CADTH Reimbursement Review

Dupilumab (Dupixent)

Sponsor: Sanofi-Aventis Canada Inc.

Therapeutic area: Asthma

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

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

Table 1: Submitted for Review

EOS = eosinophils; FeNO = fractional exhaled nitric oxide; ICS = inhaled corticosteroid; NOC = Notice of Compliance; SCS = systemic corticosteroid.

Introduction

Asthma is a chronic respiratory disorder characterized by reversible airway obstruction.¹ In Canada, it is estimated that 14% and 19% of children aged 5 years to 9 years and 10 years to 14 years suffer from asthma, respectively.² According to the clinical experts consulted for this CADTH review, asthma has several diverse phenotypes, 1 of which is primarily driven by type 2 inflammation, presenting with an allergic or atopic profile and/or eosinophilic asthma.

The management of asthma is traditionally carried out using “reliever” medication for the acute relief of exacerbations, combined with controllers used on a regular or chronic basis, in an effort to prevent the onset of exacerbations.¹ Treatment of patients in Canada follows an asthma management continuum, with inhaled corticosteroids (ICSs) as the backbone of maintenance anti-inflammatory therapy, and other medications added on as necessary.³ Monoclonal antibodies are the newest entrants into the asthma treatment paradigm, such as immunoglobulin E (IgE) inhibitors, interleukin (IL)-5 inhibitors, and IL-4 and IL-13 inhibitors. None of the monoclonal antibodies are intended to be used first line, and are reserved for those patients whose asthma is not well controlled despite optimized controller medications.

Dupilumab is an IL-4 and IL-13 inhibitor, indicated as add-on maintenance treatment in patients aged 6 years and older with severe asthma with a type 2 or eosinophilic phenotype or with oral corticosteroid (OCS)-dependent asthma. Dupilumab was previously reviewed by CADTH for the indication of severe asthma with a type 2/eosinophilic phenotype or OCS-dependent asthma in patients aged 12 years and older and received a positive recommendation in June 2021.⁴ Dupilumab is administered by subcutaneous injection in pediatric patients aged 6 years to 11 years at the dose of 100 mg every 2 weeks or 300 mg every 4 weeks for patients with a body weight from 15 kg to less than 30 kg, 200 mg every 2 weeks or 300 mg every 4 weeks for patients with a body weight from 30 kg to less than 60 kg, and 200 mg every 2 weeks for patients with a body weight of 60 kg or more. Dupilumab also received a Health Canada indication for atopic dermatitis and for chronic rhinosinusitis with nasal polyposis.⁵ It was also previously reviewed by CADTH for the atopic dermatitis indication in patients older than 12 years of age and received a positive recommendation in April 2020.⁶

The sponsor has requested that dupilumab be reimbursed for patients aged 6 years to younger than 12 years with severe asthma with the type 2 or eosinophilic phenotype characterized by the following: symptoms that are not controlled despite optimal treatment, defined by the daily use of a medium or high-dose ICS plus 1 controller medication or high-dose ICS alone; eosinophils (EOS) of 150 cells/μL or greater, fractional exhaled nitric oxide (FeNO) of 20 parts per billion (ppb) or greater, or allergy-driven asthma; uncontrolled asthma having at least 1 severe exacerbation, defined by having experienced 1 or more hospitalizations or emergency care visits or treatment with a systemic corticosteroid (SCS) (oral or parenteral) in the past year; and a baseline assessment of asthma symptom control using a validated asthma control questionnaire (ACQ) must be completed before initiation of dupilumab treatment.

The objective of this report was to perform a systematic review of the beneficial and harmful effects of dupilumab for the add-on maintenance treatment of severe asthma with a type 2 or eosinophilic phenotype or OCS-dependent asthma in patients aged 6 years to younger than 12 years.

Stakeholder Perspectives

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

Patient Input

Input from patients was provided by Asthma Canada, based on a survey conducted between February and March 2022, clinical practice guidelines, the product monograph, non-for-profit organization websites, and research papers. More than 100 patients (92%) and caregivers (8%) across all provinces responded to survey with 4 patients having had experience with dupilumab. In addition, the Lung Health Foundation submitted patients’ input based on a survey conducted between January 2021 and June 2022 from 27 patients with asthma and 2 caregivers, all living in Ontario.

Even with currently available treatments, 1 in 4 respondents to the Asthma Canada survey indicated that they have poor symptom control. Approximately 60% of respondents worry about or have a fear of exacerbations, 47% of respondents are concerned about potential hospital admissions, and 47% of survey participants are concerned with missing school or work. The survey findings highlighted challenges for children with asthma, including difficulties in inhaler use techniques, difficulties with making and keeping friends due to fatigue and less energy, activity limitations, inability to attend and concentrate at school, and sleep disturbances. Patients, parents, and caregivers noted several barriers to accessing health care providers (e.g., respirologists, specialized asthma clinics) including travel time and cost, missed school or work, and the financial burden of prescription refills. The Lung Health Foundation input from patients indicated common symptoms of asthma, such as shortness of breath (74.2%), fatigue (67.7%), cough (51.6%), as well as difficulties in activities of daily living such as climbing stairs (43.4%), housework (40.0%), and physical activities (40.0%). Some of the negative impacts of asthma that were highlighted by the patients included: night or early morning waking due to breathing problems (34.5%), emotional well-being (37.9%), and being short-tempered or impatient with others (31.0%).

Patients and caregivers identified the following expectations for new treatment for children with severe asthma: increasing lung function, making management of symptoms easier, reducing exacerbations, and reducing reliance on OCSs. Moreover, children with asthma and their parents expect to see improved day-to-day activities affecting quality of life (school attendance, sleep, energy, participation in activities), less health care visits including those to the emergency department (ED), less anxiety and panic for potential exacerbations, less time off work, and decreased financial hardships. Respondents indicated they would like to minimize side effects of medication; however, they are willing to tolerate certain side effects to improve management of asthma. Decreasing frequency and easing the administration of medication was an additional priority reported by the participants. Finally, it was noted that children on dupilumab cannot be vaccinated with live vaccines, which can pose challenges for children who are not fully immunized.

Clinician Input

Input From Clinical Experts Consulted by CADTH

According to the clinical experts consulted by CADTH for this review, the needs of the majority of patients with asthma are met with current standard therapies; however, a subset of patients remains poorly controlled despite maximized pharmacological treatment and nonpharmacological interventions such as inhaler education and improved medication adherence.

In Canada, pediatric patients with uncontrolled moderate-to-severe type 2 inflammatory asthma have access to treatment with biologics such as anti-IgE, anti-IL5, or anti-IL4/IL13 monoclonal antibodies. Clinical experts reported that the patients who would most likely benefit from dupilumab treatment include individuals with moderate-to-severe asthma who have not achieved optimal asthma control despite conventional therapy (i.e., high-dose ICS with add-on therapy [long-acting beta agonist {LABA} and/or leukotriene receptor antagonist {LTRA}] and requiring ongoing or multiple courses of SCSs) and presenting with a clear inflammatory phenotype, as assessed by peripheral blood eosinophil levels.

According to the clinical experts consulted by CADTH, relevant outcomes to assess treatment response in children include improvements in pulmonary function testing (improvement or stabilization of forced expiratory volume in 1 second [FEV₁], elimination of airflow reversibility to bronchodilator), decreases in acute asthma exacerbations, improvements in symptom control, and improvements in health-related quality of life (HRQoL). The clinical experts believed that the primary factor in deciding whether to discontinue dupilumab treatment would be a lack of improvement in asthma control outcomes over many months. Moreover, treatment with dupilumab should be discontinued in case of serious adverse events (SAEs) (e.g., serious immune or allergic reactions, serious dermatological reactions, malignancy, and ophthalmologic adverse events [AEs]). Initiation of the drug should be limited to pediatric respirologists or allergy specialists with significant pediatric asthma experience.

Clinician Group Input

Input was received from 6 clinicians, on behalf of the Canadian Thoracic Society. There were no contrary views reported between the clinician group and the clinical experts consulted for this review. The clinician group indicated that children with severe asthma have limited treatment options compared to the adult population. In addition, there is a lack of effective add-on therapies in younger children with severe asthma with nontype 2 inflammation involving neutrophilic inflammation and recurrent exacerbations caused by viral respiratory infections. According to the clinician group, key outcomes in asthma management include prevention of asthma exacerbations, maximization of quality of life, symptom prevention, and maximization of exercise tolerance. Members of the Canadian Thoracic Society agreed that the use of dupilumab should be restricted to patients aged 6 years to 11 years with type 2 inflammation, moderate-to-severe asthma not adequately controlled on medium-dose ICS plus LABA (or other second controller) or high-dose ICS (or OCS), and who experienced a severe exacerbation in the past year. The Canadian Thoracic Society clinicians suggested that dupilumab should be discontinued if a lack of clinically meaningful positive outcomes over an expected time frame is observed, as well as in case of safety concerns. Assessment of pediatric patients’ eligibility for biologic asthma therapy should be limited to asthma specialists (e.g., respirologists, allergists, pediatricians with a focus on childhood asthma), according to the clinician group input.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for dupilumab.

• Relevant comparators

• Considerations for initiation of therapy

• Considerations for continuation or renewal of therapy

• Considerations for discontinuation of therapy

• Considerations for prescribing of therapy

• System and economic issues

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

The VOYAGE study is a multinational, multicentre, randomized, double-blind, placebo-controlled study that compared dupilumab to placebo in patients aged 6 years to younger than 12 years with asthma who were already receiving standard of care. Four hundred and 8 patients with persistent asthma were randomized in 2:1 ratio to 1 dose of dupilumab (100 mg or 200 mg) every 2 weeks or placebo every 2 weeks, over a treatment course of 52 weeks. The primary outcome was the annualized rate of severe exacerbations, while the key secondary outcome was pulmonary function measurement (i.e., change from baseline in prebronchodilator percent predicted FEV₁ at week 12). There were 2 main efficacy populations assessed in the trial: type 2 inflammatory asthma phenotype population, characterized by a baseline blood eosinophil count of 150 cells/µL or greater or baseline FeNO of 20 ppb or greater, and baseline blood eosinophils of 300 cells/µL or greater.

The median age of patients included in the VOYAGE trial was 9 years (range = 6 to 11). Across both efficacy populations, the majority of patients were male (range = 64.4% to 69%), White (range = 86.3% to 89.5%), and had a body weight of greater than 30 kg (range = ||||||||||||||||||||). Greater than 60% of patients in the VOYAGE study had experienced 1 or 2 severe asthma exacerbations in the past year. At baseline, FEV₁ reversibility was slightly higher in the dupilumab versus placebo group, with a mean (standard deviation [SD]) of 21.5% (21.37) versus 15.81% (16.40) in the type 2 asthma population, and with a mean (SD) of 22.9% (23.23) versus 16.2 (15.8) in the population with baseline eosinophils of 300 cells/µL or greater. Regarding ICS dosing, greater than 40% of patients were on high dosing (dupilumab versus placebo: 43.2% versus 43.9% in the type 2 asthma population and 42.3% versus 48.8% in the baseline blood eosinophils ≥ 300 cells/µL population) and greater than 50% of patients were receiving medium ICS dosing (dupilumab versus placebo: 55.5% versus 56.1% in the type 2 population and 56.0% versus 51.2% in the baseline blood eosinophils ≥ 300 cells/µL population).

Efficacy Results

Mortality

In the VOYAGE trial, there were no deaths reported across the dupilumab and placebo groups.

Acute Asthma Exacerbation

The adjusted annualized rates of severe asthma exacerbations over 52 weeks in the type 2 inflammatory asthma population were 0.305 (95% CI, 0.223 to 0.416) with dupilumab and 0.748 (95% CI, 0.542 to 1.034) with placebo, for a relative risk (RR) of 0.407 (95% CI, 0.274 to 0.605; P < 0.0001) and a risk difference of ||||||||||||||||||||||||||||||. In the population with a baseline eosinophil count of at least 300 cells/µL at baseline, the adjusted rates of exacerbations were 0.235 (95% CI, 0.16 to 0.345) in the dupilumab and 0.665 (95% CI, 0.467 to 0.949) in the placebo group (RR = 0.353; 95% CI, 0.222 to 0.562; P < 0.0001; risk difference = |||||||||||||||||||||||||||||||||||||||| (Table 2).

RRs for the dupilumab versus placebo comparison of severe exacerbation events associated with ED visits or hospitalizations were |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| for the populations with type 2 asthma and baseline blood eosinophils of 300 cells/µL or greater, respectively. Rates associated with hospitalizations only were not estimable due to |||||||||||||||||||||||||||||| events experienced by the patients during the trial.

Asthma Symptoms

Symptoms were assessed using the 7-item ACQ (ACQ-7). At week 24, ACQ-7 scores decreased (improved) in both the dupilumab and placebo groups. The least squares (LS) mean (standard error [SE]) was –1.33 (0.05) in the dupilumab group and –1.00 (0.07) in the placebo group, for a LS mean difference versus placebo of –0.33 (95% CI, –0.50 to –0.16; P = 0.0001) in the type 2 population. In the population with a baseline blood eosinophil count of 300 cells/µL or greater, the LS mean (SE) change from baseline to week 24 was –1.34 (0.06) with dupilumab and –0.88 (0.09) with placebo, for a difference between groups of –0.46 (95% CI, –0.66 to –0.26; P < 0.0001).

Results were maintained during the trial period (to week 52) across both efficacy populations.

