as psoriasis.⁵⁹ A study by Holm et al. (2006) looked at 101 patients with AD (66 adults and 35 children) along with 30 healthy controls who completed the SF-36 at 2 time points with a 6-month interval.⁴⁷ The physical component summary and mental component summaries showed little change between the assessments and between patient and control groups. Furthermore, using Wilcoxon rank scores, the investigators noted only small differences between patients with moderate and mild AD and those with mild AD and healthy controls. No MID was identified in patients with AD.

EQ-5D 5-Levels Questionnaire

The EQ-5D is a generic quality-of-life instrument that has been applied to a wide range of health conditions and treatments, including AD.^60,61 The first of 2 parts of the EQ-5D is a descriptive system that classifies respondents (aged ≥ 12 years) into 1 of 243 distinct health states. The descriptive system consists of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 possible levels (1, 2, or 3) representing “no problems,” “some problems,” and “extreme problems,” respectively. Respondents are asked to choose 1 level that reflects their own health state for each of the 5 dimensions. A scoring function can be used to assign a value (EQ-5D index score) to self-reported health states from a set of population-based preference weights.^60,61 The second part is a 20 cm Visual Analogue Scale (EQ VAS) that has end points labelled 0 and 100, with respective anchors of “worst imaginable health state” and “best imaginable health state,” respectively. Respondents are asked to rate their own health by drawing a line from an anchor box to the point on the EQ VAS that best represents their own health on that day. The EQ-5D index and EQ VAS scores can be summarized and analyzed as continuous data.^62,63 The EQ-5D-5L has been validated in terms of feasibility, ceiling effects, discriminatory power, and convergent validity in a diverse patient population from 6 countries with chronic conditions⁶³; however, no literature was found that assessed the EQ-5D-5L for validity, reliability, or responsiveness in patients with AD.

A Canadian-specific estimate of a MID for the EQ-5D-5L was generated by simulating the effects of single-level transitions in each dimension.⁶⁴ The results yielded MIDs with a summarized mean of 0.056 (SD = 0.011), and a summarized median of 0.056 (interquartile range = 0.049 to 0.063). No MID was identified in patients with AD.

Work Productivity and Activity Impairment–General Health

The impact of AD on the patient’s ability to perform both paid work and unpaid work and engage in regular activities was assessed by the Work Productivity and Activity Impairment–General Health (WPAI-GH) instrument.⁶⁵ It consists of 6 items and measures absenteeism, presenteeism, and impairments in unpaid activity because of health problems during the past 7 days. The following 4 main outcomes can be generated from the WPAI-GH: percent of work time missed due to health for those who were currently employed, percent impairment while working due to health for those who were currently employed and actually worked in the past 7 days, percent of overall work impairment due to health for those who were currently employed, and percent activity impairment due to health for all respondents. No reports were found in the literature that assessed the instrument for validity, reliability, or responsiveness in patients with AD. No MID was identified in patients with AD.

Statistical Analysis

ECZTRA 1 and ECZTRA 2 Trials

Sample size: The investigators assumed a screening failure rate of 25%. Approximately 1,040 patients were expected to be screened and approximately 780 patients were planned to be randomized 3:1 to initial treatment (585 patients to tralokinumab and 195 patients to placebo). The sample sizes was chosen to ensure that sufficient safety information was collected and that a sufficient number of responders were re-randomized to maintenance treatment.

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Multiplicity adjustment: To control the overall type I error rate, the primary analyses for the primary and secondary end points for the initial and maintenance treatment followed the testing. For the global (non-US) submission testing procedure, an IGA of 0 or 1 at week 16 between tralokinumab and placebo was evaluated at a 5% significance level. If the test was significant, an EASI-75 score at week 16 between tralokinumab and placebo was evaluated at a 5% significance level. If both these tests were significant, the significance level (alpha) was split between the analyses of the 3 secondary end points at week 16 and the analyses of the 2 maintenance end points at week 52. These groups of tests were tested in parallel with an alpha of 1% for the end points at week 16 and with an alpha of 4% for the maintenance end points at week 52. Evaluations of the 3 secondary end points at week 16 between tralokinumab and placebo used the Holm method⁶⁶ for 3 ordered P values at a 1% significance level to adjust for multiplicity. The hypotheses for the maintenance treatment end points were tested sequentially in the specified order at the 4% significance level. The next hypothesis was only to be tested if the former was significant. If all P values for the 3 secondary end points at week 16 were significant, then the hypotheses for the maintenance treatment end points could be evaluated at a 5% significance level. Conversely, if all P values for the maintenance end points were significant, then the hypotheses for the 3 secondary end points at week 16 could be evaluated at a 5% significance level. The US submission testing procedure was executed as above, except that a reduction in the worst daily pruritus NRS weekly average of at least 4 at week 16 was tested after the sequential testing of an IGA of 0 or 1 and an EASI-75 score if these tests showed statistical significance.

Rescue medication: Rescue medication was summarized separately for the initial treatment period and the maintenance treatment period, and organized in a tabular format by type (topical and systemic) and group (corticosteroids, immunosuppressants, and other). For patients continuing with maintenance or open-label treatment at week 16, the summary tabulation of rescue medication during the initial treatment period included rescue medication taken between the first dose of initial treatment and the first dose of either maintenance or open-label treatment. For patients who did not continue with maintenance or open-label treatment, the summary tabulation of rescue medication during the initial treatment period included medications taken after the first dose and before the week 16 visit. The summary tabulation of rescue medication during the maintenance treatment period included rescue medication taken (but not necessarily initiated) after the first maintenance dose and excluded rescue medication initiated during the safety follow-up period.

Analysis: Categorical data were summarized using the number and percentage of patients in each category and treatment group. Continuous data were summarized using the mean, median, SD, and minimum and maximum values. Unless otherwise stated, all significance tests were 2-sided using the 5% significance level. All P values were nominal. All CIs were presented with a 95% degree of confidence.

