Reimbursement Review

Delgocitinib (Anzupgo)

Sponsor: Leo Pharma Inc.

Therapeutic area: Chronic hand eczema

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

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

Table 1: Background Information of the Application Submitted for Review

NOC = Notice of Compliance.

Introduction

Hand eczema is a painful, pruritic, inflammatory, noninfectious skin disease that primarily affects the hands and wrists.^1-3 Chronic hand eczema (CHE) is defined by the European Society of Contact Dermatitis, as well as Canadian and German consensus-based guidelines, as hand eczema persisting for at least 3 months or recurring at least twice per year.^1,4,5 Its severity is typically assessed through clinical signs, disease duration, treatment history, and impact on patient function.^1,6

CHE has a multifactorial etiology, with both exogenous and endogenous triggers.^2,5 Risk factors include a personal history of childhood eczema, asthma, or hay fever, as well as occupations involving frequent wet work or exposure to irritants and allergens, such as those in health care, food processing, and hairdressing.^5,7-9 The pathophysiology involves dysregulated immune responses and a breakdown of skin barrier function.^2,9 Activation of the Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway contributes to inflammation and suppresses the expression of structural proteins such as filaggrin, leading to skin barrier impairment.^2,9 Long-term exposure to environmental factors like mechanical irritation, extreme temperatures, or chemicals further exacerbates this dysfunction.¹⁰

The main symptoms of CHE include itch and pain, but people with CHE often also report dryness, cracking, thickening of the skin, and bleeding. These signs and symptoms fluctuate over time, with many people experiencing periodic flares.^3,11 CHE imposes a substantial burden, contributing to impaired hand function, sleep disturbance, psychological distress, reduced work capacity, and negative social impacts.^1,5,10,12

In Canada, the prevalence of CHE among adults is estimated at 6.2%, with a higher occurrence in females.¹³ In the Canada-based cohort of the international CHECK study, approximately 70% of patients were female (30% male), the median patient age was 41 years, and about 44% of patients had moderate to severe CHE.^14,15

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of the input provided by the patient and clinician groups that responded to the Canada’s Drug Agency (CDA-AMC) call for input and from the clinical expert(s) consulted by CDA-AMC for the purpose of this review.

Patient Input

Two patient groups, the Eczema Society of Canada (ESC) and the Canadian Association of Neonatal Nurses (CANN), submitted input for this review. Another patient group, the Canadian Skin Patient Alliance, did not directly provide input for this submission but provided a letter of support for the patient submission developed and submitted by the ESC. The ESC group obtained information related to CHE through questionnaires and interviews with patients, caregivers, and health care professionals, as well as survey data on various topics (e.g., impact on quality of life, experience with treatments, patient journeys) from more than 3,000 people in Canada who live with eczema. CANN collected anonymous data through qualitative interviews with nurses conducted in July 2024 and obtained their perspectives of living and working with CHE. The group also conducted an online quantitative survey between October 23 and November 10, 2024, of its nursing members living with CHE (n = 27), which was distributed through CANN’s email communication list and established membership channels. All information was gathered in Canada.

Both patient groups highlighted a significant impairment to everyday living and quality of life due to CHE. The groups reported that people with CHE experienced negative impacts on sleep quality (due to pain), skin (burning, itching lesions, blisters, bleeding skin), work (loss of productivity, change in careers due to CHE), social interactions, fitness, intimacy, family life, and hygiene. CANN further noted that survey respondents reported itchy skin as the symptom that caused the greatest burden, followed by dry or chapped skin; dyshidrotic blisters; cracking skin or fissures; open wounds with bleeding; and painful, stinging, and throbbing hands. Both patient groups highlighted that current treatment regimens may not be sufficient and expressed concerns regarding long-term steroid use. In the survey conducted by CANN, 52% of the respondents reported that their current treatment and management regimen could not control or could only somewhat help them manage their hand eczema.

Both patient groups highlighted the need for a treatment that provided better disease management, including relief from itching, stinging, burning, and pain; improvement in skin disease; and reduction of flares. CANN further highlighted that people with CHE want to function normally, return to work, experience reduced severity of flares, and have decreased risk of blisters and open wounds. The ESC also noted that people with CHE were looking for treatments suitable for long-term use that could allow them to regain their confidence and self-esteem and improve their social life and quality of life. In both patient groups, those who had had the opportunity to be treated with delgocitinib noted positive experiences with the treatment. The ESC further highlighted that delgocitinib offered patients relief; was well tolerated, without stinging or burning; and was not greasy on the hands.

Clinician Input

Input From Clinical Experts Consulted for This Review

The experts identified a clear unmet need for effective, well-tolerated, nonsystemic therapies for adults with moderate to severe CHE, particularly for those who do not experience a response to topical corticosteroids (TCS) or who experience intolerance to systemic therapies such as alitretinoin due to side effects or contraindications. According to the experts, delgocitinib may fill this gap by offering a topical, nonsteroidal option that can be used earlier in the treatment pathway and may delay or prevent the need for systemic treatment.

The experts considered patients with moderate to severe CHE for whom first-line TCS has failed as the population most likely to benefit from delgocitinib. The patients least likely to benefit may include those with primarily irritant-driven eczema, those who would experience difficulty in adhering to the treatment regimen, or those with very limited disease that can be managed with intermittent topical steroids. The experts emphasized that treatment should begin once TCS have proven insufficient to achieve control of the disease, especially in patients with persistent symptoms affecting function or quality of life.

Response to treatment should be assessed based on improvements in visible skin signs, reduction in itching and pain, and enhanced ability to perform daily tasks, including work. Clinical tools such as the Investigator’s Global Assessment of Chronic Hand Eczema (IGA-CHE) and the Hand Eczema Severity Index (HECSI), along with patient-reported outcomes like the Dermatology Life Quality Index (DLQI) and symptom diaries, were viewed as useful for monitoring treatment response. The experts recommended discontinuing delgocitinib if no meaningful clinical improvement is observed within 8 to 12 weeks, or sooner if the disease worsens or adverse reactions occur.

Additional considerations raised by the experts included the importance of patient education on appropriate treatment application and expectations for treatment response. They also highlighted the potential role of delgocitinib in reducing the need for systemic immunosuppressants or biologics and its practical advantages for long-term management, especially for patients requiring maintenance therapy with a lower side-effect burden.

Clinician Group Input

Five clinician groups provided input for this review: the Dermatology Association of Ontario (DAO), the Atlantic Dermatology Group, the Canadian Dermatology Association’s Pharmacy and Therapeutics Advisory Board, the Saskatchewan Dermatology Association, and dermatologists practising in Canada with an interest in CHE. Information for this submission included input from 21 clinicians and was gathered through reviews of published literature, research and trial experience, clinical practice experience, and national and international meetings.

The input from clinician groups was generally consistent with the input from the clinical experts consulted for this review, emphasizing the ongoing unmet need for new topical prescription therapy options for CHE that would control the signs and symptoms of eczema, normalize quality of life, and reduce or abolish occupational impacts. The DAO group further emphasized the need to include therapies for long-term control of CHE that are safe, effective, and accessible. The clinician groups highlighted the limitations of current therapies, including adverse events (AEs) related to topical corticosteroid use such as skin atrophy, skin infections, pain, burning, fissures, reduced hand dexterity, and bleeding; limited efficacy and poor access to phototherapy; and contraindications related to alitretinoin use (e.g., pregnancy, breastfeeding). The DAO group noted that while topical calcineurin inhibitors like tacrolimus are sometimes used in mild cases of CHE when a steroid-sparing therapy is required due to AEs related to steroid use, they are not effective treatment alternatives for moderate and severe forms of CHE. The DAO group also highlighted several off-label systemic options for patients with CHE in cases when phototherapy and alitretinoin are not suitable, are not accessible, or fail to control the condition; these options include traditional immunosuppressants (i.e., methotrexate and cyclosporine), biologics (particularly ones used in atopic dermatitis [AD], such as dupilumab), and oral JAK inhibitors (i.e., upadacitinib). However, the group noted limitations related to these off-label options as well, including accessibility and cost (i.e., coverage criteria may make a biologic therapy inaccessible, or the co-pay cost to the patient may be a barrier), safety considerations (e.g., black box warnings and contraindications across the oral systemic therapies), and expected effectiveness (i.e., traditional immunosuppressants are not as effective in managing CHE as biologics or oral JAK inhibitors). The groups indicated that people involved in certain professions with frequent exposure to irritants and allergens — such as people working in health care, cleaning, and hairdressing — report higher incidence rates of CHE.

The DAO and the Canadian Dermatology Association’s Pharmacy and Therapeutics Advisory Board groups considered topical delgocitinib as a second-line treatment for patients with moderate to severe CHE (i.e., a Physician’s Global Assessment [PGA] score of 3 to 4) whose disease was refractory to TCS, or who experienced intolerance to TCS, or for whom TCS were contraindicated. The Atlantic Dermatology Group considered topical delgocitinib as a first-line or second-line treatment for adult patients with moderate to severe CHE for whom TCS are inadequate or inappropriate. The groups noted that delgocitinib is expected to cause a shift in the current treatment paradigm as a new targeted topical prescription therapy for CHE. The DAO group highlighted delgocitinib’s ease of access and treatment administration over phototherapy and noted that it did not require laboratory monitoring and had no contradictions (e.g., pregnancy, breastfeeding, or renal or hepatic insufficiency) as is the case for alitretinoin. Referring to the clinical trials, the groups also noted the efficacy and favourable safety profile of delgocitinib in patients with moderate to severe CHE. The clinician groups provided additional details on patient selection, noting that delgocitinib may be particularly appropriate for patients with moderate to severe CHE who have experienced an inadequate response to TCS or for whom TCS are not advisable or are contraindicated. The groups also noted that patients with mild CHE for whom TCS have not yet been used or whose CHE is being adequately managed by emollients, avoidance strategies, or TCS are less appropriate candidates for treatment with delgocitinib.

The clinician groups noted that an initial assessment of treatment response at approximately 3 to 6 months (around 16 weeks) after initiation would be reasonable. The DAO group further highlighted that both the timing and criteria used to assess response may vary among clinicians, depending on clinical practice wait times, availability of follow-up, and patient-specific factors. The clinician groups added that outcome measures are not formally standardized in routine clinical practice for CHE, and that clinicians typically rely on an informal PGA. The clinician groups agreed that reasons for discontinuation of delgocitinib may include inadequate or loss of efficacy, recurrent flares, disease worsening or nonresponse despite an adequate therapeutic trial, or intolerance and adverse effects.

Drug Program Input

The drug programs raised several questions related to the implementation of delgocitinib. First, they questioned the appropriateness of comparing delgocitinib to vehicle cream rather than other topicals like vitamin D3 derivatives (e.g., calcipotriol) or calcineurin inhibitors (e.g., tacrolimus, pimecrolimus). The clinical experts acknowledged this concern but emphasized that alitretinoin remains the only treatment with a Notice of Compliance in Canada for CHE, supporting the relevance of the chosen comparator despite regional differences in drug coverage.

Questions were also raised about the use of the IGA-CHE as the primary outcome measure rather than the more commonly used Eczema Area and Severity Index score. The experts clarified that the IGA-CHE and the EASI score are clinically comparable and can be used interchangeably in practice. They endorsed the use of the IGA-CHE in the trials.

The experts noted that delgocitinib is not approved for children, though interest in off-label use may arise. They referenced the existence of trials investigating related drugs in pediatric populations and pointed to systemic JAK inhibitors that already have pediatric indications.

Finally, the drug programs inquired about positioning delgocitinib in the treatment sequence — whether it should follow failure of topical steroids and/or nonsteroidal topicals like calcipotriol or tacrolimus. The experts indicated that delgocitinib would most often be used after the failure of TCS or intolerance to TCS but could also be considered when TCS are contraindicated. They did not suggest that systemic therapies like methotrexate must be attempted before delgocitinib is initiated.

Clinical Evidence

Systematic Review

Description of Studies

Three phase III randomized controlled trials (RCTs) evaluated the efficacy and safety of delgocitinib cream 20 mg/g in adults with moderate to severe CHE. Two vehicle-controlled trials, the DELTA 1 trial (N = 487) and the DELTA 2 trial (N = 473), assessed whether delgocitinib improved IGA-CHE treatment success and HECSI scores over 16 weeks compared to vehicle cream. An active-controlled trial, the DELTA FORCE trial (N = 513), compared delgocitinib to oral alitretinoin over 24 weeks in patients with severe CHE. The primary and key secondary outcomes included change in HECSI score, IGA-CHE treatment success, at least a 75% improvement in HECSI score from baseline (HECSI-75), at least a 90% improvement in HECSI score from baseline (HECSI-90), and patient-reported measures such as Hand Eczema Symptom Diary (HESD) itch and DLQI scores.

Across all trials, the baseline demographic and disease characteristics were generally well balanced between groups. The mean age of the participants ranged from 44 to 46 years, with most having had CHE symptoms for at least 4 to 6 years. The population was predominantly white (more than 90%) and slightly more than half were female. The baseline severity scores (e.g., HECSI, IGA-CHE) were consistent with moderate to severe CHE, and no notable imbalances were observed across treatment arms.

Efficacy Results

Vehicle-Controlled Studies

In the vehicle-controlled trials (DELTA 1 and DELTA 2 trials), delgocitinib cream 20 mg/g twice daily demonstrated superior efficacy over vehicle cream at week 16 across clinician-reported and patient-reported outcomes.

IGA-CHE treatment success was experienced by 64 of 325 patients (19.7%) treated with delgocitinib in the DELTA 1 trial versus 16 of 162 patients (9.9%) treated with vehicle cream (difference = 9.8%; 95% confidence interval [CI], 3.6 to 16.1) and by 91 of 313 patients (29.1%) treated with delgocitinib in the DELTA 2 trial compared to 11 of 159 patients (6.9%) treated with vehicle cream (difference = 22.2%; 95% CI, 15.8 to 28.5; P = 0.005).

More patients treated with delgocitinib experienced HECSI-75 than patients treated with vehicle cream (DELTA 1 trial: 49.2% [160 of 325] versus 23.5% [38 of 162]; DELTA 2 trial: 49.5% [155 of 313] versus 18.2% [29 of 159]). The same was true of HECSI-90 (DELTA 1 trial: 29.5% [96 of 325] versus 12.3% [20 of 162]; DELTA 2 trial: 31.0% [97 of 313] versus 8.8% [14 of 159]). The mean change from baseline (CFB) in HECSI score also favoured delgocitinib in both studies (DELTA 1 trial: difference = –35.2; 95% CI, –46.7 to –23.8; P < 0.001; DELTA 2 trial: difference = –45.5; 95% CI –56.4 to –34.6; P < 0.001).

A 4-point or greater reduction in HESD itch score was reported by 47.1% of patients treated with delgocitinib (152 of 323) in the DELTA 1 trial versus 23.0% of patients treated with vehicle cream (37 of 161). In the DELTA 2 trial, these values were 47.2% of patients treated with delgocitinib (146 of 309) versus 19.9% of patients treated with vehicle cream (31 of 156).

In terms of quality of life, an improvement in DLQI score of 4 points or greater was reported in 74.4% of patients treated with delgocitinib (227 of 305) in the DELTA 1 trial versus 50.0% of patients treated with vehicle cream (74 of 148) and in 72.2% of patients treated with delgocitinib (216 of 299) in the DELTA 2 trial versus 45.8% of patients treated with vehicle cream (70 of 153). The mean DLQI score improved by –7.6 and –7.0 points in the delgocitinib groups in the DELTA 1 and DELTA 2 trials, respectively, compared to –3.9 and –3.1 points in the vehicle cream groups. The mean difference was –3.6 (95% CI, –4.7 to –2.6) in the DELTA 1 trial and –3.9 (95% CI, –5.0 to –2.8) in the DELTA 2 trial. Hand Eczema Impact Scale (HEIS) scores also improved more with delgocitinib in the DELTA 1 trial (difference = –0.6; 95% CI, –0.8 to –0.5) and in the DELTA 2 trial (difference = –0.8; 95% CI, –1.0 to –0.6). All effects across these outcomes in the DELTA 1 and DELTA 2 trials were considered clinically meaningful.

Active-Controlled Study

In the active-controlled DELTA FORCE trial, delgocitinib demonstrated greater efficacy than oral alitretinoin 30 mg once daily. At week 12, IGA-CHE treatment success was experienced by 68 of 250 patients (27.2%) receiving delgocitinib versus 42 of 253 patients (16.6%) receiving alitretinoin (difference = 10.6%; 95% CI, 3.3 to 17.9; P = 0.004). The mean change CFB in HECSI score was –67.6 versus –51.5 at week 12 (difference = –16.1; 95% CI, –23.28 to –8.86; P < 0.001) and –69.6 versus –45.1 at week 24 (difference = –24.5; 95% CI, –32.55 to –16.36; P < 0.001), favouring delgocitinib. HECSI-90 was experienced by 96 of 249 patients (38.6%) receiving delgocitinib versus 65 of 250 patients (26.0%) receiving alitretinoin at week 12 (difference = 12.6%; 95% CI, 4.3 to 20.8; P = 0.003). While the observed differences in HESD itch score reduction of 4 points or more, in DLQI score, and in HEIS score were smaller and consistently favoured delgocitinib, they were judged to not be clinically meaningful.

These outcomes were exploratory and not adjusted for multiplicity.

Harms Results

Across the DELTA 1, DELTA 2, and DELTA FORCE trials, delgocitinib cream 20 mg/g twice daily demonstrated a favourable safety profile. In the vehicle-controlled studies (DELTA 1 and DELTA 2 trials), the proportion of patients experiencing at least 1 AE was similar between groups: 45.2% with delgocitinib versus 50.6% with vehicle cream in the DELTA 1 trial and 45.5% versus 44.7% in the DELTA 2 trial. Most AEs were mild to moderate. The most commonly reported AEs included COVID-19, nasopharyngitis, and headache.

In the active-controlled DELTA FORCE study, AEs occurred in 49.4% of patients treated with delgocitinib versus 76.1% of patients treated with oral alitretinoin. Some notable AEs occurred more frequently with alitretinoin, such as headache (32.4% versus 4.0%), nausea (5.7% versus 0.4%), dry skin (3.6% versus 1.2%), and hypercholesterolemia (3.6% versus 0%).

Serious AEs (SAEs) were infrequent across all studies: reported in no more than 2.0% of patients treated with delgocitinib in all trials, compared to up to 4.9% of patients treated with alitretinoin in the DELTA FORCE trial. No SAE led to major safety concerns or deaths. AEs leading to treatment discontinuation were also rare with delgocitinib (≤ 1.2% of patients) and notably higher with alitretinoin (10.1% of patients). No AEs of special interest (AESIs) occurred in the delgocitinib groups, and 1 patient in the alitretinoin group experienced a deep vein thrombosis. No deaths occurred in any of the trials.

Critical Appraisal

The vehicle-controlled trials (DELTA 1 and DELTA 2 trials) were methodologically robust, with low risk of bias across outcomes. Randomization, allocation concealment, and blinding were well executed, and outcome assessments used instruments that were overall validated (although some were validated within the sponsored study) and aligned with the trial objectives. Missing data were minimal and handled appropriately using standard imputation methods. In contrast, the DELTA FORCE trial employed an open-label design in which patients and treating physicians were aware of treatment allocation; however, efficacy assessments were conducted by blinded assessors to mitigate potential detection bias. Differential dropout rates between treatment arms (36% for alitretinoin versus 13% for delgocitinib) likely reflect differences in tolerability and clinical effects inherent to systemic versus topical products. However, this degree of imbalance raises concerns about attrition bias, particularly for longer-term and subjective outcomes, and the direction of this bias would likely favour delgocitinib.

