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.

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

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

Primary Outcome of the Study

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).

Table 9

Statistical Analysis of Efficacy End Points.

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.

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).

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) .

Table 13

Redacted.

Table 14

Redacted.

Table 15

Redacted.

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) .

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.

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.

Table 17

Total SCS Usage During the Treatment Period.

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) .

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) .

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) .

Table 21

Redacted.

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.

Table 22

Redacted.

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.

Figure 5

Redacted.

Figure 6

Redacted.

Table 24

Redacted.

Reduction in Use of Rescue Medication

Regarding the use of reliever medications in the VOYAGE trial, a decrease in number of puffs in 24-hour period was observed in both treatment arms. The LS mean difference versus placebo for the number of puffs of reliever medication in a 24-hour period at week 24 was |||||||||| |||||||||| ||||||||||||||| |||||||||| ||||| and |||||||||| |||||||||| ||||||||||||||| |||||||||| ||||| for the 2 populations, respectively. At week 52, |||||||||| |||||||||| ||||||||||||||| |||||||||| ||||||||||||||| |||||||||| ||||| (Table 25).

Table 25

Redacted.

Improvements in Symptoms of Atopic Dermatitis and Rhinosinusitis

In patients with comorbid allergic rhinitis, PRQLQ–Interviewer Administered global scores at weeks 24 were improved in favour of dupilumab (LS mean difference between groups = |||||||||| |||||||||| ||||||||||||||| |||||||||| |||||, in the type 2 phenotype population. Improvements in allergic rhinitis related quality of life were also observed in the baseline blood EOS of 300 cells/µL or greater population (LS mean difference between groups = |||||||||| |||||||||| ||||||||||||||| |||||||||| ||||||||||||||| |||||||||| |||||) (Table 24).

Adverse Events

AEs in the dupilumab versus placebo groups occurred in 83% versus 79.9% of patients in the safety population of the VOYAGE trial, respectively (Table 26). The most common AEs for dupilumab versus placebo 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%).

Serious Adverse Events

SAEs occurred in 4.8% patients receiving dupilumab and 4.5% of patients receiving placebo, most common of which were asthma (dupilumab versus placebo: 1.5% versus 0%) and eosinophilia (dupilumab versus placebo: 0.7% versus 0%).

Withdrawals Due to AEs

AE resulting in discontinuation of study drug occurred in 1.8% versus 1.5% of patients of the VOYAGE study, in the dupilumab versus placebo groups, respectively.

Notable Harms

Injection site reactions were the most commonly reported notable harms, with 17.7% patients versus 13.4% of patients in the dupilumab versus placebo groups, respectively. Hypersensitivity and anaphylactic reactions occurred in 1.8% of dupilumab patients versus 3.7% of placebo patients and 0.0% of dupilumab patients versus 1.5% of placebo patients, respectively. Severe infections occurred in |||||||||| of patients in the dupilumab and |||||||||| of patients in the placebo group. Parasitic infections were reported among 7 patients (2.6%) in the dupilumab group, and no patients in the placebo arm. There were no opportunistic infections reported in the trial. Eosinophilia was more frequently occurring in dupilumab arm compared to placebo (6.6% versus 0.7%, respectively). Conjunctivitis, classified using a narrow custom Medical Dictionary for Regulatory Activities (MedDRA) Query search, occurred in 2.6% of the dupilumab group versus 6.7% of the placebo group. Similarly, conjunctivitis classified using a broad MedDRA search, occurred in 3.0% of the dupilumab group versus 7.5% of the placebo group.

Table 26

Summary of Harms (Safety Population) .

Internal Validity

The VOYAGE trial is a multinational, multicentre, randomized, double-blind, placebo-controlled study. Treatment allocation was appropriately performed through a central interactive voice and web response systems. However, the randomization ratio of 2:1 was implemented in the trial, and no justification was provided from the sponsor. Furthermore, the study randomization was stratified by ICS dose level (medium or high) at screening, patients’ blood eosinophil count (< 300 cells/µL and ≥ 300 cells/µL populations) at screening, and region (Latin America, Eastern Europe, and Western countries).

The study was double-blind, and both the patients and investigators were blinded to the study treatment. Additional steps to maintain blinding were undertaken by using a matching placebo in the trial (i.e., 2 different volumes of injection solutions, corresponding to the 2 different doses of dupilumab were used; these were each matched to corresponding volumes of placebo injection). However, this meant that patients and investigators were aware of the dose or volume of the injections administered in the trial. Even though dosing awareness might have introduced the possibility of bias, the fact that both patients and investigators were blinded to the type of treatment would have mitigated this bias. Furthermore, patients in the dupilumab group experienced more injection site reactions and eosinophilic reactions compared to placebo, which might have created possibilities for study participants or investigators to anticipate the AEs of active treatment, therefore, introducing unblinding in the trial. The impact of such unblinding (i.e., patients believing they were assigned to the treatment group rather than placebo) might have introduced bias in assessing patient-reported and HRQoL outcomes of the trial. During the VOYAGE trial, breaking of the blind leading to study discontinuation occurred in a limited number of patients receiving dupilumab. These irregularities were reported at the local level among 4 patients from Brazil (discontinued due to yellow fever vaccination) and 1 patient from US (reported AE of eosinophilia, headache, and blurred vision, leading to study discontinuation).

The sponsor controlled for multiplicity using a hierarchical testing procedure, which was applied for the primary outcome (annualized rate of severe exacerbation events during the 52-week placebo-controlled treatment period), key secondary outcome (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). Each hypothesis was formally tested only if the preceding 1 was significant at the 2-sided 5% level. There were 2 distinct sequential testing procedures that incorporated the same end points, but in a different order, based on the approved indication in adults and adolescents in the US and European Union. For European Union and European Union reference countries, the hierarchy procedure started with the type 2 inflammatory asthma phenotype population, and for the US and US reference countries, the hierarchy procedure started with the population with baseline blood eosinophil count of 0.3 Giga/L or greater. Of note, statistical significance was reached across all multiplicity-controlled end points in both hierarchical testing procedures.

Sample size and power calculations were based on the primary outcome for the populations with a type 2 inflammatory phenotype, baseline blood EOS of 300 cell/μL or greater, and of 150 cells/μL or greater. When calculating sample size and power of the trial, the sponsor made assumptions regarding expected RR reductions in the pediatric population, based on data previously reported from trials on individuals aged older than 12 years.³⁴ Considering that there is a paucity of data in pediatric populations, this approach was deemed reasonable for a priori estimation of the sample size.

Regarding baseline characteristics, there were slight imbalances across the groups in terms of severe exacerbations (1, 2, 3, or ≥ 4) in the year before the study enrolment, but the median number exacerbations for the dupilumab and placebo groups was the same (median = 2). Moreover, FEV₁ reversibility was slightly higher in the dupilumab compared to placebo group, which might have introduced bias in the study findings either for or against the study drug. Bias for the active treatment group might have occurred due to the fact that the VOYAGE trial included patients with uncontrolled asthma, who were more likely to respond to a new therapy and show a difference versus placebo. On the other hand, clinical experts reported that higher baseline reversibility in the dupilumab group suggested that that this group may be more uncontrolled than the placebo, making it more difficult for the active treatment group to reach a beneficial effect, compared to placebo (bias against the drug). Nevertheless, other baseline and demographic characteristics were largely balanced within the 2 study arms, suggesting that randomization was successfully implemented. Screening failure was reported in 35.3% of the initial number of patients, most commonly occurring because patients failed to meet prespecified inclusion criteria of the trial. However, clinicians consulted during this CADTH review reported that higher levels of screening out are very common in asthma biologic trials, noting that virally triggered asthma presentation, commonly reported in pediatric population, might have accounted for these screening failures.