For all analyses of the 2 primary outcomes at week 16, the difference in response rates between treatment groups were analyzed using the Cochran-Mantel-Haenszel test (single imputation analyses) or a combined inference from multiple Mantel-Haenszel risk differences and associated standard errors using the Rubin rule (multiple imputation analyses). The stratification factors included region (North America, Japan, and Europe) and baseline disease severity (IGA = 3 or 4). Treatment difference in response rates of IGA of 0 or 1 and an EASI-75 score after 16 weeks achieved without rescue medication were assessed, regardless of treatment discontinuation, and the primary estimand assessed the expected difference in response rates (defined as response obtained without initiation of any rescue medication) after 16 weeks, resulting from initiation of a treatment regimen with tralokinumab compared to a treatment regimen with placebo. For the primary analysis of primary end points at week 16, patients who had received rescue medication before the week 16 visit were considered nonresponders. Patients with missing data at week 16 and in whom rescue medication had not been used before week 16 were imputed as nonresponders. Three sensitivity analyses were conducted for the primary outcomes at week 16: a primary analysis in which all patients who permanently discontinued the investigational medicinal product (IMP) before week 16 were considered nonresponders, even if no rescue medication had been used; a primary analysis in which missing data at week 16 was imputed using last observation carried forward rather than using nonresponder imputation for patients who did not receive rescue medication and did not withdraw due to an AE or lack of efficacy; and a tipping-point analysis using multiple imputation in which patients who had received rescue medication before the week 16 visit were considered nonresponders. Missing week-16 responses were imputed from a Bernoulli distribution with a varying parameter for patients in the placebo group who did not use rescue medication. Patients in the tralokinumab group with missing week-16 data were imputed as nonresponders. Different percentages of placebo patients were considered responders for the different values of P. The tipping point is the value of P that changed the conclusion from significant to nonsignificant. Two main subgroup analyses were conducted at week 16 based on the primary outcomes: IGA of 0 or 1 by baseline IGA and IGA of 0 or 1 by region; and an EASI-75 score by baseline IGA and EASI-75 by region. For the maintenance treatment period (week 52) the 2 dichotomous maintenance end points were: an IGA of 0 or 1 at week 52 among patients with IGA of 0 or 1 at week 16 achieved without rescue medication after initial randomization to tralokinumab, and an EASI-75 score at week 52 among patients with an EASI-75 score at week 16 achieved without rescue medication after initial randomization to tralokinumab. All patients who had received rescue medication including TCS before the week-52 visit and/or had been transferred to open-label treatment with tralokinumab were considered nonresponders. Patients with missing data at week 52 were imputed as nonresponders. For each end point (IGA of 0 or 1 and an EASI-75 score at week 52) the difference in response rates between treatment groups was analyzed using the Cochran Mantel-Haenszel test stratified by region.

For the 3 secondary outcomes (reduction of worst daily pruritus NRS [weekly average] of 4 or greater from baseline to week 16, change in SCORAD from baseline to week 16, and change in DLQI score from baseline to week 16) all analyses were based on the full analysis set (FAS) at week 16. Data collected after permanent discontinuation of tralokinumab or placebo or after initiation of rescue medication were not included in the analysis. For patients who did not have any post-baseline data collected before initiation of rescue medication, the week-2 change was imputed as 0. In terms of the sensitivity analysis for the secondary outcomes at week 16, data collected after permanent discontinuation of tralokinumab or placebo or after initiation of rescue medication were not included. Multiple imputation of missing values was applied, based on regression models fitted on observed data from the placebo group.

No interim analyses were planned or conducted.

ECZTRA 3

Sample size: Assuming a screening failure rate of 25%, approximately 492 patients were planned to be screened and approximately 369 patients were planned to be randomized 2:1 to the initial treatment; 246 patients to tralokinumab q.2.w. plus TCS and 123 patients to placebo plus TCS. The sample size was chosen to ensure a sufficient combined power to demonstrate a statistically significant predefined difference between tralokinumab every 2 weeks plus TCS and placebo plus TCS for the primary end points.

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Multiplicity adjustment: The overall type I error rate for the primary analysis of the primary estimands for the primary and confirmatory secondary end points was protected by a combination of hierarchical testing and a Holm-Bonferroni multiplicity adjustment. The hypothesis relating to a specific end point could not be rejected unless all hypotheses relating to end points earlier in the hierarchy were also rejected. For the global (non-US) submission testing procedure an IGA of 0 or 1 at week 16 between tralokinumab every 2 weeks plus TCS and placebo plus TCS was evaluated at a 5% significance level. If the test was significant, an EASI-75 score at week 16 between tralokinumab every 2 weeks plus TCS and placebo plus TCS was evaluated at a 5% significance level. If both these tests were significant, the 5% significance level (alpha) was propagated to the 3 confirmatory secondary end points of pruritus, SCORAD, and DLQI at week 16. The evaluations of the 3 confirmatory secondary end points between tralokinumab every 2 weeks plus TCS and placebo plus TCS used the Holm method⁶⁶ for 3 ordered P values at a 5% significance level to adjust for multiplicity. The US testing procedure was executed in a manner similar to the non-US submission except that pruritus at week 16 was tested after the sequential testing of an IGA of 0 or 1 and an EASI-75 score if these tests showed statistical significance. If the test of pruritus at week 16 was also significant at a 5% significance level, the 2 remaining confirmatory secondary end points of SCORAD and DLQI at week 16 were evaluated using the Holm method for 2 ordered P values at a 5% significance level to adjust for multiplicity.

Rescue medication: Rescue medication was summarized separately for the initial and continuation treatment periods. In addition, a summary tabulation of rescue medication by type (topical and systemic) and overall group (corticosteroids, immunosuppressants, and other) was made. For patients who continued with continuation treatment from week 16, the summary tabulation of rescue medication during the initial treatment period included rescue medication taken between the first dose of initial treatment and the first dose of continuation treatment. For patients who did not continue with continuation treatment, the summary tabulation of rescue medication during the initial treatment period included medication taken after the first dose and before the week-16 visit. The summary tabulation of rescue medication during the continuation treatment period included rescue medication taken (but not necessarily initiated) after the first continuation dose of tralokinumab and placebo and excluded rescue medication initiated during the safety follow-up period.

Analysis: Categorical data were summarized using the number and percentage of patients in each category and treatment group. Continuous data were summarized using the mean, median, SD, and minimum and maximum values. Unless otherwise stated, all significance tests were 2-sided using the 5% significance level. All P values were nominal. All CIs were presented with a 95% degree of confidence.

For all analyses of the 2 primary outcomes at week 16, the difference in response rates between treatment groups were analyzed using the Cochran-Mantel-Haenszel test (single imputation analyses) or a combined inference from multiple Mantel-Haenszel risk differences and associated standard errors using the Rubin rule (multiple imputation analyses). The stratification factors included: region (North America and Europe) and baseline disease severity (IGA = 3 or 4). Treatment difference in response rates of an IGA of 0 or 1 and an EASI-75 score after 16 weeks achieved without rescue medication were assessed, regardless of treatment discontinuation, and the primary estimand assessed the expected difference in response rates (defined as a response obtained without initiation of any rescue medication) after 16 weeks resulting from initiation of a treatment regimen with tralokinumab every 2 weeks plus TCS compared to a treatment regimen with placebo plus TCS. For the primary analysis of primary end points at week 16, patients who had received rescue medication before the week-16 visit were considered nonresponders. Patients with missing data at week 16 and in whom rescue medication had not been used before week 16 were imputed as nonresponders. The sensitivity and subgroup analyses at week 16 for the primary outcomes are identical to those conducted in the ECZTRA 1 and ECZTRA 2 trials, with the sole difference being that tralokinumab every 2 weeks + TCS was compared to placebo plus TCS group. The primary and sensitivity analyses on the secondary outcomes at week 16 were also identical to those of the ECZTRA 1 and ECZTRA 2 trials.