The trials enrolled patients consistent with the Health Canada indication for delgocitinib, with baseline characteristics reflective of the intended population. However, the underrepresentation of racial and geographic diversity, the exclusion of patients with significant comorbidities, and the controlled trial setting may modestly limit generalizability. Nonetheless, the intervention and comparator regimens, background care, and outcomes assessed were aligned with clinical practice in Canada, supporting the overall applicability of findings to the real-world setting.

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment was based on the sponsor’s summary of clinical evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. Table 2 and Table 3 present the summary of findings for these outcomes.

Table 2: Summary of Findings for Delgocitinib Versus Vehicle Cream for Patients With CHE

AE = adverse event; AESI = adverse event of special interest; CHE = chronic hand eczema; CI = confidence interval; DLQI = Dermatology Life Quality Index; HECSI = Hand Eczema Severity Index; HECSI-75 = at least a 75% improvement in Hand Eczema Severity Index score from baseline; HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; HEIS = Hand Eczema Impact Scale; HESD = Hand Eczema Symptom Diary; HRQoL = health-related quality of life; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; RCT = randomized controlled trial; SAE = serious adverse event; SE = standard error.

Notes: Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aA clinically meaningful effect of at least 3 patients improved per 100 treated was established as the threshold for clinical importance; hence, the body of evidence was not rated down for imprecision. IGA-CHE treatment success was defined as a score of 0 or 1 with at least a 2-step improvement from baseline. Differences in effect estimates were detected between the DELTA 1 and DELTA 2 trials; however, this was likely explained by differences in patients’ baseline risk factors. Furthermore, estimates and CIs both showed a meaningful effect; hence, this outcome was not rated down for inconsistency.

^bA minimal important difference of 20 was established as the threshold for clinical importance for the HECSI values; hence, the body of evidence was not rated down for imprecision.

^cThe DLQI minimal important difference is 4 points.

^dThe HEIS minimal important difference is 0.6 points.

^eA threshold of clinical importance to determine the magnitude of effect was not possible to obtain. For SAEs and AESIs, the review team rated down the evidence by 1 level for imprecision because the magnitude of effect was uncertain and there were few or no events.

Source: Details included in the table are from the sponsor’s summary of clinical evidence.¹⁶

Table 3: Summary of Findings for Delgocitinib Versus Alitretinoin for Patients With CHE

AE = adverse event; AESI = adverse event of special interest; CHE = chronic hand eczema; CI = confidence interval; DLQI = Dermatology Life Quality Index; HECSI = Hand Eczema Severity Index; HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; HEIS = Hand Eczema Impact Scale; HESD = Hand Eczema Symptom Diary; HRQoL = health-related quality of life; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; RCT = randomized controlled trial; SAE = serious adverse event; SE = standard error.

Notes: Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aRated down 1 level due to risk of bias in the DELTA FORCE study, an open-label study with outcome completion rates higher in the delgocitinib group (86.6%) than in the alitretinoin group (64.1%), with a differential dropout rate of approximately 22%. Discontinuations in the alitretinoin group were mainly due to AEs and lack of efficacy. Although sensitivity analyses were conducted, the missingness is likely related to the outcome.

^bA clinically meaningful effect of at least 3 patients improved per 100 treated was established as the threshold for clinical importance; hence, the body of evidence was not rated down for imprecision. IGA-CHE success was defined as a score of 0 or 1 with at least a 2-step improvement from baseline.

^cA minimal important difference of 20 was established as the threshold of clinical importance for the HECSI values; hence, the body of evidence was not rated down for imprecision.

^dA 4-point or greater reduction in the HESD itch score was used as the threshold for a clinically meaningful result (minimal important difference). The effect estimate and CI do not include this threshold; there was precision in the result because it falls within a trivial or no-effect zone (between thresholds).

^eA change of at least 4 points in the DLQI score was established as the threshold for a meaningful effect or minimal important difference. The effect estimate and CI do not include this threshold; there was precision in the result because it falls within a trivial or no-effect zone (between thresholds).

^fFor the HEIS score, the minimal important difference was established as at least 0.6 points difference. The effect estimate and CI do not include this threshold; there was precision in the result because it falls within a trivial or no-effect zone (between thresholds).

^gCertainty was rated down 1 level for imprecision due to an absence of effect estimates with CIs and a lack of established thresholds for clinical importance. These limitations preclude a high-certainty judgment.

Source: Details included in the table are from the sponsor’s summary of clinical evidence.¹⁶

Long-Term Extension Studies

Description of Studies

The DELTA 3 trial was a phase III, open-label, multisite extension phase of the DELTA 1 and DELTA 2 trials and was conducted to assess the long-term safety and efficacy of twice-daily applications of delgocitinib cream 20 mg/g as needed (based on IGA-CHE score) in patients who completed 1 of the 2 pivotal phase III trials with delgocitinib cream 20 mg/g or vehicle cream. Together, the parent trials and the DELTA 3 extension trial provided 52 weeks of efficacy and safety data. The baseline visit (day 1, week 0) of this extension trial coincided with the end-of-treatment visit (week 16) of the parent trials.

Patients eligible for the DELTA 3 extension trial were those who completed the treatment period in the DELTA 1 or DELTA 2 parent trial. Participants who discontinued treatment with delgocitinib early, used rescue medication, or experienced any AE during participation in the parent trial that precluded further treatment with delgocitinib were not eligible to participate in the DELTA 3 trial. From baseline to week 36, patients were treated on an as-needed basis with delgocitinib cream 20 mg/g twice daily. At any time during the trial, if a patient had an IGA-CHE score of 2 or higher, the investigator dispensed delgocitinib cream and instructed the patient to start treatment with twice-daily applications. When the patient experienced an IGA-CHE score of 0 (clear) or 1 (almost clear), the patient could stop treatment.

The primary outcome of the DELTA 3 extension study was the number of treatment-emergent AEs (TEAEs) from baseline up to week 38. SAEs, AEs leading to discontinuation, and deaths were also reported. Long-term efficacy outcomes, including IGA-CHE score and HECSI score, were reported as secondary outcomes, and HESD itch score and DLQI score were reported as tertiary outcomes.

Patient Disposition

Of the 810 screened patients, 801 patients were eligible to participate in the DELTA 3 trial and were therefore included in the patient safety analysis. Among these 801 patients, 560 belonged to a previous delgocitinib group and 241 to a previous vehicle cream group. From the previous delgocitinib group, 88 patients (15.7%) discontinued from the extension study, as did 49 patients (20.3%) from the previous vehicle cream group. A total of 664 patients completed the extension treatment period: 472 (84.3%) from the previous delgocitinib group and 192 (79.7%) from the previous vehicle cream group.

Baseline Characteristics

The patient baseline characteristics in the DELTA 3 trial were similar to those of the parent trials. IGA-CHE and HECSI scores at parent trial baseline were similar between the treatment groups. There were some differences in terms of IGA-CHE score at extension trial baseline between the previous delgocitinib and previous vehicle cream groups. The median HECSI score, HESD itch and pain scores, HESD score, and DLQI score had decreased baseline values in both treatment groups compared to the parent trial baseline values. The distribution of CHE subtypes at parent trial baseline was similar between the groups, except for vesicular hand eczema (pompholyx): 11.3% versus 5.8% in the previous delgocitinib and previous vehicle cream groups, respectively.

Efficacy Results

In the DELTA 3 trial, efficacy outcomes were generally maintained or improved over 36 weeks of as-needed delgocitinib use. Among patients who had received delgocitinib in the parent trials, IGA-CHE treatment success was stable (24.6% at extension baseline; 30.0% at week 36). In those previously treated with vehicle cream, IGA-CHE success increased from 9.1% to 29.5% over the same period.

HECSI scores declined further in both groups during the first 16 weeks and then stabilized. The mean HECSI score fell from 23.9 to 14.8 in the former delgocitinib group and from 46.8 to 16.8 in the former vehicle cream group. Correspondingly, the percentage of patients experiencing a HECSI-75 response increased from 51.8% to 58.6% of patients in the former delgocitinib group and from 23.7% to 51.5% of patients in the former vehicle cream group. The percentage of patients experiencing a HECSI-90 response also improved, reaching 36.6% of patients in the former delgocitinib group and 35.7% of patients in the former vehicle cream group by week 36.

Symptom relief was sustained, with HESD itch reductions of 4 points or more experienced by 52.4% of patients previously treated with delgocitinib (versus 50.6% at baseline) and HESD pain reductions in 55.4% of patients previously treated with delgocitinib (versus 51.9% at baseline). Improvements were also seen in the former vehicle cream group (HESD itch reductions of 4 points or more: 26.3% to 41.3% of patients at DELTA 3 trial baseline to week 36; HESD pain reductions: 32.3% to 43.3% of patients at DELTA 3 trial baseline to week 36).

Patient-reported HEIS and DLQI scores showed modest continued improvement in the former delgocitinib group and early gains that stabilized in the former vehicle cream group, supporting durability of treatment benefit over the extension period.

Harms

Overall, 495 patients (61.8%) reported at least 1 AE, with similar rates among those previously treated with delgocitinib (61.1%) and those previously treated with vehicle cream (63.5%). The most common AEs (reported by ≥ 5% of patients) were COVID-19 and nasopharyngitis. While infection rates were slightly higher during on-treatment periods than during off-treatment periods, the difference was not clinically meaningful.

SAEs were infrequent (3.4%), with no major differences by treatment phase or prior treatment group. Nine patients permanently discontinued the study drug due to AEs (most of which were nonserious), and rates of AEs were comparable across groups. One AESI, eczema herpeticum, occurred during an on-treatment period in a patient with AD. Three deaths were reported, none of which were considered related to the study drug.

Critical Appraisal

The design of the open-label extension phase (DELTA 3 trial) may have biased the reporting of some end points because awareness of the study treatment received may have influenced the perception of improvement and/or harms by patients and clinicians, particularly for outcomes that are subjective in measurement and interpretation. As part of the eligibility criteria for the open-label extension phase, patients had to complete 1 of the prior studies, which may potentially allow for selection bias. Because all patients were taking delgocitinib during the open-label extension phase, there was no relevant randomized comparison group (for any active comparator of interest), which precludes causal conclusions.

Because the patients who took part in the DELTA 3 trial were originally from the DELTA 1 or DELTA 2 parent studies and the eligibility criteria remained the same, it is reasonable to expect that the same limitations to generalizability are relevant to the open-label extension study. For instance, because the participants were predominantly white (approximately 91%), the results from these trials may not be generalized to other racial groups who may be commonly seen at some centres in North America and Europe. One of the eligibility criteria in the extension phase was that patients who experienced any AE during participation in the parent trial that precluded further treatment with delgocitinib were not eligible to participate in the DELTA 3 trial. While this reflects, to some extent, what would be expected in clinical practice — patients who do not experience response to treatment or who discontinue treatment due to AEs are unlikely to subsequently continue with treatment — it also leads to a greater share of patients who tolerate and experience response to delgocitinib. As a result, the generalizability of the DELTA 3 trial to the overall population is uncertain.

Indirect Comparisons

Description of Studies

Due to limited head-to-head evidence, the sponsor submitted 2 indirect treatment comparisons (ITCs) to support the comparative efficacy and safety of delgocitinib for CHE. A Bayesian network meta-analysis (NMA) compared delgocitinib to phototherapy (psoralen and UVA radiation [PUVA]) and oral alitretinoin, using data from 7 RCTs, including the DELTA 1, DELTA 2, and DELTA FORCE trials. A matching-adjusted indirect comparison (MAIC) was also conducted to compare delgocitinib with dupilumab, using individual patient data (IPD) from the DELTA 1 and DELTA 2 trials and aggregate data from the LIBERTY-AD-HAFT trial, a trial involving patients with atopic hand and foot eczema.

Efficacy Results

In the NMA, delgocitinib demonstrated higher odds of achieving an IGA-CHE or PGA score of 0 or 1 end point response compared to vehicle cream (odds ratio [OR] = 2.92; 95% credible interval [CrI], 2.06 to 4.21), PUVA (OR = 2.73; 95% CrI, 1.43 to 5.25), and alitretinoin (OR = 1.88; 95% CrI, 1.23 to 2.93) at the primary end point. The results were consistent at the week 12 sensitivity analyses and across severity subgroups. Delgocitinib also showed improved odds of achieving HECSI-90 compared to vehicle cream (OR = 3.59; 95% CrI, 2.49 to 5.28) and alitretinoin (OR = 1.79; 95% CrI, 1.22 to 2.62). The MAIC found no significant difference between delgocitinib and dupilumab in achieving an IGA-CHE or Hand and Foot Investigator’s Global Assessment (HF-IGA) score of 0 or 1 (OR = 1.1; 95% CI, 0.3 to 3.4) or HECSI-90 (OR = 1.3; 95% CI, 0.4 to 4.9), with wide CIs reflecting imprecision.

Harms Results

The NMA indicated that delgocitinib was associated with lower odds of discontinuation due to AEs compared to vehicle cream (OR = 0.21; 95% CrI, 0.08 to 0.45), PUVA (OR = 0.09; 95% CrI, 0.03 to 0.32), and alitretinoin (OR = 0.09; 95% CrI, 0.04 to 0.21). These findings were consistent across severity-based sensitivity analyses. No harms data were included in the MAIC.

Critical Appraisal

The NMA was conducted using prespecified methods and included trials with a generally low risk of bias. However, key limitations include heterogeneity in outcome definitions (e.g., stricter criteria for IGA-CHE response in the DELTA trials), variation in disease severity and treatment duration across studies, and absence of closed loops, precluding formal consistency testing. Despite sensitivity analyses, residual concerns about effect modification remain. The network was sparse, particularly for phototherapy, and some outcomes (e.g., HECSI-90, cumulative response) could not be evaluated across all arms.

The MAIC used appropriate statistical methodology and adjusted for known effect modifiers (age, sex, race, HECSI score, CHE subtype). However, differences in underlying populations (CHE versus atopic hand and foot eczema), end point definitions, and the exclusion of harms limit its interpretability. The effective sample size (ESS) was reduced after matching, leading to wide CIs and increased uncertainty.

Overall, both ITCs provide exploratory comparative data, but the findings should be interpreted cautiously due to methodological and population-level differences.

Conclusions

Considering the totality of evidence, delgocitinib cream 20 mg/g is supported as a clinically effective and well-tolerated treatment option for adults with moderate to severe CHE, particularly among those who have not experienced response to TCS and are seeking nonsystemic alternatives. Across 3 RCTs and 1 long-term extension study, delgocitinib consistently demonstrated improvements — compared to vehicle cream — in outcomes that align with priorities identified by patients and clinicians, including visible skin improvement, symptom relief, and enhanced quality of life. Compared to oral alitretinoin, the only other approved treatment for severe CHE in Canada, delgocitinib showed comparable or superior efficacy in several important outcomes, with a more favourable safety profile and fewer systemic adverse effects.

Indirect comparisons provide additional context regarding the relative efficacy of delgocitinib. In an NMA, delgocitinib was favoured over both phototherapy and alitretinoin across key efficacy outcomes. In contrast, a MAIC against dupilumab showed no clear difference between treatments. These findings, while informative, should be interpreted with caution due to methodological limitations, including sparse data, residual confounding, and differences in outcome definitions across studies — all of which may bias the estimates or widen the uncertainty around treatment effects. The relevance of comparisons with PUVA therapy is limited because oral psoralen is no longer available in Canada. Similarly, the comparison with dupilumab has restricted applicability, given its current use is limited to patients who have not experienced adequate disease control with conventional systemic immunosuppressants.

Overall, delgocitinib addresses an important unmet need by offering an effective topical, nonsteroidal alternative for patients with persistent CHE. Uncertainties remain regarding its long-term efficacy and safety end points, as well as its position within the broader treatment framework, including its potential to delay or reduce the need for systemic therapies.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of delgocitinib 20 mg/g topical cream in the treatment of patients with moderate to severe CHE.

Disease Background

The contents within this section have been informed by materials submitted by the sponsor and by clinical expert input. The following has been summarized and validated by the review team.

Hand eczema is a painful, pruritic, inflammatory, noninfectious skin disease of the hands and wrists.^1-3 The European Society of Contact Dermatitis and consensus-based Canadian and German hand eczema treatment guidelines define CHE as an episode of hand eczema lasting at least 3 months or relapsing at least twice per year.^1,4,5 The severity of CHE can be assessed based on clinical signs, disease duration, treatment history, and impact on patient function.^1,6 The prevalence of CHE in adult living in Canada is estimated to be 6.2%, and it is more common in females, according to data from the Canada-based cohort in an international prospective patient survey (CHECK study).¹³ In this cohort, approximately 70% of patients were female; the median age was 41 years, and roughly 44% of patients reported having moderate to severe CHE.^14,15

The signs and symptoms of CHE arise from complex interactions between skin and immune cells that lead to a cycle of proinflammatory signalling.^2,9 The main symptoms of CHE include itch and pain. People with CHE may also experience dryness, cracking, thickened skin, and bleeding, and signs and symptoms can fluctuate in severity over time (i.e., people experiencing flares).^3,11 Pan–JAK-STAT signalling plays a crucial role in the dysregulated inflammatory response seen in CHE.^2,9 Activation of the JAK-STAT pathways leads to downregulation of antimicrobial peptides and structural proteins such as filaggrin, resulting in skin barrier dysfunction.^2,17 With long-term exposure to environmental factors like mechanical irritation, hot or dry weather, water, or other irritants, there is added harm to the skin barrier.¹⁰ The etiology is multifactorial, involving triggers that could be exogenous and endogenous.^2,5 As a result, risk factors for the development of CHE include having childhood eczema, asthma, and hay fever, as well as employment involving wet work or frequent exposure to irritants and allergens (occupations in areas such as health care, food processing, and hairdressing).^5,7-9

CHE is associated with a considerable burden to patients arising from the signs and symptoms of the disease (e.g., itch, pain, bleeding), disfigurement and loss of function of the hands, impaired sleep, psychological distress, negative impact on social life, and reduced ability to work.^1,5,10,12 A European study demonstrated that patients with hand eczema had significantly higher prevalence of clinical depression, anxiety disorder, and suicidal ideation compared with controls.¹⁸

Standards of Therapy

The contents within this section have been informed by materials submitted by the sponsor and by clinical expert input. The following has been summarized and validated by the review team.

In Canada, the management of CHE involves a stepwise therapeutic approach, combining nonpharmacologic strategies, topical therapies, and systemic agents for patients with more severe or refractory disease. Treatment typically begins with avoidance of irritants, protective hand care (e.g., gloves), and consistent use of emollients or moisturizers to repair skin barrier function.^1,4,5,19 Pharmacologic interventions start with TCS (Figure 1), sometimes followed by topical calcineurin inhibitors such as tacrolimus or pimecrolimus for steroid-sparing purposes or in steroid-resistant cases.^1,4,5,19 For patients with moderate to severe CHE that is not responsive to topicals, systemic therapy may be initiated, most commonly with oral alitretinoin — currently the only systemic agent approved by Health Canada for severe CHE. Biologic therapies for AD represent recent advancements in AD treatment (where dupilumab is the most accessible publicly reimbursed biologic), but while they are well tolerated, their mechanism of action is narrow because it targets only the type 2 inflammatory pathway associated with AD.²⁰ Oral JAK inhibitors are also a relatively recent advancement in AD treatment with broad public coverage. However, their adoption is limited by safety considerations identified by Health Canada in certain patient groups (e.g., older adults, past or current smokers, patients with cardiovascular or malignancy risk factors, patients at risk for thrombotic events).²¹

Figure 1: Current Paradigm of Treatment for Patients With Moderate to Severe CHE

CHE = chronic hand eczema; JAKi = Janus kinase inhibitor; TCS = topical corticosteroids.