Reduction in Use of OCSs

The proportions of patients experiencing treatment with SCS during the trial was higher in the placebo compared to dupilumab arm (dupilumab versus placebo: 24.2% versus 40.4% within the type 2 inflammatory asthma phenotype and 22.3% versus 41.7% within the baseline blood eosinophils ≥ 300 cells/µL population). Adjusted RRs in annualized SCS courses, for the comparison of dupilumab to placebo, were 0.407 (95% CI, 0.272 to 0.609) and 0.340 (95% CI%, 0.212 to 0.545), within the type 2 inflammatory asthma phenotype and population with baseline eosinophils of 300 cells/µL or greater, respectively.

Pulmonary Function

The percent predicted prebronchodilator FEV₁ at week 12 increased in both the dupilumab and placebo groups in the type 2 inflammatory asthma phenotype population, with an LS mean difference between groups of 5.21% (95% CI, 2.14 to 8.27%; ||||||||||). Similarly, the LS mean difference at week 12 between the dupilumab and placebo group of 5.32% (95% CI, 1.76 to 8.88%, ||||||||||), in the population with a baseline blood eosinophil count of 300 cells/µL or greater, was reported. In both primary efficacy populations, LS mean changes in the percent predicted prebronchodilator FEV₁ were sustained through week 52.

Reduction in Dose of ICSs

The VOYAGE study protocol allowed a permanent increase in background medications after 2 or more severe asthma exacerbations. During the treatment period of the trial, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, across all efficacy populations assessed.

Health-Related Quality of Life–Paediatric Asthma Quality of Life Questionnaire

In type 2 inflammatory asthma phenotype population of the VOYAGE study, Standardised Paediatric Asthma Quality of Life Questionnaire PAQLQ(S) scores increased (improved) from baseline to week 52, with an LS mean difference between dupilumab and placebo groups of 0.34 (95% CI, 0.16 to 0.52, ||||||||||). In the population with at least 300 cells/µL baseline blood eosinophils values, similar differences at week 52 between groups were observed (LS mean = 0.33; 95% CI, 0.12 to 0.53; ||||||||||).

Reduction in Use of Rescue Medication

An overall decrease in number of puffs of reliever medications across the 24-hour period was observed in both treatment arms (LS mean differences between dupilumab and placebo groups at week 52 were |||||||||||||||||||||||||||||||||||||||| and |||||||||||||||||||||||||||||||||||||||| for the type 2 and baseline blood eosinophils ≥ 300 cells/µL populations, respectively).

Harms Results

In the VOYAGE trial, AEs occurred in 83% and 79.9% of patients in the dupilumab and placebo groups, respectively. The most common AEs in the dupilumab versus placebo groups were: nasopharyngitis (18.5% versus 21.6%), viral upper respiratory tract infection (12.2% versus 9.7%), pharyngitis (8.9% versus 10.4%), bronchitis (6.3% versus 10.4%), allergic rhinitis (5.9% versus 11.9%), injection site erythema (12.9% versus 9.7%), and injection site edema (10.3% versus 5.2%). SAEs were reported by 4.8% of patients receiving dupilumab and 4.5% of patients receiving placebo, the majority of which were asthma (dupilumab versus placebo: 1.5% versus 0%) and eosinophilia (dupilumab versus placebo: 0.7% versus 0%). Discontinuation due to an AE occurred in 1.8% versus 1.5% of patients of the VOYAGE study, in the dupilumab versus placebo groups, respectively.

Regarding notable harms, injection site reactions were the most commonly reported, by 17.7% and 13.4% of patients in the dupilumab and placebo groups, respectively. Hypersensitivity and anaphylactic reactions occurred in |||||||||||||||||||||||||||||| placebo patients and 0 dupilumab patients versus 1.5% placebo patients, respectively. In terms of infections, severe cases occurred in |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| of patients in the placebo group. Parasitic infections were reported only among patients in the dupilumab group (2.6%). Eosinophilia was more frequently occurring in dupilumab arm compared to placebo (6.6% versus 0.7%, respectively). More patients in the placebo group experienced conjunctivitis compared to dupilumab group (dupilumab versus placebo: 2.6% versus 6.7% for conjunctivitis [narrow] and 3.0% versus 7.5% for conjunctivitis [broad]).

Table 2: Summary of Key Results From Pivotal and Protocol Selected Study

ACQ-7 = 7-item Asthma Control Questionnaire; AE = adverse event; CFB = change from baseline; CI = confidence interval; LS = least squares; NE = not estimable; PAQLQ(S)-IA = Standardised Paediatric Asthma Quality of Life Questionnaire–Interviewer Administered; SAE = serious adverse event; SD = standard deviation; SE = standard error; vs. = versus.

Notes: Values are n (%) unless otherwise indicated.

Type 2 inflammatory asthma phenotype population is defined as the randomized patients with baseline blood eosinophils of 0.15 Giga/L or greater, or baseline FeNO of 20 parts per billion or greater.

All severe exacerbation events that occurred during the 52-week treatment period are included, regardless of whether the patient is on treatment or not.

For the PAQLQ(S)-IA assessment, only patients aged 7 years or older at randomization are included in the analysis.

Definitions of harms: Conjunctivitis (narrow company medical query): preferred term in (conjunctivitis, conjunctivitis allergic, conjunctivitis bacterial, conjunctivitis viral, atopic keratoconjunctivitis). Conjunctivitis (broad company medical query): preferred term in (conjunctivitis, conjunctivitis allergic, conjunctivitis bacterial, conjunctivitis viral, atopic keratoconjunctivitis, blepharitis, dry eye, eye irritation, eye pruritus, lacrimation increased, eye discharge, foreign body sensation in eyes, photophobia, xerophthalmia, ocular hyperaemia, conjunctival hyperaemia).

^aDerived using negative binomial model with the total number of events onset from randomization up to week 52 visit or last contact date (whichever comes earlier) as the response variable, with the treatment group, age, baseline weight group, region, baseline eosinophil level, baseline fractional exhaled nitric oxide level, baseline inhaled corticosteroid dose level, and number of severe exacerbation events within 1 year before the study as covariates, and log-transformed standardized observation duration as an offset variable.

^bDerived using delta method.

^cDerived from mixed-effect model with repeated measures with change from baseline in ACQ-7–Interviewer Administered up to week 24 as the response variable, and treatment, age, weight group, region, baseline eosinophil level, baseline fractional exhaled nitric oxide level, baseline inhaled corticosteroid dose level, visit, treatment by-visit interaction, baseline ACQ-7–Interviewer Administered and baseline-by-visit interaction as covariates.

Source: Clinical Study Report.⁷

Critical Appraisal

The VOYAGE trial is a multinational, multicentre, randomized, double-blind, placebo-controlled study. The study used a matching placebo-controlled design, and patients and investigators were blinded to the study treatment assignment, but not the dosing of the injections. Potential for unblinding might have also occurred because of higher frequencies of injection site reactions and eosinophilic reactions in the dupilumab arm compared to the placebo arm. Multiplicity adjustments were implemented adequately for the analysis of severe exacerbation events during the 52-week treatment period, change from baseline in prebronchodilator percent predicted FEV₁ at week 12, and change in the ACQ-7–Interviewer Administered (ACQ-7-IA) at week 24. Baseline characteristics were largely balanced between the groups of the study, except for FEV₁ reversibility, which was slightly higher in the dupilumab compared to the placebo group. Clinical experts consulted by CADTH regarded the selection of specific time points for outcome assessment and their inclusion in the hierarchy (i.e., FEV₁ at week 12 and ACQ-7 at week 24) as not optimal, noting that 52-week assessments would have been more clinically relevant. Many important outcomes such as HRQoL, exposure to OCSs, and ICS dose adjustments were not controlled for multiple comparisons. Even though treatment withdrawals were higher in the dupilumab group compared to placebo, proportions of individuals discontinuing study treatment due to an AE were balanced across the 2 study arms. The number of study withdrawals was generally low (< 6%) and appropriate sensitivity analyses were implemented to handle missing data for the primary and key secondary outcomes, suggesting limited impact on the validity of observed findings.

Dupilumab is indicated as add-on maintenance treatment in patients aged 6 years and older with severe asthma with a type 2 or eosinophilic phenotype or with OCS-dependent asthma. The current review focuses on the patient population of 6 years to 11 years of age, as dupilumab was previously reviewed by CADTH and received a positive recommendation for patients aged 12 years and older. Patients who were OCS-dependent were not included in the VOYAGE trial. The type 2 population was 1 of the main efficacy populations in the trial, defined as having a baseline blood eosinophil count of 150 cells/µL or greater or baseline FeNO of 20 ppb or greater, but the clinicians noted that FeNO assessments are not routinely performed in Canadian clinical practice, which represents an implementation limitation. Most of the VOYAGE trial population was White; hence, generalizability of study findings to people living in Canada may be limited in this regard. Even though background medications administered in the trial were considered reflective of treatments used in Canadian practice by the clinician experts, it was not clear whether inhaler technique was checked throughout the trial. Despite this, adherence to background therapy was high across both treatment groups and placebo responses were robust for many outcomes, suggesting that patients may have benefited from the close attention and monitoring they received in a clinical trial setting per the clinical experts consulted by CADTH. The VOYAGE trial compared dupilumab to placebo (added on to standard of care), which represents a limitation as comparative effectiveness and safety of dupilumab to other biologics approved for management of asthma in pediatric population is limited to available indirect comparisons.

Indirect Comparisons

Description of Studies

The sponsor submitted 1 indirect treatment comparison (ITC). No published ITCs were identified after a systematic search of the literature performed by CADTH. The sponsor-submitted ITC aimed to compare dupilumab to other biologics for the treatment of pediatric patients aged 6 to younger than 12 years with uncontrolled, moderate-to-severe asthma with a type 2 inflammatory phenotype. After a systematic literature review and a feasibility assessment, a total of |||||||||| connected via placebo as a common comparator were identified as eligible. A series of pairwise Bucher ITCs were performed on various outcomes (severe exacerbations, deterioration of asthma [post hoc analysis], asthma symptoms, rescue medication use, and HRQoL), comparing dupilumab (100 mg to 200 mg every 2 weeks) with the IgE inhibitor omalizumab (75 mg to 375 mg once or twice a month). Subgroup data were generated from the dupilumab trial population to match the allergic phenotype and inclusion criteria of omalizumab trials.

Efficacy Results

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Harms Results

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Critical Appraisal

Several limitations of the sponsor-submitted ITC were noted. There was considerable heterogeneity in study characteristics, patient populations and outcomes assessed across the studies included in the network. Since the population of interest for the ITC was the type 2 inflammatory population, an assumption was made that the efficacy of the IgE inhibitor omalizumab would be maintained in these patients. Even though there is clinical overlap between severe allergic and eosinophilic asthma according to the clinical experts, the amount of population concordance and its impact on indirect estimates could not be determined as omalizumab trials were not designed to include an eosinophilic asthma population. In addition, it is unclear whether the placebo link for the ITC was sufficiently similar for making comparisons, since data from the VOYAGE trial suggested a robust placebo response on several outcomes assessed in the trial. In reference to the subgroup analysis, matching specific groups of patients with dupilumab to the omalizumab studies lead to considerable reductions in sample size. A limited number of studies as well as limited available data restricted the possibility to perform meta-regression and account for differences across trials. There were no direct comparisons between treatments; therefore, the assessment of consistency was not feasible. In summary, due to various methodological limitations, no robust conclusions can be drawn about the comparative clinical efficacy of dupilumab versus omalizumab in the treatment of patients aged 6 years to 11 years with uncontrolled moderate-to-severe asthma.

Other Relevant Evidence

Description of Studies

The LIBERTY ASTHMA EXCURSION (EXCURSION) study was an open-label, noncomparative longer-term extension study that enrolled patients who completed the VOYAGE trial. The primary objective of EXCURSION was to assess long-term safety and tolerability of dupilumab. All patients received open-label treatment with dupilumab during the period of 52 weeks. A total of 365 patients were enrolled in EXCURSION, of which 240 patients had been assigned to dupilumab treatment in the parent trial (dupilumab–dupilumab group) and 125 had been assigned to placebo treatment in the parent trial (placebo–dupilumab group). All patients in EXCURSION were receiving their background medication (ICS with or without a second controller) as well as reliever therapy, if necessary. As per the database lock of January 17, 2022, the median duration of study was ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| for the dupilumab–dupilumab and placebo–dupilumab groups, respectively.

Efficacy Results

Severe Asthma Exacerbations

As of January 17, 2022, a total of ||||||||||||||||| of patients with type 2 inflammatory asthma phenotype in the dupilumab–dupilumab and placebo–dupilumab groups, respectively, experienced a severe exacerbation event. When looking at the patients with eosinophils of 300 cells/µL or greater at baseline of the parent study, ||||||||||||||||| experienced an event in dupilumab–dupilumab and placebo–dupilumab groups, respectively. The unadjusted annualized rate of severe exacerbation was 0.118 and 0.124 for the dupilumab–dupilumab and placebo–dupilumab groups, respectively, in the type 2 inflammatory asthma phenotype population. Similarly, in the subgroup with baseline eosinophils of 300 cells/µL or greater, the unadjusted annualized severe exacerbation event rate was 0.120 and 0.119, for the dupilumab–dupilumab and placebo–dupilumab groups, respectively.

Pulmonary Function

At week 52, mean (SD) changes from baseline in percent predicted prebronchodilator FEV₁ were |||||||||||||||||||||||||||||||||| for the dupilumab–dupilumab and placebo–dupilumab groups, respectively, in the type 2 inflammatory population, and ||||||||||||||||||||||||||||||||||||||||||||||||||| for the 2 groups, respectively, in the population with eosinophils of 300 cells/µL or greater.