Descriptive statistics were used for end points in the continuation treatment period. For the continuation treatment period (week 32) the 2 dichotomous end points were an IGA of 0 or 1 at week 32 among patients with an IGA of 0 or 1 at week 16 achieved without rescue medication after initial randomization to tralokinumab and an EASI-75 score at week 32 among patients with an EASI-75 score at week 16 achieved without rescue medication after initial randomization to tralokinumab.

No interim analyses were planned or conducted.

ECZTRA 7

Sample size: With a significance level of 5%, a sample size of 250 patients would provide 99% power to detect a treatment difference for the primary end point, assuming an EASI-75 response rate at week 16 of 40% versus 15% for tralokinumab plus TCS and placebo plus TCS, respectively. Assuming a response rate of 30% versus 15% in a reduction of worst daily pruritus NRS (weekly average) score of at least 4 from baseline to week 16 for tralokinumab plus TCS and placebo plus TCS, respectively, the trial would provide at least 80% power to reject the hypotheses related to the primary end point and the secondary end point evaluating pruritus at week 16.

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Multiplicity adjustment: The primary and secondary end points were evaluated hierarchically in the order shown in Figure 5. The hypothesis relating to a specific end point could not be rejected unless all hypotheses relating to end points earlier in the hierarchy were also rejected at the 5% significance level. Hypothesis testing was based on the primary analysis of the primary estimand for each associated end point.

Figure 5: Testing Hierarchy for Primary and Secondary End Points in the ECZTRA 7 Trial

α = statistical significance level; DLQI = Dermatology Life Quality Index; EASI75 = 75% or greater reduction in Eczema Area and Severity Index from baseline; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; SCORAD = Scoring Atopic Dermatitis.

Source: Clinical Study Report for ECZTRA 7.⁴

Rescue medication: Rescue medication was summarized for the entire treatment period as well as for the period up until the week 16 visit. Rescue treatment was also summarized for the periods before and after the start of the COVID-19 pandemic, within the treatment period. Additionally, rescue treatment was summarized for the entire treatment period by the variables of prior cyclosporine A use (yes or no), country (Germany: yes or no), and baseline disease severity (IGA = 3 or 4). A summary table of rescue treatment by type (topical and systemic) and by overall group (corticosteroids, immunosuppressants, and other) was made for the entire treatment period as well as for the period up until the week-16 visit.

Analysis: For the primary analysis for the primary end point (EASI-75 score at week 16) the difference in response rates between treatment groups was analyzed using the Cochran-Mantel-Haenszel test (single imputation analyses) or multiple Mantel-Haenszel risk differences and associated standard errors for a combined inference using the Rubin rule (multiple imputation analyses). The 2 stratification factors were prior cyclosporine A use (yes or no) and baseline disease severity (IGA = 3 or 4). Patients who received rescue treatment before the week-16 visit or permanently discontinued IMP, without prior patient onset of COVID-19, were considered nonresponders at all visits after the relevant event occurred. Any missing or collected data from patients who had COVID-19 as their first prior intercurrent event were handled differently and instead imputed assuming they were missing at random (MAR) following the start of patient onset of COVID-19. Data missing before any intercurrent event were handled as nonresponses, unless data were missing due to COVID-19, in which case they were imputed using the MAR assumption. The procedure for imputing values according to the rules described was implemented in 2 steps, with all missing or ignored data (irrespectively of reason) initially imputed using the MAR assumption based on available data from all patients. The nonresponder imputation of data not affected by COVID-19 was handled subsequently. For the sensitivity analysis, a tipping-point analysis tested the MAR assumption among patients in the tralokinumab plus TCS group who had missing data imputed at the week-16 visit due to patient onset of COVID-19 or data missing due to the COVID-19 pandemic. A quantity, delta, was added to all imputed week-16 values for patients in the tralokinumab plus TCS group who had patient onset of COVID-19 before week 16 or had data missing due to COVID-19 at week 16. Delta was defined as from the minimum to the maximum of the analyzed score (e.g., EASI). Each of the 100 modified imputed datasets was analyzed in the same manner as the primary analysis for the primary estimand. The tipping point was then considered the value of delta that changed the conclusion from significant to nonsignificant.

Analysis of the binary secondary end points was conducted as described for the primary end point. For the binary end points, subgroup analyses were applied for the primary analyses of the primary and tertiary estimands for the groups: sex, prior cyclosporine A use (yes or no), baseline disease severity (IGA = 3 or 4), country (Germany: yes or no), and baseline age (≤ 65 years or > 65 years). Interactions between subgroups and treatment effects were tested using a conditional logistic regression model. For the SCORAD and DLQI at the week-16 and week-26 continuous end points, the same subgroup analyses were performed for the primary and secondary continuous estimands. For the continuous secondary end points, data collected after permanent discontinuation of tralokinumab or placebo, after initiation of rescue treatment, or after patient onset of COVID-19 were not included in the analysis. Repeated measurements modelled the post-baseline responses up to week 16 and week 26 as change from baseline in SCORAD/DLQI = treatment × visit + baseline SCORAD/DLQI × visit + prior cyclosporine A use + country (Germany: yes or no) + baseline IGA. This model assumed that data were MAR within each treatment group.

No interim analyses were planned or conducted.

Analysis Populations

ECZTRA 1 and ECZTRA 2

In the FAS, all patients randomized to initial treatment who were exposed to tralokinumab or placebo were included and analyzed for efficacy up to week 16.

For the maintenance analysis set, all patients who received tralokinumab in the initial treatment period were re-randomized to maintenance treatment. Patients who were not exposed to maintenance treatment were excluded from the maintenance analysis set.

The safety analysis set comprised all patients randomized to initial treatment who were exposed to tralokinumab or placebo. The safety analysis set was therefore identical to the FAS.

The maintenance safety analysis set comprised all patients who were assigned to the maintenance treatment period and received at least 1 dose of maintenance treatment.

ECZTRA 3

In the FAS, patients randomized to initial treatment who were exposed to tralokinumab plus TCS or placebo plus TCS were analyzed for efficacy up to week 16.

The safety analysis set comprised all patients randomized to initial treatment who were exposed to treatment and for whom post-baseline safety data were available. Because all patients received the first dose of treatment at week 0 and were subsequently monitored for immediate drug reactions, all exposed patients were included in the safety analysis set. The safety analysis set was therefore identical to the FAS.