Withdrawals from the study were generally low in the VOYAGE study, but higher proportions were observed in the dupilumab group (dupilumab versus placebo for the type 2 population: ||||||||||||||||||||; dupilumab versus placebo for the baseline EOS ≥ 300 cells/µL population: ||||||||||||||||||||). Similarly, discontinuation from the treatment occurred in approximately 8% of individuals receiving dupilumab, compared to approximately 3.5% of patients receiving placebo across the 2 efficacy populations. According to the data presented in the study report, proportions of individuals who discontinued study treatment due to an AE were balanced across the 2 study arms (approximately 2% for both study arms in the type 2 population and approximately 1% for both study arms in the baseline EOS ≥ 300 cells/µL population), suggesting lower possibility of attrition bias. In an attempt to account for missing data for the primary and key secondary outcomes, the sponsor performed a variety of sensitivity analyses, which are appropriate for scenarios when data are not missing at random. Finding of the sensitivity analyses were aligned with the primary findings. Considering all the above, CADTH deemed that the impact of missing data on the estimated treatment effects was limited.

Annualized rate of severe exacerbation events during the 52-week placebo-controlled treatment period and change from baseline in prebronchodilator percent predicted FEV₁ at week 12 were the primary and the key secondary outcomes included in the statistical hierarchy of the VOYAGE trial, respectively. Both outcomes were considered clinically relevant for patients with severe asthma, according to the clinician experts consulted and patient input provided. The definition of the primary outcome (i.e., deterioration in asthma requiring SCSs for at least 3 days or resulting in hospitalizations or ED visits requiring SCSs) as well as the interval between which 2 events were considered as separate (28 days) were regarded as appropriate, according to the clinical experts. Assessment and recording of severe exacerbations were conducted by a treating physician through the electronic case reports. Clinical experts reported that measuring percent predicted values of prebronchodilator FEV₁, instead of absolute values, was appropriate for the pediatric population under study. However, the clinicians stated the 12-week assessment of FEV₁ was not optimal for assessing the treatment effects of dupilumab versus placebo on pulmonary function because it would not be a sufficient duration to assess the seasonal and other factors that affect this outcome. The experts regarded the 52-week assessment of FEV₁ as more clinically relevant.

In the primary analyses for the primary and key secondary outcomes, off-treatment measurements of patients prematurely discontinuing treatment were included in the models, while data of patients after study discontinuations were censored. A series of sensitivity analyses were conducted by the sponsor in an attempt to evaluate the robustness of the primary findings. Specifically, on-treatment analyses to assess treatment effects if patients adhere to the study treatment as directed and missing data imputations (PMM-MI, PMM placebo-based and tipping point analyses) were conducted for both outcomes, while censoring methods according to the SCS usage were performed only for the key secondary outcome. Considering that the multiple imputation methods applied in the VOYAGE trial are applicable to situations when data are not missing at random, CADTH evaluation deemed the methodology applied as appropriate. Findings from the sensitivity analyses were consistent with the primary analyses across the 2 main efficacy populations of the trial.

The VOYAGE trial prespecified a series of subgroup analyses for the primary and the key secondary outcome, aligned with the subgroups of interest identified in the CADTH protocol (baseline eosinophil levels, baseline ICS dose, number of previous asthma exacerbations, atopic medical history). However, only subgroups of patients with baseline blood EOS of 300 cells/µL or greater, baseline blood EOS greater than150 cells/µL and patients receiving high doses of ICS were adjusted for multiple statistical comparisons, as they were part of the hierarchical testing procedure. Statistical tests of interaction were performed to test whether treatment effects differed among subgroups. However, the analyses for other subgroups of interest were not adjusted for multiplicity, and results from these analyses were treated as supportive of the overall benefit of dupilumab but no decisive conclusion can be drawn.

Another secondary outcome included in the hierarchical testing of the VOYAGE trial covered asthma symptoms, measured by a well-established and validated questionnaire (ACQ-7). The MID of 0.5 was established, which is reviewed in detail in Appendix 4.^24,25 Although not part of the statistical hierarchy, data regarding the responders’ analysis for the ACQ-7 was reported in the trial, with a response being defined using the 0.5 MID.

Of note, multiplicity adjustments were not conducted for other secondary and exploratory end points of interest, including annualized rates of severe asthma exacerbations resulting in hospitalization or ED visits and resulting in hospitalization only, HRQoL (PAQLQ, PACQLQ, EQ-5D-Y, PRQLQ), pulmonary function (PEF), SCS exposure, reliever medication use, and ICS dose adjustment; therefore, the results for these outcomes will be considered as supportive of the treatment effect but no definitive conclusions can be made.

The results reported in the Clinical Study Report of the VOYAGE trial were based on all the data collected up to the database lock on August 26, 2020. The study protocol underwent 3 global amendments and 1 local amendment for Brazil. Notable changes included the following: change to the study primary efficacy populations (from an overall uncontrolled persistent asthma population to the population with baseline eosinophil count ≥ 300 cells/µL or with the type 2 inflammatory asthma); changes to the sample size; specification of different testing hierarchies based on the US, European Union, and their reference countries; removal of the limitations for enrolling patients according to the background therapy, and EOS levels. These amendments were made before the database lock, suggesting that their ability to affect the end results or imply bias due to patient selection is limited.

Overall, no critical deviations from the protocol were reported during the VOYAGE trial. The sponsor identified a subset of major deviations, which had the potential adverse impact on integrity of the data, patients’ rights, or safety of the participants. These occurred in about 2% of patients across both the placebo and dupilumab arms in the 2 main efficacy populations and included: missing FeNO assessments at baseline, use of prohibited concomitant medications during the treatment period, less than 80% adherence with the treatment under study, and nonadherence with mandatory background therapy during the screening period. Considering that the number of patients with important deviations was low and balanced across the 2 study groups, CADTH reviewers deemed the risk of bias owing to protocol deviations to be low and to have negligible influence on comparative efficacy findings. Moreover, some randomization and dosing irregularities happened during the trial due to a difference in the ICS dose level as reported by the investigator at randomization in comparison to the actual calculated total daily dose of all medications containing ICSs, which was derived after converting to fluticasone dose equivalent according to GINA guidelines.¹ The irregularities were fairly balanced between the study groups (7.6% and 6.1% of type 2 population patients in the dupilumab and placebo group, respectively; 6.3% and 6.0% of baseline EOS ≥ 300 cells/µL patients in the dupilumab and placebo group, respectively). To overcome this, the sponsor specified 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.

External Validity

The VOYAGE study was a multinational, multicentre trial spanning across 90 sites in 17 countries, including Canada. The population requested for the reimbursement is narrower than the population included in the Health Canada–approved indication, as the OCS-dependant individuals were not taking part in the VOYAGE trial. According to the clinical experts, the number of pediatric patients on regular OCS therapy is limited, but many patients might experience frequent and repeated short course of OCS treatment to gain control of their symptoms or for exacerbations.

Overall, the clinical experts consulted by CADTH agreed that the inclusion and exclusion criteria of the trial were reflective for the severe asthma pediatric population. They also believed that the baseline and demographic characteristics of patients in the trial were largely consistent with the population that would be expected to use the drug in the real-world practice (i.e., poorly controlled individuals experiencing high FEV₁ and high reversibility despite being on appropriate therapy). Of note, the majority of the study population included individuals who were White; hence, generalizability of study findings to people living in Canada may be limited in this regard. Moreover, 1 of the main efficacy populations in the VOYAGE trial required that the identification of eligible patients be performed based on FeNO levels. Clinical experts consulted for this review reported that FeNO assessments are not routinely performed in Canadian clinical practice, which limits the generalizability of the study population.

According to the experts, the dosing of dupilumab applied during the clinical trial was consistent with the dose that would be applied in the Canadian clinical practice per the Health Canada–approved indication. Background medications administered during the trial were considered appropriate by the clinical experts consulted and reflective of medications administered in the Canadian setting. The experts also noted that adherence to therapy is a major issue in the management of asthma. The study documentation did not report whether the inhaler technique was checked throughout the trial, which can be considered a limitation. However, adherence to background therapy was high in both groups across the 2 efficacy populations during the study, suggesting that patients might have benefited from the close attention and monitoring of the trial. This might have also explained the level of benefits observed in the placebo population, which was receiving only background medication.