Source: Sponsor’s summary of clinical evidence.¹⁶

Input from clinical experts consulted for this review confirmed this treatment paradigm. They emphasized that TCS remain the mainstay of first-line pharmacologic therapy and that calcineurin inhibitors are used selectively, often limited by tolerability or cost. Experts noted that systemic therapies are generally reserved for patients with long-standing, severe CHE that is unresponsive to topical treatments and that alitretinoin is widely used but often associated with significant adverse effects (e.g., headache, mucocutaneous dryness, teratogenicity), limiting its tolerability and long-term use in some patients. They also indicated that while use of methotrexate, cyclosporine, mycophenolate, or azathioprine may be off-label, they are frequently prescribed and may require access through special authorization or use in consultation with a specialist. Phototherapy is used in some centres, though its availability is variable across Canada. Clinical experts indicated that psoralen, a photosensitizer that is part of PUVA therapy, is not available in Canada. Instead, centres in Canada use narrow-band UVA therapy, which is deemed less effective. Experts noted that dupilumab is currently not publicly available before unsuccessful treatment with methotrexate and cyclosporine.

According to clinical experts, the primary goals of therapy for CHE include rapid and sustained reduction in inflammation and itch, restoration of skin integrity, and improvement in health-related quality of life (HRQoL). Treatment success is also measured by its ability to reduce pain and sleep disturbance, maintain productivity (e.g., ability to work, particularly with hand-dependent tasks), and minimize psychological and social burden. Experts highlighted that long-term disease control with minimal side effects is critical, particularly for patients with frequent relapses or chronic symptoms. From both patient and clinician perspectives, improved tolerability, flexibility of use, and nonsystemic alternatives were cited as highly desirable features in new treatments.

Drug Under Review

Delgocitinib is a topical cream. Each gram of cream contains 20 mg of delgocitinib. The recommended dosing regimen of delgocitinib is as follows:²²

• A thin layer of delgocitinib should be applied twice daily to the affected skin of the hands and wrists.

• Each affected area should be treated with delgocitinib twice daily until the skin is clear or almost clear.

• In the event of recurrence of the signs and symptoms of CHE (flares), twice-daily treatment of the affected areas should be reinitiated as needed.

Delgocitinib is a JAK inhibitor that targets the underlying pathophysiology in CHE, specifically the JAK-STAT pathways. This is achieved by inhibiting the activity of all 4 members of the JAK family of enzymes, consisting of JAK1, JAK2, JAK3, and tyrosine kinase 2, thus blocking downstream signalling of multiple proinflammatory cytokines driving disease severity in CHE.²²

Delgocitinib has been approved by Health Canada for the treatment of moderate to severe CHE, including the relief of pain and pruritus, in adults who have experienced inadequate response to TCS or for whom TCS are not advisable. The reimbursement request for delgocitinib is aligned with the anticipated Health Canada indication.

The key characteristics of delgocitinib are summarized in Table 4, along with those of other treatments available for CHE.

Table 4: Key Characteristics of Delgocitinib, Alitretinoin, and Dupilumab

AD = atopic dermatitis; CHE = chronic hand eczema; IL = interleukin; JAK = Janus kinase; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks.

^aHealth Canada–approved indication.

Sources: Product monographs of delgocitinib,²² alitretinoin,²³ and dupilumab.²⁴

Perspectives of Patients, Clinicians, and Drug Programs

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

Two patient groups, the ESC and CANN, submitted input for this review. Another patient group, the Canadian Skin Patient Alliance, did not directly provide input for this submission but provided a letter of support for the patient submission developed and submitted by the ESC. The ESC group obtained information related to CHE through questionnaires and interviews with patients, caregivers and health care professionals, as well as survey data on various topics from more than 3,000 people living in Canada who have eczema (e.g., impact on quality of life, experience with treatments, patient journeys). CANN collected anonymous data through qualitative interviews with nurses conducted in July 2024 and obtained their perspectives of living and working with CHE. The group also conducted an online quantitative survey between October 23 and November 10, 2024, of its nursing members living with CHE (n = 27), which was distributed through CANN’s email communication list and established membership channels. All information was gathered in Canada.

Both patient groups highlighted a significant impairment to everyday living and quality of life due to CHE. The groups reported that people with CHE experienced negative impacts on sleep quality (due to pain), skin (burning, itching lesions, blisters, bleeding skin), work (loss of productivity, change in careers due to CHE), social interactions, fitness, intimacy, family life and hygiene. CANN further noted that survey respondents reported itchy skin as the symptom that caused the greatest burden, followed by dry or chapped skin; dyshidrotic blisters; cracking skin or fissures; open wounds with bleeding; and painful, stinging and throbbing hands. Both patient groups highlighted that current treatment regimens may not be sufficient and expressed concerns regarding long-term steroid use. In the survey conducted by CANN, 52% of the respondents reported that their current treatment and management regimen could not control or could only somewhat help them manage their hand eczema.

Both patient groups highlighted a need for a treatment that provided better disease management, including relief from itching, stinging, burning, and pain; improvement in skin disease; and reduction of flares. CANN further highlighted that people with CHE want to function normally, return to work, experience reduced severity of flares, and have decreased risk of blisters and open wounds. The ESC also noted that people were looking for treatments suitable for long-term use that could allow them to regain their confidence and self-esteem and improve their social life and quality of life. In both patient groups, those who had had the opportunity to be treated with delgocitinib noted positive experiences with the treatment. The ESC further highlighted that delgocitinib offered patients relief; was well tolerated, without stinging or burning; and was not greasy on the hands.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC 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 CHE.

Unmet Needs

The experts identified significant unmet needs in the treatment of moderate to severe CHE. They noted that many currently available therapies, including alitretinoin and systemic immunosuppressants, are poorly tolerated, only moderately effective, or associated with significant toxicity. Topical calcineurin inhibitors were described as often ineffective, and high-potency TCS as unsuitable for long-term use due to safety concerns. The experts highlighted limited access to phototherapy across Canada and high costs of newer therapies like topical ruxolitinib. They considered that there is a need for an effective, safe, and accessible topical therapy with efficacy comparable to systemic agents, without their associated risks.

Place in Therapy

The experts indicated that delgocitinib would most likely be used after the failure of high-potency TCS. They suggested that delgocitinib could be used before the off-label systemic therapies currently used to treat CHE (e.g., immunosuppressants, dupilumab, JAK inhibitors), which carry systemic risks. Both experts emphasized a preference for topical therapies due to lower systemic exposure and ease of administration. They also noted that dupilumab is currently not available before unsuccessful treatment with methotrexate and cyclosporine. Hence, these immunosuppressants are expected to be displaced before delgocitinib can displace dupilumab or any JAK inhibitor. According to the experts, there is no evidence of JAK inhibitors being clinically superior to dupilumab.

The experts mentioned that delgocitinib can be expected to be used as monotherapy for patients whose disease is not controlled with corticosteroids or in combination with systemic treatments in more severe cases (e.g., in addition to alitretinoin). Overall, the experts considered that the introduction of delgocitinib may shift the treatment paradigm by reducing reliance on systemic agents, mainly alitretinoin, methotrexate, and cyclosporine.

Patient Population

The experts noted that CHE is not rare but that it disproportionately affects individuals in manual or caregiving professions. They identified people with functional impairment due to CHE, especially those whose work, sleep, or daily activities are impacted, as those most in need of intervention. They considered that people who are unable to use or unresponsive to corticosteroids or other topical agents, or for whom these treatments are contraindicated, could benefit most. Additionally, people with more recent disease onset and less lichenified lesions may respond better to treatment.

The experts indicated that diagnosing CHE can be challenging, with differential diagnoses including allergic contact dermatitis, psoriasis, and tinea manuum. They recommended detailed clinical history and examination, with patch testing in select cases. The experts acknowledged that misdiagnosis and underdiagnosis are likely, especially in underserved populations. While dermatologists were viewed as best suited to confirm diagnosis, the experts considered that family physicians could manage more straightforward cases.

The clinical experts considered that the people least suitable for delgocitinib would include those who found it difficult to adhere to treatment regimens, those with active infections or malignancies on the hands, and those with extensive warts (due to a theoretical risk of spreading).

Assessing the Response Treatment

The experts stated that response of CHE to treatment in clinical practice is usually assessed using clinician global assessment (e.g., IGA-CHE) and patient-reported outcomes such as symptom control and functional improvement. They noted that the HECSI is not commonly used in routine practice. A clinically meaningful response was considered to be IGA-CHE score of 0 or 1 (clear or almost clear) or a 75% improvement in the affected area. Return to function and patient satisfaction with symptom control (e.g., of itch, pain, and sleep) were also identified as important indicators.

The experts recommended assessing treatment response after 4 weeks and again at 12 weeks. They suggested that continued treatment should depend on these clinical targets being achieved or approached.

Discontinuing Treatment

The experts recommended discontinuation of delgocitinib in cases of complete lack of response after 12 weeks. They also cited failure to achieve an IGA-CHE score of 0 or 1 at 12 weeks, a lack of patient-reported improvement, or the emergence of adverse effects as appropriate reasons to reconsider or stop treatment.

Prescribing Considerations

The experts considered that delgocitinib may be initiated in either dermatology or primary care settings. While dermatologist confirmation of diagnosis may be required in some cases, the experts noted that both dermatologists and family physicians could prescribe and monitor treatment, particularly for less severe cases. They suggested this approach could help reduce referrals and wait times for dermatology care. Due to its topical formulation, delgocitinib was deemed suitable for community-based treatment and home use. However, the experts acknowledged ongoing regional disparities in access to dermatologists and advanced therapies, particularly in rural or economically disadvantaged areas.

The clinical experts also indicated that while delgocitinib is expected to be effective as monotherapy, combination with other therapies may be considered in specific cases.

Additional Considerations

The experts noted that CHE often affects visible areas, leading to stigma, social withdrawal, and reduced quality of life. They emphasized that equity-deserving populations may face additional barriers to diagnosis, access, and continuity of care. The experts considered that delgocitinib, as a safe, effective, and nonsystemic option, could reduce the use of harmful off-label systemic treatments and improve access to care for marginalized populations.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

Five clinician groups provided input for this review: the DAO, the Atlantic Dermatology Group, the Canadian Dermatology Association’s Pharmacy and Therapeutics Advisory Board, the Saskatchewan Dermatology Association, and dermatologists practising in Canada with an interest in CHE. Information for this submission included input from 21 clinicians and was gathered through reviews of published literature, research and trial experience, clinical practice experience, and national and international meetings.

The input from clinician groups was generally consistent with the input from the clinical experts consulted for this review, emphasizing the ongoing unmet need for new topical prescription therapy options for CHE that would control the signs and symptoms of eczema, normalize quality of life, and reduce or abolish occupational impacts. The DAO group further emphasized the need to include therapies for long-term control of CHE that are safe, effective, and accessible. The clinician groups highlighted the limitations of current therapies, including AEs related to topical corticosteroid use such as skin atrophy, skin infections, pain, burning, fissures, reduced hand dexterity, and bleeding; limited efficacy and poor access to phototherapy; and contraindications related to alitretinoin use (e.g., pregnancy, breastfeeding). The DAO group noted that while topical calcineurin inhibitors like tacrolimus are sometimes used in mild cases of CHE when a steroid-sparing therapy is required due to AEs related to steroid use, they are not effective treatment alternatives for moderate and severe forms of CHE. The DAO group also highlighted several off-label systemic options for patients with CHE in cases when phototherapy and alitretinoin are not suitable, are not accessible, or fail to control the condition; these options include traditional immunosuppressants (i.e., methotrexate and cyclosporine), biologics (particularly ones used in AD, such as dupilumab), and oral JAK inhibitors (i.e., upadacitinib). However, the group noted limitations related to these off-label options as well, including accessibility and cost (i.e., coverage criteria may make a biologic therapy inaccessible, or the co-pay cost to the patient may be a barrier), safety considerations (e.g., black box warnings and contraindications across the oral systemic therapies), and expected effectiveness (i.e., traditional immunosuppressants are not as effective in managing CHE as biologics or oral JAK inhibitors). The groups indicated that people involved in certain professions with frequent exposure to irritants and allergens — such as people working in health care, cleaning, and hairdressing — report higher incidence rates of CHE.

The DAO and the Canadian Dermatology Association’s Pharmacy and Therapeutics Advisory Board groups considered topical delgocitinib as a second-line treatment for patients with moderate to severe CHE (i.e., a PGA score of 3 to 4) whose disease was refractory to TCS, or who experienced intolerance to TCS, or for whom TCS were contraindicated. The Atlantic Dermatology Group considered topical delgocitinib as a first-line or second-line treatment for adult patients with moderate to severe CHE for whom TCS are inadequate or inappropriate. The groups noted that delgocitinib is expected to cause a shift in the current treatment paradigm as a new targeted topical prescription therapy for CHE. The DAO group highlighted delgocitinib’s ease of access and treatment administration over phototherapy and noted that it did not require laboratory monitoring and had no contradictions (e.g., pregnancy, breastfeeding, or renal or hepatic insufficiency) as is the case for alitretinoin. Referring to the clinical trials, the groups also noted the efficacy and favourable safety profile of delgocitinib in patients with moderate to severe CHE. The clinician groups provided additional details on patient selection, noting that delgocitinib may be particularly appropriate for patients with moderate to severe CHE who have experienced an inadequate response to TCS or for whom TCS are not advisable or are contraindicated. The groups also noted that patients with mild CHE for whom TCS have not yet been used or whose CHE is being adequately managed by emollients, avoidance strategies, or TCS are less appropriate candidates for treatment with delgocitinib.

The clinician groups noted that an initial assessment of response to treatment at approximately 3 to 6 months after initiation (i.e., around 16 weeks) would be reasonable. The DAO group further highlighted that both the timing of follow-up assessments and the criteria used to determine response may vary across clinicians, depending on clinical practice wait times, availability of follow-up, and patient-specific factors. The clinician groups added that outcome measures are not formally standardized in routine clinical practice for CHE, and that clinicians typically rely on an informal PGA. The clinician groups agreed that reasons for discontinuation of delgocitinib may include inadequate or loss of efficacy, recurrent flares, disease worsening or lack of response despite an adequate therapeutic trial, or intolerance and adverse effects.

Drug Program Input

The drug programs provide input on each drug being reviewed through the reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted for this review are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

CDEC = Canadian Drug Expert Committee; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; JAK = Janus kinase.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of delgocitinib 20 mg/g topical cream in the treatment of patients with CHE. The focus will be placed on comparing delgocitinib to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of delgocitinib is presented in 3 sections, with the CDA‑AMC critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes the pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. The CDA-AMC assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes sponsor-submitted long-term extension studies. The third section includes indirect evidence from the sponsor.

Included Studies

Clinical evidence from the following is included in the review and appraised in this document:

• 3 pivotal studies (RCTs) identified in the systematic review

• 1 long-term extension study

• 2 ITCs.

Systematic Review

The contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Description of Studies

The characteristics of the included studies are summarized in Table 6.

Table 6: Details of Studies Included in the Systematic Review

AD = atopic dermatitis; AE = adverse event; ALP = alkaline phosphatase; ALT= alanine transaminase; AST = aspartate transaminase; AUC = area under the curve; b.i.d. = twice a day; CFB = change from baseline; CHE = chronic hand eczema; DLQI = Dermatology Life Quality Index; HECSI = Hand Eczema Severity Index; HECSI-75 = at least a 75% improvement in Hand Eczema Severity Index score from baseline; HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; HEIS = Hand Eczema Impact Scale; HESD = Hand Eczema Symptom Diary; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; IMP = investigational medicinal product; JAK = Janus kinase; PDAL = proximal daily activity limitations; q.d. = every day; RCT = randomized controlled trial; TCS = topical corticosteroids; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event; TSQM= Treatment Satisfaction Questionnaire for Medication; ULN = upper limit of normal; VAS = visual analogue scale; WPAI-CHE = Work Productivity and Activity Impairment–Chronic Hand Eczema.

Sources: DELTA 1, DELTA 2, and DELTA FORCE Clinical Study Reports.^29-31

Three RCTs were identified and included in the clinical evidence for delgocitinib cream 20 mg/g: the DELTA 1, DELTA 2, and DELTA FORCE trials. These studies formed the pivotal evidence base for the sponsor’s submission, evaluating the efficacy, safety, and HRQoL impacts of delgocitinib in adults with moderate to severe CHE who had experienced inadequate response to TCS or for whom TCS were not advisable.

DELTA 1 and DELTA 2 Trials

The DELTA 1 and DELTA 2 trials were identically designed, double-blind, vehicle-controlled, parallel-group, phase III RCTs. Their primary objective was to evaluate the efficacy and safety of twice-daily topical delgocitinib cream versus vehicle cream in adults with moderate to severe CHE.

Both trials enrolled adults aged 18 years and older with a diagnosis of moderate to severe CHE (IGA-CHE score of 3 or 4) who had experienced inadequate response to TCS or for whom TCS were contraindicated. The DELTA 1 trial randomized 487 participants across 53 sites in 6 countries (including 10 sites in Canada); the DELTA 2 trial randomized 473 participants across 50 sites in 7 countries (also including 10 sites in Canada). Both trials used a 2:1 randomization ratio, stratified by baseline IGA-CHE severity (moderate versus severe) and geographic region (North America versus Europe). Randomization was conducted using an interactive response technology system. Patients applied delgocitinib cream 20 mg/g or matching vehicle cream twice daily for 16 weeks. The dosing aligns with the Health Canada product monograph; no other dosing regimens were evaluated.

Each study included a screening period of up to 4 weeks, allowing for washout from prior prohibited treatments and assessment of eligibility criteria, including adherence to nonmedicated skin care and presence of CHE flares (e.g., HESD itch score ≥ 4). Reasons for patients not proceeding beyond screening included unmet inclusion criteria or presence of an exclusion criterion, patient withdrawal, and missed visits. These aspects support external validity but may limit generalizability to patients who experience difficulty adhering to structured treatment regimens.

DELTA FORCE Trial

The DELTA FORCE trial was a phase III, assessor-blinded, open-label, active-controlled RCT designed to compare delgocitinib cream 20 mg/g twice daily with alitretinoin 30 mg once daily in adults with severe CHE (IGA-CHE score of 4). Adults aged 18 years or older with severe CHE who had experienced inadequate response to TCS or for whom TCS were contraindicated were included. A total of 513 patients were randomized across 103 sites in 10 countries, including 13 in Canada. Patients were randomized 1:1 to delgocitinib (n = 254) or alitretinoin (n = 259). Randomization was stratified by disease subtype (hyperkeratotic versus nonhyperkeratotic) and geographic region (North America versus Europe) via interactive response technology.

Delgocitinib cream 20 mg/g was applied twice daily. Alitretinoin 30 mg capsules were taken once daily, with a protocol-defined option to reduce to 10 mg in cases of AEs. The trial included a 4-week screening phase for washout, baseline symptom confirmation, and contraceptive adherence verification (for alitretinoin). The treatment period was 24 weeks, with primary efficacy outcomes assessed at week 12. Treatment could be discontinued early based on predefined response criteria or intolerance. To maintain blinding of efficacy assessments despite different treatment modalities, separate blinded assessors and unblinded investigators were used at each site.