The continuation treatment analysis set comprised patients in the FAS who did not withdraw from the trial before or at the week-16 visit and who were exposed to at least 1 dose of treatment in the continuation treatment period.

The continuation treatment safety analysis set was defined in the same way as the continuation treatment analysis set. The safety follow-up analysis set comprised patients for whom the date of last contact was after the date of exposure end. Exposure end was defined as the week-32 visit for patients completing the treatment period or otherwise the date of permanent discontinuation of treatment for patients not completing the treatment period. For the analysis of efficacy, patients were included “as randomized.” For the analysis of safety, if patients were mistakenly given a treatment other than the treatment to which they were randomized, they were analyzed “as-treated.” They were therefore included in the group according to the treatment actually received. For the continuation treatment period, data were presented as planned treatment.

ECZTRA 7

All patients randomized to treatment and exposed to the tralokinumab plus TCS or placebo plus TCS were included in FAS and analyzed for efficacy.

Two safety analysis sets were defined: a safety analysis set for all patients exposed to tralokinumab plus TCS or placebo plus TCS within the treatment period, and a safety follow-up analysis set for all patients who had a date of last contact after the date of exposure end.

Decisions regarding inclusion and exclusion of patients from the trial analysis sets were documented in the analysis set definition document before breaking the randomization code.

Results

Patient Disposition

ECZTRA 1

Overall, 189 of 991 participants (19.1%) were screening failures. Among the screening failures, ||||||||| did not meet the inclusion criteria and ||||||||| met the exclusion criteria, 40 patients withdrew consent, 5 patients were lost to follow-up, and 16 patients reported other reasons for discontinuation before randomization. This left 802 patients to be randomized in the initial treatment period. Of the 802 randomized patients, 51 of 603 patients (8.5%) in the tralokinumab every 2 weeks treatment group and 18 of 199 patients (9.0%) in the placebo treatment group permanently discontinued treatment before week 16. In total, 729 patients (90.9% of all randomized patients) completed week 16 on treatment (Table 15). A total of 185 patients were week-16 tralokinumab responders assigned to maintenance treatment (71 in the tralokinumab every 2 weeks group, 78 in the tralokinumab every 4 weeks group, and 36 in the placebo group), and ||||||||| were week-16 placebo responders. Of the week-16 tralokinumab responders, 62.0% (n = 44) on tralokinumab every 2 weeks, 67.9% (n = 53) on tralokinumab every 4 weeks, and 58.3% (n = 21) on placebo completed the maintenance period, and 51.7% (n = 15) of week-16 placebo responders completed the maintenance period. Table 16 provides the disposition of patients assigned to maintenance treatment.

ECZTRA 2

Overall, 234 of 1,028 participants (22.8%) were screening failures. Among the screening failures, ||||||||| did not meet the inclusion criteria and ||||||||| met the exclusion criteria, 39 patients withdrew consent, 8 patients were lost to follow-up, and 14 patients reported other reasons for discontinuation before randomization. This left 794 patients to be randomized in the initial treatment period. Of the 794 randomized patients, 33 of 593 patients (5.6%) in the tralokinumab every 2 weeks treatment group and 22 of 201 patients (10.9%) in the placebo treatment group permanently discontinued treatment before week 16. In total, 737 patients (92.8% of all randomized patients) completed week 16 on treatment (Table 15). A total of 227 patients were week-16 tralokinumab responders assigned to maintenance treatment (91 in the tralokinumab every 2 weeks group, 90 in the tralokinumab every 4 weeks group, and 46 in the placebo group), and ||||||||| were week-16 placebo responders. Of the week-16 tralokinumab responders, 57.1% (n = 52) on tralokinumab every 2 weeks, 55.6% (n = 50) on tralokinumab every 4 weeks, 32.6% (n = 15) on placebo completed the maintenance period, and 51.6% (n = 16) of week-16 placebo responders completed the maintenance period. Table 16 provides the disposition of patients assigned to maintenance treatment.

ECZTRA 3

Overall, 127 of 507 participants (25.0%) were screening failures. Among the screening failures, 39 patients did not meet the inclusion criteria and 51 met the exclusion criteria, 25 patients withdrew consent, 6 patients were lost to follow-up, and 7 patients reported other reasons for discontinuation before randomization. This left 380 patients to be randomized in the initial treatment period. Of the 380 randomized patients, 235 of 253 patients (92.9%) in the tralokinumab every 2 weeks plus TCS group and 120 of 127 patients (94.5%) in the placebo plus TCS group completed the initial treatment period on treatment. Table 15 provides details. A total of 353 patients were assigned to continuation treatment, including 138 week-16 tralokinumab responders (evenly split between the tralokinumab every 2 weeks plus TCS and tralokinumab every 4 weeks plus TCS), 95 week-16 tralokinumab nonresponders, ||||||| week-16 placebo nonresponders, ||||||| week-16 placebo responders. In total, 98.6% (n = 68) and 94.2% (n = 65) assigned to the tralokinumab every 2 weeks plus TCS group and the tralokinumab every 4 weeks plus TCS group, respectively, completed the continuation period (week 32).

Table 17 provides the disposition of patients assigned to continuation treatment.

ECZTRA 7

Overall, 41 of 318 participants (12.9%) were screening failures. Among the screening failures, 29 patients did not meet eligibility criteria (inclusion and/or exclusion criteria), and 12 patients withdrew consent before randomization, leaving 277 patients to be randomized in the treatment period (week 0 to week 26). Of the 277 randomized patients, 125 of 140 patients (89.3%) in the tralokinumab plus TCS group and 120 of 137 patients (87.6%) in the placebo plus TCS group completed week 26 on treatment (Table 15).

Table 15: Patient Disposition for All Trials at Week 16

q.2.w. = every 2 weeks; TCS = topical corticosteroids.

Note: Patients who received rescue treatment during the initial treatment period were considered nonresponders, but they continued investigational medicinal product treatment if the rescue treatment consisted of topical medications only.

Source: Clinical Study Reports for ECZTRA 1,⁷ ECZTRA 2,⁵ ECZTRA 3,⁶ and ECZTRA 7.⁴

Exposure to Study Treatments

ECZTRA 1

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ECZTRA 2

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ECZTRA 3

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ECZTRA 7

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Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in the following section.