The VOYAGE trial did not compare dupilumab to any of the other biologics approved for the management of asthma in pediatric population, such as IgE inhibitors or the IL-5 inhibitors. Comparison of dupilumab to placebo (added on to standard of care) may be appropriate for establishing efficacy; however, the lack of an active control represents a limitation when trying to assess the comparative effects of dupilumab, leaving indirect comparisons available to assess the relative efficacy and harms of dupilumab compared to other biologics.

Clinical experts consulted during this CADTH review highlighted that the primary and key secondary outcomes were relevant outcomes for assessing pediatric patients with asthma, notably exacerbation rate, pulmonary function (FEV₁), and symptoms (ACQ-7). One of the clinical experts consulted for this CADTH review noted that ACQ is mostly applied for research purposes, but additionally commented that the tool can be regarded as appropriate and valid for assessing symptoms in the pediatric population.

Study Selection Methods

Network Meta-Analysis Feasibility Assessment

To ensure that the assumptions inherent to ITCs were appropriate for any planned analyses, the clinical heterogeneity across all included studies was assessed. This was done by establishing a list of potential treatment effect modifiers (Table 28), which was developed by reviewing subgroup results across the included RCTs and consultations with medical experts to discuss selected subgroups as well as comparability of included trials and feasibility of the analyses.

Table 27

Study Selection Criteria and Methods for the Sponsor-Submitted ITC.

Table 28

Characteristics of Potential Treatment Effect Modifiers.

ITC Analysis Methods

The ITC technical report noted that the clinical experts consulted for the feasibility assessment were split in their assessments of the clinical importance of the heterogeneity between the identified studies. Nonetheless, an “exploratory” Bucher ITC comparing dupilumab with omalizumab was conducted. The ITC analyses included a total of 3 trials connected with placebo as a common comparator (VOYAGE: dupilumab trial; IA05 and ICATA: omalizumab trials). Data from the VOYAGE and IA05 trials were used in the base case ITCs, while data from the ICATA study were included in separate analyses of certain outcomes, such as severe exacerbations, because of differences in key characteristics between the VOYAGE and ICATA trials that “would not allow for sufficient comparability” in the base case.³⁵

The technical report specified that the type 2 inflammatory population from the VOYAGE study was selected as the primary population of interest for the ITCs, in line with the regulatory agencies’ approvals. Since the type 2 asthma population data were not available in the omalizumab trials, an assumption was made that the efficacy of omalizumab would be maintained in the population of interest.

ITC analyses were performed for the following outcomes: severe exacerbations (annualized rates); deterioration of asthma from the VOYAGE study (post hoc analysis) versus severe exacerbations from the IA05 study (annualized rates); morning asthma symptom score at 24 weeks; rescue medication use at 24 weeks; change in PAQLQ(S)-Interviewer Administer at 24 weeks; discontinuations due to AEs at 52 weeks.

Statistical Approach

Since most of the analyses included a single trial per comparison in the network, a fixed-effect model was applied to the Bucher ITCs. For the analysis of severe exacerbations data, which included additional data from the ICATA trial, random effects Bucher ITC was performed.

The P values of significance for the ITC effects were computed in 2-sided tests. The technical report states that due to the limited number of trials in the ITCs, indirectly estimated effects with a P value of 0.05 or less were classified as statistically favourable, a P value greater than 0.05 and 0.15 or greater, as numerically favourable and a P value greater than 0.15 as comparable.

Results of the Bucher ITCs were presented as a central estimate of the relative effect of interest (MID for a continuous outcome and OR or RR for a binary outcome) along with 95% CIs. Analyses were carried out using the metafor package in R 4.0.3.

In the Bucher ITC, statistical heterogeneity for a treatment effect between the same comparison (i.e., omalizumab versus placebo in the IA05 and ICATA trials when the latter study is included) was evaluated using the I² statistic for the studies. A consistency assessment between direct and indirect sources of evidence was not applicable in the ITCs because there were no head-to-head comparisons between dupilumab and other comparators.

Subgroup Analysis

To account for differences in patient traits (i.e., omalizumab trials included patients with allergic phenotype, assessed via a positive skin prick test or a positive in vitro response to ≥ 1 perennial allergen) and biomarker or clinical characteristics (baseline EOS, percent predicted FEV₁, and prior exacerbations), an additional set of analyses was conducted in the “omalizumab-eligible” subgroup with allergic phenotype and corresponding to the inclusion criteria of the IA05 study. The following criteria were used in a post hoc analysis of VOYAGE to better align type 2 inflammatory patients from the VOYAGE trial with those in the IA05 trial:

• Baseline weight between 20 kg to 50 kg and serum IgE level of 30 IU/mL to 1,300 IU/mL and weight-IgE values combinations based on omalizumab dosing table
• At least 1 positive perennial allergen-specific IgE (concentration ≥ 0.35 IU/mL) among the following allergens: Alternaria tenuis/alternata; Cladosporium herbarum/hormodendrum; Aspergillus Fumigatus; Cat Dander; D. Farinae; D. Pteronyssinus; Dog Dander; and German Cockroach

Of note, the VOYAGE trial did not include the performance of skin prick test, so the presence of 1 positive perennial allergen-specific IgE was used as a proxy for the allergic phenotype in the IA05 study.

Sensitivity Analyses

To account for differences in the definition of the outcome of interest (severe exacerbations) and increase the comparability between the 2 trials included in the ITC, an additional post hoc analyses of VOYAGE data were performed using an outcome labelled as deterioration of asthma (Table 29).

Table 29

Overview of Outcomes of Interest Assessed in the Eligible Trials and Included in the ITC.

Summary of Included Studies

The 3 double-blind, RCTs trials were VOYAGE (dupilumab 100 mg to 200 mg every 2 weeks), IA05 (omalizumab 75 to 375 mg every 1 month or every 2 months), and ICATA (omalizumab 150 mg to 375 mg every 2 weeks or every 4 weeks), connected via placebo as a common comparator. Characteristics of the study design and patient populations across the included studies are presented in Table 30 and Table 31.

Assessment of Risk of Bias of Included Trials

Methodological quality of all included studies was assessed using the Cochrane Risk of Bias Assessment Tool 1.0. The technical report for the ITC states that the assessed trials were rated as low risk of bias overall. Specifically, all studies showed no evidence of selection, performance, and attrition bias. Both omalizumab trials had unclear reporting, and the presence of detection bias was rated as unclear. Moreover, presence of reporting bias was also unclear in the IA05 study.

Table 30

Redacted.

Table 31

Redacted.

Results

The key findings of the ITC are presented in Table 32, both for the type 2 Inflammatory asthma phenotype as well as the omalizumab-eligible type 2 inflammatory asthma phenotype patient populations. A visual representation of the evidence network is provided in Figure 7.

Figure 7

Redacted.

Dupilumab Versus Omalizumab

For the type 2 population, there was an improvement in annualized rates of severe exacerbations (||||||||||||||||||||||||||||||||||||||||||||||||||), and an improvement in deterioration of asthma for the comparison of dupilumab versus omalizumab (||||||||||||||||||||||||||||||||||||||||) (Table 32). No statistically significant between-group differences were found in terms of changes from baseline in morning asthma score, rescue medication use, and PAQLQ(S)–Interviewer Administered as well as withdrawals due to AEs.

Subgroup Analyses

In the omalizumab-eligible type 2 inflammatory subgroup, no significant differences were observed for the comparison of dupilumab with omalizumab in any of the outcomes assessed.

Sensitivity Analyses

Overall, the results of the sensitivity analyses that included data from additional omalizumab trial (ICATA) were aligned with the primary analyses of reduction in severe exacerbation events.

Table 32

Redacted.