Harms Results

Among patients who entered the EXCURSION study from the VOYAGE study, 61.3% of patients in the dupilumab–dupilumab and 68.0% of patients in the placebo–dupilumab groups reported at least 1 AE as per data cut-off of January 17, 2022. SAEs were experienced by 2.5% of patients in the dupilumab–dupilumab group and 0.8% in the placebo–dupilumab group. There were no deaths reported during the study period. AEs leading to discontinuation of the treatment were reported by 3 (1.3%) patients in the dupilumab–dupilumab group (pulmonary tuberculosis, ascariasis, and allergic conjunctivitis), and no patients in the placebo–dupilumab group.

In terms of notable harms, hypersensitivity was experienced |||||||||||||||||% of patients in the dupilumab–dupilumab and placebo–dupilumab groups, respectively, with ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| experiencing anaphylactic reaction. Other notable harms of interest reported during the long-term extension study period in the dupilumab–dupilumab versus placebo–dupilumab included: injection site reactions ||||||||||||||||||||||||||||||||||||||||||||||||||| conjunctivitis (4.2% versus 4.8%), eosinophilia (3.3% versus 8.0%), severe or serious infections (|||||||||||||||||), and parasitic infections (1.7% versus 1.6%).

Critical Appraisal

The EXCURSION trial provided additional data on the longer-term safety and efficacy of dupilumab relative to placebo. The validity of observed findings is limited due to the open-label and noncomparative study design. Statistical hypothesis testing was not part of the design. Furthermore, as the EXCURSION trial is a 1-year study, rare AEs might not be captured as of the data cut-off date. Given that the patients enrolled in the long term extension study were originally from the VOYAGE parent study, and the eligibility criteria remained the same, it is reasonable to expect that the same limitations to generalizability are relevant to EXCURSION.

Conclusions

One sponsor-submitted, multicentre, randomized, double-blind, phase III trial (VOYAGE), comparing add-on therapy with dupilumab to placebo in patients aged 6 years to younger than 12 years with persistent asthma demonstrated that dupilumab reduced the annualized rate of severe exacerbations and improved pulmonary function (FEV₁) in patients whose asthma remains uncontrolled despite background therapy with medium to high doses of ICSs. There was supportive evidence on the overall treatment benefit on asthma-related symptoms, as measured by ACQ-7, but the differences between the dupilumab and placebo groups did not exceed the minimal important difference (MID). HRQoL analyses were not controlled for multiple comparisons in this randomized controlled trial (RCT); thus, it remains unclear what the effect of add-on dupilumab on patients’ HRQoL is compared to placebo. Likewise, observed reductions in OCS usage were not part of the statistical hierarchy, which precluded drawing conclusions about the effects of dupilumab on this outcome. With respect to harms, there were no obvious safety or tolerability issues associated with the use of dupilumab in children. A longer-term extension study did not identify any new safety issues. Findings from the sponsor-submitted ITC were inconclusive with respect to the efficacy and safety of dupilumab compared to omalizumab due to numerous methodological limitations.

Introduction

Disease Background

Asthma is a chronic respiratory disorder characterized by reversible airway obstruction. Hallmarks of asthma include inflammation, bronchoconstriction, and airway remodelling, as well as hyperresponsive airways and mucous production.¹ Symptoms of asthma include wheezing, dyspnea, chest tightness, sputum production, and coughing, and these symptoms can be exacerbated by exogenous influences such as allergens, upper respiratory tract infections, or environmental factors such as smoke or cold air.¹ It is estimated that 2.4 million people living in Canada aged 12 years or older have asthma, or 12% of all children and 8% of adults.⁸ Moreover, prevalence data from the population of people living in Canada in 2011 and 2012 reported asthma estimates of 14% and 19% in children aged 5 years to 9 years and 10 years to 14 years, respectively.²

According to the clinical experts consulted for this CADTH review, asthma has several diverse phenotypes, 1 of which is primarily driven by type 2 inflammation, presenting with allergic or atopic profile and/or eosinophilic asthma. Eosinophils, among other functions, promote airway inflammation and contribute to airway hyperresponsiveness and remodelling,^9,10 and eosinophilic asthma is characterized by increased peripheral blood eosinophil counts. Severe type 2 or eosinophilic asthma tends to be asthma that is poorly controlled despite optimized ICSs, plus add-on therapy with a LABA or LTRA.¹¹

Standards of Therapy

Traditionally, the management of asthma is carried out using: medications for the acute relief of exacerbations (colloquially, “asthma attacks”), often referred to as “relievers” or “rescue medications”; and controllers, or maintenance drugs, which are used on a regular or chronic basis in an effort to prevent the onset of exacerbations.¹

The Global Initiative for Asthma (GINA) guidelines support a stepwise approach for asthma treatment in children aged 6 years to younger than 12 years. Of note, detailed GINA recommendations for the management of children aged 6 years to younger than 12 years with severe asthma are currently under development and only the stepwise diagram for treatment is available in the available GINA guidance documents. In step 1, patients begin using a low-dose ICS whenever a reliever medication (short-acting beta agonist [SABA]) is used. As symptoms persist, step 2 involves a low-dose ICS with as-needed SABA, with an alternative treatment option of a LTRA. From here, patients may need to escalate to step 3, which includes a combination of low-dose ICS and LABA with as-needed reliever (SABA), or medium-dose ICS with as-needed reliever (SABA), or maintenance and reliever therapy with a very low dose of ICS plus formoterol. Step 4 includes stepping up to a medium-dose ICS and LABA combination or maintenance and reliever therapy of a low dose of ICS plus formoterol, with an alternative addition of tiotropium or LTRA and recommendation for expert advice in case the asthma is not well controlled. Finally, step 5 involves referral to a phenotypic assessment and the use of a higher-dose ICS and LABA combination, with additional possibility of add-on treatment (i.e., anti-IgE, anti-IL5/5R, anti-IL4R) in case asthma control is not achieved.¹ Similarly, The Canadian Asthma Consensus Guidelines approach to therapy proposes SABA, or budesonide plus formoterol as needed for symptom control, and outlines low-dose, medium-dose, and high-dose ICSs for anti-inflammatory maintenance therapy, with add-on LTRA, LABA, and or tiotropium as necessary.³ In case the high-dose ICS with add-on therapy does not achieve control, treatment with OCSs and/or biologic therapy can be considered. According to the clinical experts consulted for this CADTH review, a very limited proportion of pediatric patients is on daily OCS therapy, but many patients may experience frequent or repeated short courses of OCSs. Monoclonal antibodies are the newest entrants into the asthma treatment paradigm for children aged 6 years to 12 years of age, such as an IgE inhibitor (omalizumab), IL-5 inhibitor (mepolizumab), and most recently IL-4 and IL-13 inhibitors (dupilumab). Nonpharmacologic therapies include asthma education, improvement of inhaler technique, allergen avoidance, and a written asthma action plan.¹ The clinical experts consulted by CADTH stated that patients aged 6 years to younger than 12 years who are not well controlled on an ICS and another controller (e.g., GINA step 4) would receive a high-dose ICS plus a LABA (or alternative controller) when considering adding a biologic. The experts indicated that the goal would be to gain asthma control in a timely way and to lower the ICS dose when control is achieved. Aligned with previously mentioned guidelines, a Canadian Thoracic Society statement from 2017 provides guidance on the management of severe asthma.¹¹

With respect to harms associated with pharmacologic therapies, chronic ICS use in children can have a number of concerning adverse effects, including growth retardation and adrenal suppression, particularly at high doses.¹² The use of OCSs heightens the risk of harms such as fractures and decreased bone density, and their chronic use should be limited in children, according to the clinical experts.

According to the clinical experts consulted by CADTH, the goals of asthma therapy in children aged 6 years to 12 years are to achieve asthma symptom control, decrease future risk of worsening, prevent persistent airflow limitation, and decrease the frequency of exacerbations, which will improve HRQoL. Additionally, limiting complications and long-term adverse effects of current therapy is another important goal of asthma management in children.

Drug

Dupilumab is an IL-4 and IL-13 inhibitor.⁵ Both IL-4 and IL-13 are thought to play a role in inflammation and in the pathophysiology of asthma, and dupilumab is a monoclonal antibody that targets both. Dupilumab is administered by subcutaneous injection in pediatric patients aged 6 years to 11 years at the dose of 100 mg every 2 weeks or 300 mg every 4 weeks for patients with a body weight from 15 kg to less than 30 kg, 200 mg every 2 weeks or 300 mg every 4 weeks for patients with a body weight from 30 kg to less than 60 kg, and 200 mg every 2 weeks for patients with a body weight of 60 kg or more. Dupilumab is indicated as add-on maintenance treatment in patients aged 6 years and older with severe asthma with a type 2 or eosinophilic phenotype or with OCS-dependent asthma. Dupilumab is also indicated for atopic dermatitis in patients aged 6 years and older and for chronic rhinosinusitis with nasal polyposis in adults.⁵

Dupilumab was previously reviewed by CADTH for the indication of severe asthma with a type 2 or eosinophilic phenotype or OCS-dependent asthma in patients aged 12 years and older (June 2021; recommendation to reimburse with clinical criteria and/or conditions), and for the atopic dermatitis indication in patients older than 12 years (April 2020; recommendation to reimburse with clinical criteria and/or conditions).^4,6

The sponsor has requested that dupilumab be reimbursed for patients aged 6 years to younger than 12 years with severe asthma with type 2 or eosinophilic phenotype characterized by the following: symptoms that are not controlled despite optimal treatment, defined by the daily use of a medium or high-dose ICS plus 1 controller medication or high-dose ICS alone; EOS of 150 cells/μL or greater or FeNO of 20 ppb or greater, or allergy-driven asthma; uncontrolled asthma having at least 1 severe exacerbation, defined by having experienced 1 or more hospitalization/emergency care visit or treatment with an SCS (oral or parenteral) in the past year; and a baseline assessment of asthma symptom control using a validated ACQ must be completed before initiation of dupilumab treatment. These criteria are in addition to the Health Canada indication.

Key characteristics of dupilumab and other biologics used for severe asthma are summarized in Table 3.

Table 3: Key Characteristics of Dupilumab, Mepolizumab, and Omalizumab

ICS = inhaled corticosteroid; IgE = immunoglobulin E; IgG = immunoglobulin G; IL = interleukin; LABA = long-acting beta agonist; OCS = oral corticosteroid; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SC = subcutaneously.

^aHealth Canada–approved indication.

Source: Product monographs for dupilumab,⁵ mepolizumab,¹³ and omalizumab.¹⁴

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient input(s) received by CADTH have been included in the stakeholder section at the end of this report.

Asthma Canada, the only national charity advocating for people with asthma and respiratory allergies, submitted patient group input based on a survey conducted between February and March, 2022, in addition to several other sources. More than 100 patients (92%) and caregivers (8%) across all provinces responded to the survey, including 4 patients having with experience with dupilumab. Another patient group, Lung Health Foundation, a registered charity that empowers people living with or caring for others with lung disease, submitted input based on a survey conducted between January 2021 and June 2022 from 27 patients with asthma and 2 caregivers, all living in Ontario.

One in 4 Asthma Canada survey participants indicated they have poor symptom control even with currently available treatments. Furthermore, many patients reported challenges in accessing the needed health providers, such as respirologists and specialized asthma clinics, to manage their health. When patients live in rural areas and must travel to get necessary care, children miss school and parents and caregivers miss work. The respondents said that managing care can require a significant amount of time and be a burden, which can be made worse with poor asthma control. Respondents emphasized that timely access to care becomes critical when patient must urgently travel to the ED for exacerbations that can be life-threatening and to restore airway function. Approximately 60% of respondents said that they worry about or have a fear of exacerbations; 47% respondents said they are concerned about potential hospital visits or admissions, which can be stressful; and 47% of survey participants said missed work and school days are concerning. In addition, some of the challenges that affect children with asthma identified by respondents were difficult techniques involved with inhaler use, other children not adequately understanding the impact of asthma on daily lives, making and keeping friends made difficult by fatigue and less energy, activity limitations that could be worsened by environmental triggers, inability to attend and concentrate at school, sleep disturbances, and significant time spent on educating friends, daycares, schools, and others about the seriousness of asthma. According to the patient group input, financial hardships associated with paying for asthma treatments are added stress. Lastly, the respondents to Asthma Canada survey said that drug shortages caused by limited supply have also impacted children living with asthma.

The Lung Health Foundation input highlighted that asthma symptoms such as shortness of breath (74.2%), fatigue (67.7%), and cough (51.6%), as well as difficulties in activities of daily living such as climbing stairs (43.4%), housework (40.0%), and physical activities (40.0%) are the challenging part of living with asthma. In addition, respondents to the Lung Health Foundation survey said that the negative impacts of asthma included waking up at night or in the early morning due to breathing problem (34.5%), emotional well-being (37.9%), and being short-tempered or inpatient with others (31.0%). They said they want treatments that improve symptom management, energy, and quality of life, as well as reduce exacerbations. In addition, the respondents indicated they wanted treatments with a reduced cost to the patient and caregiver.

Patients indicated that they want a new medication that can be another treatment option for children with severe asthma and their families to ease burden on patients, families, caregivers, and the health care system by increasing lung function (73%), making management of symptoms easier (61%), reducing exacerbations (56%) and reducing reliance on OCSs (56%). Also, children with asthma and their parents expect to see improved day-to-day activities affecting quality of life, such as attendance at school, sleep, energy, participation in activities, as well as less health care visits including those to the ED, less anxiety and panic (for potential exacerbations), less time off work, and less financial hardships. Respondents said they would like to minimize side effects of medication; however, they are willing to tolerate certain side effects to improve management of their asthma. One in 4 survey participants indicated that they need too many daily doses, therefore, a medication that can be taken less frequently and administered easily would be helpful for children with severe asthma.

Lastly, it was noted that children receiving dupilumab cannot be vaccinated with live vaccines (e.g., hepatitis, meningococcal, and HPV vaccines), which can be challenging for children who may not be fully immunized.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding 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 asthma.