Populations

Inclusion and Exclusion Criteria

Across the 3 pivotal trials (DELTA 1 trial: N = 487; DELTA 2 trial: N = 473; DELTA FORCE trial: N = 513), patients were adults (≥ 18 years) with a clinical diagnosis of CHE persisting for at least 3 months or relapsing at least twice in the past year. The DELTA 1 and DELTA 2 trials enrolled patients with moderate to severe CHE (IGA-CHE score of 3 or 4), whereas the DELTA FORCE trial included only those with severe disease (IGA-CHE score of 4), aligning with alitretinoin’s approved indication in Canada. All studies required documentation showing either that prior treatment with TCS had provided an inadequate response or that treatment with TCS was considered medically inadvisable, as defined in the protocol, and patients had to be able to be adherent to nonmedicated skin care and avoidance of known irritants or allergens. Key exclusion criteria included other dermatologic conditions on the hands (e.g., psoriasis or active AD), prior use of JAK inhibitors, or prior use systemic immunosuppressive therapy within 28 days before the baseline. The DELTA FORCE trial had additional exclusions to ensure alitretinoin safety, including hepatic or renal impairment, uncontrolled hyperlipidemia, and pregnancy-related contraindications. These criteria collectively defined a population with moderate to severe CHE unresponsive to standard first-line therapy, and the DELTA FORCE trial further restricted inclusion to a narrower, more medically complex subgroup.

Interventions

In all 3 trials (DELTA 1, DELTA 2, and DELTA FORCE trials), the investigational intervention was delgocitinib 20 mg/g cream, applied twice daily (approximately 12 hours apart) as a thin layer to affected areas of the hands and wrists. The cream was self-administered at home by participants and did not require any special device or training for application. The treatment duration was 16 weeks in the DELTA 1 and DELTA 2 trials and up to 24 weeks in the DELTA FORCE trial, depending on treatment response.

In the vehicle-controlled studies (DELTA 1 and DELTA 2 trials), patients were randomized 2:1 to receive either delgocitinib or vehicle cream, which was identical in appearance and texture to the active formulation. In the DELTA FORCE trial, a 1:1 randomization compared delgocitinib to oral alitretinoin 30 mg once daily, with dose reduction to 10 mg permitted in cases of AEs. The DELTA FORCE trial was assessor blinded only, due to the differing routes of administration; a double-dummy design was not used to avoid confounding treatment effects.

Concomitant use of nonmedicated emollients was permitted throughout all trials, provided they were not applied within 2 hours before or after delgocitinib application. Other topical therapies (e.g., corticosteroids, immunomodulators) and systemic therapies (e.g., corticosteroids, immunosuppressants, retinoids) were prohibited during the treatment period. Use of phototherapy, tanning beds, or bleach baths was also not allowed. Vaccinations and non–skin-related medications were permitted unless otherwise contraindicated.

Rescue treatment was allowed if symptoms became intolerable during the treatment or follow-up periods. Once rescue medication was initiated, patients were required to permanently discontinue study treatment and were not permitted to restart it. In the DELTA FORCE trial, alitretinoin was not permitted as a rescue treatment for patients in either arm.

Stopping criteria in all trials included the initiation of rescue medication, pregnancy, major AEs, or investigator-assessed lack of benefit. In the DELTA FORCE trial, alitretinoin dose reductions were allowed, but no upward titration was permitted. Dose reduction was most commonly implemented by week 8 due to adverse effects, though some reductions occurred earlier for clinical improvement or at investigator discretion.

Overall, all interventions were aligned with the anticipated product monograph for delgocitinib in Canada. Self-application of the topical treatment at home and the absence of required monitoring or laboratory assessments reflected the intended outpatient use in routine clinical practice.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 7, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review according to the clinical expert(s) consulted for this review and input from patient and clinician groups and public drug plans. Using the same considerations, the review team selected the end points that were most relevant to inform expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing expert committee deliberations were also assessed using GRADE.

Table 7: Outcomes Summarized From the Studies Included in the Systematic Review

CFB = change from baseline; DLQI = Dermatology Life Quality Index; HECSI = Hand Eczema Severity Index; HECSI-75 = at least a 75% improvement in Hand Eczema Severity Index score from baseline; HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; HEIS = Hand Eczema Impact Scale; HESD = Hand Eczema Symptom Diary; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; NA = not applicable.

^aStatistical testing for these end points was adjusted for multiple comparisons (i.e., hierarchal testing).

Sources: DELTA 1, DELTA 2, and DELTA FORCE Clinical Study Reports.^29-31

Investigator’s Global Assessment of Chronic Hand Eczema

IGA-CHE is a validated, clinician-reported outcome developed specifically for CHE trials by the sponsor^29-31 and was used as the primary end point in the DELTA 1 and DELTA 2 trials at week 16 and as a key secondary end point in the DELTA FORCE trial at week 12. It employs a 5-point severity scale (0 = clear to 4 = severe) and requires a score of 0 or 1 plus at least a 2-step improvement from baseline to meet the definition of treatment success. Compared to traditional Investigator’s Global Assessment scales, IGA-CHE offers more stringent criteria — particularly for “almost clear” status — by excluding features like scaling, hyperkeratosis, or fissures. The tool evaluates global disease severity at a single time point based on visible signs, including erythema, lichenification, vesiculation, and edema. Testing from the DELTA 1 trial confirmed IGA-CHE’s reliability and construct validity, with a 2-step improvement established as a conservative threshold for meaningful clinical change. The IGA-CHE outcome measurement tool is described in Table 8, along with definitions of severity.

Table 8: Definition of Investigator’s Global Assessment of Chronic Hand Eczema

IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema.

Source: Sponsor’s clinical summary report.¹⁶

Hand Eczema Severity Index

The CFB in the HECSI score to week 12 served as the primary end point in the DELTA FORCE trial; the CFB to week 24 was assessed as a key secondary outcome. In the DELTA 1 and DELTA 2 trials, the percentage CFB in HECSI to week 16 was also a key secondary outcome, along with the proportions of patients experiencing HECSI-75 and HECSI-90 from baseline to week 16. In the DELTA FORCE trial, the proportion of patients experiencing HECSI-90 at week 12 was also a key secondary end point.

HECSI is a validated, clinician-assessed instrument used to measure both the severity and the extent of hand eczema.³² It evaluates 6 clinical signs — erythema, infiltration/papulation, vesicles, fissures, scaling, and edema — across 5 bilateral hand regions: fingertips, fingers (excluding tips), palms, backs of hands, and wrists. Each sign is rated using a 4-point severity scale (0 = none; 3 = severe), and the extent of involvement is captured using a 5-point area scale based on the percentage of the region affected. For each region, a score is generated by summing the severity scores for the 6 signs and multiplying by the area score. The total HECSI score is the sum of the 5 region scores, ranging from 0 (no disease) to 360 (most severe). A reduction in HECSI score reflects clinical improvement. The assessment is cross-sectional and based on disease status at the time of evaluation, including any new lesions on previously unaffected areas.

HECSI has been validated for use in clinical trials of CHE. In a study involving 12 physicians experienced in CHE assessment, the tool demonstrated excellent intrarater reliability (intraclass correlation coefficient = 0.90) and strong interrater reliability for absolute agreement (intraclass correlation coefficient, 0.79 to 0.84) and for consistency (intraclass correlation coefficient, 0.81 to 0.89).³² Estimates of the minimal important difference (MID) for within-group improvement vary in the literature, ranging from 8.3 to 41 points,^33,34 depending on the anchor used. The lower estimate (8.3 points) was derived using a physician-rated global severity scale that captured nuanced clinical change and is considered more sensitive. The higher value (41 points) was based solely on the PGA, a more conservative tool that may underestimate subtle but clinically meaningful improvements. Analyses from the delgocitinib phase IIb trial (NCT03683719) estimated the between-group MID to be approximately 20 points; this value was used to define the noninferiority margin in the DELTA FORCE trial (noninferiority being a secondary hypothesis). Additionally, HECSI-75 has been proposed as a clinically relevant response threshold, consistent with response definitions used in AD trials (e.g., 75% improvement in Eczema Area and Severity Index).

A calculation for the assessment of the HECSI score is presented in Figure 2.

Figure 2: Calculation of the Total HECSI Score

AS = area score; HECSI = Hand Eczema Severity Index; SS = severity score.

Source: Sponsor’s clinical summary report.¹⁶

Hand Eczema Symptom Diary

The CFB in HESD score (weekly average) to week 16 was a key secondary end point of the DELTA 1 and DELTA 2 trials. The CFBs in HESD itch score (weekly average) and HESD pain score (weekly average) to week 16 were key secondary outcomes of the DELTA 1 and DELTA 2 trials. The CFBs in HESD itch score (weekly average) and HESD pain score (weekly average) to week 12 were key secondary outcomes of the DELTA FORCE trial. The proportions of patients who experienced a reduction of at least 4 points in HESD, HESD itch, and HESD pain scores (weekly average) at week 16 were key secondary outcomes of the DELTA 1 and DELTA 2 trials.

The HESD is a patient-reported instrument developed by the sponsor and used in the phase IIb trial with delgocitinib (NCT03683719) and has been further revised for the current trials. Content validity of the HESD was confirmed through cognitive debriefing interviews with patients; psychometric validation activities using data from the phase IIb (NCT03683719) and DELTA 1 trials demonstrated construct validity, reliability, and the ability to detect change for the HESD itch score, HESD pain score, and overall HESD score. The HESD is a 6-item instrument designed to assess the severity of CHE signs and symptoms. Patients assessed the worst severity of 6 individual signs and symptoms of CHE (itch, pain, cracking, redness, dryness, and flaking) over the past 24 hours using an 11-point numeric rating scale with anchors of 0 (“no [symptom]”) and 10 (“severe [symptom]”). The overall HESD score is derived as an average of the 6 items. A decrease in score relates to an improvement in CHE signs and symptoms. Patients completed the HESD on a daily basis in an e-diary. An improvement of at least 4 points in the 7-day average HESD scores was considered a MID.³⁵

Hand Eczema Impact Scale

The CFB in HEIS score to week 16 was a key secondary end point of the DELTA 1 and DELTA 2 trials. The CFB in HEIS score to week 12 and week 24 was an exploratory outcome of the DELTA FORCE trial.

The HEIS is a patient-reported instrument developed by the sponsor. The HEIS was used in the phase IIb trial with delgocitinib (NCT03683719) and validated based on these data, providing evidence of strong content and psychometric validity.³⁶ The HEIS includes 9 items addressing the patient’s perception of the impact of hand eczema on their daily activities, embarrassment, frustration, sleep, work, and physical functioning over the past 7 days. Each item is scored on a 5-point scale (0 = not at all; 1 = a little; 2 = moderately; 3 = a lot; 4 = extremely). The HEIS score is the average of the 9 items. The highest possible score is 4, and a high score is indicative of a high impact. Six domain scores can be calculated for HEIS: proximal daily activity limitations (average of 3 items), embarrassment with the appearance of the hands (average of 2 items), frustration with CHE (1 item), sleep (1 item), work (1 item), and physical functioning (1 item). A decrease in score indicates an improvement in the impact of hand eczema on the patient’s quality of life. Anchor-based analyses suggested a within-group MID ranging from 0.90 to 1.35 points in HEIS score and a between-group MID of around 0.6 points in HEIS score.³⁶

Dermatology Life Quality Index

The CFB in DLQI score to week 16 was a key secondary end point of the DELTA 1 and DELTA 2 trials. Additionally, the CFB in DLQI score to week 12 and week 24 was an exploratory outcome of the DELTA FORCE trial. The proportion of patients who experienced a reduction of at least 4 points in DLQI score at week 16 was a key secondary outcome of the DELTA 1 and DELTA 2 trials, and the proportion of patients who experienced a reduction of at least 4 points in DLQI score at week 12 and week 24 was a key secondary outcome of the DELTA FORCE trial.

The DLQI is a validated questionnaire with content specific to those with dermatologic conditions. It consists of 10 items addressing the patient’s perception of the impact of their skin disease on different aspects of their quality of life over the last week, such as dermatology-related symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the treatment.³⁷ Each item is scored on a 4-point Likert scale (0 = not at all/not relevant; 1 = a little; 2 = a lot; 3 = very much). The DLQI score is the sum of the 10 items (score ranging from 0 to 30); a high score is indicative of a poor quality of life. The threshold of an improvement of at least 4 points is aligned with the MID established in the literature for inflammatory skin diseases.³⁸

The patient-reported outcome measures HEIS and DLQI used in this report are summarized in Table 9, along with their measurement properties and MIDs.

Table 9: Summary of Patient-Reported Outcome Measures and Their Properties

CHE = chronic hand eczema; DLQI = Dermatology Life Quality Index; HECSI = Hand Eczema Severity Index; HEIS = Hand Eczema Impact Scale; ICC = intraclass correlation coefficient; MID = minimal important difference; PDAL = proximal daily activity limitations.

Source: Sponsor’s clinical summary report.¹⁶

Statistical Analysis

Sample Size and Power Calculation

The DELTA 1 and DELTA 2 trials were designed to enrol approximately 470 and 450 patients, respectively, randomized in a 2:1 ratio to receive either delgocitinib cream or vehicle cream. These sample sizes were calculated to provide at least 99% power to detect a statistically significant difference in the primary outcome — IGA-CHE treatment success at week 16 — assuming response rates of 40% in the delgocitinib group and 10% in the vehicle cream group, using a 1-sided significance level of 2.5%. The assumptions for response rates were informed by findings from the phase IIb dose-ranging study (NCT03683719). The planned sample sizes also ensured sufficient safety data, including adequate exposure to delgocitinib over the study period, to support regulatory evaluation.

The DELTA FORCE trial was planned to randomize approximately 510 participants to receive either delgocitinib or alitretinoin (1:1 ratio). The sample size was powered to detect superiority of delgocitinib over alitretinoin with respect to the CFB in HECSI score at week 12, based on a 1-sided hypothesis test at a 2.5% significance level. The calculation assumed a between-group difference in mean HECSI CFB of 7.5 points, with a standard deviation (SD) of 30, yielding at least 80% power. Because limited data were available for alitretinoin using the HECSI scale, assumptions about treatment effect were guided by prior IGA-CHE–based outcomes from the phase IIb trial (NCT03683719). To achieve the target sample size, approximately 660 patients were expected to be screened.

Statistical Testing

For binary outcomes (e.g., IGA-CHE treatment success, HECSI-75, HECSI-90, HESD itch reduction ≥ 4 points), analyses across all 3 trials (DELTA 1, DELTA 2, and DELTA FORCE trials) used the Cochran-Mantel-Haenszel test, stratified by geographic region and either baseline IGA-CHE score (DELTA 1 and DELTA 2 trials) or hyperkeratotic versus nonhyperkeratotic subtype (DELTA FORCE trial). Missing data for binary outcomes were handled using imputation of nonresponse, and additional estimands (e.g., treatment policy, pandemic-modified composite) were employed in sensitivity analyses (refer to Table 10).

For continuous outcomes (e.g., CFB in HECSI scores, HESD scores, HEIS scores, and DLQI scores), data were analyzed using analysis of covariance models, adjusting for treatment group, region, baseline IGA-CHE severity, and the baseline value of the outcome measure. These models provided standard errors, 95% CIs, and P values. The sponsor used a composite estimand approach to account for intercurrent events (i.e., events that occur after treatment initiation and affect either the interpretation or the existence of the outcome data, such as treatment discontinuation, use of rescue therapy, or missing assessments), and worst observation carried forward (WOCF) imputation was applied for missing data after intercurrent events (refer to Table 10 and Table 11).

Across all 3 trials, the full analysis set (FAS) — defined as all participants who were randomized and exposed to treatment — was used for efficacy analyses.

Table 10: Statistical Analysis of Efficacy End Points for the DELTA 1, DELTA 2, and DELTA FORCE Trials

ANCOVA = analysis of covariance; CFB = change from baseline; DLQI = Dermatology Life Quality Index; HECSI = Hand Eczema Severity Index; HECSI-75 = at least a 75% improvement in Hand Eczema Severity Index score from baseline; HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; HEIS = Hand Eczema Impact Scale; HESD = Hand Eczema Symptom Diary; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; WOCF = worst observation carried forward.

^aData after initiation of rescue treatments or permanent discontinuation of investigational medicinal product were treated as missing (primary and sensitivity analysis).

Sources: DELTA 1, DELTA 2, and DELTA FORCE Clinical Study Reports.^29-31

Table 11: Definitions of Estimand and Imputation Methods

IE = intercurrent event; IMP = investigational medicinal product; MAR = missing at random; WOCF = worst observation carried forward.

Note: IEs include the initiation of rescue treatment, permanent discontinuation of the IMP independent of the COVID-19 pandemic, and permanent discontinuation of the IMP related to the COVID-19 pandemic.

Sources: DELTA 1, DELTA 2, and DELTA FORCE Clinical Study Reports.^29-31

Multiple Testing Procedures

Vehicle-Controlled Studies

In the DELTA 1 and DELTA 2 trials, a closed testing procedure with hierarchical tests, alpha splitting, and alpha recycling was used to control the overall type I error at a nominal 1-sided 2.5% level for the primary and key secondary end points. The statistical testing strategy was built on the principle that the IGA-CHE treatment success (IGA-CHE score of 0 or 1) superiority at week 16 had to be established before testing for additional benefits (key secondary end points) related to efficacy and HRQoL. The superiority of delgocitinib in the primary end point was tested at the overall 1-sided significance level of 2.5%. If a test was significant, the significance level was reallocated according to the weight and the direction of the arrows, as specified in Figure 3. Each of the hypotheses presented in Figure 3 were tested at their local significance level (alpha local). This process was to be repeated until no further tests were significant. The 1-sided (superiority) hypotheses were evaluated by deriving the 2-sided P value; the null hypothesis was to be rejected if the P value was smaller than 2 times the alpha and if the point estimate was in favour of the alternative hypothesis.

Figure 3: Closed Testing Procedure for Primary and Key Secondary End Points of the DELTA 1 and DELTA 2 Trials

DLQI = Dermatology Life Quality Index; HECSI = Hand Eczema Severity Index; HECSI-75 = at least 75% improvement in Hand Eczema Severity Index score from baseline; HECSI-90 = at least 90% improvement in Hand Eczema Severity Index score from baseline; HEIS = Hand Eczema Impact Scale; HESD = Hand Eczema Symptom Diary; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; PDAL = proximal daily activity limitations; TS = treatment success defined as a score of 0 or 1 with at least a 2-step improvement from baseline.

Sources: DELTA 1 and DELTA 2 Clinical Study Reports.^29,30

Active-Controlled Study

A closed testing procedure with a hierarchical fixed-sequence design was used in the DELTA FORCE trial to control the overall type I error rate at a nominal 1-sided 2.5% level. The statistical testing strategy required that superiority of delgocitinib over alitretinoin in CFB in HECSI score at week 12 be demonstrated before any testing of subsequent key secondary end points related to efficacy and HRQoL could proceed. Hypotheses were tested sequentially according to a predefined order (Figure 4), with the significance level passed on to the next test only if the previous comparison was statistically significant. The final hypothesis in the sequence was the noninferiority of delgocitinib at week 24 with respect to CFB in HECSI score, using a noninferiority margin of 10 points, which was justified as a conservative value (less than half the MID) based on psychometric analyses from a prior phase IIb trial (NCT03683719). If noninferiority was confirmed, superiority was then formally tested.

Figure 4: Closed Testing Procedure for Primary and Key Secondary End Points of the DELTA FORCE Trial

AUC = area under the curve; DLQI = Dermatology Life Quality Index; HECSI = Hand Eczema Severity Index; HECSI-90 = at least 90% improvement in Hand Eczema Severity Index score from baseline; HESD = Hand Eczema Symptom Diary; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; TS = treatment success.

Source: DELTA FORCE Clinical Study Report.³¹

Analysis Populations

The analysis populations were the FAS (all participants randomized and exposed to the investigational product) and the safety analysis set in the DELTA 1, DELTA 2, and DELTA FORCE trials, as described in Table 12. The FAS can be considered the intention-to-treat (ITT) population.

Table 12: Analysis Populations of the DELTA 1, DELTA 2, and DELTA FORCE Trials

HRQoL = health-related quality of life; IMP = investigational medicinal product.