Methods

The EXCURSION study (N = 365) is a multicentre (involving 17 countries including Canada), open-label, noncomparative study evaluating dupilumab given subcutaneously to pediatric patients aged 6 years to younger than 12 years with asthma who participated in the VOYAGE study. All patients enrolled in EXCURSION received open-label treatment with dupilumab for a period of 52 weeks. After completion of the 1-year treatment period, all patients were to continue into the 12-week posttreatment period. This study was designed to evaluate the long-term safety and tolerability of dupilumab, as well as its long-term efficacy.

Populations

To be eligible for enrolment into the EXCURSION study, pediatric patients with asthma must have completed the parent study, the VOYAGE trial. The placebo–dupilumab group is defined as the patients who were in the placebo group of the parent study and then exposed to dupilumab in the long term study. The dupilumab–dupilumab group is defined as the patients who were in the dupilumab group of the parent study and exposed to dupilumab in the long term study.

The baseline characteristics were reported from the time of enrolment in the parent study, VOYAGE. For a full list of baseline characteristics of the VOYAGE study, refer to Table 7. At week 0 of the EXCURSION study, age, weight, height, body mass index, ICS dose level, serum total IgE, blood eosinophil count, and FEV₁ (pre- and postbronchodilator, percent predicted, and reversibility [%]) were re-assessed; however, these are not reported in this section.

Interventions

The dosing regimens in the EXCURSION study are the same as the ones evaluated in the VOYAGE trial.

Patients whose weight changed from 30 kg or less to greater than 30 kg during the study switched their dosing regimen from 100 mg every 2 weeks or 300 mg every 4 weeks to 200 mg every 2 weeks and maintained the same dosing regimen regardless of further weight changes.

All patients in EXCURSION were receiving ICSs with or without a second controller (e.g., LABA, LTRA, LAMA, or methylxanthines) as background maintenance therapy. Also, patients were allowed to use albuterol/salbutamol or levalbuterol/levosalbutamol as a reliever therapy as needed during the study.

All patients were required to remain on stable dosing regimens of their background medications. During deterioration, the ICS dose could be increased or switched to SCS (for a severe exacerbation) temporarily as indicated by the physician and/or the sponsor. When the exacerbation resolved, patients could change back to the original ICS dose or modified ICS dose depending on their control of asthma symptoms.

Outcomes

The primary objective of the EXCURSION study was to assess the long-term safety and tolerability of dupilumab. The efficacy outcome definitions in the EXCURSION study are the same as those in the VOYAGE study.

Statistical Analysis

The results from the EXCURSION study were presented as descriptive summary statistics with observed data only. No model-based imputation for missing data was performed. Also, statistical adjustment including multiplicity adjustment was not conducted. The results were presented by treatment categories according to the actual treatment group in the parent study VOYAGE (i.e., the dupilumab–dupilumab and the placebo–dupilumab groups).

The full analysis set contained all data observed in the study without excluding any data or censoring and was used for the planned analyses. For efficacy outcomes, results are presented by 2 main subgroups, namely patients with type 2 inflammatory asthma phenotype at baseline of the parent study (blood eosinophil ≥ 0.15 Giga/L or FeNO ≥ 20 ppb) and patients with blood eosinophil of 300 cells/µL or greater at baseline of the parent study.

The term “baseline” refers to the baseline of the parent study VOYAGE, while the term “week 0” refers to the beginning of the EXCURSION study (at enrolment, before the first dupilumab administration). The full analysis set includes data collected from all enrolled patients regardless of the dosing schedules they had been assigned to in the parent trial, VOYAGE.

Patient Disposition

Patient disposition in the EXCURSION study as of both interim analyses is summarized in Table 33. A total of 365 patients (ITT population from the VOYAGE study, ||||||||||||||||||| from dupilumab group, ||||||||||||||||||| from placebo group) were rolled over from the parent study and received open-label dupilumab for an additional 52 weeks in the EXCURSION study. Of |||||||||||||||||||||||||||||||||||||| previously received dupilumab and ||||||||||||||||||| previously received placebo in the VOYAGE study.

At the cut-off date of August 18, 2020, |||||||||||| of the dupilumab–dupilumab group and |||||||||||| of the placebo–dupilumab group completed the study treatment, respectively. It was noted that more patients in the dupilumab–dupilumab group discontinued treatment compared to the placebo–dupilumab group (||||||||||||) due to AEs, poor treatment adherence, voluntary withdrawal, and other reasons A total of |||||| additional patients (|||||| in dupilumab–dupilumab group and |||||| in placebo–dupilumab group) discontinued study after completion of treatment period due to AEs, poor treatment adherence, or other reasons (|||||| in dupilumab–dupilumab group versus |||||| in placebo–dupilumab group).

As of the database lock date of January 17, 2022, almost all patients either completed treatment (95% in the dupilumab–dupilumab group and 97.6% in the placebo–dupilumab group) or the study period (95% and 94.4%, respectively). Compared to the previous data cut-off date, 1 more patient discontinued treatment due to an AE in the dupilumab–dupilumab group and 1 more patient discontinued study for other reason in the placebo–dupilumab group. Overall, 12 (5.0%) and 3 (2.4%) patients prematurely discontinued treatment in dupilumab–dupilumab and placebo–dupilumab groups, respectively. The number (%) of patients who did not complete the end of study visit were 12 (5%) and 7 (5.6%) in the dupilumab–dupilumab and placebo–dupilumab arms, respectively (Table 32).

Table 33

Patient Disposition (EXCURSION) .

Exposure to Study Treatments

Exposure to study treatments is summarized in ||||||||||||||||||||||||.

At the cut-off date of August 18, 2020, the median duration of the study was 372 days (range = 1 to 488) and 375 days (range = 2 to 518 days) for the dupilumab–dupilumab and placebo–dupilumab groups, respectively. The total cumulative study duration was 217 patient-years and 116 patient-years for the dupilumab–dupilumab and placebo–dupilumab groups, respectively, reflecting a 2:1 randomization scheme from the parent trial.

As of the January 17, 2022, data cut-off date, the median duration of study was |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| for the dupilumab–dupilumab and placebo–dupilumab groups, respectively. The cumulative study duration |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| for the dupilumab–dupilumab and placebo–dupilumab groups, respectively. All enrolled patients received ICSs with or without a second controller in addition to dupilumab. In general, all patients had high treatment adherence with nearly everyone having achieved equal or more than |||||||||||||||||||||||||||||||||||||||||||||||| in the dupilumab–dupilumab group and placebo–dupilumab groups, respectively, in the August 18, 2020, dataset; |||||||||||||||||||||||||||||||||||||||||||||||| respectively, in the January 17, 2022, dataset).

Table 34

Redacted.

Efficacy

All efficacy end points were secondary end points in the EXCURSION study.

Severe Asthma Exacerbation

Exacerbation data are summarized in ||||||||||||||||||||||||.

When analyzed as a subgroup, patients with type 2 inflammatory asthma phenotype at baseline of the parent study |||||||||||||||||||||||| experienced an event in the dupilumab–dupilumab and placebo–dupilumab groups, respectively. When analyzed as a subgroup, patients with EOS of 300 cells/µL or greater at baseline of the parent study |||||||||||||||||||||||| experienced an event in the dupilumab–dupilumab and placebo–dupilumab groups, respectively. The unadjusted annualized rate of severe exacerbation was |||||||||||||||||||||||| for the dupilumab–dupilumab and placebo–dupilumab groups, respectively |||||||||||||||||||||||| in a type 2 inflammatory asthma phenotype subgroup; |||||||||||||||||||||||| in an eosinophil ≥ 300 cells/µL subgroup).

As of the January 17, 2022, data cut-off, for both the type 2 inflammatory asthma and EOS of 300 cells/µL or greater at baseline subgroups, there was |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| whereas the numbers |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| compared to the previous dataset. Compared to the previous dataset, in a type 2 inflammatory asthma phenotype subgroup, the unadjusted annualized severe exacerbation event rate decreased from ||||||||||||||| to 0.118 and from ||||||||||||| to 0.124 for the dupilumab–dupilumab and placebo–dupilumab groups, respectively. Similarly, in the subgroup with eosinophil of 300 cells/µL or greater, the unadjusted annualized severe exacerbation event rate decreased from |||||||||||| to 0.120 and from |||||||||||| to 0.119, for the dupilumab–dupilumab and placebo–dupilumab groups, respectively. There were |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| who experienced a severe exacerbation requiring hospitalization or ED visit during the treatment period.