Unmet Needs

According to the clinical experts consulted by CADTH, the main goals of asthma therapy in children include achieving asthma symptom control, decreasing the risk and frequency of acute asthma exacerbations, and preventing sequelae of long-term uncontrolled asthma (i.e., fixed or only partially reversible airflow limitation). Additionally, limiting complications and long-term adverse effects of inhaled and OCSs among children was identified as important goal by the clinicians.

There are no treatments available that would cure asthma, but long-term control can be achieved for many patients, according to the experts. The clinical experts reported that the majority of patients achieve excellent control with existing medications and treatments, aligned with the Canadian Asthma Consensus Guidelines.³ The experts noted that increasing medication adherence, adopting self-management techniques and inhaler education are also important, yet challenging to adopt, factors in reaching asthma treatment goals. The clinical experts also stressed that a subset of patients will remain poorly controlled despite adoption of the best practices for asthma treatment.

Place in Therapy

The clinical experts reported that dupilumab would be utilized in treating children and youth with uncontrolled moderate-severe type 2 inflammatory asthma (i.e., individuals who remain uncontrolled on high-dose ICSs with add-on therapy [LABA and/or LTRA] and requiring ongoing or multiple courses of SCSs). Hence, they indicated that dupilumab would not be implemented as a first-line therapy, but would be a therapy used when conventional treatment has not achieved asthma control.

According to the clinical experts, biologic agents targeting IgE-mediated disease (e.g., the anti-IgE drug omalizumab) and decreasing eosinophilic inflammation (e.g., the anti-IL5 drug mepolizumab) have found limited use among pediatric patients in the Canadian setting so far. The clinicians noted that dupilumab therapy addresses a specific aspect of the inflammatory cascade (the IL-4 and IL-13 pathway) and highlighted its novelty in this regard.

Patient Population

The clinical experts reported that the target population for dupilumab would include individuals with moderate-to-severe asthma who have not achieved optimal asthma control despite conventional therapy and clearly present with an inflammatory phenotype. The type 2 inflammatory profile can be assessed by peripheral blood eosinophil levels in the Canadian context to determine initiation of therapy. The experts highlighted that the VOYAGE trial enrolled patients with type 2 inflammatory asthma (i.e., peripheral blood EOS > 150 cells/μL or FeNO > 20 ppb), and that the eosinophilic criteria might have implementation difficulties in certain laboratory facilities across Canada, which routinely measure rounded values of EOS (i.e., 100 cells/μL, 200 cells/μL, 300 cells/μL, and so forth). Furthermore, clinicians noted that FeNO assessments are not routinely performed in most Canadian centres.

Both clinical experts stated that misdiagnosis of asthma is common. Clinicians felt that 6 years of age represents a limit for reliable and reproducible pulmonary function measurement. Therefore, children older than 6 years can undergo pulmonary function and reversibility testing, which is required for confirming the diagnosis of asthma. According to the pediatric clinical experts, under-diagnosis of patients with moderate-to-severe asthma can sometimes be observed in the clinical practice.

Assessing Response to Treatment

The clinical experts reported that outcomes used clinically to assess response to treatment are typically targeting assessment of asthma control. Specifically, clinicians reported the following outcomes to be of relevance: improvements in pulmonary function testing, decreases in acute asthma exacerbations, improvements in symptom control, and improvements in quality of life scores. A validated measure such as the ACQ can be used to objectively assess improved control; however, 1 clinician reported that the instrument is mostly used for research purposes and is not used on a regular basis within the everyday clinical care. In addition, the experts reported that decreased health care resource utilization, improvement in ability to perform activities of daily living, and ability to participate in recreational activities can be considered supportive of a positive treatment effect of dupilumab. Regarding the frequency of disease assessments, the clinical experts reported that patients with moderate-to-severe asthma would be assessed in specialty asthma clinics approximately 2 to 4 times per year, depending on the asthma severity and clinic resources.

Discontinuing Treatment

According to the clinical experts, evidence of lack of impact on pulmonary function testing, asthma symptom control, acute exacerbations, and quality of life assessment need to be accounted for when considering discontinuation from therapy. Moreover, treatment with dupilumab should be discontinued the in case of SAEs (e.g., serious immune/allergic reactions, serious dermatological reactions, malignancy, and ophthalmologic AEs).

Prescribing Conditions

Clinical experts indicated that treatment with dupilumab should be initiated by a pediatric respirologist or allergy specialist with significant pediatric experience. For patients living in rural or remote areas, physician care could be provided in liaison with 1 of the previously mentioned specialists, while optimal access to care can be achieved though the implementation of telehealth practices.

Additional Considerations

One clinician reported that concomitant treatment of atopic dermatitis as an outcome should be considered, as atopic dermatitis may have significant adverse effects upon quality of life of patients.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The full original clinician group input(s) received by CADTH have been included in the stakeholder section at the end of this report.

A total of 6 clinicians from the Canadian Thoracic Society (2 Canadian Thoracic Society Asthma Assembly Co-chairs and 4 pediatric respirologists from the Asthma Assembly Steering Committee) submitted clinician group input. The Canadian Thoracic Society is a national professional association for health care providers in respiratory care and research. The Canadian Thoracic Society promotes lung health and enhances the ability of health care providers through leadership, collaboration, research, learning, and advocacy, as well as providing the best respiratory practices in Canada. The Canadian Thoracic Society is also an accrediting body for specialist education and continuing professional development.

Unmet Needs

The clinician group stated that key goals of asthma control are to prevent asthma exacerbations, which can be life-threatening, maximize quality of life, prevent symptoms, and maximize exercise tolerance.

Secondary goals in asthma management include normalizing lung function, reducing airway inflammation, avoiding permanent airway remodelling, avoiding chronic use of OCSs, and using the lowest effective dose of ICSs to avoid growth suppression, adrenal suppression, and other significant side effects of corticosteroids in children.

The clinician group reported that in a relatively small subgroup of children with severe asthma, acceptable control requires high doses of ICSs and/or OCSs and add-on therapies, which puts them at a high risk of significant AEs. In some children, acceptable control cannot be achieved with these therapies and these patients experience frequent exacerbations that require OCSs. The clinician group indicated that chronic OCSs are not a viable treatment option given their side effect profile and highlighted that the recurrent use of OCSs is associated with a high risk of side effects.

According to the clinicians, children with severe asthma have limited treatment options compared to the adult population. Currently, the American Thoracic Society/European Respiratory Society,¹⁵ but not the Canadian Thoracic Society³ recommend tiotropium. However, tiotropium is not approved for those younger than 18 years in Canada and is not regularly used off-label in children aged 6 years to 11 years. The Canadian Thoracic Society and the American Thoracic Society/European Respiratory Society both recommend omalizumab for children aged 6 years to 11 years who meet the initiation criteria. However, the guidelines only include clinical trials published up to 2018. Lastly, mepolizumab is approved in Canada for children aged 6 years to 11 years with severe asthma but has not been widely used.

The clinician group identified other unmet needs. In younger children with severe asthma who have nontype 2 inflammation involving neutrophilic inflammation and recurrent severe exacerbations caused by viral acute respiratory tract infections, effective add-on therapies have not been identified when ICSs fail. Similarly, in a subgroup of older children with severe asthma who have neutrophil-triggered inflammation, effective add-on therapies are also needed.

Place in Therapy

The clinician group stated that dupilumab (an anti-IL4/IL-13 drug) targets different inflammatory pathways than omalizumab (an anti-IgE drug) and mepolizumab (an anti-IL5 drug); therefore, complements other available treatments. Following the Canadian Thoracic Society³ Severe Asthma Management Continuum, dupilumab would be considered as an add-on therapy in severe asthma when other biologics are indicated. Also, the group reported dupilumab could be helpful when asthma is not well controlled on a combination of a high-dose ICS, LABA, and LTRA, or when a child experiences significant side effects from these medications, or when these medications are contraindicated. The clinician group emphasized that since injectable medications can be less acceptable due to a higher burden on families and higher costs for the health care system, it is recommended to use biologics based on the child’s inflammatory profile and only after standard therapy has been adequately tried with good adherence.

Moreover, the clinician group suggested that when children with severe asthma concomitantly have atopic dermatitis, when children are allergic to or have had SAEs with mepolizumab, or when there is supply issue with mepolizumab, dupilumab can be a therapeutic option.

Patient Population

Based on input, patients aged 6 years to 11 years with type 2 inflammation, moderate-to-severe asthma not adequately controlled on a medium-dose ICS plus LABA (or other second controller) or high-dose ICS (or OCS) and who experienced a severe exacerbation in the past year are most likely to respond to dupilumab treatment. (Type 2 inflammation is defined as having a serum eosinophil count ≥ 150 cells/μL and FeNO ≥ 20 ppb or a serum eosinophil count ≥ 300 cells/μL.) The group added that those with an eosinophil count of greater than 300 cells/μL and a baseline FeNO of 25 ppb have shown to have the best response to dupilumab. However, the group said that there is still a good response with a lower-level eosinophil count as long as it is greater than 150 cells/μL.

According to the clinician group, the 2 markers of type 2 inflammation, namely an eosinophil count of greater than 150 cells/μL and FeNO elevation, are the only disease characteristics that would make differences in responses.

The clinician group indicated that the best-suited physicians to identify eligible patients are respirologists or allergists, who must confirm diagnosis based on symptoms and airway reversibility measured by spirometry (FEV₁ change > 10%). If not under the care of a respirologist or allergist, the clinician group indicated that patients must be referred and assessed with spirometry, clinical exam, differential complete blood count (serum EOS), and FeNO, if available.

Assessing Response to Treatment

The clinician group said that clinically meaningful outcomes include reduced frequency and severity of symptoms, improved quality of life, and minimized side effects from existing maximal therapy (e.g., corticosteroids). Reducing daily medication burden and improving compliance are also noted as potential outcomes to measure response. Other outcomes, such as reduced inflammatory markers, improved lung function, and prevention of long-term airway remodelling are additional outcomes to determine response to treatment. The clinical measures, such as ACQs, FEV₁, and exacerbation rates are routinely used in clinical practice and do not differ among specialists. However, according to the clinician group, the inflammatory markers may not be routinely used or accessible in clinical practice and may vary in their application.

Discontinuing Treatment

The clinician group said that a lack of clinically meaningful positive outcomes over an expected time frame, such as similar (or worse) rate of exacerbation, prebronchodilator FEV_1, or patient symptom scores compared to pretreatment levels, is a reason to consider discontinuing treatment. Additionally, the group mentioned that safety concerns and patient’s choice could also play roles in making decision to discontinue treatment.

Prescribing Conditions

The clinician group cited the Canadian Thoracic Society Position Statement for the Recognition and Management of Severe Asthma¹¹ for prescribing conditions. They said that “asthma specialists,” including but not limited to respirologists, allergists, and pediatricians with a focus on childhood asthma or who are specialists in asthma, general respirology, or allergy/immunology, and who have access to lung function tests and certified asthma or respiratory educators or nurse practitioners should assess a child for eligibility for biologic asthma therapy. According to the clinician group, an asthma specialist should diagnose, treat, and monitor for adherence and correct administration techniques.

The clinician group suggested the first 1 or more doses of dupilumab be administered by a health care practitioner in a hospital or medical setting. Following this, injection by a caregiver who has received proper training on correct administration can be undertaken in the community setting, such as in the home, if the health care practitioner determines it appropriate.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s 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 by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

CDEC = Canadian Drug Expert Committee; EOS = eosinophils; ER = emergency room; FeNO = fractional exhaled nitric oxide; ICS = inhaled corticosteroid; IgE = immunoglobulin E; LABA = long-acting beta agonist; LAMA = long-acting muscarinic antagonist; LTRA = leukotriene receptor antagonist; OCS = oral corticosteroid; pCPA = pan-Canadian Pharmaceutical Alliance.

Clinical Evidence

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

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of dupilumab (200 mg/1.14 mL [prefilled syringe)] and 300 mg/2 mL [prefilled syringe]) for the add-on maintenance treatment of severe asthma with a type 2 or eosinophilic phenotype or OCS-dependent asthma in patients aged 6 years to younger than 12 years.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

ACQ = Asthma Control Questionnaire; AE = adverse event; ED = emergency department; FEV₁ = forced expiratory volume in 1 second; HRQoL = health-related quality of life; ICS = inhaled corticosteroid; IgE = immunoglobulin E; IL = interleukin; OCS = oral corticosteroid; PEF = peak expiratory flow; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; RCT = randomized controlled trial; SABA = short-acting beta agonist; SAE = serious adverse event; SAMA = short-acting muscarinic antagonist; WDAE = withdrawal due to adverse event.

^aFor children (6 years to 11 years) with asthma, no initial loading dose is recommended.⁵

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.¹⁶

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Dupixent (dupilumab) and asthma. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

CADTH-developed search filters were applied to limit retrieval to RCTs or controlled clinical trials. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on July 27, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on November 23, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.¹⁷ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

One study was identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of Included Studies

ACQ-5-IA = 5-item Asthma Control Questionnaire–Interviewer Administered; AE = adverse event; EQ-5D-Y = EQ-5D-Youth; FEF = forced expiratory flow; FeNO = fractional exhaled nitric oxide; FEV₁ = forced expiratory volume in 1 second; FVC = forced vital capacity; GINA = Global Initiative for Asthma; ICS = inhaled corticosteroid; IgE = immunoglobulin E; IgG = immunoglobulin G; LABA = long-acting beta agonist; LAMA = long-acting muscarinic antagonist; LOAC = loss of asthma control; LTRA = leukotriene receptor antagonist; PACQLQ = Paediatric Asthma Caregiver's Quality of Life Questionnaire; PAQLQ(S)-IA = Standardised Paediatric Asthma Quality of Life Questionnaire–Interviewer Administered; PEF = peak expiratory flow; PRO = patient-reported outcome; PRQLQ-IA = Pediatric Rhinoconjunctivitis Quality of Life Questionnaire–Interviewer Administered; q.2.w. = every 2 weeks; SCS = systemic corticosteroid; TARC = thymus and activation regulated chemokine.

