Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseases

Abstract

Background: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD).

Methods: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure.

Results: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results.

Conclusion: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD.

Keywords: Connective tissue disease associated lung disease; Hypersensitivity pneumonitis; Idiopathic pulmonary fibrosis; Interstitial Fibrosis; Rheumatoid lung disease.

Figure 1

Strengths and challenges of REMAP trials as compared with conventional randomised controlled trials. REMAP, Randomised Embedded Multifactorial Adaptive Platform.

Figure 2

Study overview. Patients with fibrotic ILD will be assessed for platform eligibility criteria (step 1), after which, screening for domain-specific eligibility criteria will be performed (step 2). Patients who meet eligibility criteria for at least one domain will be randomised to an intervention (factor) from each domain (step 3), which could include a variety of different options depending on the available interventions (indicated by subscripts). Patients would then be initiated on therapy and complete study assessments that allow analysis of efficacy, safety and cost-effectiveness outcomes (step 4). Predefined stopping criteria for each intervention will be assessed throughout the study (step 5), with termination of completed interventions (factors) and/or domains and initiation of new interventions (factors) and/or domains. Patients will be continuously assessed throughout their participation in the study for eligibility of previously existing and newly added domains. Domain refers to a group of interventions that are mutually exclusive. Interventions are called factors in the REMAP terminology. Ctrl, control arm; ILD, interstitial lung disease; REMAP, Randomised Embedded Multifactorial Adaptive Platform.

Figure 3

REMAP-ILD governance structure and their related documents. Dotted line boxes: desirable but not yet activated. Embedding refers to scenarios where REMAP-ILD will be embedded in clinical registries. Of note, if we succeed to embed REMAP-ILD in a clinical registry, patients will still be randomised to interventions within the registry. ILD, interstitial lung disease; REMAP, Randomised Embedded Multifactorial Adaptive Platform; Stats, statistical.