Table 35

Redacted.

Change in Percent Predicted FEV₁

Data for change in the percent predicted FEV₁ are presented in Table 35.

As of the August 18, 2022, data cut-off, at week 52, improvement in percent predicted prebronchodilator FEV₁ was |||||||||||||||||||||||||||||||||||||||||||||||||| for the dupilumab–dupilumab and placebo–dupilumab groups, respectively, in the type 2 inflammatory asthma subgroup. In the same dataset, at week 52, improvement in percent predicted prebronchodilator FEV₁ was ||||||||||||||||||||||||| and ||||||||||||||||||||||||| for the dupilumab–dupilumab and placebo–dupilumab groups, respectively, in the baseline blood EOS of 300 cells/µL or greater subgroup. Of note, the total number of patients contributing to the analysis reduced to almost half (n = 111 versus n = 58 for the dupilumab–dupilumab and placebo–dupilumab groups, respectively) compared to the number of enrolled patients (n = 240 versus n = 125) at week 52 in data from the August 18, 2020, cut-off .

The second interim analysis based on the updated dataset (as of January 17, 2022) included more patients (n = ||||||||||||||||||||||||| for the dupilumab–dupilumab and placebo–dupilumab groups, respectively) than previous analysis. Additional data showed sustained lung function improvement in the type 2 inflammatory asthma subgroup as shown by the FEV₁ increase from baseline by |||||||||||||||||||||||||||||||||||||||||||||||||| in the dupilumab–dupilumab and placebo–dupilumab groups, respectively, at week 52. Similarly, in subgroup with baseline blood EOS of 300 cells/µL or greater, improvement in FEV₁ was sustained at week 52 as shown by increase of |||||||||||||||||||||||||||||||||||||||||||||||||| in the dupilumab–dupilumab and placebo–dupilumab groups, respectively.

Table 36

Change From Baseline in Percent Predicted Prebronchodilator FEV₁ Over Time (EXCURSION) .

Harms

Only those harms identified in the review protocol outlined in Table 5 are reported below. Refer to Table 36 for detailed harms data.

Adverse Events

In the initial analysis with data from the August 18, 2020, cut-off, the most frequently reported (≥ 5%) treatment-emergent AEs were nasopharyngitis (7.5% and 8.8% for the dupilumab–dupilumab and placebo–dupilumab groups, respectively), pharyngitis (5.0% and 8.8% for the dupilumab–dupilumab and placebo–dupilumab groups, respectively), and upper respiratory tract infection (6.7% and 3.2%, for the dupilumab–dupilumab and placebo–dupilumab groups, respectively). As of the January 17, 2022, data cut-off, the number of treatment-emergent AEs reported slightly increased for both groups (8.8% and 9.6% for nasopharyngitis, 6.3% and 9.6% for pharyngitis, and 7.9% and 4.0% for upper respiratory tract infections for the dupilumab–dupilumab and placebo–dupilumab groups, respectively).

Serious Adverse Events

As of the data cut-off date of August 18, 2020, there were 4 (1.7%) and 1 (0.8%) patient(s) from the dupilumab–dupilumab and placebo–dupilumab groups, respectively, who experienced SAEs during the EXCURSION study period. ||||||||||||||||||||||||||||||||||||||||||||||||||. As of the January 17, 2022, data cut-off, 2 more cases of SAEs were reported in the dupilumab–dupilumab group (for a total of 6 patients or 2.5%); whereas the number remained the same for the placebo–dupilumab group compared to the previous data cut-off.

Withdrawals Due to AEs

Based on data from the cut-off date of August 18, 2020, there were 2 (0.8%) patients in the dupilumab–dupilumab group who discontinued treatment due to AEs (pulmonary tuberculosis and allergic conjunctivitis). As of January 17, 2022, 1 more patient discontinued treatment due to ascariasis and a total of 3 (1.3%) patients discontinued treatment. No patient in the placebo–dupilumab group discontinued treatment due to an AE.

Mortality

No deaths were reported during the EXCURSION study period.

Notable Harms

As of the August 18, 2020, data cut-off, a total of |||||||||||||||||||||||||||||||||||||||||||||||||| patient(s) in the dupilumab–dupilumab and placebo–dupilumab groups, respectively, experienced hypersensitivity (medically reviewed) reactions with ||||||||||||||||||||||||| patients in the dupilumab–dupilumab group and none in the placebo–dupilumab group experiencing anaphylactic reaction. According to the study report, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| in intensity and none led to treatment interruption or discontinuation.

As of the August 18, 2020, data cut-off, severe or serious infection was reported in |||||||||||| patients in the dupilumab–dupilumab group (complicated appendicitis, pulmonary tuberculosis, and upper respiratory tract infection) and |||||||||||| patient in the placebo–dupilumab group (pneumonia). One (0.4%) patient from the dupilumab–dupilumab group and none in the placebo–dupilumab group experienced an opportunistic infection (pulmonary tuberculosis). |||||||||||||||||||||||||||||||||||| patient(s) in the dupilumab–dupilumab and placebo–dupilumab groups, respectively, reported to have had parasitic infections during the study period.

As of the August 18, 2020, data cut-off, injection site reaction was reported more frequently in the placebo–dupilumab group than the dupilumab–dupilumab group (||||||||||||||||||||||||).

As of the August 18, 2020, data cut-off, conjunctivitis occurred in |||||||||||||||||||||||||||||||||||| of patients in the dupilumab–dupilumab and placebo–dupilumab groups, respectively. Based on the Clinical Study Report, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Lastly, eosinophilia was reported in |||||||||||||||||||||||||||||||||||| patients in the dupilumab–dupilumab and placebo–dupilumab groups, respectively as of the August 18, 2020, data cut-off. According to the study report, all cases of eosinophilia were asymptomatic and a transient increase in blood eosinophil counts that showed a gradual decrease over time. For some eosinophilia episodes, corrective treatment was administered.

As of January 17, 2022, the number of patients who experienced hypersensitivity (medically reviewed), parasitic infections, injection site reaction, conjunctivitis (broad), and eosinophilia increased by 1 to 3 patients per category from those of the earlier cut-off date, August 18, 2020. For a detailed description, refer to Table 37.

Table 37

Summary of Harms–FAS (EXCURSION) .

Critical Appraisal

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

[Search -- Studies with results | dupixent OR dupilumab OR SAR-231893 OR SAR231893 OR REGN-668 OR REGN668 | asthma]

WHO ICTRP

International Clinical Trials Registry Platform, produced by the World Health Organization. Targeted search used to capture registered clinical trials.