Source: Clinical Study Report.⁷

Description of Studies

The VOYAGE RCT was designed with a primary objective to assess the efficacy of add-on dupilumab compared to placebo in children aged 6 year to younger than 12 years with uncontrolled persistent asthma who were already receiving standard of care. Secondary goals of the VOYAGE trial were to investigate safety and tolerability of dupilumab, evaluate patient-reported outcomes and HRQoL, and assess systemic exposure and association between treatment and pediatric immune responses to vaccines.

There were 2 primary efficacy populations in the trial: the type 2 inflammatory population, defined as either a baseline blood eosinophil count of 150 cells/µL or greater or baseline FeNO of 20 ppb or greater; and a population with a baseline blood eosinophil count of 300 cells/µL or greater.

The study randomized patients in a 2:1 ratio to receive a subcutaneous injection of dupilumab or placebo. Patients were randomized from 90 centres in 17 countries, including Canada. Patients and investigators were blinded to the study treatment assignment, but not to the dose of the injections. Dupilumab and placebo were provided in identically matched prefilled syringes, labelled with a treatment kit number generated by the sponsor.

The randomized treatment kit number list was generated centrally using interactive voice response system or interactive web response system. Randomization was stratified by ICS dose level (medium or high) at screening, blood eosinophil count (< 300 cells/µL and ≥ 300 cells/µL) at screening, and region (Latin America, Eastern Europe, and Western countries).

The study consisted of 3 periods (Figure 2):

• Screening (4 ± 1 weeks) to collect baseline data on asthma control and assure eligibility criteria

• Randomized double-blind treatment (up to 52 weeks)

• Posttreatment period (12 weeks)

Eligible patients who completed the randomized treatment period of the study were offered the opportunity to participate in the 1-year long-term extension study, EXCURISON.²⁰ Patients who enrolled in the extension study were excluded from the posttreatment period of the trial.

The first patient was randomized on April 21, 2017, and the last patient completed the study on August 26, 2020. According to the VOYAGE trial protocol, the database lock was planned based on the time when all randomized patients completed the week 52 visit or discontinued from the study before week 52.

Figure 2: Study Design of the VOYAGE Trial

D = day; EOS = end of study; EOT = end of treatment; ICS = inhaled corticosteroids; q.2.w. = every 2 weeks; R = randomization; SC = subcutaneous.

Note: Background medications include medium-dose ICS plus second controller, or high-dose ICS alone, or high-dose ICS plus second controller.

Source: Clinical Study Report.⁷

Populations

Inclusion and Exclusion Criteria

VOYAGE included patients with asthma aged 6 years to younger than 12 years who were on existing background therapy of medium-dose ICSs in combination with a second controller (i.e., LABA, LTRA, long-acting muscarinic antagonist [LAMA], or methylxanthines) or high-dose ICSs alone or in combination with a second controller for at least 3 months and on a stable dose of at least 1 month before the study. Patients had to have a prebronchodilator FEV₁ of 95% or less of predicted normal or postbronchodilator reversibility of at least 10% or greater, showed evidence of uncontrolled asthma during the screening period and had either been treated with an SCS or been hospitalized or visited an ED for worsening asthma within the past year.

Patients were excluded if their body weight was less than 16 kg, if they had other chronic lung diseases or history of life-threatening asthma (e.g., requiring intubation), and if they had a history of any malignancies or current comorbidities that may interfere with the drug under study. Moreover, nonadequate adherence with background therapy during the screening period (< 80% of total number of prescribed doses) was also an exclusion criterion in the trial.

Baseline Characteristics

In the VOYAGE trial, median age of patients was 9 years (range = 6 to 11) across type 2 inflammatory asthma phenotype and population with baseline blood EOS of 300 cells/µL or greater. Most patients were male (range = 64.4% to 69% across the study groups in the 2 efficacy populations), White (range = 86.3% to 89.5% across the study groups in the 2 efficacy populations) and weighed more than 30 kg (range = 66.7% to 68.4% across the study groups in the 2 efficacy populations). Within the type 2 inflammatory asthma phenotype population, a greater proportion of individuals had blood eosinophilic counts of 300 cells/µL or greater (74.2% in the dupilumab and 73.7% in the placebo group). Although slight imbalances were observed across the groups in terms of number severe exacerbations (1, 2, 3, or ≥ 4) in the year before the study enrolment, the average number of exacerbations (mean [SD]) reported were 2.61 (2.58) in the dupilumab and 2.18 (1.55) in the placebo groups for the type 2 asthma population, and 2.78 (2.90) in the dupilumab and 2.37 (1.71) in the placebo groups for the population with baseline blood EOS of 300 cells/µL or greater. FEV₁ reversibility was larger in the dupilumab than placebo group, with a mean (SD) of 21.5% (21.37) versus 15.81 (16.4) in the type 2 asthma population, and with a mean (SD) of 22.9% (23.23) versus 16.2 (15.8) in the population with baseline blood EOS of 300 cells/µL or greater. Regarding the ICS dosage, approximately 43% of patients were on a high-dose ICS and 55% were on a medium-dose ICS within the type 2 asthma population. In the population with baseline blood EOS of 300 cells/µL or greater, approximately 45% of patients were using high doses of an ICS (dupilumab versus placebo: 42.3% versus 48.8%), and approximately 53% of patients were using medium doses of an ICS (dupilumab versus placebo: 56.0% versus 51.2%). Three patients in the dupilumab group were on a low-dose ICS, which was a protocol violation (Table 7).

Baseline characteristics of other efficacy populations (intention-to-treat [ITT] and baseline EOS ≥ 150 cells/µL populations) are presented in the Appendix 3.

Table 7: Summary of Baseline Characteristics

ACQ-5-IA = 5-item Asthma Control Questionnaire–Interviewer Administered; ACQ-7-IA = 7-item Asthma Control Questionnaire–Interviewer Administered; FeNO = fractional exhaled nitric oxide; FEV₁ = forced expiratory volume in 1 second; ICS = inhaled corticosteroid; IgE = immunoglobulin E; PEF = peak expiratory flow; SD = standard deviation.

Notes: Values are n (%) unless otherwise indicated.

A patient is considered to have an ongoing atopic medical condition if they have any of the following ongoing conditions: atopic dermatitis, allergic conjunctivitis, allergic rhinitis, eosinophilic esophagitis, food allergy, or hives or has baseline total IgE of 100 IU/mL or greater and at least 1 aeroantigen-specific IgE is positive (≥ 0.35 IU/mL) at baseline.

^aLatin America includes Argentina, Brazil, Colombia, Chile, and Mexico; Eastern Europe includes Poland, Hungary, Romania, Lithuania, Russia, Ukraine, and Turkey; Western Countries include Australia, Canada, Italy, South Africa, Spain, and US.

^bSevere asthma exacerbation before the study is defined as any treatment with 1 systemic (oral or parenteral) steroid burst or more for worsening asthma or hospitalization or an emergency/urgent medical care visit for worsening asthma.

Source: Clinical Study Report.⁷

Interventions

In the VOYAGE trial, the dupilumab 100 mg dose was administered subcutaneously in a 0.67 mL syringe (for patients with a body weight ≤ 30 kg) and the 200 mg dose was administered in a 1.14 mL syringe (for patients with a body weight > 30 kg), once every 2 weeks. To maintain blinding, the 100 mg dose was matched to a 0.67 mL placebo and the 200 mg dose was matched to a 1.14 mL placebo delivered once every 2 weeks.

After week 12, parents, caregivers, and legal guardians of patients were allowed to perform home administration of dupilumab if they elected to do so and if they followed a training demonstration and completed administration under close supervision by the investigator or delegate at not less than 3 visits.

Temporary treatment discontinuation could be considered by the investigator because of AEs, infections or infestations that do not respond to medical treatment, and laboratory abnormalities. Re-initiation of treatment was conducted after close monitoring, once clinical consideration that the AEs occurrence was not related to the treatment under study was complete and if the eligibility criteria for the study were still met.

Permanent discontinuation from the treatment and the study may have occurred on patients’ or patients’ legal representative request or based upon clinical investigators’ decision. Moreover, patients’ study withdrawal occurred for the following additional reasons: specific request from the sponsor, in case of protocol deviation, pregnancy, occurrence of anaphylactic reactions or systemic allergic reactions related to the treatment under study, malignancy diagnosis, opportunistic infections, levels of serum alanine transaminase greater than 3 times the upper limit of normal, and total bilirubin greater than 2 times the upper limit of normal.

After permanent treatment discontinuation, patients were encouraged to complete the remaining study visits according to the visit schedule until the end of study or up to recovery or stabilization of any AEs.

Background medications, including ICSs and second controller and reliever medications were administered during the trial and their usage was recorded. Patients supplied their controller medication.

Prior to study entry, patients needed to be on a stable dose of a medium-dose ICS with a second controller medication, high-dose ICS alone, or high-dose ICS for at least 3 months with at least 1 month of stable dose before the first visit. Dosing levels considered as medium- or high-dose ICS in children aged 6 years to younger than 12 years were aligned with the GINA guidelines, 2015 version.¹⁸ Only 1 second controller medication (LABA, LTRA, LAMA, or methylxanthines) for combined use with medium- or high-dose ICS was permitted. Use of a reliever medication other than albuterol/salbutamol or levalbuterol/levosalbutamol was discouraged.

During the treatment period, patients were on their baseline dose regimen of the controller medication(s) used during screening. Patients who experienced a deterioration of asthma during the trial were allowed to have an up to 4-fold increase in their ICS dose temporarily, for a maximum of 10 days (recorded as a loss of asthma control event). At that point, treatment could have been changed to SCSs (severe exacerbation event) or reverted to the original ICS dose depending on the progression of symptoms. Permanent adjustments to the controller medication dosing (i.e., step up in medium- to high-dose ICS or addition of second controller for patients on high-dose ICS monotherapy) were allowed only if the patient experienced 2 or more severe exacerbations events at any time during the trial. SCSs were allowed at any time in case of clinical symptoms of severe asthma exacerbation event, per the judgment of the study investigator.

During the posttreatment period, patients not continuing with the long-term open-label extension study, were treated with the controller medication regimen and dose used during the randomized treatment period. Adjustments were possible based on patients’ status and clinical judgment of the investigator.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 8. These end points are further summarized in the following. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Table 8: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

ACQ-5 = 5-item Asthma Control Questionnaire; ACQ-7 = 7-item Asthma Control Questionnaire; AE = adverse event; ED = emergency department; EQ-5D-Y = EQ-5D-Youth; FeNO = fractional exhaled nitric oxide; FEV₁ = forced expiratory volume in 1 second; HRQoL = health-related quality of life; ICS = inhaled corticosteroid; ITT = intention to treat; OCS = oral corticosteroid; PEF = a.m./p.m. peak expiratory flow; PACQLQ = Paediatric Asthma Caregiver's Quality of Life Questionnaire; PAQLQ(S)-IA = Standardised Paediatric Asthma Quality of Life Questionnaire–Interviewer Administered; PRQLQ-IA = Pediatric Rhinoconjunctivitis Quality of Life Questionnaire–Interviewer Administered; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

Source: Clinical Study Report.⁷

Severe Exacerbation Events

The annualized rate of severe asthma exacerbations during the 52-week period was the primary outcome of the VOYAGE trial. Severe exacerbations were defined as a deterioration in asthma that required the use of SCSs for at least 3 days or resulted in hospitalizations or ED visits requiring SCSs. Two events were considered as different if the interval between their start dates was at least 28 days. The reasons behind any exacerbation event (e.g., infections including viral and bacterial, allergen exposure, exercise, and others) were recorded in the electronic case report form. Study investigators were responsible for maintaining accurate and timely electronic case report forms, which were initially designed by the sponsor.

Patients who permanently discontinued the study medication were asked and encouraged to continue with all the remaining study visits and their additional off-treatment severe exacerbation events up to week 52 were recorded. Patients who discontinued treatment were not eligible for the 1-year long-term extension study.

Pulmonary Function

Spirometry was performed following American Thoracic Society/European Respiratory Society 2005 guidelines.²¹ The key secondary outcome was change from baseline in prebronchodilator percent predicted FEV₁ at week 12, while the measurements at other time points (weeks 2, 4, 8, 24, 36, and 52) were considered secondary end points. Spirometry was to be performed preferably during morning hours and at the same time every day, using the same spirometer and standardized techniques.

Measurements of morning and evening peak expiratory flow (PEF) were recorded through daily assessments and collection using an electronic diary and PEF metre by caregiver(s) of the patients. Both morning and evening PEF measurements were performed before intake of any reliever medications. Three values were collected and the highest 1 was used for evaluation.

Electronic diaries were also used to record the number of inhalations of relievers used for symptom relief in a day, number of inhalations of background medication, and record OCS use for an exacerbation event.

ACQ-7-IA and 5-item ACQ–Interviewer Administered

The ACQ is a questionnaire designed to assess the degree of asthma control with questions on symptoms (completed by the patient and/or their caregiver), including activity limitation, nocturnal waking, shortness of breath, wheezing, and symptoms on waking. Moreover, the average number of daily doses of rescue inhaler used, as well as spirometry measured as FEV₁ (completed by clinic staff, including prebronchodilator use, percent and percent predicted use). The ACQ-7 has 7 items with each measured on a 7-point scale scored from 0 (totally controlled) to 6 (severely uncontrolled). Clinical staff score the percent predicted FEV₁ on a 7-point scale based on the spirometry result.^22-24 The ACQ-7 score is computed as the unweighted mean of the responses to the 7 questions. Changes of at least 0.5 are considered to be clinically meaningful.^24,25 ACQ assessments were conducted every 2 weeks up to the week 12, and then every 4 weeks until end of study visit of the VOYAGE trial.