Sources: DELTA 1, DELTA 2, and DELTA FORCE statistical analysis plans.^42-44

Results

Patient Disposition

Patient disposition (Table 13) was generally balanced between arms in the DELTA 1 and DELTA 2 trials, but the DELTA FORCE trial showed a higher discontinuation rate in the alitretinoin group, mostly due to tolerability issues. While all studies achieved target sample sizes, the dropout was slightly higher in the DELTA FORCE trial.

Across all 3 trials, randomized sample sizes were achieved as planned, with no evidence of recruitment shortfalls. In the DELTA 1 trial (N = 487), completion rates were 93.8% in the delgocitinib group (20 of 325 patients [6.2%] discontinued) and 87.0% in the vehicle cream group (21 of 162 patients [13.0%] discontinued). In the DELTA 2 trial (N = 473), 93.0% of patients receiving delgocitinib completed the study (22 of 314 patients [7.0%] discontinued), compared with 76.7% in the vehicle cream group (37 of 159 [23.3%] discontinued). Withdrawal due to AEs and lack of efficacy were more common in the vehicle cream groups of both trials, but overall discontinuation rates remained modest.

In the DELTA FORCE trial (N = 513), completion rates diverged more substantially: 86.6% of patients in the delgocitinib group (34 of 254 patients [13.4%] discontinued) versus 64.1% in the alitretinoin group (93 of 259 patients [35.9%] discontinued). The most common reasons for early withdrawal in the alitretinoin group were AEs (24 of 259 patients [9.3%]) and lack of efficacy (26 of 259 patients [10.0%]). In contrast, only 2 of 254 patients (0.8%) in the delgocitinib arm discontinued due to AEs.

Table 13: Patient Disposition in the DELTA 1, DELTA 2, and DELTA FORCE Trials

FAS = full analysis set; IMP = investigational medicinal product; NR = not reported.

Sources: DELTA 1, DELTA 2, and DELTA FORCE Clinical Study Reports.^29-31

Baseline Characteristics

The baseline characteristics outlined in Table 14 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. No clinically meaningful imbalances were observed between arms within individual studies in terms of age, sex, race, region, or baseline disease severity. Overall, the populations enrolled align with the Health Canada indication for moderate to severe CHE, though the DELTA FORCE trial focused exclusively on severe disease.

In the DELTA 1 and DELTA 2 trials, the median patient age ranged from 42.0 to 46.0 years across arms, and there was a slight predominance of females (ranging from approximately 62% to 68% of patients across arms). Most participants in both trials (88.9% to 93.9%) were white, and most (approximately 80%) were recruited from European sites, with consistent representation from North America (approximately 20%). The median disease duration ranged from 4 to 6 years, and most patients (67% to 76%) had moderate CHE, as expected based on the inclusion criteria.

In the DELTA FORCE trial, which enrolled only patients with severe CHE (100% in the delgocitinib group and 99.6% in the alitretinoin group), the median age (44 to 46 years), the sex distribution (66% female; 34% male), and the racial composition (more than 92% white) were similar to the DELTA 1 and DELTA 2 trials. However, the geographic distribution differed, with more than 90% of participants recruited in Europe and fewer from North America (< 10%). Additionally, patients in the DELTA FORCE trial had slightly higher baseline HECSI scores (median of 80, versus 59 to 66) and lower median HESD itch and pain scores than in the DELTA 1 and DELTA 2 trials, consistent with these patients’ more severe clinical phenotype but possibly differing symptom burden.

Across all studies, the DLQI scores at baseline indicated moderate to severe impact on quality of life, with median scores ranging from 11.0 to 12.0. Almost all patients (> 99%) in the DELTA 1 and DELTA 2 trials had HESD itch scores of at least 4 at baseline; this percentage was lower in the DELTA FORCE trial (approximately 70%). Similarly, pain scores of 4 or higher were reported in 90% of patients in the DELTA 1 and DELTA 2 trials versus 66% in the DELTA FORCE trial. This difference may reflect variability in symptom reporting or subtype distribution.

The CHE subtypes also varied by study. In the DELTA 1 and DELTA 2 trials, atopic hand eczema and hyperkeratotic eczema were the most frequent diagnoses, whereas the DELTA FORCE trial included more patients with irritant contact dermatitis (approximately 29%) and fewer with atopic hand eczema (approximately 24%). Also, vesicular and hyperkeratotic hand eczema types were more common in the DELTA 2 study.

Table 14: Summary of Baseline Characteristics of the DELTA 1, DELTA 2, and DELTA FORCE Trials

b.i.d. = twice a day; CHE = chronic hand eczema; DLQI = Dermatology Life Quality Index; HECSI = Hand Eczema Severity Index; HESD = Hand Eczema Symptom Diary; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; IQR = interquartile range; NR = not reported; q.d. = every day.

Note: Racial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

^aOne patient with mild CHE was included in the DELTA FORCE trial.

Sources: DELTA 1, DELTA 2, and DELTA FORCE Clinical Study Reports.^29-31

Exposure to Study Treatments

Vehicle-Controlled Studies

In both the DELTA 1 and DELTA 2 trials, exposure to delgocitinib cream was generally comparable to exposure to vehicle cream in terms of treatment duration, amount used, and adherence (table 15). In the DELTA 1 trial, the mean duration of exposure was 109.4 days (SD = 18.7 days) in the delgocitinib group and 103.9 days (SD = 26.6 days) in the vehicle cream group. The mean total amounts of the study drug applied were 134.2 g and 130.5 g in the delgocitinib and vehicle cream groups, respectively, with similar weekly usage throughout the 16-week treatment period. Results from the DELTA 2 trial showed slightly longer exposure in the delgocitinib group (108.9 days, versus 97.0 days in the vehicle cream group) and a small difference in total cream use (121.6 g versus 116.8 g). In both studies, adherence was high and similar between groups: more than 50% of patients in each arm missed less than 10% of scheduled applications, and around 16% to 23% of patients had perfect adherence.

Rescue medication (Table 16) use was infrequent and consistently lower in the delgocitinib arms. In the DELTA 1 trial, 2.2% of patients treated with delgocitinib required rescue therapy, compared with 4.3% in the vehicle cream group. In the DELTA 2 trial, the difference was more pronounced (1.0% versus 7.5%). TCS were the most common rescue therapies, and their use was defined in the protocol as requiring immediate discontinuation of the study treatment. Concomitant medication use was common across arms (approximately 70% to 80% of patients) and included nonsteroidal anti-inflammatory drugs, analgesics, antihistamines, and hormonal contraceptives. No imbalances were observed that would be expected to affect the interpretation of efficacy or safety.

Table 15: Patient Exposure in the DELTA 1 and DELTA 2 Trials

b.i.d. = twice a day; SD = standard deviation.

Notes: A patient was considered as having missed a day of application of the investigational medicinal product when no drug was applied for that day. In cases of permanent discontinuation, only days missed before the permanent discontinuation were included. Treatment compliance was evaluated daily by the patient in the e-diary.

Sources: DELTA 1 and DELTA 2 Clinical Study Reports. ^29,30

Table 16: Concomitant Medications and Rescue Treatment in the DELTA 1, DELTA 2, and DELTA FORCE Trials

b.i.d. = twice a day; q.d. = every day; TCS = topical corticosteroids.

^aAt least 10% of patients in any treatment group at Anatomical Therapeutic Chemical level 3.

Sources: DELTA 1, DELTA 2, and DELTA FORCE Clinical Study Reports.^29-31

Active-Controlled Study (DELTA FORCE Trial)

In the DELTA FORCE trial, differences in exposure patterns (Table 17) were evident between the delgocitinib and alitretinoin treatment arms.

The mean total amount of delgocitinib cream used during the total treatment period (16 weeks of continuous use, then as-needed dosing for remaining 8 weeks) was 207.8 g (SD = 93.1 g). The mean duration of exposure to delgocitinib was 149.7 days (SD = 34.4 days), corresponding to approximately 21 weeks. The mean duration of exposure to alitretinoin was 119.8 days (SD = 55.0 days), corresponding to approximately 17 weeks, with 52 participants (21.1%) reducing their alitretinoin dose from 30 mg to 10 mg. This discrepancy likely reflects higher discontinuation and dose reduction rates in the alitretinoin group. The overall treatment compliance was high and similar in both treatment groups of the DELTA FORCE trial, with 56.0% of patients in the delgocitinib group and 56.2% of patients in the alitretinoin group having at most 10% of days with missed treatment application or missing compliance data.

Rescue treatment use (Table 16) was again lower in the delgocitinib group (4.7%) than in the alitretinoin group (8.1%). The most frequently used class of rescue treatment was dermatological preparations, primarily TCS. Concomitant medication use was balanced (75.2% in the delgocitinib group versus 79.9% in the alitretinoin group), with frequent use of nonsteroidal anti-inflammatory drugs, analgesics, systemic antihistamines, and hormonal contraceptives. No major differences in co-interventions were observed that would affect the interpretation of treatment efficacy or safety.

Table 17: Patient Exposure in the DELTA FORCE Trial

b.i.d. = twice a day; NA = not applicable; NR = not reported; q.d. = every day; SD = standard deviation.

Notes: Treatment compliance was evaluated daily from participant entries in the e-diary. A participant was considered as having missed a day’s administration when no drug was administered or if e-diary compliance data were missing on an on-treatment day. In cases of permanent discontinuation, only days missed before permanent discontinuation were included.

^aAmong patients with less than 50% missing compliance data during period.

Source: DELTA FORCE Clinical Study Report.³¹

Efficacy

Vehicle-Controlled Studies

In both the DELTA 1 and DELTA 2 trials, treatment with delgocitinib cream 20 mg/g twice daily resulted in greater improvements in clinical and symptom-based outcomes at week 16 than treatment with vehicle cream (Table 18, Figure 5 and Figure 6).

The proportion of patients who experienced IGA-CHE treatment success at week 16 was higher with delgocitinib than with vehicle cream: 19.7% versus 9.9% in the DELTA 1 trial (absolute difference = 9.8%; 95% CI, 3.6% to 16.1%; P = 0.0055) and 29.1% versus 6.9% in the DELTA 2 trial (absolute difference = 22.2%; 95% CI, 15.8% to 28.5%; P < 0.0001).

Patient-reported improvement in itch, defined as a reduction of 4 points or more in the HESD itch score, also favoured delgocitinib. In the DELTA 1 trial, 47.1% of patients in the delgocitinib group reported this level of improvement, compared to 23.0% in the vehicle cream group (difference = 24.1%; 95% CI, 15.5% to 32.6%; P < 0.0001). A similar pattern was observed in the DELTA 2 trial (47.2% versus 19.9%; difference = 27.4%; 95% CI, 19.0% to 35.8%; P < 0.0001).

For clinician-assessed signs of hand eczema, HECSI-75 and HECSI-90 response rates were consistently higher in the delgocitinib groups. In the DELTA 1 trial, 49.2% of patients in the delgocitinib group experienced a HECSI-75 response and 29.5% experienced a HECSI-90 response, compared to 23.5% and 12.3% of patients in the vehicle cream group. The absolute differences were 25.7% (95% CI, 17.2% to 34.3%; P < 0.0001) for HECSI-75 and 17.2% (95% CI, 10.1% to 24.3%; P < 0.0001) for HECSI-90. The corresponding values in the DELTA 2 trial were 49.5% versus 18.2% for HECSI-75 (difference = 31.3%; 95% CI, 23.1% to 39.5%) and 31.0% versus 8.8% for HECSI-90 (difference = 22.2%; 95% CI, 15.4% to 29.0%), both with a P value less than 0.0001.

In terms of percentage CFB in HECSI score, delgocitinib demonstrated greater reductions than vehicle cream in both studies. The mean difference in the DELTA 1 trial was –35.2 percentage points (95% CI, –46.7 to –23.8 percentage points; P < 0.0001) and in the DELTA 2 trial was –45.5 percentage points (95% CI, –56.4 to –34.6 percentage points; P < 0.0001), favouring delgocitinib.

Table 18: Key Efficacy Outcomes of the DELTA 1 and DELTA 2 Trials

b.i.d. = twice a day; CI = confidence interval; HECSI = Hand Eczema Severity Index; HECSI-75 = at least a 75% improvement in Hand Eczema Severity Index score from baseline; HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; HESD = Hand Eczema Symptom Diary; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; SE = standard error.

^aBased on a Cochran-Mantel-Haenszel test stratified by region and baseline IGA-CHE score.

^bBased on an analysis of covariance model adjusted for region, baseline IGA-CHE score, and tool score baseline value.

Sources: DELTA 1 and DELTA 2 Clinical Study Reports.^29,30

Figure 5: IGA-CHE Treatment Success by Study Visits in the DELTA 1 Trial

IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema.

Notes: Composite estimand: Data considered to indicate nonresponse if observed after the initiation of rescue treatment or after permanent discontinuation of the investigational medicinal product. Missing data are imputed as nonresponse. Patients were considered to have experienced a response if they experienced an IGA-CHE score of 0 (clear) or 1 (almost clear) with at least a 2-step improvement from baseline.

Sources: DELTA 1 and DELTA 2 Clinical Study Reports.^29,30

Figure 6: IGA-CHE Treatment Success by Study Visits in the DELTA 2 Trial

IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema.

Notes: Composite estimand: Data considered to indicate nonresponse if observed after the initiation of rescue treatment or after permanent discontinuation of the investigational medicinal product. Missing data are imputed as nonresponse. Patients were considered to have experienced a response if they experienced an IGA-CHE score of 0 (clear) or 1 (almost clear) with at least a 2-step improvement from baseline.

Sources: DELTA 1 and DELTA 2 Clinical Study Reports.^29,30

Active-Controlled Study

In the DELTA FORCE trial (Table 19), delgocitinib cream 20 mg/g twice daily demonstrated greater clinical and symptom improvement than oral alitretinoin 30 mg once daily at week 12 in adults with severe CHE.

IGA-CHE treatment success at week 12 was experienced by 27.2% of patients treated with delgocitinib, compared to 16.6% with alitretinoin, corresponding to an absolute difference of 10.6% (95% CI, 3.31% to 17.87%; P = 0.004).

Improvements in HECSI score, a clinician-assessed measure of disease severity, were also greater with delgocitinib. At week 12, the mean CFB in HECSI score was –67.6 percentage points (standard error = 3.37) in the delgocitinib group and –51.5 (standard error = 3.36) in the alitretinoin group, resulting in a between-group difference of –16.1 points (95% CI, –23.28 to –8.86; P < 0.001). At week 24, this difference increased further to –24.5 points (95% CI, –32.55 to –16.36; P < 0.001), favouring delgocitinib.

The proportion of patients experiencing a HECSI-90 response at week 12 was also higher in the delgocitinib group (38.6%) than in the alitretinoin group (26.0%), for a difference of 12.6% (95% CI, 4.34% to 20.78%; P = 0.003). Additionally, the mean change in HESD itch score at week 12 was greater in the delgocitinib group (–3.0 points) than in the alitretinoin group (–2.4 points), with a mean difference of –0.7 (95% CI, –1.12 to –0.20; P = 0.005), indicating greater symptom relief with topical treatment.

Table 19: Key Efficacy Outcomes of the DELTA FORCE Trial

b.i.d. = twice a day; CI = confidence interval; HECSI = Hand Eczema Severity Index; HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; HESD = Hand Eczema Symptom Diary; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; q.d. = every day; SE = standard error.

^aBased on a Cochran-Mantel-Haenszel test stratified by region and hyperkeratotic or nonhyperkeratotic subtype.

^bBased on an analysis of covariance model adjusted for region, hyperkeratotic or nonhyperkeratotic subtype, and tool score baseline value.

Source: DELTA FORCE Clinical Study Report. ³¹

In the DELTA FORCE trial, the results of all prespecified sensitivity analyses for the primary end point CFB in HECSI score at week 12 were consistent with the primary analysis results.

Health-Related Quality of Life

Vehicle-Controlled Studies

In both the DELTA 1 and DELTA 2 trials, treatment with delgocitinib was associated with greater improvements in quality-of-life outcomes than vehicle cream at week 16, as measured by the HEIS and the DLQI as shown in Table 20.

The mean CFB in HEIS score was –1.5 in both trials for the delgocitinib groups, compared to –0.8 and –0.6 in the vehicle cream groups in the DELTA 1 and DELTA 2 trials, respectively. The between-group difference in the DELTA 1 trial was –0.6 (95% CI, –0.8 to –0.5; P < 0.001) and in the DELTA 2 trial was –0.8 (95% CI, –1.0 to –0.6; P < 0.001), favouring delgocitinib.

A 4-point or greater improvement in DLQI, a commonly accepted threshold for meaningful improvement, was reported in 74.4% of patients treated with delgocitinib in the DELTA 1 trial, compared to 50.0% of those receiving vehicle cream (difference = 24.5%; 95% CI, 15.0% to 33.9%; P < 0.001). Similar results were observed in the DELTA 2 trial (72.2% versus 45.8%; difference = 26.4%; 95% CI, 17.0% to 35.9%; P < 0.001).

The mean CFB in DLQI scores was also more favourable in the delgocitinib groups: –7.6 versus –3.9 in the DELTA 1 trial (difference = –3.6; 95% CI, –4.7 to –2.6; P < 0.001) and –7.0 versus –3.1 in the DELTA 2 trial (difference = –3.9; 95% CI, –5.0 to –2.8; P < 0.001), reflecting clinically meaningful improvements in dermatology-related quality of life.

Table 20: Key Health-Related Quality of Life Outcomes of the DELTA 1 and DELTA 2 Trials, Week 16

b.i.d. = twice a day; CI = confidence interval; DLQI = Dermatology Life Quality Index; HEIS = Hand Eczema Impact Scale; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; SE = standard error.

^aBased on an analysis of covariance model adjusted for region, baseline IGA-CHE score, and tool score baseline value.

^bBased on a Cochran-Mantel-Haenszel test stratified by region and baseline IGA-CHE score.

Sources: DELTA 1 and DELTA 2 Clinical Study Reports.^29,30

Active-Controlled Study

In the DELTA FORCE trial, delgocitinib resulted in greater improvements in HRQoL than alitretinoin at both week 12 and week 24. At week 24, the mean CFB in HEIS score was –1.3 with delgocitinib versus –0.8 with alitretinoin (difference = –0.5; 95% CI, –0.7 to –0.3; P < 0.001), and 71.2% of patients receiving delgocitinib experienced at least a 4-point improvement in DLQI compared to 47.6% with alitretinoin (difference = 23.6%; 95% CI, 14.8% to 32.5%; P < 0.001). The mean change in DLQI score was also greater with delgocitinib (–7.1 versus –4.6; difference = –2.5; 95% CI, –3.7 to –1.4; P < 0.001). The results were consistent at week 12, although all HRQoL outcomes were classified as exploratory with nominal P values due to lack of multiplicity adjustment.

Table 21: Key Health-Related Quality of Life Outcomes of the DELTA FORCE Trial

b.i.d. = twice a day; CI = confidence interval; DLQI = Dermatology Life Quality Index; HEIS = Hand Eczema Impact Scale; q.d. = every day; SE = standard error.

^aBased on an analysis of covariance model adjusted for region, hyperkeratotic or nonhyperkeratotic subtype, and tool score baseline value.

^bExploratory end point; P value is considered nominal as no adjustments for multiple testing were conducted.

^cBased on a Cochran-Mantel-Haenszel test stratified by region and hyperkeratotic or nonhyperkeratotic subtype.