[Search terms -- (dupixent OR dupilumab OR SAR-231893 OR SAR231893 OR REGN-668 OR REGN668) AND asthma]

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

[Search terms -- (dupixent OR dupilumab) AND asthma]

EU Clinical Trials Register

European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

[Search terms -- (dupixent OR dupilumab OR SAR-231893 OR SAR231893 OR REGN-668 OR REGN668) AND asthma]

Validity

Content validity of ACQ has been ensured by having involved pediatric asthma clinicians during development phase. They selected the items in ACQ that are considered the most important to determine asthma control.⁴⁶

Juniper et al.²⁴ tested measurement properties of the ACQ-7 in 35 children (aged 6 – 16 years) with a wide range of asthma severity and had current symptoms of asthma (ACQ score > 0.5) in England. The cross-sectional construct validity has been demonstrated by strong Pearson correlation coefficients (r > 0.5⁴⁷) between established measures (Mini Pediatric Asthma Quality of Life Questionnaire [MiniPAQLQ], Royal College of Physicians’ “3 questions” [RCP], Asthma Control Diary [ACD], PACQLQ) and ACQs (ACQ-7 = -0.83, 0.52, 0.77, -0.63; ACQ-5 = -0.84, 0.57, 0.71, -0.56, respectively). Longitudinal construct validity has also been shown by similarly strong Pearson correlation coefficients (r > 0.5⁴⁷) between established health status measures,⁵³ (changes in MiniPAQLQ, RCP, ACD, PACQLQ) and changes in ACQ scores over 1-4 weeks (ACQ-7 = -0.89, 0.81, 0.83, -0.49; ACQ-5 = -0.93, 0.81, 0.79, -0.84, respectively). Multiple measures were used since there is no gold standard for measuring asthma control in children. These correlations were close to a priori predications about the degrees of correlations expected of the ACQ if it truly measures change in asthma control. Strong correlations demonstrated that established instruments and ACQ measure a similar concept. However, the author of the study noted that asthma control and quality of life are 2 distinct components of clinical asthma assessment, therefore, some degree of discrepancies are expected between ACQ and the HRQoL measurement instruments.⁵⁴

The study by Juniper, et al.²⁴ has several limitations in that it tested ACQ in 35 pediatric patients from a single centre with a UK version that had alternative wording to younger children and was administered by a trained interviewers. To overcome some of the limitations, Nguyen, et al.²⁵ tested measurement properties of ACQ in 305 pediatric patients (aged 6 – 17 years old) with inadequately controlled asthma on ICS that were enrolled in a clinical trial using the North American English version of ACQ. They confirmed the moderate to strong construct validity of ACQ by measuring Pearson correlation coefficients with Asthma Control Test (ACT for ages 12 to 17; r = -0.73) or childhood ACT (cACT for ages 6 to 11; r = -0.57), the Asthma Symptom Utility Index (ASUI; for ages 6 to 11, r = -0.74; for ages 12 to 17, r = -0.74), and the PAQLQ (for ages 6 to 11, r = -0.71; for ages 12 to 17 r = -0.66). Furthermore, ACQ differentiated patients who had an episode of poor asthma control from those who did not (for ages 6 to 11, mean difference [SD] = 0.46 [0.01]; P < 0.0001; for ages 12 to 17, mean difference [SD] = 0.30 [0.02]; P < 0.0001) in all aspects such as decrease in PEF rate, increase in rescue medication use, urgent care (ED, hospital, clinic or doctor visit), and SCS use. However, the group did not find such correlation between exhaled NO (n = 146) or expired breath condensate pH (n = 239) and ACQ scores.²⁵

Reliability

Juniper, et al.²⁴ categorized 2 groups of children, e.g., a group of children who remained clinically stable and another group who experienced change in their asthma control between clinic visits (weeks 0-1 and 1-4) based on the Clinician’s Global Rating of Change score. Pearson correlation coefficients between ACQ changes and Global Rating of Change Questionnaire over a period of 1 – 4 weeks were considered to be strong (r > 0.5).⁴⁷ Test-retest reliability was determined from the stable group by estimating intraclass correlation coefficient (ICC estimated as the within-patient SD and related to the total SD). The group made a priori predications about the level of correlation expected if the ACQ truly measures asthma control. In 19 children who remained stable, there was good evidence for reliability as ICC for the ACQ-7 was 0.79 and ACQ-5 was 0.67.

Even though the concordance between the ACQ-7 and ACQ-5 was high (ICC = 0.93), there was statistical difference between the ACQ-7 and ACQ-5 scores (mean ± SD = 0.12 ± 0.26; P = 0.010) with the greater change in the ACQ-5 than ACQ-7 in scores between baseline and 4 weeks (mean ± SD = 0.17 ± 0.34; P = 0.006).²⁴ Therefore, the 2 versions of ACQ should not be used interchangeable.²⁴

Another group²⁵ found that Cronbach alpha for the ACQ to be 0.74 (n = 305), 0.75 for ages 6 to 11 group (n = 164) and 0.72 for ages 12 to 17 group (n = 141), all of which are considered acceptable for group-level internal consistency (alpha > 0.7).⁵⁵ Of note, a value of alpha > 0.9 is considered necessary for an individual-level comparison. The ICC for ACQ scores between 2 consecutive visits (total 8 visits) among stable patients who reported no episode of poor asthma control for that period ranged between 0.42 to 0.82 for the overall group, 0.34 to 0.95 for the 6 to 11 age group and 0.22 to 0.74 for the 12 to 17 age group.²⁵ The reliability for ACQ in the overall group and younger patient group was moderate to strong,⁴⁷ whereas that for older children varied from weak to strong depending on a period of visit measured.

Responsiveness to Change

Responsiveness was measured by detecting within-patient change in the unstable group of children using a paired t-test and between-group changes (stable vs. unstable) using an unpaired t-test. The ACQ-7 and the ACQ-5 both were able to detect changes in asthma control in unstable patients between clinic visits 4 weeks apart (P = 0.026 and 0.007, respectively) and were able to distinguish between stable and unstable patients during the same period (P = 0.072 and 0.027, respectively), with ACQ-5 showing statistically better responsiveness than ACQ-7.²⁴

Similarly, Nguyen, et al.²⁵ demonstrated responsiveness of ACQ to changes in asthma control. Mean changes in ACQ scores between consecutive visits in continuously well-controlled (n = 196 over 547 days) and continuously poorly controlled patients (n = 148 over 337 days) were -0.02 (95% CI = -0.05, 0.01) and 0.06 (95% CI = 0.00, 0.12), respectively. For those who had worsening control (n = 155 over 177 days) and improved control (n = 165 over 200 days), mean changes in ACQ scores were 0.26 (95% CI = 0.11, 0.41) and -0.33 (95% CI = -0.44, -0.22), respectively. Also, mean changes in ACQ scores differed significantly across groups of patients categorized based on their health status for the overall group (P < 0.0001), 6 to 11 age group (P < 0.001), and 12 to 17 age group (P = 0.01).

MID

With the Global Rating of Change method (n = 11), Juniper, et al. estimated the MID for ACQ-7 to be 0.52 (SD = 0.45) and for ACQ-5 to be 0.65 (SD = not reported). The estimated MID was confirmed with the geometric mean regression method (n = 31), which gave a similar result with 0.50 (SEM = 0.05).²⁴ The sponsor used an MID estimate of 0.5 based on the same reference as identified by CADTH literature search.²⁴

Nguyen, et al.²⁵ estimated MID to be 0.375 and 0.382 based on the distribution-based method using 0.5*SD and SEM for the overall group. For those aged 6 to 11 years, MID was estimated to be 0.40 and for those between the ages of 12 and 17 years old, estimated MID was 0.35 using both 0.5*SD and SEM. The group also estimated MIDs based on various anchors. Using the mean ACQ scores among patients experiencing a specified clinical event compared to those who did not as anchor, Nguyen, et al. estimated MID to be 0.4-0.5 for the combined age group, 0.5-0.6 for the 6 to 11 age group, and 0.3-0.4 for the 12 to 17 age group. Anchoring the ACQ against the ACT that uses MID of 3 points, an estimated MID for ACQ was 0.42 for the 12 to 17 age group, and against a 3-point change in the cACT, estimated MID was 0.33 for children ages 6 to 11. Lastly, using the triangulation method,⁵⁶ the estimated MID was 0.40 for the overall group.