The 5-item ACQ–Interviewer Administered (ACQ-5-IA) scores were deduced from the responses to the first 5 questions of ACQ-7-IA and were applied to patients aged 6 years to younger than 12 years in the VOYAGE trial.

PAQLQ(S)–Interviewer Administered

The PAQLQ(S) disease-specific instrument comprises 23 items across 3 domains: symptoms (10 items), activity limitation (5 items), and emotional function (8 items), which are graded on a 7-point Likert scale (1 = maximum impairment, 7 = no impairment).A standardized format of the instrument was used in the trial, which included generic activity questions (physical activity, activities with animals, and activities with friends and family). It was applied to patients who were aged 7 years and older in the VOYAGE trial. A global score ranges from 1 to 7, with higher score representing better HRQoL.^26-28 The MID of approximately 0.5 was identified for the overall quality of life score.²⁷ Assessments during VOYAGE trial were conducted every 12 weeks until end of study visit.

Paediatric Asthma Caregiver's Quality of Life Questionnaire

The PACQLQ is a self-administered 13-item questionnaire capturing the impact of child’s asthma on quality of life of the parent(s), caregiver(s), and legal guardian(s). The items are organized in 2 domains (4 items concern activity limitations and 9 concern emotional function). Responses to the individual items are given on a 7-point Likert scale where 1 (all of the time/very very worried or concerned) represents severe impairment and 7 (none of the time/not worried or concerned) represents no impairment. In the VOYAGE trial, the instrument was administered among parent(s), caregiver(s), and legal guardian(s) of children aged 7 years to younger than 12 years of age. Both domain and overall scores range from 1 to 7, with higher score representing better HRQoL.^27,29 The estimated MID identified through the CADTH literature search is 0.5 for the overall score.²⁷ Assessments during VOYAGE trial were conducted every 12 weeks until end of study visit.

Pediatric Rhinoconjunctivitis Quality of Life Questionnaire–Interviewer Administered in Patients With Comorbid Allergic Rhinitis

Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ)–Interviewer Administered is a disease-specific instrument developed to measure HRQoL in children aged 6 years to younger than 12 years diagnosed with seasonal allergic rhinoconjunctivitis or hay fever. Twenty-three items of the instrument are organized into 5 domains (nose symptoms, eye symptoms, practical problems, activity limitation, and other symptoms), which are assessed on a 7-point Likert scale (0 = no impairment, 6 = maximum impairment). Both domain and overall scores range from 0 to 6, with higher score representing worse HRQoL.^30,31 The CADTH literature search could not identify studies reporting MID values for this instrument. Assessments during VOYAGE trial were conducted every 12 weeks until end of study visit.

EQ-5D-Youth

The EQ-5D-Youth (EQ-5D-Y) is a generic preference-based HRQoL measure that contains a descriptive system comprising of 5 dimensions using child-friendly wording (mobility, looking after myself, doing usual activities, having pain or discomfort, feeling worried, sad or unhappy), each of which has 3 levels (no problems, some problems, a lot of problems). The next component of the instrument consists of a visual analogue scale (VAS) on which the respondent rates their perceived health from 0 to 100, with respective anchors of “worst imaginable health state” and “best imaginable health state.”^32,33 Patients enrolled in the VOYAGE trial, who could read, were encouraged to complete the questionnaire by themselves.

The instrument produces 3 types of data for each respondent, a profile indicating the extent of problems on each of the 5 dimensions represented by a 5-digit descriptor, a population preference-weighted health index score based on the descriptive system, and a self-reported assessment of health status based on the VAS. The index score is arrived at by applying a multiattribute utility function to the descriptive system. Scores of 0 represent the health state “dead” and 1 represents “perfect health.” Lower scores on 5-digit health status and higher scores on index and VAS represent better HRQoL.^32,33 No MID specific to asthma in children was identified during the CADTH literature review. Assessments during VOYAGE trial were conducted on weeks 2, 24, and 52.

Harms

For each patient, SAEs and AEs of special interest were monitored and documented from the initial visit until the end of the study or rollover to the extension study. AEs that were ongoing at database lock were also captured. An independent data monitoring committee was reviewing the safety data on a periodic basis throughout the course of the trial.

Statistical Analysis

Primary Outcome of the Study

Power Calculation

The sample size of this study was based on the primary outcome (i.e., annualized rate of severe exacerbations over 52 weeks of treatment) for the following populations: baseline blood EOS of 300 cells/µL or greater, baseline blood EOS of 150 cells/µL or greater, and patients with type 2 inflammatory phenotype (baseline blood EOS ≥ 150 cells/µL or baseline FeNO ≥ 20 ppb).

The following assumptions were made: the number of severe exacerbations follows a negative binomial distribution, a randomization ratio of 2:1 was used, and a linear discontinuation rate of 20% at 1 year (i.e., average exposure duration for patients of 0.9 year). Moreover, the assumed RR reductions were based on the results in the phase III study EFC13579 (QUEST) for dupilumab in adolescent and adult patients with asthma.³⁴

For patients with baseline EOS of 300 cells/µL or greater, assuming a placebo annualized severe exacerbation rate of 0.8 and a dispersion parameter of 1.5, with approximately 255 patients randomized (170 for dupilumab and 85 for matching placebo group), there was 96% power to detect a RR reduction of 60% (i.e., annualized rate of 0.32 for the dupilumab group) at a 2-sided significance of 5%.

For patients with baseline EOS of 150 cells/µL or greater, assuming a placebo annualized severe exacerbation rate of 0.7 and a dispersion parameter of 1.5, with approximately 327 patients randomized (218 for dupilumab and 109 for matching placebo group), there was 93% power to detect a RR reduction of 54% (i.e., annualized rate of 0.322 for the dupilumab group) at a 2-sided significance of 5%.

For patients with type 2 inflammatory phenotype, assuming a placebo annualized severe exacerbation rate of 0.7 and a dispersion parameter of 1.5, with approximately 345 patients randomized (230 for dupilumab and 115 for matching placebo group), there was 94% power to detect a RR reduction 54% (i.e., annualized rate of 0.322 for the dupilumab group) at a 2-sided significance of 5%.

According to the sponsor, approximately 402 patients in the overall population (268 for dupilumab and 134 for placebo) needed to be randomized to achieve target sample sizes, with an assumption that 86%, 81%, and 64% of patients have a type 2 inflammatory phenotype, baseline blood EOS of 150 cells/µL or greater, and baseline blood EOS of 300 cells/µL or greater, respectively.

Multiplicity Considerations

In VOYAGE, a hierarchical testing strategy was implemented to test for superiority of dupilumab over placebo in the primary (annualized rate of severe exacerbation events during the 52-week placebo-controlled treatment period), key secondary (change from baseline in prebronchodilator percent predicted FEV₁ at week 12), and secondary outcomes (change in ACQ-7-IA at week 24, change from baseline in FeNO at week 12), while controlling the overall type I error rate at 0.05 (2-sided). The sponsor included 2 distinct sequential testing procedures, based on approved indication in adults and adolescents.

• For the US and US reference countries: testing hierarchy started with the population with a baseline blood EOS of 300 cells/µL or greater (Appendix 3; Table 40)

• For European Union and European Union reference countries: testing hierarchy started with the population with a type 2 inflammatory phenotype (Appendix 3; Table 41)

Statistical Test or Model

The analysis of the primary end point estimated annualized exacerbation rates over 52 weeks for treatment groups as well as the RR, 95% CIs, and P values between treatment and placebo arms, and was performed using a negative binomial model. Details of the statistical model, adjustments, and populations analyzed are provided in Table 9. In the primary analysis approach, off-treatment measurements of patients who prematurely discontinued treatment were included in the analysis since patients who permanently discontinued study medication were encouraged to complete remaining study visits. For patients discontinuing the study before week 52, analyses were censored at the time of study discontinuation, and all observed severe exacerbation events up to the last contact date were included in the analysis. No imputations were performed for the unobserved events after study discontinuation and up to week 52.

An assessment of time to first severe asthma exacerbation event was conducted via Cox regression model that yielded hazard ratio estimates (dupilumab versus placebo) along with its 95% CIs. Kaplan-Meier curves were used to derive the proportion of patients with a severe asthma exacerbation event at various time points in each treatment group (Table 9).

Preplanned sensitivity analyses were conducted on the primary outcome in the VOYAGE trial for the type 2 inflammatory phenotype and baseline blood EOS of 300 cells/µL or greater populations (Refer to Table 9).

Key Secondary Outcome

The change from baseline in prebronchodilator percent predicted FEV₁ at week 12 was compared to placebo using a mixed-effect model with repeated measures (MMRM), and LS mean of each treatment group as well as difference of LS means between treatment and placebo arms, 95% CIs, and P values were reported. Details of the statistical model, adjustments, and populations analyzed is provided in Table 9.

The primary analytical approach included additional off-treatment percent predicted FEV₁ values measured up to week 12 for patients discontinuing the treatment before week 12, who were encouraged to complete all remaining study visits. Data from patients who withdrew from the study before week 12 were considered as missing after study discontinuation and no imputation was performed in the primary analysis.

Preplanned sensitivity analyses were conducted on the key secondary outcome in the VOYAGE trial for the type 2 inflammatory phenotype and baseline blood EOS of 300 cells/µL or greater populations (Refer to Table 9).

Subgroup Analyses

Preplanned subgroup analyses were conducted on the primary and key secondary outcome in the VOYAGE trial for the following subgroups identified in the CADTH review protocol:

• baseline eosinophil counts ( < 300 cells/µL, ≥ 300 cells/µL; < 150 cells/µL, ≥ 150 cells/µL; < 150 cells/µL, ≥ 150 to < 300 cells/µL, ≥ 300 to < 500 cells/µL, ≥ 500 cells/µL) (performed in the ITT population)

• ICS dose at baseline (medium or high) (performed in the type 2 inflammatory asthma phenotype population and baseline blood EOS ≥ 0.3 Giga/L population)

• Number of exacerbations in the past year (≤ 1, 2, > 2) (performed in the type 2 inflammatory asthma phenotype population and baseline blood EOS ≥ 0.3 Giga/L population)

• Atopic medical condition (yes, no) and comorbid atopic dermatitis (yes, no) (performed in the type 2 inflammatory asthma phenotype population and baseline blood EOS ≥ 0.3 Giga/L population)

For the primary outcome, treatment by subgroup interaction and its P value was derived from a negative binomial model. Similarly, treatment by subgroup interaction at week 12 and its P value was derived from an MMRM for the key secondary outcome of interest. RRs and risk differences for the primary outcome, and LS mean differences for the key secondary outcome comparing dupilumab versus placebo for the subgroups were reported. In both cases, evidence of quantitative treatment by subgroup interaction with nominal P < 0.05 for any subgroup would follow-up with an assessment of qualitative interaction via Gail-Simon test.

In VOYAGE, the specific subgroup of patients with eosinophil counts of 150 cells/μL or greater, with eosinophil counts of 300 cells/μL or greater, and with high ICS dosing at baseline were included as part of the statistical hierarchy. All other subgroups were not adjusted for multiplicity.

Other Secondary Outcomes

Analyses of change from baseline in other secondary end points with a continuous nature was derived through a similar MMRM (Table 9).

In addition to the MMRM analyses, a responder analysis was performed for the ACQ-7, 5-item ACQ (ACQ-5), and Asthma Quality of Life Questionnaire total scores at weeks 12, 24, 36, and 52. Specifically, a logistic regression model was used to obtain the odds ratio (OR) of being a responder comparing dupilumab and placebo group along with the corresponding 95% CI and P value (Table 9).

Analysis Populations

In the VOYAGE trial, there were 2 primary efficacy populations, for which all efficacy outcomes were analyzed:

• Type 2 inflammatory asthma phenotype (randomized patients with baseline blood eosinophil count ≥ 150 cells/µL or baseline FeNO ≥ 20 ppb)

• Baseline blood EOS count of 300 cells/µL or greater (randomized patients with baseline blood EOS count ≥ 0.3 Giga/L)

There were additional efficacy populations, for which primary and selected secondary end points were analyzed in a multiplicity-controlled manner, including patients with baseline blood eosinophil count of 150 cells/µL or greater.

Safety analyses were conducted according to the treatment patients actually received and were based on the safety population (i.e., all patients receiving at least 1 dose or part of a dose of the trial treatment).

Protocol Deviations

The sponsor identified major protocol deviations that may have a potential adverse impact on data integrity, patients’ rights, or safety. These were reported, within the type 2 inflammatory asthma phenotype population, in 5 (2.1%) and 3 (2.6%) patients in the dupilumab and placebo group, respectively. Within the population with a baseline blood EOS count of 300 cells/µL or greater, these were reported in 4 (2.3%) and 2 (2.4%) patients in the dupilumab and placebo group, respectively. The types of protocol deviations included missing assessments of FeNO or blood EOS at baseline, low adherence to background and study treatments, and use of prohibited concomitant medications.

Randomization and Dosing Irregularities

In the 2 primary efficacy populations, randomization and drug allocation irregularities were reported in 19 (8.1%) in the dupilumab and 8 (7.0%) patients in the placebo group (type 2 inflammatory asthma phenotype population) and in 12 (6.9%) in the dupilumab and 6 (7.1%) patients in the placebo group (baseline blood EOS ≥ 300 cells/µL population). The majority of errors were related to the ICS dose level stratum classification reported by the investigators, which occurred in both directions (i.e., medium erroneously classified as high and vice versa). Specifically, misclassification according to the ICS dose levels occurred in 18 (7.6%) and 7 (6.1%) of type 2 population patients in the dupilumab and placebo group, respectively, and in 11 (6.3%) and 5 (6.0%) patients in the population with baseline EOS of 300 cells/µL or greater in the dupilumab and placebo group, respectively. The sponsor reported that the analyses factoring ICS dose levels were conducted according to the actual calculated total daily dose of all medications containing ICSs and not on the investigators’ reported classification.