Source: DELTA FORCE Clinical Study Report.³¹

Harms

The DELTA 1, DELTA 2, and DELTA FORCE trials conducted safety analyses based on the safety analysis set. AEs were coded using the Medical Dictionary for Regulatory Activities, version 24.0. In the DELTA 1 and DELTA 2 trials, AEs were evaluated from the time the patient signed the informed consent form until week 16 (or week 18 for patients not participating in the open-label extension trial [DELTA 3 trial]). In the DELTA FORCE trial, AEs were evaluated from the signing of the informed consent form until the end of the trial (defined as the last visit in the trial [the early termination visit, the nominal week 24 visit, or the last follow-up visit, whichever came last]). For all DELTA trials, AESIs were prespecified in the protocol and included the following: eczema herpeticum, deep vein thrombosis, and pulmonary embolism.

The key harms are described in Table 22.

Table 22: Key Harms Data in the DELTA 1, DELTA 2, and DELTA FORCE Trials

b.i.d. = twice a day; q.d. = every day.

Sources: DELTA 1, DELTA 2, and DELTA FORCE Clinical Study Reports.^29-31

Adverse Events

In the DELTA 1 and DELTA 2 trials, the incidence of any AE was similar between treatment groups. In the DELTA 1 trial, 45.2% of patients receiving delgocitinib experienced at least 1 AE, compared to 50.6% in the vehicle cream group. In the DELTA 2 trial, AEs occurred in 45.5% of patients in the delgocitinib group and 44.7% of patients in the vehicle cream group. Most AEs were mild or moderate in intensity. The most common AEs (occurring in ≥ 5% of patients in either group) were COVID-19 and nasopharyngitis. Headache occurred in 6.1% of patients treated with delgocitinib in the DELTA 2 trial, slightly higher than in the DELTA 1 trial (2.8%).

In the DELTA FORCE trial, the overall incidence of AEs was lower in the delgocitinib group (49.4%) than in the alitretinoin group (76.1%), despite a similar treatment duration of up to 24 weeks. The most frequently reported AEs in the alitretinoin group were headache (32.4%), nasopharyngitis (13.8%), and nausea (5.7%). In contrast, delgocitinib was associated with substantially lower rates of these events: headache (4.0%), nasopharyngitis (11.9%), and nausea (0.4%). Other AEs, such as dry skin, erythema, lip dryness, and hypercholesterolemia, occurred more frequently in the alitretinoin group.

Serious AEs

SAEs were infrequent across all 3 studies and balanced between treatment arms in the DELTA 1 and DELTA 2 trials. In the DELTA 1 trial, SAEs occurred in 1.8% of patients treated with delgocitinib and 1.9% of patients treated with vehicle cream. In the DELTA 2 trial, SAEs were reported in 1.6% and 1.9% of patients in the delgocitinib and vehicle cream groups, respectively. Most events were isolated, with no clear pattern, and all were resolved or resolving by the study’s end. No SAE led to major safety concerns.

In the DELTA FORCE trial, SAEs were more common in the alitretinoin group (4.9%) than in the delgocitinib group (2.0%). Most SAEs were single events, but 1 instance of increased blood potassium in the delgocitinib group was determined to be a lab artifact. No SAE in any group was associated with serious long-term harm.

Discontinuation Due to AEs

Treatment discontinuations due to AEs were rare with delgocitinib across all studies and more frequent with vehicle cream or alitretinoin. In the DELTA 1 trial, 0.6% of patients treated with delgocitinib discontinued treatment due to AEs, compared to 3.7% in the vehicle cream group. In the DELTA 2 trial, the corresponding rates were 0.3% and 3.1%. Hand dermatitis was the most common AE leading to discontinuation in the vehicle cream groups.

In the DELTA FORCE trial, 1.2% of patients in the delgocitinib group discontinued treatment due to AEs versus 10.1% in the alitretinoin group. Headache (4.5%) and nausea (1.2%) were the most frequently reported AEs leading to discontinuation in the alitretinoin group, consistent with its known safety profile.

AEs of Special Interest (Notable Harms)

No AESIs occurred in the DELTA 1 or DELTA 2 trial. In the DELTA FORCE trial, 1 patient (0.4%) in the alitretinoin group experienced an AESI: a postoperative deep vein thrombosis that resolved with treatment. No AESIs were reported in the delgocitinib group in any of the studies.

Mortality

No deaths were reported during the conduct of the DELTA 1, DELTA 2, or DELTA FORCE trials.

Critical Appraisal

Internal Validity

The DELTA 1 and DELTA 2 trials demonstrated good internal validity overall, with low risk of bias across most outcomes evaluated in this review. Randomization and allocation concealment were appropriately conducted using centralized methods. Baseline characteristics were well balanced across treatment arms, and the double-blind design minimized the risk of performance and detection bias for both clinician-assessed and patient-reported outcomes. The primary and key secondary outcomes were assessed using several outcome measures (e.g., IGA-CHE, HECSI, HESD, DLQI). The IGA-CHE and HEIS instruments were developed by the sponsor specifically for CHE and validated internally using analyses from the DELTA trials; however, these instruments lack external validation. In contrast, HECSI and DLQI are well-established, externally developed tools with demonstrated reliability and validity across dermatological conditions, including hand eczema. The HESD itch and pain scales, while based on widely used numeric rating scale formats, were developed by the sponsor and validated within the DELTA program; their stand-alone external validation is unclear. This blend of novel and established measures supports internal validity but limits the generalizability of some newer tools without broader external validation.

Statistical analyses followed the ITT principle. Key outcomes were adjusted for relevant covariates, and control for multiplicity was implemented through hierarchical testing. Data imputation for missing values was appropriate — nonresponse imputation for binary outcomes and mixed model for repeated measures or WOCF for continuous end points — with sensitivity analyses supporting the robustness of the findings. Although some patient-reported outcomes are prone to missingness, in the DELTA 1 and 2 trials the proportion of missing data was low and balanced across arms, and outcome measurement methods were considered valid. Few SAEs and AESIs were reported, leading to imprecision, but no concerns were raised about the validity of how these events were collected or adjudicated.

In contrast, the DELTA FORCE trial was associated with some concerns of risk of bias. Although randomization was adequately conducted and baseline characteristics were balanced, the trial was not double blinded; participants and treating physicians were aware of treatment assignment (topical versus oral), raising concerns about deviations from intended interventions, particularly in patient adherence and tolerability-driven dose reductions. While outcome assessors were blinded and outcome measures were objective and structured, the open-label design may have influenced the reporting of AEs and patient-reported outcomes. Importantly, more patients in the alitretinoin group (12 of 259 [4.6%]) did not receive the intervention than in the delgocitinib arm (1 of 254 [0.4%]). Furthermore, differential dropout was a concern, with 35.9% of patients in the alitretinoin arm discontinuing treatment, compared to 13.4% in the delgocitinib arm, mainly due to AEs and lack of efficacy. This imbalance in attrition introduces a risk of biased estimation of treatment effects (against alitretinoin and in favour of delgocitinib), particularly for later time points and subjective outcomes such as DLQI and HESD scores. Although ITT and per-protocol analyses were performed, and imputation methods (e.g., WOCF, nonresponse imputation) were applied consistently, the large differential in missing data may have influenced results.

No major issues were identified with statistical power, control for multiplicity, or interim analyses across the 3 trials. Subgroup analyses were prespecified and exploratory, with no statistical interaction testing reported. The clinical instruments used (e.g., DLQI, HECSI, IGA-CHE) were validated, and the MIDs applied for interpretation were appropriate and consistent with published literature.

External Validity

The DELTA 1, DELTA 2, and DELTA FORCE trials enrolled adult patients with moderate to severe CHE, consistent with the Health Canada–approved indication for delgocitinib. Baseline demographics, such as age, sex, and disease duration, were representative of patients seen in practice in Canada. However, the study populations were predominantly white and recruited primarily from European sites, with limited North American representation. Patients with significant comorbidities or recent systemic immunosuppressive therapy were excluded, potentially limiting generalizability to individuals with more complex disease. Importantly, the outcomes assessed — including IGA-CHE treatment success, HECSI, HESD, and DLQI — were clinically relevant, validated, and meaningful to patients and clinicians, with follow-up durations sufficient to capture short-term efficacy and harms (16 weeks in the DELTA 1 and DELTA 2 trials; 24 weeks in the DELTA FORCE trial), according to the clinical experts consulted by CDA-AMC.

The intervention (delgocitinib cream 20 mg/g twice a day) and comparator regimens were aligned with practice in Canada. The cream was applied at home without the need for special devices or training, supporting its use in real-world outpatient settings. In the DELTA FORCE trial, the comparator (oral alitretinoin 30 mg) was administered per Health Canada guidelines, though the irreversible dose reductions used in the trial may differ from real-world titration flexibility. Background care, including skin moisturizers, was standardized and similar to standards in Canada, although patients in trials likely received more frequent follow-up and monitoring. Overall, the trial findings are considered applicable to the intended population living in Canada, with modest limitations related to geography, trial intensity, and the exclusion of certain subgroups.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for the outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited — The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate — The true effect is likely to be substantially different from the estimate of the effect. We describe evidence of very low certainty as “very uncertain.”

• For RCTs: Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

For the GRADE assessments, findings from the DELTA 1 and DELTA 2 trials were considered together and summarized narratively per outcome because these studies were similar in population, interventions, design, and outcome measures.

Afterwards, the DELTA FORCE trial was assessed individually because it represents a different PICO (population, intervention, comparison, and outcome) question (i.e., delgocitinib versus alitretinoin).

Results of GRADE Assessments

Vehicle-Controlled Studies (Delgocitinib Versus Vehicle Cream)

Table 2 presents the GRADE summary of findings for delgocitinib compared to vehicle cream, based on the DELTA 1 and DELTA 2 trials. The certainty of the evidence was rated high for all efficacy outcomes. Although differences in effect estimates were observed between the DELTA 1 and DELTA 2 trials, these were likely attributable to differences in patients’ baseline risk profiles. Importantly, both the point estimates and CIs indicated a meaningful treatment effect; therefore, the review team did not rate down the effect estimate for inconsistency. The outcomes related to SAEs and AESIs were rated as moderate certainty, primarily due to the small number of events and lack of established thresholds for judging imprecision.

Active-Controlled Study (Delgocitinib Versus Alitretinoin)

Table 3 presents the GRADE summary of findings for delgocitinib compared to the active control, alitretinoin, based on the DELTA FORCE trial. For this body of evidence, the certainty for all outcomes was rated as moderate, due to study limitations related to risk of bias, particularly concerning deviations from intended interventions and missing outcome data. The results were considered precise, and no concerns were identified for other GRADE domains.

Long-Term Extension Studies

The contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Description of Studies

The DELTA 3 trial was a phase III, open-label, multisite extension phase of the DELTA 1 and DELTA 2 trials conducted to assess the long-term safety and efficacy of twice-daily applications of delgocitinib cream 20 mg/g as needed (based on IGA-CHE score) in patients who completed 1 of the 2 pivotal phase III trials with delgocitinib cream 20 mg/g or vehicle cream. The extension phase started in August 2021 and ended in September 2023. The DELTA 3 trial included a screening period of up to 4 weeks (week –4 to week 0) conducted during the parent DELTA 1 and DELTA 2 trials, followed by a treatment period of 36 weeks. Together, the parent trials and the extension trial (DELTA 3 trial) provided 52 weeks of efficacy and safety data. The baseline visit (day 1, week 0) of this extension trial coincided with the end-of-treatment visit (week 16) of the parent trials. During the treatment period, patients attended site visits every 4 weeks, until week 36. At the end of treatment, patients attended a safety follow-up of 2 weeks (week 36 to week 38).⁴⁵ The efficacy end points included in this section are IGA-CHE treatment success, HECSI score at week 36, HECSI-75 at week 36, HECSI-90 at week 36, HESD itch reduction of at least 4 points at week 36, HESD pain reduction of at least 4 points at week 36, and HEIS score over time. Long-term harm outcomes (AEs, SAEs, AESIs) were also included in this report. The DELTA 3 study design is presented in Figure 7.

Figure 7: DELTA 3 Study Design

IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; W = week.

Source: DELTA 3 Clinical Study Report.⁴⁵

Populations

Patients eligible for the DELTA 3 extension trial were those who completed the treatment period and complied with the clinical trial protocol in the parent DELTA 1 or DELTA 2 trials. Participants who discontinued treatment with delgocitinib early, used rescue medication, or experienced any AE during participation in the parent trial that precluded further treatment with delgocitinib were not eligible to participate in the DELTA 3 trial.⁴⁵

Interventions

From baseline to week 36, patients were treated on an as-needed basis with delgocitinib cream 20 mg/g twice a day. At any time during the trial, if a patient had an IGA-CHE score of 2 or more, the investigator dispensed delgocitinib cream and instructed the patient to start treatment with twice-daily applications. When the patient experienced an IGA-CHE score of 0 (clear) or 1 (almost clear), the investigator instructed the patient to stop treatment. If the patient experienced worsening of CHE signs and symptoms between scheduled visits, an unscheduled visit was planned as soon as possible to decide if treatment with delgocitinib should be started. Similarly, once symptoms resolved, the patient visited the study site as soon as possible (either at a planned visit or for an unscheduled visit) so that the investigator could assess if treatment should be stopped. Concomitant medications and procedures surrounding the use of rescue therapy during the DELTA 3 trial were the same as defined for the parent DELTA 1 and DELTA 2 trials.⁴⁵

Outcomes

The primary outcome of the DELTA 3 extension study was the number of TEAEs from baseline up to week 38. TEAEs encompassed drug-related AEs, AEs categorized by severity, SAEs, AEs leading to discontinuation of the study drug, and death. Long-term efficacy outcomes, including IGA-CHE score and HECSI score, were reported as secondary outcomes; HRQoL outcomes, such as HESD itch score and DLQI score, were reported as tertiary outcomes for the extension phase.⁴⁵

Statistical Analysis

The safety analysis set, defined as all enrolled patients, was used for the analysis of all end points for the open-label safety trial in the DELTA 3 trial. The overall safety profile was presented as the number and percentage of all participants treated with delgocitinib who reported TEAEs, related TEAEs, AESIs, serious TEAEs, and TEAEs leading to treatment and study discontinuation. AEs were allocated to treatment status (on or off treatment) based on the onset day of the AE. If the onset day was an on-treatment day, excluding days of treatment reinitiation, the AE was assigned to “on treatment.” If the onset day was a day of treatment reinitiation, the AE was assigned to “off treatment” if the AE originated from a safety assessment performed at the visit; otherwise, it was assigned to “on treatment.” If the onset day was an off-treatment day, the AE was assigned to “off treatment.” Additionally, the number and percentage of participants treated with delgocitinib reporting each TEAE experienced by 5% or more of the treated participants were summarized.

IGA-CHE, HECSI, HESD and DLQI scores were summarized based on observed data, with no imputation of missing values. Descriptive statistics were used to summarize all measures. These measures were grouped by parent trial treatment. For the proportion of patients experiencing an IGA-CHE score of 0 or 1, HECSI-75, HECSI-90, or a reduction in HESD itch or pain scores of at least 4 points from baseline in the parent trial, patients who discontinued treatment with the investigational medicinal product before week 36, who initiated rescue treatment, or who withdrew from the trial were imputed as not experiencing a response. Baseline measurements were defined as the latest available observation at or before the baseline visit (day 1), except for HECSI-75 or HECSI-90 and reduction in HESD itch or pain scores of at least 4 points, because the baseline values for these outcomes were derived from the baseline value in the parent trial (DELTA 1 or DELTA 2 trials).⁴⁵

Results

Patient Disposition

Patient disposition for the DELTA 3 trial by parent trial treatment is presented in Table 23. Of the 810 patients screened from both trials, 801 patients were considered eligible to participate in the DELTA 3 trial and were therefore included in the patient safety analysis. From the DELTA 1 trial, 427 out of 487 patients (87.7%) were transferred to the extension trial, and from the DELTA 2 trial, 374 out of 473 patients (79.1%) were transferred to the extension trial. Among these 801 patients, 560 were included in the previous delgocitinib group and 241 in the previous vehicle cream group. Eighty-eight patients (15.7%) from the previous delgocitinib group and 49 patients (20.3%) from the previous vehicle cream group discontinued treatment. A total of 664 patients completed the treatment period, 472 (84.3%) from the previous delgocitinib group and 192 (79.7%) from the previous vehicle cream group. Among the 801 patients enrolled in the extension trial, 11 patients were enrolled in error despite not meeting the eligibility criteria (1 related to exclusion criteria and 10 related to inclusion criteria). After a safety evaluation of each incident, the sponsor allowed all 10 patients whose enrolment error related to inclusion criteria to continue the extension trial. The patient whose enrolment error related to exclusion criteria had withdrawn from the trial.⁴⁵

Table 23: Summary of Patient Disposition From the DELTA 3 Trial

Source: DELTA 3 Clinical Study Report.⁴⁵ Details included in the table are from the sponsor’s summary of clinical evidence.¹⁶

Baseline Characteristics

The baseline characteristics outlined in Table 24 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. The characteristics are similar to those of the parent trials. IGA-CHE and HECSI scores at parent trial baseline were similar between the treatment groups. There were some differences in terms of IGA-CHE score at extension trial baseline between the previous delgocitinib and previous vehicle cream groups. A higher proportion of patients previously treated with delgocitinib had IGA-CHE scores of clear to mild, and a higher proportion of patients previously treated with vehicle cream had IGA-CHE scores of moderate to severe. The median HECSI score, HESD itch and pain scores, HESD score, and DLQI score had decreased baseline values in both treatment groups compared to the parent trial baseline values. The baseline values in the previous delgocitinib group were lower than in the previous vehicle cream group for all the HRQoL outcomes in the extension phase. The distribution of CHE subtypes at parent trial baseline was similar between the groups, except for vesicular hand eczema (pompholyx), which was present in 11.3% versus 5.8% of patients in the previous delgocitinib and previous vehicle cream groups, respectively. The most frequently reported CHE subtype was atopic hand eczema (reported by approximately one-third of the trial population).⁴⁵

Exposure to Study Treatments

In the DELTA 3 extension trial, the total patient-years of observation was higher in the group that had previously received delgocitinib in the parent trial (378.0 patient-years) than in the group that had received vehicle cream (157.6 patient-years). The total amount of investigational medicinal product used, as well as the weekly average amount (calculated over the entire treatment period), was similar in both groups. Notably, patients spent more time on treatment than off treatment (patient-years of observation on treatment: 407.5, versus 128.1 off treatment), both in the group previously treated with delgocitinib and the group previously treated with vehicle cream in the parent trial. Overall, the number and the duration of on-treatment periods were similar between both groups. However, among all patients entering the extended trial, despite having a similar mean number of on-treatment periods, the mean duration of on-treatment periods was shorter in those who had experienced IGA-CHE treatment success at extension trial baseline than in those who had not. There were no relevant differences in treatment compliance between patients who received delgocitinib and those who received vehicle cream in the parent trials.⁴⁵

Table 24: Summary of Baseline Characteristics From the DELTA 3 Trial

b.i.d. = twice a day; CHE = chronic hand eczema; DLQI = Dermatology Life Quality Index; HESD = Hand Eczema Symptom Diary; IQR = interquartile range.

Note: Racial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Source: DELTA 3 Clinical Study Report.⁴⁵ Details included in the table are from the sponsor’s summary of clinical evidence.

Concomitant Medications and Co-Interventions

Table 25 provides a summary of concomitant medications and rescue treatments used among patients in the DELTA 3 trial.

The use of concomitant medications was comparable between the group treated with delgocitinib in the parent trial (79.1%) and the group treated with vehicle cream in the parent trial (79.3%). The concomitant medications most frequently reported were other analgesics and antipyretics (23.0%), anti-inflammatory and antirheumatic products (22.8%), and systemic antihistamines (22.8%), across all patients from the previous treatment groups.

The majority of patients did not use any rescue treatment during the trial: rescue treatment was used by 19 patients (3.4%) who received delgocitinib cream in the parent trial and 10 patients (4.1%) who received vehicle cream in the parent trial. Dermatologicals were the most frequently used class of rescue treatment, mainly driven by dermatological preparations of corticosteroids (used by 13 patients [2.3%] who received delgocitinib cream in the parent trial and 4 patients [1.7%] who received vehicle cream in the parent trial).