Disease Severity

Investigator’s Global Assessment

One of the primary outcomes for the ECZTRA 1 and ECZTRA 2 trials was achieving an IGA score of 0 or 1 at week 16. In the ECZTRA 1 trial, 15.8% of patients in the intervention group achieved an IGA score of 0 or 1 at week 16 compared to 7.1% in the placebo group. The difference between tralokinumab and placebo (8.6%; 95% CI, 4.1 to 13.1; P = 0.002) was statistically significant, with the sensitivity analysis yielding the exact same result (Table 18). At week 52, of patients in the tralokinumab every 2 weeks group, 51.3% achieved an IGA score of 0 or 1 compared to 38.9% in the tralokinumab every 4 weeks group, and 47.4% in the placebo group (Table 19). The difference between tralokinumab every 2 weeks and placebo at week 52 (6.0%; 95% CI, −21.8 to 33.7; P = 0.68) was not statistically significant, nor was it statistically significant in the sensitivity analysis |||||||||||||||||||||||||||||||||||. The difference between tralokinumab every 4 weeks and placebo at week 52 (−9.5%; 95% CI, −37.1 to 18.0 P = 0.50) was also not statistically significant.

In the ECZTRA 2 trial, 22.2% of patients in the intervention group achieved an IGA score of 0 or 1 at week 16 compared to 10.9% in the placebo group. The difference between tralokinumab and placebo (11.1%; 95% CI, 5.8 to 16.4; P < 0.001) was statistically significant, and the sensitivity analysis yielded the exact same result (Table 20). At week 52, of patients in the tralokinumab every 2 weeks group, 59.3% achieved an IGA score of 0 or 1 compared to 44.9% in the tralokinumab every 4 weeks group, and 25.0% in the placebo group (Table 21). The difference between the tralokinumab every 2 weeks and placebo groups at week 52 (34.1%; 95% CI, 13.4 to 54.9; P = 0.004) was statistically significant, as was the result of the sensitivity analysis ||||||||||||||||||||||||||||||||||||||||||. The difference between the tralokinumab every 4 weeks and placebo groups at week 52 (19.9%; 95% CI, −1.2 to 40.9; P = 0.084) was not statistically significant, nor was the result of the sensitivity analysis ||||||||||||||||||||||||||||||||||||||||||.

In the ECZTRA 3 trial, 38.9% of patients in the intervention group achieved an IGA score of 0 or 1 at week 16 compared to 26.2% in the placebo group. The difference between tralokinumab and placebo (12.4%; 95% CI, 2.9 to 21.9; P = 0.015) was statistically significant, and the sensitivity analysis yielded the same result (Table 22). At week 32, of patients in the tralokinumab every 2 weeks plus TCS group, 89.6% achieved an IGA score of 0 or 1 without rescue medication compared to 77.6% in the tralokinumab every 4 weeks plus TCS group (Table 23). The IGA score of 0 or 1 was first in the testing hierarchy for the ECZTRA 3 trial.

In the ECZTRA 7 trial, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Due to the insignificant difference between tralokinumab plus TCS and placebo plus TCS in the reduction of worst daily pruritus NRS (weekly average) outcome, which is first in the testing hierarchy, P values are not reported for the IGA score at weeks 16 and 26 for the ECZTRA 7 trial.

Table 18: Summary of Efficacy Outcomes for the ECZTRA 1 Trial: Full Analysis Set

CI = confidence interval; DLQI = Dermatology Life Quality Index; EASI-50 = 50% or greater reduction in Eczema Area and Severity Index from baseline EASI-75 = 75% or greater reduction in Eczema Area and Severity Index from baseline; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ VAS = EQ-5D Visual Analogue Scale; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SCORAD = Scoring Atopic Dermatitis; SCORAD-50 = 50% decrease in Scoring Atopic Dermatitis; SCORAD-75 = 75% decrease in Scoring Atopic Dermatitis; SD = standard deviation; SE = standard error; SF-36 = Short Form (36) Health Survey; vs. = versus; WPAI-GH = Work Productivity and Activity Impairment–General Health.

^aThe primary and secondary end points were tested sequentially under the hierarchical testing strategy in the following order: IGA score of 0 or 1 at week 16 (primary end point), EASI-75 at week 16 (primary end point), pruritus NRS scores at week 16 (secondary end point), SCORAD at week 16 (secondary end point), and DLQI at week 16 (secondary end point). These secondary end points were tested in parallel with an alpha of 1% for the end points at week 16 and with an alpha of 4% for the maintenance end points at week 52. The maintenance end points were tested sequentially in the following order: IGA 0 or 1 at week 52 between q.2.w. and placebo, EASI-75 at week 52 between q.2.w. and placebo, IGA 0 or 1 at week 52 between q.4.w. and placebo, and EASI-75 at week 52 between q.4.w. and placebo.

^bMantel-Haenszel risk difference, stratified by region and baseline IGA.

Source: Clinical Study Report for ECZTRA 1.⁷

Table 19: Outcomes — ECZTRA 1 Trial Maintenance End Points

CI = confidence interval; DLQI = Dermatology Life Quality Index; EASI-75 = 75% or greater reduction in Eczema Area and Severity Index from baseline; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ VAS = EQ-5D Visual Analogue Scale; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; q.4.w = every 4 weeks; SCORAD = Scoring Atopic Dermatitis; SD = standard deviation; SF-36 = Short Form (36) Health Survey; vs. = versus; WPAI-GH = Work Productivity and Activity Impairment–General Health.

Note: Patients who achieved a clinical response at week 16 were eligible to continue maintenance treatment and were included in this dataset, and the outcomes reported were achieved without rescue medication.

^aThe primary and secondary end points were tested sequentially under the hierarchical testing strategy in the following order: IGA score of 0 or 1 at week 16 (primary end point), EASI-75 at week 16 (primary end point), pruritus at week 16 (secondary end point), SCORAD at week 16 (secondary end point), and DLQI at week 16 (secondary end point). These secondary end points were tested in parallel with an alpha of 1% for the end points at week 16 and with an alpha of 4% for the maintenance end points at week 52. The maintenance end points were tested sequentially in the following order: IGA 0 or 1 at week 52 between q.2.w. and placebo, EASI-75 at week 52 between q.2.w. and placebo, IGA 0 or 1 at week 52 between q.4.w. and placebo, and EASI-75 at week 52 between q.4.w. and placebo.

^bMantel-Haenszel risk difference compared to placebo, stratified by region.

Note: Redacted rows have been deleted.

Source: Clinical Study Report for ECZTRA 1.⁷

Table 20: Summary of Efficacy Outcomes for the ECZTRA 2 Trial: Full Analysis Set

CI = confidence interval; DLQI = Dermatology Life Quality Index; EASI-50 = 50% or greater reduction in Eczema Area and Severity Index from baseline; EASI-75 = 75% or greater reduction in Eczema Area and Severity Index from baseline; EASI-90 = 90% or greater reduction in Eczema Area and Severity Index from baseline; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ VAS = EQ-5D Visual Analogue Scale; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SCORAD = Scoring Atopic Dermatitis; SCORAD-50 = 50% decrease in Scoring Atopic Dermatitis; SCORAD-75 = 75% decrease in Scoring Atopic Dermatitis; SD = standard deviation; SE = standard error; SF-36 = Short Form Health Survey; vs. = versus; WPAI-GH = Work Productivity and Activity Impairment–General Health.

