FormalPara Key Summary Points

Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13, key and central drivers of type 2 inflammation in multiple diseases, including asthma.

In randomized controlled trials (RCTs), dupilumab significantly reduced the rate of severe asthma exacerbations and improved prebronchodilator forced expiratory volume in 1 s (FEV1) in patients with uncontrolled, moderate-to-severe asthma.

The Registry of Asthma Patients Initiating DUPIXENT® (RAPID; NCT04287621) is the first global, prospective, observational registry to characterize patients with asthma who initiated dupilumab in clinical practice and will provide real-world data to supplement prior clinical studies.

RAPID will enroll around 1000 patients aged 12 years and over with asthma from 150 sites globally, two-thirds of which will be USA-based.

The objectives of RAPID are to (1) characterize patients who initiate treatment for asthma with dupilumab in a real-world setting, including characterization of patient demographics and baseline characteristics, (2) characterize real-world use patterns of dupilumab for asthma, (3) assess long-term effectiveness of dupilumab (spirometry, patient-reported outcomes, blood biomarkers of type 2 inflammation), including in a subset of patients with comorbid type 2 inflammatory conditions, and (4) collect long-term safety data (adverse events) on study participants in the real-world setting.

Introduction

Despite receiving appropriate standard-of-care treatment, up to 58% of patients with asthma develop uncontrolled, moderate-to-severe asthma with persistent symptoms and exacerbations [1,2,3,4]. These patients are at higher risk for subsequent exacerbations and lung function deterioration, with the consequent burden on patients and caregivers [4, 5]. Patients with uncontrolled, moderate-to-severe asthma also utilize substantial health-care resources [4, 5].

Between 50% and 70% of patients with asthma present with type 2 phenotype inflammation-driven disease [6]. Dupilumab, a fully human monoclonal antibody [7, 8], blocks the shared receptor component for interleukin-4 and interleukin-13, key and central type 2 inflammatory cytokines implicated in numerous type 2 inflammatory diseases, including asthma, atopic dermatitis, and chronic rhinosinusitis with nasal polyposis [9, 10], thus inhibiting their signaling.

In previous dupilumab asthma clinical trials (dupilumab asthma phase 2b, QUEST, VENTURE), dupilumab significantly reduced the rate of severe asthma exacerbations and improved prebronchodilator forced expiratory volume in 1 s (FEV1) in the overall population of patients with uncontrolled, moderate-to-severe asthma [4, 11,12,13]. While these randomized controlled trials (RCTs) provided crucial data on dupilumab efficacy and safety, the characteristics of dupilumab-treated patients with asthma in real-world conditions, as well as treatment patterns and outcomes in this setting, are still to be fully understood. Real-world evidence is important in confirming real-world effectiveness and safety beyond the necessarily tightly controlled conditions of RCTs, with the potential to include large, diverse, and heterogenous patient populations, managed in routine practice across a wide range of clinical settings and locations. To date, evidence for real-world effectiveness of dupilumab has been provided by small, retrospective studies [14,15,16,17,18]. These studies have confirmed the findings of clinical trials, reporting significant improvements in asthma control and lung function [14,15,16,17], with decreases in the rate of asthma exacerbations [14, 16,17,18], and reduced oral steroid use [16, 17]. These effects were seen in both patients who had not previously received treatment with biologic therapy for asthma and those who had failed such therapy [14, 16,17,18]. While these results are encouraging, further real-world data from a larger cohort of patients are needed to confirm and expand on these findings. Real-world data collected as part of a registry study can be a valuable tool in providing such data and for improving patient health care [19].

The Registry of Asthma Patients Initiating DUPIXENT® (RAPID; NCT04287621) is the first global, prospective registry enrolling adolescent and adult patients with asthma initiating treatment with dupilumab in a real-world setting, as per the label indication of dupilumab. Studies based on RAPID will expand on data from previous clinical studies and provide key information to fill knowledge gaps regarding real-world use patterns and outcomes with dupilumab in a diverse, global population.

