Title: HElping Alleviate the Longer-term consequences of COVID-19 (HEAL-COVID): A national platform trial
Funder: Department of Health and Social Care

Abstract: Background_x000D_ In December 2019, patients with a lung infection of unknown cause were identified in Wuhan, China. A virus later named SARS-CoV-2 was found to be responsible. COVID-19 is the disease caused by SARS-CoV-2. Despite unprecedented public health measures, SARS-CoV-2 has rapidly spread across the world. Though much is now known about the virus and the short-term effects of the disease it causes; the longer-term complications associated with COVID-19 are only starting to become apparent. Currently, all of the treatments available for COVID-19 focus on the period when the patient is acutely unwell. This does not address on-going problems that may be experienced after discharge from hospital. At time of writing, 1 in 10 hospitalised patients die within the first four months after discharge. We do not yet have full information on longer-term outlook from COVID-19, but as many as 1 in 4 survivors still experience significant symptoms some weeks after the initial illness. This study will assess several different treatments that may be of benefit in reducing or preventing the complications that patients with COVID-19 are reporting after their acute illness. _x000D_ _x000D_ Aims_x000D_ To develop treatments for COVID-19 that reduce the longer-term death and disability. _x000D_ _x000D_ Design and methods_x000D_ We propose a large, multi-centre clinical trial designed to assess whether several different treatments are better than the current “standard care” (the best available evidence-based treatment). The study is designed to learn from ongoing existing National Institute of Health Research studies looking in-depth at the issues experienced by patients with COVID-19. In practice, this means the study will be flexible enough to include new treatments not specified at the start of the trial as our understanding of COVID-19 changes. Patients will be randomly assigned to treatments or standard care. There will be no placebo, therefore patients will be aware of which therapy arm they have been allocated to. The presence of more than one treatment in the trial will ensure that a majority of patients will be offered an active treatment. Information will be collected from their routinely collected health records (mortality and subsequent hospitalisations) to minimise the burden on study participants, alongside collection of remotely entered patient reported data (telephone or smartphone app) and quality of life assessments. These have been and will continue to be informed by engagement with patients with COVID-19 to prioritise the areas important to them._x000D_ _x000D_ Patient and public involvement_x000D_ Formal feedback from the Long COVID Support Group identified non-acute treatment as a key question to be addressed, both to aid recovery and as an early intervention to prevent patients developing longer-term problems. Previous patient engagement in convalescent treatment in lung infections has underlined the importance of prevention of readmissions to hospital and prolonging life, and these have formed the basis of our main outcome measures to determine if treatments are of benefit. We have an extensive patient and public involvement plan that will continue to guide the trial._x000D_ _x000D_ Dissemination_x000D_ The study findings will be disseminated to public, patient and healthcare audiences via a range of mediums including social media, presentations, open access journal publications and updated clinical management guidelines.

Lay abstract: Research question:_x000D_ Can interventions in the convalescent phase of COVID-19 improve longer-term outcomes?_x000D_ _x000D_ Background:_x000D_ COVID-19 is a new disease for which the natural history remains uncertain. However, recent data suggest that >10% of patients die and >25% of patients require readmission to hospital within 4 months of discharge. A unique feature of COVID-19 is the high incidence of cardiovascular and pulmonary complications including venous thromboembolism, persistent lung inflammation, and pulmonary fibrosis; These may not be confined to the acute phase of the illness, but rather may also occur during the convalescent phase of the illness, thus providing a major contribution to the ill-defined syndrome “long COVID”._x000D_ _x000D_ Aims and objectives:_x000D_ The primary aim of the proposal is to set up a pragmatic phase 3 adaptive clinical trial platform designed to provide reliable evidence on the efficacy of post-hospitalisation treatments aiming to improve clinical outcomes from COVID-19._x000D_ _x000D_ Methods:_x000D_ We propose to establish a clinical trial platform, integrated into the current national COVID-19 clinical characterisation (ISARIC4C, GenoMICC, PHOSP-C) and acute clinical trial landscape (RECOVERY, REMAP-CAP, PRINCIPLE). The platform will be an pragmatic open-label adaptive trial, with the flexibility to add intervention arms as evidence from partner studies emerges. The primary endpoint of the trial will be hospital free survival at 12 months after randomisation, and will be assessed using linkage to routinely collected clinical data via NHS Digital. Secondary endpoints will include patient reported outcome measures (based on Core Outcome Sets for COVID-19 and long-term follow up for pattens with acute respiratory failure) and quality of life assessment._x000D_ _x000D_ Timelines for delivery:_x000D_ Study set-up will run in parallel with this grant application and with a planned start date of March 2021. The study is proposed as a UK-wide national Urgent Public Health platform trial; set-up to close-down is projected to take three years._x000D_ _x000D_ Anticipated impact and dissemination:_x000D_ The aim of the trial is to change the standard of care for patients with COVID-19 by determining which interventions do and do not alter longer-term clinical outcomes. We propose to disseminate the outputs of the study to both patient and public audiences, as well as healthcare audiences via open access peer reviewed publications, presentations to conferences as well as patient/participant groups, press releases (where appropriate), social media, and clinical management guidelines. In addition we aim to establish an online digital patient community to ensure the findings of our work are effectively shared with people who experience Long COVID.

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