Validity

Wing, et al.²⁸ tested measurement properties in 42 children with asthma (mean age = 11.3 years of old, SD = 2.7; ranges 7 – 17) receiving standard asthma care in UK. All data from Wing, et al. study was generated from interviewer-led questionnaires and none from the self-administered versions. Criterion validity was ensured by comparing PAQLQ(S) overall and domain scores to those of the PAQLQ, which had been developed based on guidelines for a dozen validated disease-specific quality of life instruments and input from patients, parents and health professionals.²⁷ There was no statistically significant difference in scores between the original PAQLQ and the PAQLQ(S), apart from the “activities” subscale (P < 0.03). Both cross-sectional (which demonstrates that the observed differences between children truly reflect differences in asthma-specific quality of life) and longitudinal construct validity (which demonstrates that observed changes in scores over a period of time correlate in a predictable manner with changes in other measures of health status) were evaluated by the Pearson’s correlation coefficients with the original PAQLQ. The cross-sectional construct validity measured at week 9 against ACQ, % predicted PEF, ACD, Health Utilities Index (HUI), and PACQLQ showed Pearson’s coefficients of -0.77 (P < 0.001), 0.25 (P < 0.05), -0.68 (P < 0.001), -0.40 (P < 0.01), and 0.51 (P < 0.001), respectively, for overall scores (data for domain scores are not shown). The longitudinal construct validity measured by Pearson coefficients between weeks 5 and 9 for ACQ, PEF, ACD, HUI, and PACQLQ were -0.79 (P < 0.001), 0.41 (P < 0.01), -0.45 (P < 0.001), -0.46 (P < 0.001), and 0.43 (P < 0.01), respectively for overall scores (data for domain scores are not shown).²⁸

Reliability

The concordance between the original PAQLQ and PAQLQ(S) was measured by ICC (Pearson correlation coeifficient) with a paired Student’s independent t-test and was 0.974, 0.669, 0.955, and 0.863 for overall, activity, symptom, and emotion scores, respectively (P value < 0.001). Internal consistency estimated by Cronbach alpha values at baseline for overall, activity, symptom, and emotion scores were 0.96, 0.90, 0.90, and 0.94, respectively. Of note, reliability in activity domain was higher for PAQLQ(S) compared to PAQLQ probably due to generic questions included to standardize responses. These measures indicate that the correlation with PAQLQ is strong (r > 0.5⁴⁷) and PAQLQ(S) has an acceptable internal consistency (alpha > 0.7⁵⁵), all exceeding alpha = 0.90 set for individual monitoring. Test-retest reliability assessed in patients with stable asthma between weeks 1 – 5 and 5 – 9 (n = 16) was also strong (ICC [95% CI] = 0.92 [0.82, 0.97], 0.81 [0.63, 0.92], 0.89 [0.77, 0.96], and 0.92 [0.84, 0.97] for overall, activity, symptom, and emotion scores, respectively). These results exceed 0.70, which is commonly accepted minimal standard for reliability coefficients.²⁸ However, Wing, et al. expected ICC for test-retest stability greater than 0.85 based on ICCs reported in previous studies.

Responsiveness to Change

The PAQLQ(S) was able to detect the changes in patients who either improved or deteriorated by a score > 0.5 between weeks 1 – 5 and 5 – 9 (paired Student’s t-test, all P < 0.0001) and differences between stable and unstable groups for each of the measures (unpaired Student’s t-test, overall differences all < 0.0003).²⁸

MID

Juniper, et al.²⁷ used anchor-based method to estimate an MID in children with asthma. Briefly, the group took the mean difference in PAQLQ score in patients who score -3, -2, +2, or +3 on the global rating of change as MIDs. According to this method, MID estimates for overall quality life, symptom, activity, and emotion domains were 0.42 ± 0.55 (n = 29), 0.54 ± 0.64 (n = 0.29), 0.70 ± 1.17 (n = 26), and 0.28 ± 0.67 (n = 17), respectively. The sponsor took 0.5 as an MID estimate for PAQLQ(S)-IA based on the same reference.²⁷

Validity

Content validity has been ensured by incorporating several measures during development period: 1) item pools from the Rhinoconjunctivitis Quality of Life Questionnaire, the Adolescent Rhinoconjunctivitis Quality of Life Questionnaire, and the PAQLQ; 2) discussion with children 6 to 12 years old with allergic rhinoconjunctivitis; 3) discussion with clinicians; and 4) a review of the pediatric HRQoL literature.³⁰

Juniper, et al.³⁰ conducted validation study in 75 children (a mean age of 9.8 years, SD = 1.9) who had troublesome allergic rhinoconjunctivitis that required additional medication during the fall pollen season in the US. They assessed longitudinal construct validity by correlating within-patient changes in quality of life scores with within-patient changes in diary symptom scores and global rating of change. The a priori prediction was that if the PRQLQ truly could measure rhinoconjunctivitis-specific quality of life, the correlations should be similar to those observed in adults with rhinoconjunctivitis. Actual and predicated correlations between change in the PRQLQ and diary symptom scores were close across all domains of the PRQLQ and the different symptoms of the diary. For example, stuffy nose (r = 0.58) and mean nose symptoms (r = 0.67) in symptom diary were highly correlated with nose symptom in the PRQLQ (r = 0.55 – 0.7 a priori prediction).

The group also assessed cross-sectional construct validity by correlating quality of life scores with daily symptom diary scores. Again, a priori prediction was that the correlations should be close to those observed in adults. Correlations between the PRQLQ and diary symptoms were very similar to those observed in adults and adolescents with rhinoconjunctivitis, with the highest correlations observed between the nasal domain of the PRQLQ and diary nasal symptoms (r = 0.47 actual vs. r = 0.45 – 0.6 for a priori prediction) and between the eye domain of the PRQLQ and eye symptom scores in the diary (r = 0.59 actual vs. r = 0.45 – 0.6 for a prior prediction). The poorest correlations were found between other symptom domain of the PRQLQ and the diary stuffy nose scores (r = 0.06 actual vs. r < 0.25 a priori prediction).³⁰

Reliability

Juniper, et al.³⁰ measured reliability in 13 children whose rhinoconjunctivitis remained stable between clinic visits at weeks 1 and 3 using ICC. The result shows that ICC was 0.93 for overall quality of life and 0.57, 0.91, 0.79, 0.88, and 0.87 for nose symptoms, eye symptoms, practical problems, other symptoms, and activity limitations, respectively. High ICCs indicate that within-patient variance was consistent in general, except for nose symptoms that showed lower ICC possibly as a result of a low between-patient variance.

Responsiveness to Change

Responsiveness was measured in 61 children who experienced a change in their rhinoconjunctivitis between weeks 1 and 3.³⁰ Using a paired t-test, within-patient changes in children who changed (n = 61) between visits were detected (change in mean score ranges from 0.37 to 0.80). No such changes were found in children (n = 13) who had stable rhinoconjunctivitis (change in mean score ranges from -0.22 to 0.12). Using an unpaired t-test to examine the ability of the instrument to distinguish between patients whose quality of life changed from the beginning to end of the study period and those whose quality of life remained unchanged for the same period was tested. The PRQLQ was able to detect the difference on in overall quality of life (P = 0.005), not each domain (P value ranges from 0.061 to 0.087).

MID

An estimate for MID has not been identified through literature search. The sponsor has taken 0.5 to be an MID for the VOYAGE study based on their literature search.⁴⁸ However, CADTH could not verify the MID estimate referenced by the sponsor.