The primary objective of RAPID is to collect data to characterize the patients who initiate dupilumab treatment for asthma in routine clinical practice. Secondary objectives are (1) to describe the real-world patterns of dupilumab use in this patient population; (2) to assess the effectiveness of dupilumab, including in a subset of those patients with comorbid type 2 inflammatory conditions; and (3) to assess the long-term safety of dupilumab in a real-world setting.

Methods

Study Design

RAPID will enroll approximately 1000 adolescent and adult patients who initiate dupilumab for the treatment of asthma per their health-care provider’s prescription as part of their normal care. Up to 150 sites worldwide are expected to be included, with about 60% of those located in the USA, after local health authority and ethics committee/institutional review board approvals have been granted.

Sample Selection

Patient selection will aim to ensure that the cohort is representative of patient and prescriber communities in terms of the type of clinical setting (academic versus nonacademic health-care centers) and prescriber specialty. RAPID was initiated in March 2020 and is currently recruiting patients.

Patients with asthma as diagnosed by clinician assessment will be eligible to enroll if they are 12 years or older at baseline visit; provide a signed informed consent (if less than 18 years old, patient assent and parental/legal guardian consent are required); initiate treatment with dupilumab for a primary indication of asthma according to the country-specific prescribing information; are able and willing to comply with the required visits, procedures, and assessments of the study; and can understand and complete study-related questionnaires. Patients who meet any one of the following criteria will be excluded: having a contraindication to dupilumab according to the country-specific prescribing information; having received dupilumab within the 6 months prior to the screening visit; or presenting with any condition that, according to the investigator, may interfere with their ability to participate in the study.

Planned Outcomes

The primary endpoint of RAPID-based analysis is the descriptive assessment of patient and disease characteristics, including patient demographics (e.g., gender, age, race, ethnicity) and patient characteristics at baseline (including prior medications and procedures, medical history, asthma history, type 2 inflammation-related comorbidities [e.g., allergic rhinitis, chronic rhinosinusitis, nasal polyps, atopic dermatitis, allergic bronchopulmonary aspergillosis], weight, height, highest level of education, employment status, insurance information). Secondary endpoints comprise descriptive summaries of the use of dupilumab and other asthma treatments, and other concomitant medications at each study visit, including their dose and frequency, treatment duration, treatment combinations, and reasons for initiation and discontinuation/switching of dupilumab; assessment of effectiveness through a time course of clinical outcome variables, including patient-reported outcomes for asthma and relevant comorbidities (see next paragraph); summary and assessment of any adverse events reported at each visit throughout the study.

Measurements

The effectiveness of asthma treatments will be evaluated using a variety of assessments that capture different aspects of disease status (Fig. 1). At each visit, spirometry will be performed according to the standard of care at the study center. Postbronchodilator FEV1 and fractional exhaled nitric oxide will be measured if consistent with the standard of care at the respective study center. Physicians will complete the Health-Care Resource Utilization Questionnaire (HCRUQ) every 3 months. In addition, patients will complete the 6-item Asthma Control Questionnaire (ACQ-6), Work Productivity and Activity Impairment Questionnaire-asthma (WPAI-asthma), Patient Global Assessment, and Physical Activity Limitation Questionnaire (PALQ) every 3 months, and the Mini Asthma Quality of Life Questionnaire (MiniAQLQ) every 6 months. Patients with comorbid type 2 inflammatory diseases will complete additional questionnaires such as the 22-item Sino-Nasal Outcome Test (SNOT-22) for patients with chronic (rhino)sinusitis and/or nasal polyposis, allergic rhinitis Visual Analog Scale (VAS) and Standardized Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ[S] + 12) for those with allergic rhinitis, and Patient-Oriented Eczema Measure (POEM) for those with comorbid atopic dermatitis. All standardized questionnaires will be provided in the patient’s language. Compensation for completion of patient questionnaire at fair market value will be allowed per investigator institution and country guidelines. RAPID will also record dates and results of any standard-of-care laboratory testing for total IgE, allergen-specific IgE, and eosinophil count, to provide information on biomarkers of type 2 phenotype inflammation-driven disease.

