HElping Alleviate the Longer-term Consequences of COVID-19 (HEAL-COVID)

BACKGROUND: In December 2019, a cluster of patients with pneumonia of unknown cause was described in Wuhan, China. Named SARS-CoV-2 due to its resemblance to the coronavirus responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 is the infectious disease caused by SARS-CoV-2. Despite historically unprecedented public health measures, SARS-CoV-2 has rapidly spread across the world. The World Health Organisation (WHO) declared the COVID-19 outbreak a public health emergency of international concern on 30th January 2020.

The acute effects of COVID-19 are now well described. Evidence is emerging of serious longer-term complications occurring in the convalescent phase of the illness in a significant proportion of patients. COVID-19 is a new disease, the natural history of which remains uncertain. Recent data highlight that ~20% of patients develop new or worsened cardiopulmonary symptoms at 40-60-days after hospital discharge. A unique feature of COVID-19 is the high incidence of these cardiovascular and pulmonary complications that may carry long-term implications for morbidity and mortality including venous thromboembolism, persistent lung inflammation, and pulmonary fibrosis; increasingly it appears 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".

"Long COVID" is likely to include a constellation of different conditions traversing post-ICU syndromes, significant cardiopulmonary complications, post-viral syndromes and exacerbations of underlying conditions. Patients have reported a range of long-term symptoms associated with Long COVID that have significant impact on their quality of life. Though there have been effective acute treatments, there has been little work evaluating longer-term treatment aimed at reducing longer-term complications. To investigate the role of medium-term convalescent treatment targeting known and emerging complications, an adaptive platform trial will enrol patients at the point of hospital discharge from across centres in the UK.

OBJECTIVES: HEAL-COVID is an adaptive platform trial design to provide reliable evidence on the efficacy of post-hospitalisation treatments to improve longer-term clinical outcomes from COVID-19.

In early 2021, when the trial commenced, there were no treatments being assessed in randomised controlled trials targeting the post-hospital phase of COVID-19. Longer-term outcomes for COVID-19 are currently unclear, but early data suggest a significant burden of mortality and morbidity. In this situation, even treatments with only a moderate impact on survival or on hospital resource use are worthwhile. Therefore, the focus of HEAL-COVID is the impact of candidate treatments on mortality and the need for rehospitalisation.

The primary objective is to determine whether interventions in the post-hospital (convalescent) phase of COVID-19 improve longer-term mortality/morbidity outcomes.

The secondary objectives of HEAL-COVID are to evaluate treatment-specific and patient reported outcomes of COVID-19 and their response to intervention, as well as to estimate the cost-effectiveness of treatments.

ELIGIBILITY AND RANDOMISATION: The HEAL-COVID trial aims to recruit 877 patients per active arm and an equal number of matched controls based on sample size calculations described further in the publicly available trial protocol (www. heal-covid.net). All patients or a representative must provide written, informed consent before any study procedures occur and must meet all eligibility criteria.

ADAPTIVE DESIGN: New therapeutic arms will be commenced on the recommendation of the UK COVID-19 Therapeutics Advisory Panel (UK-CTAP), in discussion with the Chief Medical Officer for England, if approved by the Chief Investigator/Sponsor. New treatments will be added to the platform by recruiting additional participants to the study.

Interim analyses will be undertaken once 181 events have been observed across both arms in the comparison. The Independent Data \& Safety Monitoring Committee (IDSMC) may recommend that the treatment arms be discontinued for lack of benefit, or safety reasons.

SIMPLICITY OF PROCEDURES: To facilitate collaboration, even in hospitals that suddenly become overloaded, patient enrolment (via a secure web-based randomisation and data capture system) and all other trial procedures are greatly streamlined. Informed consent is simple and data entry is minimal. Randomisation via the internet is simple and quick, at the end of which the allocated treatment is displayed on the screen and can be printed or downloaded. Follow-up information is collected via routinely collected data.