Breaking of the Blind

In the VOYAGE trial, breaking of the blind for regulatory purposes occurred due to serious adverse reactions suspected to be related to treatment (2 patients in the dupilumab group: 1 reported pneumonia and 1 patient had eosinophilia, headache, and blurred vision; 1 patient had lymphadenitis viral in the placebo group)

Local breaking of the blind by the investigators occurred only in the dupilumab group, among 4 patients from Brazil (discontinuation due to yellow fever vaccination) and 1 patient from the US (reporting AE of eosinophilia, headache, and blurred vision).

The sponsor specified that patient withdrawal from treatment would occur only in the case of breaking of the blind occurring at a local level, not a study level.

Amendments to the Protocol

The original protocol, dated August 04, 2016, was modified per 3 global amendments (Amendment 1: March 10, 2017; Amendment 2: June 18, 2018; Amendment 3: October 1, 2019) and 1 local amendment for Brazil (February 2, 2018).

Notably, Amendment 3 included following modifications:

• Changes to the study primary efficacy analysis population (from an overall uncontrolled persistent asthma population to the population with baseline eosinophil count ≥ 0.3 Giga/L or with the type 2 inflammatory asthma phenotype)

• Changes to the sample size

• Specification of different hierarchy orders used for US and US reference countries and European Union and European Union reference countries

• Removal of the limit in enrolling patients according to background therapy with medium-dose ICS or blood eosinophil count level

• Defining the planned database lock

• Classification of FeNO as a secondary end point instead of an exploratory end point

Additional changes to the Study Analysis plan were made as per regulatory agency request on August 14, 2020, to provide a detailed elaboration of the primary estimate and to provide further analyses to evaluate whether baseline FeNO values can independently predict treatment effect. Moreover, addition of outcome measures (SCS exposure, loss of asthma control), COVID-19 relevant analysis, and adjustments to subgroup analyses (removal of elevated IgE [yes/no] and age subgroup analyses; addition of treatment exposure-adjusted analysis for key AE end points) were implemented.

Post hoc analyses (i.e., implemented after database lock) was added to evaluate effects of dupilumab on some end points of interest. These included annualized rate of the subtype of severe asthma exacerbation resulting in hospitalization or ED visits resulting in hospitalization (for the type 2 inflammatory asthma phenotype and with baseline blood EOS ≥ 300 cells/µL populations), responder analyses for ACQ-7-IA (based on minimal clinically important difference cut-off points of 0.75,1, and 1.5 as a responder definition), and biomarker analyses (interaction of biomarkers of type 2 inflammation, baseline EOS and FeNO levels) on the effect of dupilumab on the primary end point and key secondary end point based on the ITT population.

Results

Patient Disposition

A total of ||||||||| patients were screened for the study. The screening failure rate was ||||||||| and the major reason for screening out of the study was failure to meet inclusion criteria described in the Table 6 (|||||||||), consisting of lack of appropriate background therapy, exceeding the specified maximum prebronchodilator FEV₁, reversibility in FEV₁ that was lower than specified minimum, or lack of evidence of uncontrolled asthma.

Out of ||||||||| screened patients, 408 underwent randomizations (ITT population). In the type 2 inflammatory phenotype and population with baseline blood EOS of 300 cells/µL or greater, there were a total of 350 (236 in dupilumab and 114 in the placebo arm) and 259 patients (175 in dupilumab and 84 in the placebo arm), respectively (Table 10). Three patients in the dupilumab group were randomized, but not treated (due to erroneous randomization despite ineligibility of 2 patients and withdrawal from the study before treatment by 1 patient).

Treatment discontinuations were generally below ||||||||| in each group across both efficacy populations, and were higher in the dupilumab group, compared to placebo group (dupilumab versus placebo: |||||||||||||||||| in the type 2 population; |||||||||||||||||| in the baseline EOS ≥ 300 cells/µL population). The most common reason for discontinuation was “other,” occurring in ||||||||||||||||||||||||||| of dupilumab versus placebo patients in both efficacy populations, respectively. The sponsor reported that |||||||||||||||||||||||||||||||||||| due to “other” reasons was related to the safety issues. Specifically, in the dupilumab group (ITT population), discontinuation due to “other reasons” included: |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Discontinuation for “other reasons” in the placebo group (ITT population) was due to |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Percentage of patients who withdrew due to AEs was similar in dupilumab and placebo arms, across all efficacy populations. Study withdrawals were reported in ||||||||||||||||||||||||||| of type 2 patients of the dupilumab and placebo group, and in ||||||||||||||||||||||||||| of patients with baseline EOS of 300 cells/µL or greater in the dupilumab and placebo groups, respectively.

Overall, more patients in the placebo group, compared to dupilumab group, continued to the long-term extension study (dupilumab versus placebo: ||||||||||||||||||||||||||| in the type 2 population; ||||||||||||||||||||||||||| in the baseline EOS ≥ 300 cells/µL population).

Disposition of study patients in the ITT and baseline blood EOS of 150 cells/µL or greater populations is presented in the Appendix 3.

Table 10: Patient Disposition (VOYAGE Trial)

ITT = intention to treat; LTE = long-term extension.

Values are n (%) unless otherwise indicated.

Source: Clinical Study Report.⁷

Exposure to Study Treatments

Study duration for the dupilumab and placebo groups of the VOYAGE trial was similar, with mean values of ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| for dupilumab and placebo arm, respectively, in the type 2 inflammatory asthma population and mean values of |||||||||||||||||||||||||||||||||||||||||||||||||||||| for dupilumab and placebo arm, respectively, in the population with baseline blood EOS of 300 cells/µL or greater. Median duration of the study treatment was the same for both groups (365 days) in both efficacy populations.

Regarding the adherence to study treatment, an average of |||||||||||||||||||||||||||||||||||| of adherence to injections was observed among the patients in dupilumab and placebo groups in the type 2 inflammatory asthma population, respectively. For the population with baseline blood EOS of 300 cells/µL or greater, mean adherence to injections was ||||||||||||||||||||||||||||||||||||||||||||| in the dupilumab and placebo arms, respectively.

Mean percentage of days in which patients were compliant with all background controller medications was ||||||||||||||||||||||||||| in the dupilumab group and ||||||||||||||||||||||||||| in the placebo group (for the type 2 population) and ||||||||||||||||||||||||||| in the dupilumab group and ||||||||||||||||||||||||||| in the placebo group (baseline blood EOS ≥ 300 cells/µL population).

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in the following. Refer to Appendix 3 for detailed efficacy data.

Mortality

In the VOYAGE trial, there were no deaths reported across the dupilumab and placebo groups.

Asthma Exacerbations

The adjusted rate over 52 weeks in the type 2 inflammatory asthma population was 0.31 (95% CI, 0.22 to 0.42) with dupilumab and 0.75 (95% CI, 0.54 to 1.03) with placebo, for a RR of 0.41 (95% CI, 0.27 to 0.61; P < 0.0001) and a risk difference of –0.44 (95% CI, –0.68 to –0.20) (Table 11). In the patients with an EOS count of at least 300 cells/µL at baseline, the adjusted rate of severe asthma exacerbations across 52 weeks was 0.24 (95% CI, 0.16 to 0.35) in the dupilumab group and 0.67 (95% CI, 0.47 to 0.95) in the placebo group (RR = 0.35; 95% CI, 0.22 to 0.56; P < 0.0001; risk difference: –0.43; 95% CI, –0.66 to –0.20).

Table 11: Outcome: Severe Asthma Exacerbations During the 52-Week Randomized Treatment Period (Type 2 Inflammatory Asthma Phenotype Population; Population With Baseline Blood Eosinophils of 300 cells/µL or Greater)

CI = confidence interval; ED = emergency department; FeNO = fractional exhaled nitric oxide; HR = hazard ratio; ICS = inhaled corticosteroid; NE = not estimable.

Note: All severe exacerbation events occurred during the 52-week treatment period are included, regardless of whether the patient is on treatment or not.

Type 2 inflammatory asthma phenotype population is defined as the randomized patients with baseline blood eosinophils of 0.15 Giga/L or greater or baseline FeNO of 20 parts per billion or greater.

The time-to-event variable is defined as (date of the first event - randomization date + 1). For patients who have no event on or before week 52 or the last contact date, the time will be censored at the date of date of visit at week 52 or the last contact date, whichever happens earlier.

^aOutcome was part of statistical hierarchy testing and adjusted for multiplicity.

^bThe total number of event that occurred during the 52-week treatment period divided by the total number of patient-years followed in the 52-week treatment period.

^cDerived using negative binomial model with the total number of events onset from randomization up to the week 52 visit or last contact date (whichever comes earlier) as the response variable, with the treatment group, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, and number of severe exacerbation events within 1 year before the study as covariates, and log-transformed standardized observation duration as an offset variable.

^dDerived using the delta method.

^eDerived using Cox regression model including the time to the first event as the dependent variable, and treatment groups, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, and number of severe exacerbation events within 1 year before the study as covariates.

Source: Clinical Study Report.⁷

Various sensitivity analyses were conducted to account for missing data, and results were consistent with that of the primary analysis, (Appendix 3).

RRs for the comparison of severe exacerbations associated with an ED visit or hospitalization between dupilumab and placebo were ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, while the risk differences were ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| for the populations with type 2 asthma and baseline blood EOS of 300 cells/µL or greater, respectively. Adjusted rates of severe exacerbations associated with a hospitalization were not estimable due to ||||||||| events reported in the placebo group.

Subgroup analyses for the primary outcome were performed for several subgroups relevant to the CADTH protocol (baseline eosinophil levels, baseline ICS dose, number of previous asthma exacerbations, atopic medical history) (Table 12, Table 13, Table 14, and Table 15). In the subgroup of patients with baseline blood EOS of 150 cells/µL or greater, RRs between dupilumab and placebo were 0.390 (95% CI, 0.261 to 0.583 to |||||||||||||) and the risk difference ||||||||||||||||||||||||||||||||||||, with a P value for the interaction of ||||||||||||||||||. Other subgroup analyses did not yield statistically significant interaction.

Results of the primary end point analyses in the ITT and baseline blood EOS of 150 cells/µL or greater populations were aligned with those presented in the type 2 and baseline blood EOS of 300 cells/µL or greater populations (Table 12, Appendix 3).

Table 12: Subgroup Analysis Results From VOYAGE Trial for the Primary Outcome by Baseline Blood Eosinophil Count (Adjusted Annualized Rate of Severe Exacerbation Events During the 52-Week Treatment; ITT population)

CI = confidence interval; FeNO = fractional exhaled nitric oxide; ICS = inhaled corticosteroid; ITT = intention to treat.

^aOutcome was part of statistical hierarchy testing and adjusted for multiplicity.

^bDerived using negative binomial model with the total number of events onset from randomization up to week 52 visit or last contact date (whichever comes earlier) as the response variable, with the treatment group, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, and number of severe exacerbation events within 1 year before the study as covariates, and log-transformed standardized observation duration as an offset variable.

^cDerived using the delta method.

^dSimilar mode as mentioned in footnote “b”, except replacing the biomarker level with corresponding subgroup and additionally including treatment by subgroup interaction as the covariate.

Source: Clinical Study Report.⁷

Table 13: Redacted

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Source: Clinical Study Report.⁷

Table 14: Redacted

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Source: Clinical Study Report.⁷

Table 15: Redacted

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Source: Clinical Study Report.⁷

Asthma Symptoms

ACQ-7 scores decreased (improved) from baseline to week 24 in both the dupilumab and placebo groups, for an LS difference versus placebo of –0.33 points (95% CI, –0.50 to –0.16; |||||||||||| in the type 2 population and of –0.46 points (95% CI, –0.66 to –0.26; |||||||||||| in the baseline blood eosinophil count of 300 cells/µL or greater population. In the type 2 inflammatory asthma population, there were |||||||||||| of dupilumab patients and |||||||||||| of placebo patients who were responders at week 24, for an OR of ||||||||||||||||||||||||||||||||||||||||||||||||. In the baseline eosinophil count of 300 cells/µL or greater population, there were |||||||||||| responder patients in the dupilumab and |||||||||||| responder patients in the placebo arm at week 24, with an OR of |||||||||||||||||||||||||||||||||||||||||||||||| (Table 16).

Results were maintained during the trial period (to week 52) |||||||||||||||||||||||||||||||||||||||||||||||| (Table 16, Figure 3, and Figure 4). Appendix 3 contains findings from the ACQ-7 assessments conducted across additional efficacy populations of the VOYAGE trial (ITT and baseline blood EOS ≥ 150 cells/µL populations), as well as results obtained from the ACQ-5 assessments in the type 2 inflammatory asthma phenotype and baseline eosinophil count of 300 cells/µL or greater populations.

Table 16: Symptoms According to the ACQ-7 (Weeks 24 and 52)

ACQ-7 = 7-item Asthma Control Questionnaire; CFB = change from baseline; CI = confidence interval; FeNO = fractional exhaled nitric oxide; ICS = inhaled corticosteroid; LS = least squares; OR = odds ratio; SD = standard deviation; SE = standard error.

Note: Type 2 inflammatory asthma phenotype population is defined as the randomized patients with baseline blood eosinophils of 0.15 Giga/L or greater or baseline FeNO of 20 parts per billion or greater.

