HEAL-COVID is jointly Sponsored by Cambridge University Hospitals NHS Foundation Trustand The University of Cambridge.The acute effects of COVID-19 are now well described. Evidence is emerging of seriouslonger-term complications occurring in the convalescent phase of the illness in asignificant proportion of patients; particularly cardiovascular and pulmonarycomplications.The ill-defined syndrome, "Long COVID" is likely to include a constellation of differentconditions traversing post-ICU syndromes, significant cardiopulmonary complications,post-viral syndromes and exacerbations of underlying conditions. Patients have reported arange of longer-term symptoms associated with Long COVID that have significant impacts ontheir quality of life.To date, there has been little work evaluating treatments in the convalescent phase ofCOVID-19. HEAL-COVID aims to evaluate the impact of treatments on longer-term morbidity,mortality, re-hospitalisation, symptom burden and quality of life associated withCOVID-19.The first two treatment arms are Apixaban and Atorvastatin, with further treatment armsto be added at the direction of the UK COVID-19 Therapeutic Advisory Panel (UKCTAP).
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.
Drug: Apixaban
Apixaban 2.5mg orally twice daily for 14 days.
Other Name: Elquis
Drug: Atorvastatin
Atorvastatin 40mg orally once daily for 12 months.
Inclusion criteria:
- greater than or equal to 18 years of age.
- hospitalised with estimated hospital discharge within 5 days.
- SARS-CoV-2 infection associated disease (laboratory confirmed SARS-CoV-2 infection)
on this hospital admission.
- written informed consent obtained from participant or participant's legal
representative.
Exclusion criteria:
- known hypersensitivity to trial medication (patient will be excluded from specific
arm).
- long-term pre-hospital administration of trial medication (patient will be excluded
from specific arm).
- previous medical history of significant complication with trial medication or trial
medication drug class.
- medical history that might, in the opinion of the attending clinician, put the
patient at significant risk if he/she were to participate in the trial.
- participant not expected to survive 14 days from hospital discharge.
The presence of any of the following will preclude participant inclusion in the Apixaban
arm:
- active clinically significant bleeding.
- Childs-Pugh C, or worse, chronic liver disease
- known pregnancy or breast-feeding
- coagulopathy: INR greater than 1.7 or platelet count below 70
- lesion or condition considered by the investigator as a significant risk factor for
major bleeding. This may include recent gastrointestinal ulceration, presence of
malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent
brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or
suspected oesophageal varices, arteriovenous malformations, vascular aneurysms, or
major intraspinal or intracerebral vascular abnormalities.
- concomitant treatment following discharge with any other anticoagulant agent,
including but not limited to unfractionated heparin, low molecular weight heparins
(e.g. enoxaparin, dalteparin), heparin derivatives (e.g. fondaparinux), and other
oral anticoagulants (e.g. warfarin, rivaroxaban, dabigatran).
The presence of any of the following will preclude participant inclusion in the
Atorvastatin arm:
- Childs-Pugh C, or worse, chronic liver disease
- unexplained persistent elevations of serum transaminases exceeding five times the
upper limit of normal.
- known pregnancy or breast-feeding.
- treatment with the hepatitis C antivirals lecaprevir/pibrentasvir, ciclosporin or
HIV protease inhibitors.
- serum creatine kinase concentration exceeding 10 times the upper limit of normal.
Addenbrookes Hospital
Cambridge, United Kingdom
Investigator: Charlotte Summers
HEAL-COVID Team
+44 (0) 151 794 0222
trial.team@heal-covid.net
Charlotte Summers, Principal Investigator
University of Cambridge