Table 25: Summary of Concomitant Medications and Rescue Treatment From the DELTA 3 Trial

^aAt least 10% of patients in any treatment group at Anatomical Therapeutic Chemical level 3.

Source: DELTA 3 Clinical Study Report.⁴⁵ Details included in the table are from the sponsor’s summary of clinical evidence.

Efficacy

The summary of key efficacy outcomes from the DELTA 3 extension trial is presented in Table 26.

IGA-CHE Treatment Success From Baseline up to Week 36

Among patients who received delgocitinib cream in the parent trial and subsequently enrolled in the DELTA 3 trial, the proportion of patients with an IGA-CHE score of 0 or 1 (i.e., IGA-CHE treatment success) was similar at all visits throughout the 36-week extension trial while on the “as-needed” dosing regimen (Figure 8). Specifically, 24.6% of these patients had experienced IGA-CHE treatment success at the baseline of the extension trial and 30.0% had by the end of the extension trial (week 36). Among patients who received vehicle cream in the parent trial, the proportion of patients who experienced IGA-CHE treatment success increased over time, rising from 9.1% at the extension trial baseline to 29.5% at week 36 of the extension trial.

Figure 8: IGA-CHE Score of 0 or 1 by Visit, Parent Trial Treatment, and Baseline IGA-CHE Treatment Success

IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema.

Notes: “Responders” in this figure indicates as patients who experienced an IGA-CHE score of 0 (clear) or 1 (almost clear). Patients who discontinued the investigational medicinal product, started rescue treatment, withdrew from the trial, or had missing data for other reasons are imputed as not experiencing response.

Source: DELTA 3 Clinical Study Report.⁴⁵

HECSI Score at Week 36

A total of 472 patients who received delgocitinib cream and 192 patients who received vehicle cream in the parent trial had a week 36 visit. Among patients who received delgocitinib cream in the parent trial, the mean HECSI score further decreased within the first 16 weeks of the extension trial and then remained stable. The mean HECSI score for these patients was 23.9 (SD = 29.1) at the baseline of the extension trial and 14.8 (SD = 19.4) at week 36 of the extension trial. Similarly, among patients who received vehicle cream in the parent trial, the mean HECSI score decreased within the first 16 weeks of the extension trial and then remained stable. At the baseline of the extension trial, the mean HECSI score was 46.8 (SD = 46.0) for these patients; at week 36 of the extension trial, it was 16.8 (SD = 23.4).

HECSI-75 at Week 36

Among patients who received delgocitinib cream in the parent trial, the proportion of patients experiencing a HECSI-75 response in the extension trial was maintained over time. The proportion of patients who experienced a HECSI-75 response from the parent trial baseline was 51.8% at the baseline of the extension trial and 58.6% at week 36 of the extension trial. More specifically, in patients who had experienced IGA-CHE treatment success at the extension trial baseline, the proportion of experiencing a HECSI-75 response decreased within the first 4 weeks and then stabilized. In those who did not experience IGA-CHE treatment success at baseline, the proportion experiencing a HECSI-75 response increased within the first 16 weeks and then stabilized. Among patients who received vehicle cream in the parent trial, an increase in the proportion of patients experiencing a HECSI-75 response was observed within the first 4 weeks of the extension trial. The proportion of patients experiencing this response subsequently remained stable. The proportion of patients who experienced a HECSI-75 response from the baseline of the parent trial was 23.7% at the baseline of the extension trial and 51.5% at week 36 of the extension trial.

HECSI-90 at Week 36

Among patients who received delgocitinib cream in the parent trial, the proportion of patients who experienced a HECSI-90 response in the extension trial was maintained over time. The proportion of patients who experienced a HECSI-90 response from the parent trial baseline was 31.8% at the baseline of the extension trial and 36.6% at week 36 of the extension trial. More specifically, in patients who experienced IGA-CHE treatment success at the extension trial baseline, the proportion of patients who experienced a HECSI-90 response decreased within the first 4 weeks and then remained largely stable. In those who did not experience IGA-CHE treatment success at baseline, the proportion of patients experiencing a HECSI-90 response increased over time. Similarly, in patients who received vehicle cream in the parent trial, the proportion of patients who experienced a HECSI-90 response increased during the extension trial. The proportion of patients who experienced a HECSI-90 response from the baseline of the parent trial was 12.0% at extension trial baseline and 35.7% at week 36 of the extension trial.

HESD Itch Reduction of at Least 4 Points From Parent Trial Baseline at Week 36

Among patients who received delgocitinib cream in the parent trial, the proportion of patients experiencing a reduction of at least 4 points in HESD itch score from the parent trial baseline was maintained over time. The proportion of patients with a reduction of at least 4 points in HESD itch score from the parent trial baseline was 50.6% at the baseline of the extension trial and 52.4% at week 36 of the extension trial. Among patients who received vehicle cream in the parent trial, the proportion of patients experiencing a reduction of at least 4 points in HESD itch score from the parent trial baseline increased from 26.3% to 41.3% during the extension trial.

HESD Pain Reduction of at Least 4 Points From Parent Trial Baseline at Week 36

Among patients who received delgocitinib cream in the parent trial, the proportion of patients experiencing a reduction of at least 4 points in HESD pain score from the parent trial baseline was maintained over time. The proportion of patients with a reduction of at least 4 points in HESD pain score from the parent trial baseline was 51.9% at the baseline of the extension trial and 55.4% at week 36 of the extension trial. Among patients who received vehicle cream in the parent trial, the proportion of patients experiencing a reduction of at least 4 points in HESD pain score from the parent trial baseline increased from 32.3% to 43.3% during the extension trial.

HEIS Score Over Time

Among patients who received delgocitinib cream in the parent trial, the mean HEIS score slightly decreased (indicating improvement) over time in the extension trial. Among patients who received vehicle cream in the parent trial, the mean HEIS score decreased within the first 8 weeks of the extension trial and then remained stable (Figure 9).

Figure 9: HEIS Score by Visit, Parent Trial Treatment, and Baseline IGA-CHE Treatment Success — Observed Cases, Treatment Period (Safety Analysis Set)

HEIS = Hand Eczema Impact Scale; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; SE = standard error.

Source: DELTA 3 Clinical Study Report.⁴⁵

DLQI Score Over Time

Among patients who received delgocitinib cream in the parent trial, the mean DLQI score slightly decreased (indicating improvement) over time in the extension trial. Among patients who received vehicle cream in the parent trial, the mean DLQI score decreased within the first 8 weeks of the extension trial and then remained stable over time (Figure 10).

Figure 10: DLQI Score by Visit, Parent Trial Treatment, and Baseline IGA-CHE Treatment Success — Observed Cases, Treatment Period (Safety Analysis Set)

DLQI = Dermatology Life Quality Index; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; SE = standard error.

Source: DELTA 3 Clinical Study Report.⁴⁵

Table 26: Summary of Key Efficacy Outcomes From the DELTA 3 Trial

b.i.d. = twice a day; DLQI = Dermatology Life Quality Index; HECSI = Hand Eczema Severity Index; HECSI-75 = at least a 75% improvement in Hand Eczema Severity Index score from baseline; HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; HEIS = Hand Eczema Impact Scale; HESD = Hand Eczema Symptom Diary; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; IQR = interquartile range; SD = standard deviation.

^aNumber of patients contributing to the analysis is the same for the baseline and week 36 analyses.

Source: DELTA 3 Clinical Study Report.⁴⁵ Details included in the table are from the sponsor’s summary of clinical evidence.

Harms

Table 27 and Table 28 present a summary of harms data from the DELTA 3 trial.

In total, 495 patients (61.8%) reported experiencing at least 1 AE, with the overall incidence of AE of any grade being comparable between the group previously treated with delgocitinib (61.1%) and the group previously treated with vehicle cream (63.5%) in the parent trials. The most common AEs (reported in ≥ 5% of patients) were COVID-19 and nasopharyngitis. There was a slightly higher rate of infections during on-treatment periods than during off-treatment periods, but this difference was not considered to be of clinical relevance. The rate of SAEs was low (3.4% in total), and similar rates were observed between on-treatment periods and off-treatment periods and between patients with different parent trial treatments. Nine patients discontinued the investigational medicinal product permanently or withdrew from the trial due to AEs, with similar rates observed between on-treatment periods and off-treatment periods and between patients with different parent trial treatments. All events leading to permanent discontinuation of the investigational medicinal product or withdrawal from the trial were nonserious, except for the fatal SAEs associated with 3 deaths. Regarding AESIs, 1 event of eczema herpeticum (neck and eyelids) was reported during an on-treatment period in a patient with a history of AD. Three deaths were reported during the trial. None of the deaths were assessed to be related to the investigational medicinal product by the investigator or the sponsor.

Table 27: Summary of Harms Results From the DELTA 3 Trial by Parent Trial Treatment (Safety Analysis Set)

AE = adverse event; b.i.d. = twice a day; SAE = serious adverse event.

Source: DELTA 3 Clinical Study Report.⁴⁵

Table 28: Summary of Harms Results From the DELTA 3 Trial by Treatment Status (Safety Analysis Set)

AE = adverse event; SAE = serious adverse event.

Source: DELTA 3 Clinical Study Report.⁴⁵

Critical Appraisal

Internal Validity

The open-label extension phase design of the DELTA 3 trial may have biased the reporting of some end points because awareness of the study treatment received may have influenced the perception of improvement and/or harms by patients and clinicians, particularly for outcomes that are subjective in measurement and interpretation (e.g., HESD, HEIS, and DLQI scores and subjective AEs). The parent trial delgocitinib group would have lost anyone who experienced particular intolerance or nonresponse to delgocitinib, and the vehicle cream group might have lost patients with more severe disease who needed rescue medication and withdrew from the study. More than half the patients who initially experienced response (a baseline IGA-CHE score of 0 or 1) in both groups ceased to experience response by week 4 while off treatment in the as-needed regimen. Although a substantial proportion subsequently regained response upon reinitiation of delgocitinib (median 8 weeks; approximately 81% by the end of the treatment period), this on/off design introduces variability and possible regression to the mean, limiting the certainty with which durability of response can be interpreted.

Because all patients were taking delgocitinib during the open-label extension phase, there was no relevant randomized comparison group (i.e., for any active comparator of interest), which precludes causal conclusions. Because AEs were allocated to treatment status (on or off treatment) based on the onset day of the AE, the safety analysis loses the history and mixes new with longer-term treatment. While the assumption is that there will be no carryover effect, there may be misattribution of AEs in patients who had an event just after crossing over, especially from on treatment to off treatment. This issue raises concerns about undercounting or potentially missing a signal for AEs. In terms of HRQoL measures, 466 out of 558 patients (83.5%) from the parent trial delgocitinib group and 192 out of 240 patients (80%) from the parent trial vehicle cream group participated until week 36 for the HEIS score change measure, indicating 16.5% and 20% dropout rates in the previous delgocitinib group and previous vehicle cream group, respectively. The dropout rates were same for the DLQI score change measure. In terms of protocol deviations, 204 important deviations were reported up to the date of the data lock. Eleven patients were enrolled despite the violation of eligibility criteria, which may bias the trial results. The sponsor acknowledged that 14 important patient-level protocol deviations, which were not related to violation of eligibility criteria, were considered to impact the interpretability of the trial results for the individual patients. Additionally, the sponsor acknowledged 5 important site-level protocol deviations that were considered to impact the interpretability of the trial results, involving 34 patients in the extension phase. All these incidents of protocol deviation in different levels of the extension phase might have impacted the trial outcomes, though the direction of the potential impact is unclear.

External Validity

Because the patients who took part in the DELTA 3 trial were originally from the DELTA 1 or DELTA 2 parent studies and the eligibility criteria remained the same, it is reasonable to expect that the same limitations to generalizability are relevant to the open-label extension study. For instance, because the participants were predominantly white (approximately 91%), the results from these trials may not be generalized to other racial groups that may be commonly seen at some centres in North America and Europe. One of the eligibility criteria in the extension phase was that patients who experienced any AE during participation in the parent trial that precluded further treatment with delgocitinib were not eligible to participate in the DELTA 3 trial. This might have led to a greater share of patients who experience good tolerance of the drug being included in the extension phase, though the impact on the generalizability of the results will be small, considering only 6 patients were screened out on the basis of eligibility criteria.

Indirect Evidence

The contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Objectives for the Summary of Indirect Evidence

Although 1 head-to-head RCT (DELTA FORCE trial) has compared delgocitinib to alitretinoin — an agent currently used as second-line treatment for patients with moderate to severe CHE who do not experience response to TCS or for whom TCS are not appropriate — there remains a lack of direct comparative evidence between delgocitinib and other relevant therapeutic options. Phototherapy is commonly considered a second-line treatment option in both clinical guidelines and routine care for patients with moderate to severe CHE. Additionally, dupilumab (though not specifically approved for CHE) is frequently used off-label and is broadly reimbursed in Canada for the treatment of moderate to severe AD. According to the sponsor, this may be relevant in jurisdictions where access to phototherapy is limited or in jurisdictions where alitretinoin is not reimbursed or in patients who are ineligible for or for whom such therapies are contraindicated.

The objective of the systematic literature review (SLR) submitted by the sponsor was to identify any additional randomized trials directly comparing delgocitinib to other treatments used in practice in Canada.

Description of Indirect Comparisons

Given these gaps in direct evidence, ITCs were conducted to estimate the relative efficacy of delgocitinib versus phototherapy (PUVA) through an NMA incorporating randomized trial data and of delgocitinib versus dupilumab through a MAIC based on IPD from delgocitinib trials and aggregate data from a dupilumab study. These analyses aim to inform decision-making in the context of clinical practice in Canada and pharmacoeconomic modelling, where comparative evidence is needed to support the evaluation of treatment alternatives for moderate to severe CHE in adults.

An SLR was conducted by the sponsor that followed the PRISMA-P guidelines for systematic reviews and meta-analyses and adhered to the methodological standards outlined by the National Institute for Health and Care Excellence (NICE) technology appraisal process and the Cochrane Handbook.^46-48 The search strategy, completed on October 8, 2024, included MEDLINE, Embase, and the Cochrane Library (including the Cochrane Database of Systematic Reviews and CENTRAL). To complement these electronic sources, pragmatic searches of grey literature were conducted, including reviews of bibliographies (e.g., SLRs, NMAs), clinical trial registries, conference proceedings, and health technology assessment submissions. Following de-duplication, titles and abstracts were independently screened by 2 experienced reviewers. Full-text articles were assessed for eligibility, and studies meeting predefined criteria were included in the SLR.

The eligibility criteria for the SLR were intentionally broad with respect to population, comparators, and outcomes to support potential submissions across different geographies. A narrower subset of evidence was then selected for the ITCs, as outlined in Table 29. For the purpose of this review, alitretinoin and phototherapy were considered the most relevant second-line comparators. Therefore, the ITC focused on studies involving these treatments and reporting outcomes aligned with those in the delgocitinib phase III program (DELTA 1, DELTA 2, and DELTA FORCE trials). Eligible outcomes included the proportion of patients experiencing an IGA-CHE or PGA score of 0 or 1 (end point response), IGA-CHE cumulative response, and HECSI-90 for efficacy, as well as discontinuation due to AEs and all-cause discontinuation for harms. Although the broader SLR included additional clinical and patient-reported outcomes such as HECSI-75, HECSI CFB, and DLQI CFB, these were not submitted in the ITC report because they were not used in the pharmacoeconomic analysis submitted by the sponsor.

Table 29: Study Selection Criteria and Methods for Indirect Comparisons

AE = adverse event; CHE = chronic hand eczema; HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; NMA = network meta-analysis; PGA = Physician’s Global Assessment; PUVA = psoralen and UVA radiation; RCT = randomized control trial; SLR = systematic literature review.

^aThe target population for delgocitinib is adults with moderate to severe CHE. However, trials that recruited participants both ≥ 18 years and < 18 years were considered eligible.

Source: Delgocitinib NMA technical report.⁴⁹

Indirect Comparison Analysis Methods

Two ITCs were conducted based on the evidence identified during the SLR:

• an NMA to compare the relative efficacy of delgocitinib versus phototherapy

• an anchored MAIC to compare the relative efficacy of delgocitinib versus dupilumab.

Due to the considerable heterogeneity between the delgocitinib and dupilumab trials identified, specifically that the dupilumab trial was conducted in a specific subgroup of patients with CHE (i.e., patients with atopic CHE subtype, rather than all forms of CHE), it was deemed not feasible to include dupilumab in the NMA. Thus, a MAIC was judged to be most appropriate. The following section describes, separately, the methods of each ITC in greater detail.

Network Meta-Analysis

Objectives

The objective of the NMA was to estimate — using a connected network of evidence derived from randomized trials — the relative efficacy and harms of delgocitinib compared to other relevant treatment options for adults with moderate to severe CHE who have not experienced response to, or are not candidates for, TCS.

Specifically, the NMA aimed to compare delgocitinib to alitretinoin, phototherapy (PUVA), or placebo or vehicle cream to inform the relative treatment effects within and across studies.

Outcomes of interest included both efficacy end points (e.g., IGA-CHE or PGA of 0 or 1, HECSI-90, and cumulative response) and AE end points (e.g., discontinuation due to AEs). The findings were intended to support the pharmacoeconomic evaluation and inform decision-making in the context in Canada, where direct evidence is limited.

Feasibility Assessment

Before conducting the NMA, a feasibility assessment was performed to determine potential sources of heterogeneity across the trials identified in the SLR and to ensure trial comparability for synthesis.

The similarity of the trial characteristics across the RCTs identified in the SLR evaluating delgocitinib or phototherapy was assessed qualitatively. The assessment of trial characteristics focused on the following:

• study design characteristics (i.e., study phase, interventions, and eligibility criteria)

• outcome reporting (definition and time points).

Additional steps were undertaken during the feasibility assessment, including assessment of connections, analysis of risk of unobserved variables, and consideration of specific assumptions. Specifically, several assumptions were made to indirectly compare delgocitinib to comparators of interest.

Assumptions Made in the Network Meta-Analysis

Based on the available evidence, the following key assumptions were made in the NMA:

• IGA-CHE and PGA are sufficiently comparable to synthesize. While there are inherent differences between the PGA and IGA-CHE scale, notably an IGA-CHE score of 1 being more strict (barely perceptible erythema), for the purpose of estimating the relative efficacy of phototherapy compared to delgocitinib in an ITC anchored on alitretinoin, the sponsor assumed the scales to be comparable.

• In the ALPHA trial, all missing patients were assumed not to experience response; therefore, it is appropriate to estimate the IGA-CHE or PGA data for the ALPHA trial using nonresponse imputation based on observed cases (i.e., participants with available data who experienced response).

• Week 12 and week 16 outcomes are sufficiently similar to synthesize. The trials included in the NMAs reported results at distinct time points, ranging from 12 to 24 weeks. To facilitate comparison of different treatments in the NMAs, it was assumed that the data reported for efficacy outcomes at weeks 12 and 16 were unlikely to introduce statistically significant bias to treatment effect estimates. This assumption stemmed from the similar ORs of patients who experienced response at week 12 and week 16 in the delgocitinib trials.

• Cream vehicle and placebo are sufficiently similar to synthesize in a single node. It was assumed that placebo and vehicle cream were clinically equivalent and, when these were reported in the same network, they were merged into a common placebo–vehicle cream node.

• Baseline disease severity was not expected to be an effect modifier. The trials included in the NMAs recruited patients with different levels of CHE severity (i.e., moderate to severe versus severe only). To compare the efficacy of different treatment options, mixed populations (i.e., populations with both moderate and severe disease) were included in the base-case analysis, assuming that baseline severity was not an effect modifier.