Fig. 1
figure 1

Study design of RAPID (NCT04287621). *Day 1: initiation of dupilumab as prescribed by a physician as part of normal care. ACQ-6 6-item Asthma Control Questionnaire; AR-VAS Allergic Rhinitis Visual Analogue Scale; FeNO fractional exhaled nitric oxide; FEV1 forced expiratory volume in 1 s; HCRUQ Health-Care Resource Utilization Questionnaire; MiniAQLQ Mini Asthma Quality of Life Questionnaire; PALQ Physical Activity Limitation Questionnaire; PGA Patient Global Assessment; POEM Patient-Oriented Eczema Measure; RQLQ(S) + 12 Standardized Rhinoconjunctivitis Quality of Life Questionnaire ≥ 12 years; SNOT-22 22-item Sino-Nasal Outcome Test; WPAI-Asthma Work Productivity and Activity Impairment Questionnaire-Asthma

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Adverse events will be recorded and evaluated systematically at each study visit. Possible relatedness to dupilumab will be determined by the investigator.

Data Collection

RAPID will collect data prospectively in a longitudinal cohort of patients for 36 months (Fig. 1). After a screening period of up to 12 weeks, a baseline visit (day 1) will take place on the day that patients initiate dupilumab treatment as per routine care. The 12-week screening period is to allow time for patients to obtain reimbursement for and receipt of dupilumab prior to baseline visit. It is allowable for screening and baseline to occur at the same visit. Postbaseline scheduled visits are planned at months 1 (± 2 weeks), 3 (± 4 weeks), and then every 3 months (± 6 weeks) until month 36 post day 1. This study intends to capture usual practice at each study site. Adherence to the visit schedule is advised, but occasional missed visits are expected and acceptable. Ideally, patients should not miss two or more consecutive visits or more than 50% of visits overall; however, if these targets are not met, patients will remain eligible and will be encouraged to stay in the study. The frequency and acceptable windows of the scheduled visits intend to reproduce the real-world environment as much as possible, while providing consistency to support the analysis and interpretation of the data obtained.

Data Analysis

There will be no confirmatory analysis or formal hypothesis testing for the effectiveness or safety variables. All analyses and summaries will be conducted descriptively.

Strengths and Limitations

The landmark RAPID registry is the first global, prospective registry to collect data on the characteristics of patients with asthma who initiate treatment with dupilumab in a real-world setting. Outcomes from RAPID aim to provide longitudinal, prospective data on dupilumab’s safety and effectiveness in adolescents and adults with asthma and examine the effectiveness of dupilumab on comorbid type 2 inflammatory conditions, as well as provide further insight into the burden of disease in these patients in a real-world setting. The broad array of both clinical and patient-reported outcomes collected from RAPID will expand on data from prior clinical studies and fill knowledge gaps regarding treatment patterns and outcomes with dupilumab in patients with asthma. Additionally, this registry will provide valuable insight into how dupilumab is utilized in different countries.

Anticipated limitations of this study, as pertain to most registry studies, are the potentials for selection bias due to the voluntary nature of enrollment, and no control arm to facilitate robust statistical analyses. Additionally, we can predict for incomplete data collection and the resultant underreporting of some outcomes, as much of the data collected will only be generated if the assessment is performed as per standard of care, with great variability among sites as to if or when those assessments occur.

Ethics

Approval by an appropriately constituted ethics committee/institutional review board, as described in International Council for Harmonisation (ICH) guidelines for Good Clinical Practice, will be required for all participating institutions and centers. The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki consistent with applicable regulatory requirements. Written informed consent will be obtained from each patient or his/her parent(s) or legal guardian(s), as applicable, according to local regulations.

Dissemination

When available, the results will be published in international peer-reviewed journals as well as presentation at regional and international conferences.