^aThe primary and secondary end points were tested sequentially under the hierarchical testing strategy in the following order: IGA score of 0 or 1 at week 16 (primary end point), EASI-75 at week 16 (primary end point), pruritus NRS scores at week 16 (secondary end point), SCORAD at week 16 (secondary end point), and DLQI at week 16 (secondary end point). These secondary end points were tested in parallel with an alpha of 1% for the end points at week 16 and with an alpha of 4% for the maintenance end points at week 52. The maintenance end points were tested sequentially in the following order: IGA 0 or 1 at week 52 between q.2.w. and placebo, EASI-75 at week 52 between q.2.w. and placebo, IGA 0 or 1 at week 52 between q.4.w. and placebo, and EASI-75 at week 52 between q.4.w. and placebo.

^bMantel-Haenszel risk difference, stratified by region and baseline IGA.

Note: Redacted rows have been deleted.

Source: Clinical Study Report for ECZTRA 2.⁵

Table 21: Outcomes — ECZTRA 2 Trial Maintenance End Points

CI = confidence interval; DLQI = Dermatology Life Quality Index; EASI-75 = 75% or greater reduction in Eczema Area and Severity Index from baseline; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ VAS = EQ-5D Visual Analogue Scale; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SCORAD = Scoring Atopic Dermatitis; SD = standard deviation; SF-36 = Short Form (36) Health Survey; vs. = versus; WPAI-GH = Work Productivity and Activity Impairment–General Health.

Note: Patients who achieved a clinical response at week 16 were eligible to continue maintenance treatment and were included in this dataset, and the outcomes reported were achieved without rescue medication.

^aThe primary and secondary end points were tested sequentially under the hierarchical testing strategy in the following order: IGA score of 0 or 1 at week 16 (primary end point), EASI-75 at week 16 (primary end point), pruritus NRS scores at week 16 (secondary end point), SCORAD at week 16 (secondary end point), and DLQI at week 16 (secondary end point). These secondary end points were tested in parallel with an alpha of 1% for the end points at week 16 and an alpha of 4% for the maintenance end points at week 52. The maintenance end points were tested sequentially in the following order: IGA 0 or 1 at week 52 between q.2.w. and placebo, EASI-75 at week 52 between q.2.w. and placebo, IGA 0 or 1 at week 52 between q.4.w. and placebo, and EASI-75 at week 52 between q.4.w. and placebo.

^bMantel-Haenszel risk difference compared to placebo, stratified by region.

Note: Redacted rows have been deleted.

Source: Clinical Study Report for ECZTRA 2.⁵

Table 22: Summary of Efficacy Outcomes for the ECZTRA 3 Trial: Full Analysis Set

CI = confidence interval; DLQI = Dermatology Life Quality Index; EASI-50 = 50% or greater reduction in Eczema Area and Severity Index from baseline; EASI-90 = 90% or greater reduction in Eczema Area and Severity Index from baseline; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ VAS = Visual Analogue Scale; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; SCORAD = Scoring Atopic Dermatitis; SD = standard deviation; SE = standard error; TCS = topical corticosteroids.

^aThe primary and secondary end points were tested sequentially under the hierarchical testing strategy in the following order: IGA score of 0 or 1 at week 16 (primary end point), EASI-75 at week 16 (primary end point), pruritus NRS scores at week 16 (secondary end point), SCORAD at week 16 (secondary end point), and DLQI at week 16 (secondary end point).

^bMantel-Haenszel risk difference, stratified by region and baseline IGA.

Note: Redacted rows have been deleted.

Source: Clinical Study Report for ECZTRA 3.⁶

Table 23: Outcomes — ECZTRA 3 Trial Continuation Treatment Period End Points

CI = confidence interval; DLQI = Dermatology Life Quality Index; EASI-50  = 50% or greater reduction in Eczema Area and Severity Index from baseline; EASI-75 = 75% or greater reduction in Eczema Area and Severity Index from baseline; EASI-90 = 90% or greater reduction in Eczema Area and Severity Index from baseline; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ VAS = EQ-5D Visual Analogue Scale; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SCORAD = Scoring Atopic Dermatitis; SD = standard deviation; TCS = topical corticosteroids.

Note: Patients treated with tralokinumab q.2.w. plus TCS in the initial treatment period who had a clinical response at week 16 were re-randomized in a 1:1 ratio to tralokinumab 300 mg q.2.w. or tralokinumab 300 mg q.4.w. stratified by region (Europe and North America) and IGA response at week 16 (IGA 0 or 1, or IGA > 1). Patients re-randomized to tralokinumab 300 mg every 4 weeks were treated with alternating dose administration of tralokinumab 300 mg and placebo every second week.

^aMantel-Haenszel risk difference compared to placebo, stratified by region.

Note: Redacted rows have been deleted.

Source: Clinical Study Report for ECZTRA 3.⁶

Table 24: Summary of Efficacy Outcomes for the ECZTRA 7 Trial: Full Analysis Set

CI = confidence interval; DLQI = Dermatology Life Quality Index; EASI-50 = 50% or greater reduction in Eczema Area and Severity Index from baseline; EASI-75 = 75% or greater reduction in Eczema Area and Severity Index from baseline; EASI-90 = 90% or greater reduction in Eczema Area and Severity Index from baseline; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ VAS = EQ-5D Visual Analogue Scale; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SCORAD = Scoring Atopic Dermatitis; SD = standard deviation; SE = standard error; SF-36 = Short Form (36) Health Survey; TCS = topical corticosteroid; vs. = versus.

^aThe primary and secondary end points that were tested sequentially under the hierarchical testing strategy in the following order: EASI-75 at week 16 (primary end point), and then the following secondary end points were tested sequentially: reduction of worst daily pruritus NRS (weekly average) of at least 4 from baseline to week 16, change in SCORAD from baseline to week 16, change in DLQI score from baseline to week 16, IGA score of 0 or 1 at week 16, EASI-75 at week 26, reduction of worst daily pruritus NRS (weekly average) scores of at least 4 from baseline to week 26, change in SCORAD from baseline to week 26, change in DLQI score from baseline to week 26, IGA score of 0 or 1 at week 26.

^bMantel-Haenszel risk difference, stratified by prior cyclosporine A use and baseline IGA.

Note: Redacted rows have been deleted.