^aOutcome was part of statistical hierarchy testing and adjusted for multiplicity.

^bDerived from mixed-effect model with repeated measures with change from baseline in ACQ-7–Interviewer Administered up to week 24 as the response variable, and treatment, age, weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline ACQ-7–Interviewer Administered, and baseline-by-visit interaction as covariates.

^cPatients who met the corresponding criterion are considered as responders. Patients who did not meet the criterion or had missing value are considered as nonresponders.

^dDerived from logistic regression model with treatment, age, weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, and baseline ACQ-7–Interviewer Administered score as covariates.

Source: Clinical Study Report.⁷

Figure 3: LS Mean Change From Baseline in ACQ-7-IA Over Time (MMRM Including Measurements Up to Week 52): Type 2 Inflammatory Asthma Phenotype Population

ACQ-7-IA = 7-item Asthma Control Questionnaire–Interviewer Administered; MMRM = mixed-effect model with repeated measures.

Source: Clinical Study Report.⁷

Reduction in Use of OCSs

Total SCSs usage during the treatment period was captured in the VOYAGE trial. Overall, more patients in the placebo arm (40.4% and 41.7%) compared to patients in the dupilumab arm (24.2% and 22.3%) received treatment with SCS during the trial within the type 2 inflammatory asthma phenotype and baseline blood EOS of 300 cells/µL or greater populations, respectively (Table 17).

The adjusted RR in annualized number of SCS courses, comparing dupilumab to placebo, was 0.407 (95% CI, 0.272 to 0.609) for the type 2 inflammatory asthma phenotype population and 0.340 (95% CI, 0.212 to 0.545) for the baseline blood EOS of 300 cells/µL or greater population.

Figure 4: Least Squares Mean Change From Baseline in ACQ-7-IA Over Time (MMRM Including Measurements Up to Week 52): Population With Baseline Blood Eosinophils of 300 cells/µL or Greater

ACQ-7-IA = 7-item Asthma Control Questionnaire–Interviewer Administered; MMRM = mixed-effect model with repeated measures.

Source: Clinical Study Report.⁷

Table 17: Total SCS Usage During the Treatment Period

CI = confidence interval; HR = hazard ratio; IQR = interquartile range; SCS = systemic corticosteroid; SD = standard deviation.

^aThe total dose per number of SCS days for each patient divided by the number of patient-years followed in the treatment period for that patient.

^bA course of SCSs is considered continuous if treatment is separated by less than 7 days.

^cThe number of SCS courses for each patient divided by the number of years followed in the treatment period for that patient.

^dDerived using negative binomial model with the total number of courses of SCSs intake during the treatment period as the response variable, and the treatment groups, age, baseline weight group, region, baseline eosinophil level, baseline fractional exhaled nitric oxide level, baseline inhaled corticosteroid dose, and number of severe exacerbation events within 1 year before the study as covariates, and log-transformed standardized observation duration as an offset variable.

^eDerived from Kaplan-Meier estimates.

^fDerived using Cox regression model including the time to the first event as the dependent variable, and treatment groups, age, baseline weight group, region, baseline eosinophil level (not available for the population with baseline eosinophils of 0.3 Giga/L or greater), baseline fractional exhaled nitric oxide level, baseline inhaled corticosteroid dose, and number of severe exacerbation events within 1 year before the study as covariates.

Source: Clinical Study Report.⁷

Pulmonary Function

For the key secondary outcome (change from baseline in percent predicted prebronchodilator FEV₁ at week 12) within the type 2 inflammatory asthma phenotype population, LS mean difference between the groups was 5.21% (95% CI, 2.14 to 8.27%; P = 0.0009). Similarly, in the baseline blood eosinophil count of 300 cells/µL or greater population, at week 12 the LS mean difference between groups was 5.32% (95% CI, 1.76 to 8.88%; P = 0.0036). In both primary efficacy populations, LS mean changes in the percent predicted prebronchodilator FEV₁ were sustained through week 52 (Table 18).

Findings from other multiplicity-controlled analyses for the ITT and baseline blood EOS of 150 cells/µL or greater populations were similar to those observed in the 2 primary efficacy populations (Appendix 3).

A series of sensitivity analyses were conducted to account for missing data as well as the effects of SCS exposure, showing consistent and similar findings to the primary analysis (Appendix 3).

Subgroup analyses for change from baseline in percent predicted prebronchodilator FEV₁ at week 12 in patients with baseline blood EOS of 300 cells/µL or greater and 150 cells/µL or greater were generally consistent with the primary analyses. Other subgroup analyses reported were not adjusted for multiplicity (Table 19, Table 20, Table 21, and Table 22).

In both the type 2 inflammatory asthma phenotype and baseline blood eosinophil count of 300 cells/µL or greater populations, there was an improvement in morning PEF scores at week 12 in both treatment groups, with the LS mean difference versus placebo of 14.02 L/min (95% CI, 4.92 to 23.12; P = 0.0026) and 14.48 L/min (95% CI, 3.49 to 25.47; P = 0.01) for the 2 populations, respectively (Table 18).

Changes at week 12 of evening PEF values were reported among the 2 populations, with LS mean differences versus placebo of 17.97 L/min (95% CI, 8.98 to 26.95; P = 0.0001) and 19.10 L/min (95% CI, 8.36 to 29.83; P = 0.0005) for the 2 populations (Table 18).

Table 18: Pulmonary Function Measurements (Percent Predicted Prebronchodilator FEV₁, a.m. and p.m. PEF)

CFB = change from baseline; CI = confidence interval; FEV₁ = forced expiratory volume in 1 second; LS = least squares; MMRM = mixed-effect model with repeated measures; PEF = peak expiratory flow; SD = standard deviation; SE = standard error.

Note: Type 2 inflammatory asthma phenotype population is defined as the randomized patients with baseline blood eosinophils of 0.15 Giga/L or greater or baseline fractional exhaled nitric oxide of 20 parts per billion or greater.

^aOutcome was part of statistical hierarchy testing and adjusted for multiplicity.

^bDerived from an MMRM with change from baseline in prebronchodilator percent predicted FEV₁ values up to week 12 as the response variable, and treatment, baseline weight group, region, ethnicity, baseline eosinophil level, baseline fractional exhaled nitric oxide level, baseline inhaled corticosteroid dose, visit, treatment by-visit interaction, baseline percent predicted FEV₁ value, and baseline-by-visit interaction as covariates.

^cDerived from an MMRM with change from baseline in prebronchodilator percent predicted FEV₁ values up to week 52 as the response variable, and treatment, baseline weight group, region, ethnicity, baseline eosinophil level, baseline fractional exhaled nitric oxide level, baseline inhaled corticosteroid dose, visit, treatment by-visit interaction, baseline percent predicted FEV₁ value, and baseline-by-visit interaction as covariates.

^dDerived from an MMRM with change from baseline in a.m. PEF (L/min) values up to week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline fractional exhaled nitric oxide level, baseline inhaled corticosteroid dose, visit, treatment by-visit interaction, baseline a.m. PEF (L/min) value, and baseline-by-visit interaction as covariates.

^eDerived from an MMRM with change from baseline in p.m. PEF (L/min) values up to week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline fractional exhaled nitric oxide level, baseline inhaled corticosteroid dose, visit, treatment by-visit interaction, baseline p.m. PEF (L/min) value, and baseline-by-visit interaction as covariates.

Source: Clinical Study Report.⁷

Table 19: Subgroup Analysis Results From VOYAGE Trial for the Key Secondary Outcome by Baseline Blood Eosinophil Count (Change From Baseline in Prebronchodilator Percent Predicted FEV₁ at Week 12; ITT population)

CFB = change from baseline; CI = confidence interval; FEV₁ = forced expiratory volume in 1 second; ITT = intention to treat; LS = least squares; MMRM = mixed-effect model with repeated measures; SD = standard deviation; SE = standard error.

^aOutcome was part of statistical hierarchy testing and adjusted for multiplicity.

^bDerived from an MMRM with change from baseline in prebronchodilator percent predicted FEV₁ values up to week 12 as the response variable, and treatment, baseline weight group, region, ethnicity, baseline eosinophil level, baseline fractional exhaled nitric oxide level, baseline inhaled corticosteroid dose, visit, treatment by-visit interaction, baseline percent predicted FEV₁ value, and baseline-by-visit interaction as covariates.

^cSimilar an MMRM as mentioned in footnote “b”, except replacing baseline eosinophil level and baseline fractional exhaled nitric oxide level with corresponding subgroup level when performing relevant subgroup analysis, and additionally including treatment by subgroup interaction as covariate.

Source: Clinical Study Report.⁷

Table 20: Subgroup Analysis Results From VOYAGE Trial for the Key Secondary Outcome by Baseline ICS Dose (Change From Baseline in Prebronchodilator Percent Predicted FEV₁ at Week 12)

CFB = change from baseline; CI = confidence interval; FEV₁ = forced expiratory volume in 1 second; ICS = inhaled corticosteroid; LS = least squares; MMRM = mixed-effect model with repeated measures; SD = standard deviation; SE = standard error.

^aDerived from an MMRM with change from baseline in prebronchodilator percent predicted FEV₁ values up to week 12 as the response variable, and treatment, baseline weight group, region, ethnicity, baseline eosinophil level, baseline fractional exhaled nitric oxide level, visit, treatment by-visit interaction, baseline percent predicted FEV₁ value, and baseline-by-visit interaction as covariates.

^bSimilar model as that mentioned in footnote “a”, except additionally including the subgroup and subgroup-by-treatment interaction as covariate.

Source: Clinical Study Report.⁷

Table 21: Redacted

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Source: Clinical Study Report.⁷

Reduction in Dose of ICSs

The VOYAGE study protocol allowed a permanent increase in background medications after 2 or more severe asthma exacerbations. During the treatment period of the trial, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, across all efficacy populations assessed.

Health-Related Quality of Life

PAQLQ(S)–Interviewer Administered was assessed in the VOYAGE trial among children aged 7 years to younger than 12 years at randomization. LS mean values of PAQLQ(S) scores showed increases (improvements) from baseline to week 24 in type 2 inflammatory asthma phenotype population, with a difference between groups of 0.19 points (95% CI, –0.03 to 0.40, |||||||||||||||) (Table 23). In the baseline blood EOS of 300 cells/µL or greater population, the LS mean difference between groups at week 24 was 0.30 points (95% CI, 0.06 to 0.54; ||||||||||).

PAQLQ(S) responders at week 24 were also reported, defined as a change from baseline of 0.5 or greater, and in type 2 inflammatory asthma population there were |||||||||| of dupilumab patients and |||||||||| of placebo patients who were responders (OR = |||||||||| |||||||||| |||||||||| ||||||||||. In the baseline blood EOS of 300 cells/µL or greater population, there were 72.8% of dupilumab responder patients and 63% placebo responder patients (OR = 1.84; 95% CI, 0.92 to 3.65).

Improvements in the PAQLQ(S) scores were maintained through the week 52 of the VOYAGE trial, across both efficacy populations (Figure 5 and Figure 6).

Findings from the PAQLQ(S) assessments conducted across additional efficacy populations of the VOYAGE trial (ITT and baseline blood EOS ≥ 150 cells/µL populations) are reported in the Appendix 3.

The EQ-5D-Y VAS also showed improved HRQoL from baseline in both analysis populations in favour of dupilumab at week 24 (Table 24).

Impact of children’s (≥ 7 years and < 12 years old) asthma on the caregivers’ quality of life was assessed with PACQLQ. Increases from baseline to week 24 in the PACQLQ global score compared to placebo were observed in both the type 2 inflammatory asthma phenotype population (LS mean difference between groups = 0.25; 95% CI, 0.00 to 0.50; P = 0.0531) and baseline blood EOS of 300 cells/µL or greater population (LS mean difference between groups = 0.34; 95% CI, 0.01 to 0.67; P = 0.0445). At week 52, observed PACQLQ LS mean differences for comparison of dupilumab versus placebo were 0.47 (95% CI, 0.22 to 0.72; P = 0.0003) and 0.50 (95% CI, 0.21 to 0.79; P = 0.0007), in the 2 populations, respectively (Table 24).

Table 23: PAQLQ(S)-IA Global Score

CFB = change from baseline; CI = confidence interval; LS = least squares; MMRM = mixed-effect model with repeated measures; OR = odds ratio; PAQLQ(S)-IA = Standardised Paediatric Asthma Quality of Life Questionnaire–Interviewer Administered; SD = standard deviation; SE = standard error.

Notes: Type 2 inflammatory asthma phenotype population is defined as the randomized patients with baseline blood eosinophils of 0.15 Giga/L or greater or baseline fractional exhaled nitric oxide of 20 parts per billion or greater.

Only patients of aged 7 years or older at randomization are included in the analysis.

^aDerived from an MMRM with change from baseline in PAQLQ(S)-IA global score values up to week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline fractional exhaled nitric oxide level, baseline inhaled corticosteroid dose, visit, treatment by-visit interaction, baseline PAQLQ(S)-IA global score value, and baseline-by-visit interaction as covariates.

^bA responder is defined as a patient with improvement from baseline in PAQLQ(S)-IA global score of 0.5 or greater. Patients with an improvement of less than 0.5 or with missing value are considered to be nonresponders.

^cDerived from a logistic regression model with treatment, age, baseline weight group, region, baseline eosinophil level, baseline fractional exhaled nitric oxide level, baseline inhaled corticosteroid dose, and baseline PAQLQ(S)-IA global score as covariates.

Source: Clinical Study Reportt.⁷

Figure 5: Redacted

Note: This figure has been redacted.

Source: Clinical Study Report.⁷

Figure 6: Redacted

Note: This figure has been redacted.

Source: Clinical Study Report.⁷

Table 24: Redacted