Title: Randomized Embedded, Multifactorial, Adaptive Platform trial for Interstitial Lung Diseases (REMAP-ILD)
Funder: Medical Research Council

Abstract: The goal of this study is to develop a new approach to clinical trial design which finds treatments more quickly for patients with lung scarring. Background A group of diseases known as Interstitial Lung Diseases may cause scarring to the lungs. When this scarring gets worse over time it is known as Fibrotic Interstitial Lung Disease. The build-up of progressive scar tissue in the lung starts gradually and most patients do not realise that their symptoms of breathlessness on exertion are anything serious. Anti-scarring drugs are available that slowdown the damage to the lungs. However, these drugs are expensive, have numerous side effects and can only be prescribed when the scarring is significant or progressing. Despite treatment with anti-scarring medication, progressive scarring is remorseless leading to considerable suffering, disability and ultimately death. Outcomes for patients are worse than for most cancers and there is an urgent need to develop new therapies. Unfortunately, drug development is slow with many programs taking up to 10 years to understand if a single treatment works. This is because of challenges with monitoring lung scarring over time and practical challenges with trial designs that assess treatments one at a time. The nature of lung scarring also means it is difficult to predict how fast the disease will get worse in any given patient which can make it hard to understand whether a drug used in a clinical trial worked or not. Aims The goal of this proposal is to design a clinical trial which can speed up the assessment of therapies for patients with Fibrotic Interstitial Lung Disease. We will achieve this by creating an international platform to carry out clinical trials that rapidly assess potential treatments. We will use a new approach to trial design that will enable multiple therapies to be assessed at the same time, which are known as Randomized, Embedded, Multifactorial, Adaptive Platform (REMAP) trials. We will shorten the time it takes to decide if a therapy is working or not to 3 months. We want to make it easy for patients to take part in the trial by minimising the number of hospital visits and disruption to their lives. We will use information that patients collect by monitoring their health at home and through electronic health care records to understand if a treatment is working. What we are going to do We are going to work with people affected by progressive lung scarring, healthcare professionals and researchers to develop the new clinical trial design. We will be engaging with organisations who will enable the trial to take place around the world, including regulators and pharmaceutical companies. Sharing our findings We will share how we designed the study with other people so that they can learn how to do the same to help other patients. We are going to apply for another grant so that we can start the new clinical trial. We will tell people affected by lung scarring what is happening so they know how they can take part in the trial. The results of the clinical trial will allow many more treatments including currently available medicines, new therapies and non-drug treatments to be assessed in a much shorter period of time. Ultimately, this will mean patients diagnosed with this devasting disease will have access to therapies that will enable them to live well for longer.

Lay abstract: Research question: Can a Randomized Embedded, Multifactorial, Adaptive Platform (REMAP) trial accelerate the identification of effective new treatments for Interstitial Lung Diseases? Background: Interstitial Lung Diseases (ILDs) represent a group of fibro-inflammatory disorders that occur following exposure to a variety of dusts, in association with diseases (e.g. rheumatoid arthritis, sarcoid), or, in cases of Idiopathic Pulmonary Fibrosis (IPF), without known cause. In many cases the fibrosis becomes autonomous and progressive with worse outcomes than many cancers. Anti-fibrotic therapy (nintedanib and pirfenidone) is available, however, they are expensive and have numerous side effects. Furthermore, these drugs do not represent a cure and offer no improvement in long-term survival or quality of life. Unfortunately, at the current time , drug development can take many years for a single asset, and therefore there is an urgent need to accelerate drug develop for patients with pulmonary fibrosis. Aims and objectives: This proposal will develop an internationally agreed protocol to develop the first global modular adaptive platform trial that will maximise trial enrolment and participation for patients with Fibrotic ILD (FILD) aiming to achieve equitable trial access. Our specific aims are to: 1) Develop a statistical model for REMAP-ILD 2) Refine the protocol for REMAP-ILD 3) Engage key stakeholders to ensure successful delivery of REMAP-ILD Methods: We will make extensive use of computer simulation to optimise and define a Bayesian adaptive platform trial design capable of evaluating multiple promising treatments, both alone and in combination in patients living with FILD. We will undertake robust Public Patient Involvement and Engagement events (PPIE) to provide feedback into protocol development, feasibility and acceptability of the platform design. Workshops including patient representatives and key clinical opinion leaders from around the world will be undertaken to develop the trial protocol, including eligibility criteria, strata definition, and refine clinical endpoints as well as international harmonisation of the governance structure of the platform. We will meet with regulatory bodies (FDA and EMA) to obtain feedback on the protocol, and the statistical design of the trial. Finally, engagement events with pharmaceutical companies will be arranged to ensure a sustainable platform. Timelines for delivery: Sept 2022 Funding starts, project manager post approved and advertised, drafting version 1 (V1) of REMAP-ILD Protocol. Oct 2022 Update will be presented at a REMAP-ILD engagement event. Oct 2022-April 2023 iterative development of the adaptive design with multiple rounds of simulation, and feedback from Protocol Development Group. Nov 2022 Presentation to National Heart Lung and Blood Institute, USA. Jan 2023 Meeting with FDA Mar 2023 Submit Regulatory Authority documents. Apr 2023 Work with Imperial Clinical Trials Unit (ICTU) to finalise protocol operationalisation. May 2023 Submit stage 1 application. Jun 2023 Finalise Protocol for registration, submission, and publication. Aug 2023 Submit stage 2 application. Anticipated impact and dissemination: Development of first international platform trial in Interstitial Lung Disease, accelerating identification of effective and novel therapies in FILD. Outputs will lead to practice changing data that can be incorporated into clinical guidelines.

Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: RESPIRATORY