Source: Clinical Study Report for ECZTRA 7.⁴

Sleep Disturbance

In the ECZTRA 1 trial, there was significantly greater improvement in how much eczema interfered with sleep, based on the eczema-related sleep NRS (weekly average) score, in the tralokinumab every 2 weeks group compared to the placebo group at week 16 (−0.7%; 95% CI, −1.2 to −0.2; P = 0.007) (Table 18). |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| In the ECZTRA 2 trial, there was also greater improvement in how much eczema interfered with sleep in the tralokinumab every 2 weeks group compared to the placebo group at week 16 (−1.4%; 95% CI, −1.9 to −0.9; P < 0.001) (Table 20). ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| In the ECZTRA 3 trial, there was greater improvement in how much the eczema interfered with the sleep in the tralokinumab every 2 weeks plus TCS group compared to the placebo plus TCS at week 16 group (−1.3%; 95% CI, −1.8 to −0.8; P < 0.001) (Table 22). At week 32, the mean eczema-related sleep NRS (weekly average) score was 1.3 (SD = 1.7) compared to 1.7 (SD = 1.9) for placebo. In the ECZTRA 7 trial, there was greater improvement in how much eczema interfered with sleep at week 16 (−0.8%; 95% CI, −1.3 to −0.2; P = 0.005) and week 26 (−0.6%; 95% CI, −1.1 to −0.0; P = 0.037) (Table 24). Eczema-related sleep NRS (weekly average) scores were not part of the testing hierarchy in any RCT.

Health-Related Quality of Life

Dermatology Life Quality Index

In the ECZTRA 1 trial, the adjusted mean change from baseline in the DLQI was statistically significantly larger in the tralokinumab group compared with the placebo group at week 16 (−2.1; 95% CI, −3.4 to −0.8; P = 0.002), and the sensitivity analysis also yielded a statistically significant result. (Table 18). The DLQI at week 16 fell within the testing hierarchy for ECZTRA 1. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The proportion of patients with a reduction in the DLQI of at least 4 points from baseline, among patients with a DLQI score of at least 4 at baseline, was higher in the tralokinumab group compared with the placebo group at week 16 (13.0%; 95% CI, 5.4 to 20.5; P = 0.001).

In the ECZTRA 2 trial, the adjusted mean change from baseline in the DLQI was statistically significantly larger in the tralokinumab group compared with the placebo group at week 16 (−3.9; 95% CI, −5.2 to −2.6; P < 0.001), and the sensitivity analysis also yielded a significant difference (−3.4; 95% CI, −4.8 to −2.0; P < 0.001) (Table 20). The DLQI at week 16 fell within the testing hierarchy for the ECZTRA 2 trial. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The proportion of patients with a reduction in the DLQI of at least 4 points from baseline, among patients with a DLQI of at least 4 at baseline, was higher in the tralokinumab group compared with the placebo group at week 16 (28.9%; 95% CI, 21.4 to 36.3; P < 0.001).

In the ECZTRA 3 trial, the adjusted mean change from baseline in the DLQI was statistically significantly larger in the tralokinumab every 2 weeks plus TCS group compared with the placebo plus TCS group at week 16 (−2.9; 95% CI, −4.3 to −1.6; P < 0.001), and the sensitivity analysis also yielded a significant result (Table 22). The proportion of patients with a reduction in the DLQI of at least 4 points from baseline, among patients with a DLQI of at least 4 at baseline, was statistically significantly higher in the tralokinumab every 2 weeks plus TCS group compared with the placebo plus TCS group at week 16 (17.6%; 95% CI, 8.0 to 27.1; P < 0.001). The DLQI outcome fell within the testing hierarchy for the ECZTRA 3 trial.

In the ECZTRA 7 trial, the adjusted mean change from baseline in the DLQI was larger in the tralokinumab every 2 weeks plus TCS group compared with the placebo plus TCS group at week 16 (−1.5; 95% CI, −2.6 to −0.4), ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| At week 26, the adjusted mean change from baseline in the DLQI was larger in the tralokinumab every 2 weeks plus TCS group compared with the placebo plus TCS group (−1.6; 95 CI, −2.7 to −0.5). The proportion of patients with a reduction in the DLQI of at least 4 points from baseline, among patients with a DLQI of at least 4 at baseline, was not higher in the tralokinumab every 2 weeks plus TCS group compared with the placebo plus TCS group at week 16 (4.9%; 95% CI, −4.8 to 14.6). |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Due to the insignificant difference between tralokinumab plus TCS and placebo plus TCS in the reduction of worst daily pruritus NRS (weekly average) scores outcome, which is first in the testing hierarchy, P values are not reported for the DLQI at weeks 16 and 26 for the ECZTRA 7 trial.

Short Form (36) Health Survey

In the ECZTRA 1 trial, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The SF-36 was not part of the testing hierarchy in the ECZTRA 1 trial.

In the ECZTRA 2 trial, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The SF-36 was not part of the testing hierarchy in the ECZTRA 2 trial.

In the ECZTRA 7 trial, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The SF-36 was not part of the testing hierarchy in the ECZTRA 7 trial.

EQ-5D 5-Levels Questionnaire

In the ECZTRA 1 trial, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||The EQ-5D-5L was not part of the testing hierarchy in the ECZTRA 1 trial.

In the ECZTRA 2 trial, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The EQ-5D-5L was not part of the testing hierarchy in the ECZTRA 2 trial.

In the ECZTRA 3 trial, 3 trial, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The EQ-5D-5L was not part of the testing hierarchy in the ECZTRA 3 trial.

In the ECZTRA 7 trial ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The EQ-5D-5L was not part of the testing hierarchy in the ECZTRA 7 trial.

Mood

Hospital Anxiety and Depression Scale

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The HADS anxiety and depression scores were not part of the testing hierarchy in the ECZTRA 1 trial.

In ECZTRA 2, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The HADS anxiety and depression scores were not part of the testing hierarchy in the ECZTRA 2 trial.

In the ECZTRA 3 trial, the mean improvement (reduction) in HADS anxiety scores from baseline to week 16 was larger in the tralokinumab group compared to placebo (−1.3; 95% CI, −2.1 to −0.6; P < 0.001) (Table 22). The mean improvement (reduction) in HADS depression scores from baseline to week 16 was also larger in the tralokinumab group compared to placebo (−0.8; 95% CI. −1.5 to −0.2; P = 0.015) (Table 22). |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The HADS anxiety and depression scores were not part of the testing hierarchy in the ECZTRA 3 trial.

In ECZTRA 7, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The HADS anxiety and depression scores were not part of the testing hierarchy in the ECZTRA 7 trial.

Productivity

Work Productivity and Activity Impairment–General Health

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The WPAI-GH scores were not part of the testing hierarchy for the ECZTRA 1 trial.

In the ECZTRA 2 trial, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The WPAI-GH scores were not part of the testing hierarchy for the ECZTRA 2 trial.