Validity

Content validity has been ensured during development of PACQLQ. Briefly, a pool of items was generated from interviews with parents of children with asthma, a literature review, and discussion with health professionals. The items that were identified most frequently and rated most bothersome by caregivers were selected for the final questionnaire.²⁷

Juniper, et al.²⁷ assessed measurement properties of PACQLQ in 52 children with current symptoms of asthma and their primary caregivers. The children were between 7 and 17 years and represented a wide range of asthma severity. The primary caregiver (age ranged from 30 to 63 years; mean 40.94, SD = 5.6 years) was usually a parent and lived with the child at least 75% of the time. The a priori predictions for both longitudinal and cross-sectional validity was that correlations would be observed if investigators can truly measure quality of life in caregivers. The longitudinal construct validity was measured by correlating within-patient changes in the caregiver’s quality of life scores over a 4-week period with within-patient changes in caregiver burden of illness (generic questionnaire), child’s asthma severity (FEV₁% predicted, PEF, beta agonist use, and so forth), global ratings of change, and perception of change in child’s asthma survey. The highest correlations were observed between the PACQLQ emotional function and caregiver global ratings of change – emotions (r = 0.55 vs. r > 0.50 a priori prediction) or caregiver perception of change in child’s’ asthma survey (r = 0.52 vs. r = 0.20 – 0.35 a priori prediction). The poorest correlations were between the change in caregiver burden of illness – mastery and the PACQLQ emotional function (r = -0.0007 vs. r = 0.20 – 0.35 a priori prediction) or activity limitation (r = 0.02 vs. r = no a priori prediction made). The cross-sectional construct validity was measured by correlating caregiver quality of life scores at each clinic visit with the measures of the child’s asthma severity and with generic caregiver quality of life scores. The highest correlations were observed between the PACQLQ activity limitation and caregiver burden of illness – overall (r= -0.65), family/social (r = -0.62 vs. r = 0.20 – 0.35 a priori prediction), and personal strain (r = -0.70). The poorest correlations were observed between the caregiver burden of illness – mastery and the PACQLQ emotional function (r = 0.28 vs. r = 0.20 – 0.35 a priori prediction) and activity limitation (r = 0.26 vs. no a priori prediction). Similarly, such poor correlations were observed between child’s’ asthma severity – beta agonist use and the PACQLQ emotional function (r = -0.22 vs. r = 0.20 – 0.35 a priori prediction) or activity limitation (r = -0.28).²⁷

As predicted, the correlation between the PACQLQ and change in child’s peak flow rates or asthma control was weak, with FEV₁ even lower than predicted. In general, correlations between the PACQLQ and the global ratings of change or parental rating of change in the children’s severity of asthma were moderate to high as predicted, with the Impact on Family Scale substantially higher than predicted. These results suggest that problems associated with caring for a child with asthma is not entirely the same as general problems of looking after a sick child.²⁷

Reliability

Reliability was measured in 44 caregivers who were stable between consecutive clinic visits.²⁷ The ICCs for overall quality of life, emotional function, and activity limitation were 0.85, 0.80, and 0.84, respectively. The PACQLQ showed a high degree of reliability with a low within-patient variance (within-patient SD = 0.31 – 0.39) and ability to detect differences in quality of life between caregivers (between-patient SD = 0.71 – 0.88).

Responsiveness to Change

Responsiveness was measured using a paired t-test as ability to detect important within-patient changes when caregivers changed over 4 weeks.²⁷ Caregivers who changed (n = 23) showed the change in mean score per item as 0.72, 0.71, and 1.80 for overall quality of life, emotional function, and activity limitation, respectively (P < 0.001 for all), whereas those who were stable showed -0.03, -0.02, and -0.01, respectively. Also, using an unpaired t-test of the differences between the beginning and end of each period, the ability of the instrument to distinguish between patients who remained stable and those who changed was measured. Changes in those caregivers who changed over 4 weeks were significantly different from the changes in score in the caregivers who reported staying stable (P < 0.0003 for all). The questionnaire proved highly responsive to within-patient changes over time.

MID

Based on global rating of change as anchor, the MID for overall quality of life was estimated to be 0.50 (SD = 0.51; n = 16) with similar values for the emotional function domain (0.64, SD = 0.56; n = 18) and activity limitation domain (0.67, SD = 0.63; n = 9).²⁷

Validity

Mayoral et al.⁴⁹ assessed measurement properties of EQ-5D-Y administered through a smartphone app in 119 children with asthma (81 self-responded and 38 through proxy response) in Spain between 2018 and 2020. Children aged 8 – 11 years completed self-response version. For those under the age of 8 years, their parents filled out the proxy response version of EQ-5D-Y.

For convergent validity, a hypothesis for a moderate correlation between the Patient-Reported Outcomes Measurement Information System-Pediatric Asthma Impact (PROMIS-PAIS) and the EQ-5D-Y utility index (except for certain questions where a weak correlation is expected) was made considering their asthma-specific and generic aspects, respectively. For divergent validity, a priori hypothesis was a weak correlation between the EQ-5D-Y utility index and the ACQ (except for certain questions that were expected to be moderately correlated), since they differ on the construct being measured (HRQoL and disease control, respectively). Multitrait–multimethod matrix method confirmed the associations for the EQ-5D-Y utility index with the PROMIS-PAIS to be moderate⁴⁷ (Spearman r = 0.38) and with ACQ to be weak⁴⁷ (r = 0.28). With the EQ VAS, the correlation coefficients with both PROIMS-PAS and ACQ were weak⁴⁷ (r = 0.16 and 0.26, respectively).

Another research group tested convergent validity of EQ-5D-Y with PAQLQ in Swedish children (aged 8 – 16 years) with asthma (n = 53 – 90).⁵⁰ This group hypothesized that most of the domains of 2 questionnaires would be correlated since they do not capture the same aspects of HRQoL as they are constructed differently. The absolute Spearman’s rank correlations between 5 domains of EQ-5D-Y and 3 subdomain scores of PAQLQ ranged from 0.015 (weak) to 0.583 (strong).⁴⁷ The highest correlations were found in ‘doing usual activities’ and ‘having pain or discomfort’ domains, whereas the lowest correlation was found in ‘looking after myself’ domain of EQ-5D-Y. Also, in general, EQ VAS was moderately to strongly⁴⁷ correlated with symptoms (r = 0.435), activity limitations (r = 0.567), emotional functions (r = 0.411), and total score (r = 0.517) of PAQLQ. Patients who reported no problems on the EQ-5D-Y consistently reported fewer problems on the PAQLQ.⁵⁰

Based on the known-groups approach, a priori hypothesis was made by Mayoral, et al.⁴⁹ that patients with worse control asthma (according to ACQ: well-controlled, immediate, and not well controlled), asthmatic exacerbations last 6 months, higher frequency of SABA inhaler use during the previous 4 weeks, and second-hand smoke exposure would have worse HRQoL. Statistically significant differences were found in the EQ-5D-Y utility index and EQ VAS between groups defined by asthma control, reliever inhalers use, and second-hand smoke exposure, but not with asthmatic exacerbations (which could be attributed to attrition bias effect). Of note, EQ-5D-Y utility index and second-hand smoke exposure were moderately correlated (effect size [ES] = -0.45 [95% CI = -1.01 to 0.1]), but not statistically significant (P = 0.35). The absolute ES coefficients (mean change over SD of change) ranged from 0.38 to 0.75 indicating moderate to strong relationship between the 3 known groups and EQ-5D-Y utility index and EQ VAS.

Reliability

In the same study,⁴⁹ Mayoral et al. showed test-retest reproducibility of EQ-5D-Y in pediatric patients with asthma who remained stable (n = 19 – 30) and completed the questionnaire twice 6 months apart. When subsample of patients was classified to be stable based on EQ VAS, the ICC was 0.81 with EQ-5D-Y utility index. When the stable patients were classified according to the ACQ, the ICC was 0.79 with EQ-5D-Y utility index and 0.70 with EQ VAS. Based on high ICC values obtained, it can be concluded that EQ-5D-Y reliably reproduces results over time.

Responsiveness to Change

Regarding responsiveness, Mayoral, et al.⁴⁹ hypothesized that the EQ-5D-Y would be able to detect change over time, though with a lower sensitivity than the asthma-specific instrument PROMIS-PAIS. At 10 months follow-up, responsiveness of EQ-5D-Y utility index for worsening subsamples (n = 6 – 17) presented a degree of change (ES = 0.68 based on EQ VAS and ES = 0.78 based on ACQ), though without statistical significance (P = 0.12 and 0.50, respectively). With respect to EQ VAS, the ES was 1.15 in worsening subsample as measured by ACQ, however, the statistical significance was not detected (P = 0.67), either. In contrast, the PROMIS-PAIS demonstrated better responsiveness in worsening subsample of patients over the same period when patients were evaluated by EQ VAS (ES = 1.08, P = 0.07) or ACQ (ES = 1.28, P = 0.82), though still not be able to detect statistically significant differences.

Minimal Important Difference

The MID for EQ-5D-Y in pediatric patients with asthma has not been estimated based the literature search results.