• Nonresponse imputation was used to harmonize outcome reporting across trials. The numbers of patients who experienced response in the ALPHA trial were presented as observed cases, meaning that the missing data in the ALPHA trial were not included in the outcome analyses. This method of treating missing data did not align with the DELTA trials, which used nonresponse imputation. To align with delgocitinib trials, the ITC authors reprocessed ALPHA trial data using nonresponse imputation, counting missing patients as patients who did not experience response (instead of excluding them). Of note, the ALPHA trial considered patients who received rescue therapy as experiencing response, whereas the delgocitinib trials considered these patients as not experiencing response; hence, it was not possible to align the methods of handling rescue therapy in the ALPHA trial and other trials.

Statistical Model

The NMAs were conducted using a Bayesian framework, consistent with guidance from the NICE Decision Support Unit (DSU).⁵⁰ Analyses were implemented in WinBUGS using binomial logit models to estimate relative treatment effects for dichotomous outcomes. Markov chain Monte Carlo simulation methods were employed to generate posterior distributions. An initial burn-in of 20,000 iterations was followed by 50,000 sampling iterations across 3 chains. Convergence was assessed using trace plots and Brooks-Gelman-Rubin diagnostics, with shrink factors approaching 1 indicating convergence.^51,52 The Brooks-Gelman-Rubin plots for each outcome are presented in the Results section.

Both fixed-effect and random-effects models were explored. Fixed-effect models were generally preferred due to the limited number of studies and the sparse connections within the network, which led to imprecise estimates under random-effects models. A baseline risk model was used to estimate absolute event rates for the delgocitinib arms using a random-effects approach. These models estimates were based on the mean and SD of the predictive distribution as described in NICE DSU Technical Support Document 5.⁵⁰

Prior Distributions

Noninformative (vague) priors were used to ensure that the analysis results were primarily informed by observed trial data. Normal priors with a mean of 0 and a variance of 10,000 were applied for treatment effects, consistent with NICE DSU Technical Support Document 2.⁵⁰ For the between-study heterogeneity parameter in the random-effects model, a uniform prior distribution ranging from 0 to 2 was used.

Model Fit

Model fit was evaluated using the deviance information criterion (DIC) and posterior mean residual deviance. The DIC combines a measure of model fit with a penalty for complexity (effective number of parameters). Models with lower DIC values are generally preferred, with a difference of more than 3 to 5 points considered meaningful. A posterior residual deviance close to the number of data points also supports adequate model fit. Results for the preferred models for each end point are presented in the Results section.

Homogeneity Assessment

A feasibility assessment was conducted to evaluate the assumption of clinical and methodological homogeneity across trials. This included review of study design characteristics, outcome definitions, timing of assessments, and baseline population characteristics. Minor sources of heterogeneity (e.g., estimand definitions, handling of intercurrent events) were addressed by standardizing imputation strategies and aligning outcome definitions where possible. Sensitivity analyses were conducted to assess the impact of baseline severity and the timing of outcome reporting.

Consistency Assessment

An assessment of consistency between the direct and indirect evidence was not applicable to this NMA as there were no closed loops in the networks.

Outcomes

The outcomes assessed in the NMA included the following:

• Efficacy outcomes:

  • IGA-CHE or PGA score of 0 or 1 end point response (proportion of patients experiencing a score of 0 or 1 at a specified time point)

  • IGA-CHE score of 0 or 1 cumulative response (proportion of patients experiencing the score at any time point during the assessment period)

  • HECSI-90 (proportion of patients experiencing a HECSI-90 response).

• Harms:

  • discontinuation due to AEs

  • all-cause discontinuation.

However, due to a lack of data relating to phototherapy, it was not possible to conduct an NMA for cumulative response or HECSI-90. In addition, all-cause discontinuation was excluded from the analysis due to inconsistencies within the network and between-trial heterogeneity in the handling of patients who experienced response early and the handling of treatment discontinuations.

Base-Case Analysis

The base-case analysis for efficacy outcomes included all patients with available data from studies that reported outcomes at their primary end point (typically week 12 or week 16). An additional analysis was performed using week 12 data only. For discontinuation due to AEs, the base case included all studies reporting treatment-level data at the end of treatment, ranging from week 16 to week 24 (refer to Table 30).

Table 30: Overview of the Analyses — Efficacy and Harms

Source: Delgocitinib network meta-analysis report.⁴⁹

Sensitivity Analysis

Sensitivity analyses were conducted to assess the potential influence of baseline disease severity (moderate versus severe CHE) and timing of outcome assessment on the estimated treatment effects (week 12 or week 16). These analyses followed the same methodological framework as the base-case analysis but applied to stratified populations and alternative time points.

For the primary efficacy outcome — IGA-CHE or PGA score of 0 or 1 response — 2 separate analyses were conducted: 1 restricted to patients with moderate CHE and another restricted to those with severe CHE. Each analysis included studies that reported outcomes at either the trial-defined primary end point (week 12 or week 16) or specifically at week 12. These analyses were intended to evaluate whether disease severity modified treatment effects and whether the results were robust across different assessment time points.

For the outcome of discontinuation due to AEs, a sensitivity analysis was performed among patients with severe CHE using outcome data reported at week 24. This analysis was intended to assess whether the risk of AE-related discontinuation varied by disease severity over a longer treatment duration.

A summary of the sensitivity analyses conducted, including population, outcome, and time point specifications, is provided in Table 31.

Analysis Set

The analysis set used in the NMA was dependent on the results reported by the authors of the individual studies (i.e., ITT population or FAS). Intercurrent events handling, including missing data and rescue therapy, were also different depending on the trials included. Further details on the analysis sets and imputation strategies used in the NMAs are provided in the Results section. A summary of the NMA methods is shown in Table 31.

Table 31: Summary of Network Meta-Analysis Methods

CHE = chronic hand eczema; DAE = discontinuation due to adverse events; DIC = deviance information criterion; HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; NMA = network meta-analysis; PGA = Physician’s Global Assessment.

Source: Delgocitinib NMA report.⁴⁹

Results

Summary of Included Studies

The SLR identified 128 records comprising 44 unique trials. After considering heterogeneity for study design characteristics (namely, study phase, interventions, and eligibility criteria) and for outcome reporting, definition, and time points, 29 trials were excluded from the feasibility assessment, leaving 15 trials for further detailed assessment of study design and baseline characteristics. Of the 15 trials included in the feasibility assessment, 3 assessed the efficacy of delgocitinib compared with vehicle cream, and a fourth performed a head-to-head comparison between delgocitinib and alitretinoin. The remaining 11 trials reported data for 8 treatments for CHE positioned as second or later lines of therapy (alitretinoin, immersion PUVA, dupilumab, upadacitinib, abrocitinib, narrow-band UVB, ciclosporin, and azathioprine), as well as placebo.

Ultimately, 7 RCTs were identified for inclusion in the NMA (Table 32) based on potentially relevant global comparators (namely, vehicle cream, alitretinoin, and phototherapy) and outcomes: the DELTA 1⁵ (NCT04871711), DELTA 225 (NCT04872101), Worm 2022⁵³ (NCT03683719), DELTA FORCE⁵⁴ (NCT05259722), BACH⁵⁵ (NCT00124475), HANDEL⁵⁶ (NCT00817063), and ALPHA⁵⁷ (ISRCTN80206075) trials.

Three trials (DELTA 1, DELTA 2, and Worm 2022 trials) compared delgocitinib to vehicle cream, whereas the DELTA FORCE trial compared delgocitinib to alitretinoin. The BACH and HANDEL trials compared alitretinoin to placebo, and the ALPHA trial compared alitretinoin to PUVA. The Worm 2022 trial⁵³ is a dose-finding trial with 5 arms; however, only the vehicle cream and delgocitinib 20 mg arms were interventions of interest and were therefore eligible for inclusion in the feasibility assessment. The technical report submitted does not explicitly include a detailed risk of bias assessment for the included studies.

The outcomes measured in these studies include IGA-CHE or PGA score of 0 or 1 end point response, IGA-CHE score of 0 or 1 cumulative response, HECSI-90 end point response, and discontinuation due to AEs at various time points (Table 32). The 3 delgocitinib trials against vehicle cream (DELTA 1, DELTA 2, and Worm 2022 trials) reported outcomes at week 12 and week 16 for IGA-CHE or PGA score of 0 or 1 end point response, IGA-CHE score of 0 or 1 cumulative response, and HECSI-90 end point response, with discontinuation due to AEs noted at the end of treatment (week 16). The DELTA FORCE trial measured for IGA-CHE or PGA score of 0 or 1 end point response and HECSI-90 end point response at week 12, IGA-CHE score of 0 or 1 cumulative response at both week 12 and week 24, and discontinuation due to AEs at the end of treatment (week 24). Alitretinoin trials reported limited efficacy outcome data, with cumulative response assessed at week 12 and week 24 (BACH trial) and week 24 (HANDEL trial), and end point response assessed at week 12 (ALPHA trial). The 3 alitretinoin trials reported discontinuation due to AEs at the end of treatment (i.e., at week 24).

Table 32: Characteristics of Included Studies From the SLR

CHE = chronic hand eczema; DAE = discontinuation due to adverse events; HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; M = moderate; NR = not reported; PGA = Physician’s Global Assessment; PUVA = psoralen and UVA radiation; S = severe.

Notes: The BACH trial was included only in the IGA-CHE score of 0 or 1 cumulative response base-case analysis at week 24. The BACH trial was initially included in all base-case analyses for cumulative response. However, inconsistency was identified in the primary end point analysis and week 12 analysis; thus, both analyses were conducted again with the BACH trial excluded.

Source: Delgocitinib network meta-analysis report.⁴⁹

Assessment of Homogeneity Among Trials Included in the NMA

Study Design

The studies included in the NMA were all RCTs. The DELTA FORCE trial was a phase III study, and the ALPHA trial was a phase IV study. The DELTA 1, DELTA 2, and Worm 2022 trials were phase III, double-blind, vehicle-controlled RCTs. The DELTA FORCE trial was open label, although outcome assessors were blinded to mitigate bias in evaluating CHE severity. The ALPHA trial was a double-blind, parallel-group RCT. The BACH and HANDEL studies were both double-blind, placebo-controlled RCTs evaluating oral alitretinoin. No studies were excluded based on design.

Disease Severity

The DELTA FORCE, ALPHA, BACH, and HANDEL trials included only patients with severe CHE. The DELTA 1, DELTA 2, and Worm 2022 trials included populations with both moderate and severe CHE. Sensitivity analyses in the NMA were stratified by disease severity to assess its impact on treatment effects.

Eligibility Criteria

All trials included adults with CHE of at least 3 months’ duration who had not experienced response to TCS or for whom TCS use was inappropriate. What was considered prior TCS failure varied widely (e.g., from 4 weeks up to 1 year). Use of systemic agents or phototherapy before the study was generally permitted with an appropriate washout period. The DELTA FORCE trial excluded patients previously treated with alitretinoin. The exclusion criteria included active skin infection and AD requiring treatment beyond the hands. The ALPHA trial excluded patients with known allergic contact dermatitis unless avoidance measures had been taken, but the DELTA FORCE trial allowed such patients.

Patient Demographic

Across all trials, the baseline demographics were generally comparable. The median patient age ranged from 40 to 50 years, and 40% to 60% of patients were female. More than 90% of participants were white. CHE subtypes varied: the DELTA FORCE trial predominantly included patients with atopic CHE, while the ALPHA trial enrolled primarily those with hyperkeratotic CHE.

Trial Population

The DELTA FORCE trial used an FAS that included all randomized participants, while the ALPHA trial used the ITT population. The Worm 2022, DELTA 1, and DELTA 2 trials used similar estimands for binary efficacy outcomes. However, missing data and intercurrent events were handled differently: the DELTA FORCE trial applied nonresponse imputation, whereas the ALPHA trial used observed case analysis at 12 weeks. To harmonize estimands for the NMA, ALPHA trial data were reanalyzed using nonresponse imputation. Patients who discontinued due to AEs were consistently reported. However, all-cause discontinuation was not analyzed due to differences in how the trials handled patients who experienced response early and how they handled rescue therapy (e.g., the ALPHA trial permitted continuation with added treatment; the DELTA FORCE trial treated rescue use as treatment failure).

Administration Form and Dosing of Comparators

Delgocitinib was administered topically at 20 mg/g, twice daily. Alitretinoin was administered orally at 30 mg daily, with optional dose reduction to 10 mg. PUVA therapy in the ALPHA trial consisted of twice-weekly sessions over 12 weeks. Vehicle comparators (placebo creams) were used in the DELTA 1, DELTA 2, and Worm 2022 trials.

Definitions of End Points

The primary efficacy end point was an IGA-CHE or PGA score of 0 or 1, defined as achieving a score of 0 (clear) or 1 (almost clear). Delgocitinib trials required an additional 2-point or greater improvement from baseline. Despite this stricter criterion, the end points were deemed sufficiently comparable for synthesis. Cumulative response and HECSI-90 were of interest but could not be evaluated across all arms due to missing data (e.g., HECSI-90 data were not available in the ALPHA trial). All-cause discontinuation was excluded due to inconsistencies in the handling of patients who experienced response. The cumulative response end points were reported but considered secondary to the more relevant end point results, in alignment with input from the clinical experts consulted by CDA-AMC. The cumulative response outcomes are not included in this report.

Timing of End Point Evaluation

The primary end point (IGA-CHE or PGA score of 0 or 1) was evaluated at week 12 for the ALPHA and DELTA FORCE trials. The DELTA 1, DELTA 2, and Worm 2022 trials assessed outcomes at week 16 (with additional reporting at week 12). Cumulative response could not be analyzed due to lack of data at comparable time points for PUVA. For discontinuation due to AEs, the last available time point was used (week 24 for both the ALPHA and DELTA FORCE trials).

Efficacy

IGA-CHE or PGA Score of 0 or 1 End Point Response

The evidence network for the NMA of IGA-CHE or PGA score of 0 or 1 end point response is shown in Figure 11. The network addressing the end point response at week 12 is the same (same studies and comparisons). The DELTA 1, DELTA 2, DELTA FORCE, Worm 2022, and ALPHA trials informed this end point. In these networks, the delgocitinib trials (DELTA 1, DELTA 2, DELTA FORCE, and Worm 2022 trials) used IGA-CHE to measure the efficacy of CHE treatments, whereas the ALPHA trial used PGA.

Figure 11: Network Diagram for IGA-CHE or PGA Score of 0 of 1 End Point Response — Primary End Point (Base Case)

IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; M = moderate chronic hand eczema; PGA = Physician’s Global Assessment; PUVA = psoralen and UVA radiation; S = severe chronic hand eczema.

Source: Delgocitinib network meta-analysis report.⁴⁹

The total residual deviance and the DIC were similar for both fixed-effect and random-effects models; the difference in the DIC between models was less than 5 for all NMAs of this outcome. Therefore, no clear recommendation could be made for selecting one model over the other based on model fit statistics alone. Due to the small number of trials included in the network, the random-effects model showed wide 95% CrIs when estimating treatment effects compared to the fixed-effect model. Considering the sparsity of the network and the resulting imprecise treatment effect estimates generated by the random-effects model, the authors preferred the fixed-effect model for this outcome.

Table 33 presents the median OR and 95% CrIs for delgocitinib versus all treatments across different disease severity levels (sensitivity analyses 1 and 2) for the IGA-CHE or PGA score of 0 or 1 end point response, incorporating all primary end point analyses, and the same outcomes at 12 weeks.

Table 33: IGA-CHE or PGA Score of 0 or 1 End Point Response — Primary End Point Analysis

CrI = credible interval; IGA-CHE = Investigator’s Global Assessment of Chronic Hand Eczema; OR = odds ratio; PGA = Physician’s Global Assessment; PUVA = psoralen and UVA radiation.

^aPrimary end point analysis includes the primary end point for all relevant studies.

^bWeek 12 analysis includes the week 12 end point for all relevant studies.

Source: Delgocitinib network meta-analysis report.⁴⁹

Overall, all active treatments showed higher treatment response than vehicle cream. Across all analyses of this outcome, the results favoured delgocitinib over vehicle cream, PUVA, and alitretinoin. For the fixed-effect model, all results favoured delgocitinib. The results were generally consistent across all analyses of this outcome. However, for the primary end point sensitivity analysis assessing the population with severe disease, the OR median point estimates comparing delgocitinib to vehicle cream were noticeably higher (favouring delgocitinib) than the other estimates generated by the NMAs of this outcome.

HECSI-90 End Point Results

The HECSI-90 end point response base-case networks consist of 4 treatments reported in 5 studies for the primary end point analysis and week 12 analysis (Figure 12). For each network, sensitivity analyses were also conducted. All trials in these networks used IGA-CHE to measure the efficacy of CHE treatments.

Figure 12: Network Diagram for HECSI-90 End Point Response — Primary End Point and Week 12 End Point (Base Case)

HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; M = moderate chronic hand eczema; S = severe chronic hand eczema.

Source: Delgocitinib network meta-analysis report.⁴⁹

The total residual deviance and the DIC were similar for both fixed-effect and random-effects models; the difference in the DIC between models was less than 5 points for all NMAs of this outcome. Therefore, no clear recommendation could be made to select one model over the other based on model fit statistics alone. Due to the small number of trials included in the network, there were wide 95% CrIs for the random-effects model, compared to the fixed-effect model, when estimating treatment effects. Considering the sparsity of the network and the resulting imprecise treatment effect estimates generated by the random-effects model, the fixed-effect model was preferred by the authors for this outcome.

The median ORs and 95% CrIs for delgocitinib versus all treatments across different disease severity levels and time points for the HECSI-90 end point response are presented in Table 34.

Table 34: HECSI-90 End Point Response

CrI = credible interval; HECSI-90 = at least a 90% improvement in Hand Eczema Severity Index score from baseline; OR = odds ratio.

^aPrimary end point analysis includes the primary end point for all relevant studies.

^bWeek 12 analysis includes week 12 end point for all relevant studies.

Source: Delgocitinib network meta-analysis report.⁴⁹

Across all analyses of this outcome, the results favoured delgocitinib versus vehicle cream and alitretinoin. For the fixed-effect model, all results favoured delgocitinib. For the sensitivity analyses assessing the population with severe disease, the OR and relative risk median point estimates comparing delgocitinib to vehicle cream were noticeably higher (favouring delgocitinib) than for the other NMAs of this outcome.

Discontinuation Due to AEs

The discontinuation due to AEs base-case network consists of 4 treatments reported in 7 studies for the primary end point analysis (Figure 13). The second sensitivity analysis assessed discontinuation due to AEs at week 24. Based on the network plot presented, a closed loop was identified, and an inconsistency assessment was conducted. No significant inconsistency was found.

Figure 13: Network Diagram for Discontinuation Due to AEs — Primary End Point (Base Case)

AE = adverse event; M = moderate chronic hand eczema; PUVA = psoralen and UVA radiation; S = severe chronic hand eczema.

Source: Delgocitinib network meta-analysis report.⁴⁹

In the model diagnostic measures for all analyses of discontinuation due to AEs, the total residual deviance and the DIC were similar for both fixed-effect and random-effects models; the difference in the DIC between models was less than 5 points for all NMAs of this outcome. Therefore, no clear recommendation was made to select one model over the other based on model fit statistics alone. Due to the small number of trials included in the network, wide 95% CrIs for the random-effects model were observed when estimating treatment effects compared to the fixed-effect model. Considering the sparsity of the network and the resulting imprecise treatment effect estimates generated by the random-effects model, the fixed-effect model was preferred by the authors for this outcome. The median ORs and CrIs for each comparison against delgocitinib are presented in Table 35.