Subgroup Analysis

In the ECZTRA 1, ECZTRA 2, and ECZTRA 3 trials, a higher number of patients who had moderate disease severity at baseline achieved an IGA score of 0 or 1 and an EASI-75 score at week 16 compared to those who had severe disease severity at baseline in both treatment groups. Irrespective of disease severity at baseline, a higher proportion of patients achieved an IGA score of 0 or 1 and an EASI-75 score at week 16 in the tralokinumab group compared with the placebo group. In the ECZTRA 7 trial a higher proportion of patients achieved an EASI-75 score in the tralokinumab plus TCS group compared with the placebo plus TCS group. A notable difference between ECZTRA 7 and the other trials is that a higher proportion of patients with severe disease at baseline achieved an EASI-75 score at week 16 compared to patients with moderate disease at baseline. Baseline disease severity is the only subgroup of interest based on this report’s protocol; failure to respond, contraindications, or intolerance to 1 or more systemic therapies or the presence of other comorbid conditions such as asthma are not reported as subgroups in the clinical trial reports.

Harms

Only those harms identified in the review protocol are reported. In all trials, exposure start was defined as the date and time of first dose of tralokinumab or placebo, and exposure end was defined as the date of the week 52 (ECZTRA 1 and ECZTRA 2) or 32 (ECZTRA 3) visit. Otherwise, exposure end was defined as the date of permanent discontinuation of tralokinumab or placebo or, if missing, the date of last treatment administration. Table 26 and Table 27 provide detailed harms data.

Adverse Events

In the ECZTRA 1 trials, AEs were reported in 76.4% (n = 460) of tralokinumab and 77.0% (n = 151) of placebo patients, and in the ECZTRA 2 trial, AEs were reported in 61.5% (n = 364) of tralokinumab patients and 66.0% (n = 132) of placebo patients during the initial treatment period (Table 26). In the ECZTRA 3 trial, AEs were reported in 71.4% (n = 180) of tralokinumab every 2 weeks plus TCS patients and 66.7% (n = 84) of placebo plus TCS patients, and in the ECZTRA 7 trial, AEs were reported in 77.5% (n = 107) of tralokinumab every 2 weeks plus TCS patients and 78.8% (n = 108) of placebo plus TCS patients in the initial treatment period (Table 27).

During the maintenance treatment period, AEs were reported in 79.4% (n = 54) of the tralokinumab every 2 weeks group, 69.7% (n = 53) of the tralokinumab every 4 weeks group, and 71.4% (n = 25) of the placebo group in the ECZTRA 1 trial (Table 28), and 68.1% (n = 62) of the tralokinumab every 2 weeks group, 62.9% (n = 56) tralokinumab every 4 weeks group, and 69.6% (n = 32) of the placebo group in the ECZTRA 2 trial (Table 29). In the continuation treatment period of the ECZTRA 3 trial, AEs occurred in 69.6% (n = 48) of the tralokinumab every 2 weeks plus TCS group, 59.4% (n = 41) of the tralokinumab every 4 weeks plus TCS group for those in the week-16 tralokinumab responders group (Table 30).

Serious Adverse Events

In the ECZTRA 1 trial, SAEs were reported in 3.8% (n = 23) of tralokinumab patients and 4.1% (n = 8) of placebo patients, and in the ECZTRA 2 trial, SAEs were reported in 1.7% (n = 10) of tralokinumab patients and 2.5% (n = 5) of placebo patients at week 16 (Table 26). In the maintenance treatment period, SAEs were reported in 1.5% (n = 1) of the tralokinumab every 2 weeks group, 3.9% (n = 3) of the tralokinumab every 4 weeks group among the week-16 tralokinumab responders in the ECZTRA 1 trial (Table 28), and 3.4% (n = 3) of the tralokinumab every 4 weeks group in the ECZTRA 2 trial (Table 29).

In the ECZTRA 3 trials, SAEs were reported in 0.8% (n = 2) of tralokinumab every 2 weeks plus TCS patients and 3.2% (n = 4) of placebo plus TCS patients, and in the ECZTRA 7 trial, SAEs were reported in 0.7% (n = 1) of tralokinumab every 2 weeks plus TCS patients and 3.6% (n = 5) of placebo plus TCS patients (Table 27). Serious adverse events were reported in 4.3% (n = 3) of the tralokinumab every 2 weeks plus TCS group (week-16 tralokinumab responders) in the ECZTRA 3 trial (Table 30).

Withdrawal Due to Adverse Events

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| During the maintenance treatment phase, 2 patients withdrew from the ECZTRA 1 trial (Table 28), 3 withdrew from the ECZTRA 2 trial (Table 29), and 10 withdrew from the ECZTRA 3 trial due to AEs (Table 30).

Mortality

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| No deaths were reported in the ECZTRA trial ||||||||| 7.

Notable Harms

Harms of special interest included dermatitis atopic, which occurred in 25.9% (n = 156) of tralokinumab patients and 38.3% (n = 75) of placebo patients in the ECZTRA 1 trial, and 16.6% (n = 98) of tralokinumab patients and 33.5% (n = 67) of placebo patients in the ECZTRA 2 trial. Viral upper respiratory tract infection occurred in 23.1% (n = 139) of tralokinumab patients and 20.9% (n = 41) placebo patients in the ECZTRA 1 trial, and in 8.3% (n = 49) of the tralokinumab patients and 18.5% (n = 17) of placebo patients in the ECZTRA 2 trial (Table 26). In the ECZTRA 3 and ECZTRA 7 trials, the most common AE was viral upper respiratory tract infection, which occurred in 19.4% (n = 49) of tralokinumab plus TCS patients and 11.1% (n = 14) of placebo plus TCS patients (ECZTRA 3) and 26.8% (n = 37) of tralokinumab plus TCS patients and 25.5% (n = 35) of placebo plus TCS patients (ECZTRA 7). Among notable harms, pruritus occurred in 5.3% (n = 32) of tralokinumab patients and 5.1% (n = 10) of placebo patients in the ECZTRA 1 trial; upper respiratory infraction occurred in 10.0% (n = 59) of tralokinumab patients and 8.5% (n = 17) of placebo patients in the ECZTRA 2 trial; conjunctivitis occurred in 11.1% (n = 28) of tralokinumab plus TCS patients and 3.2% (n = 4) of placebo plus TCS patients in the ECZTRA 3 trial; and headache occurred in 15.2% (n = 21) of tralokinumab plus TCS patients and 9.5% (n = 13) of placebo patients in the ECZTRA 7 trial (Table 27). Table 28, Table 29, and Table 30 detail the notable harms in the maintenance treatment and continuation treatment periods.

Table 26: Summary of Harms for the ECZTRA 1 and ECZTRA 2 Trials in the Initial Treatment Period: Safety Analysis Set