World Health Organization (WHO) COVID-19 Solidarity Trial for COVID-19 Treatments

Terminology: The novel coronavirus-induced disease first described in 2019 in China is
designated COVID-19 (or COVID), and the pathogen itself (an RNA virus) is SARS-coronavirus-2
(SARS-CoV-2).

Background: In early 2020 there were no approved anti-viral treatments for COVID, and WHO
expert groups advised that four re-purposed drugs, Remdesivir, Lopinavir (given with
Ritonavir, to slow hepatic degradation), Interferon (β1a), and hydroxychloroquine (HCQ)
should be evaluated in an international randomised trial. In addition, WHO provided
guidelines that local physicians may consider when COVID-19 is suspected on clinical
management of severe acute respiratory infection. However, following an interim analyses, the
interim results of HCQ vs standard of care and lopinavir/ritonavir vs standard of care from
the Solidarity/Discovery trials, the Solidarity trial Executive Group decided to stop the HCQ
and the Lopinavir/ritonavir arms on the 3rd of July, 2020 due to futility; leaving 3 arms,
i.e., remdesivir, Interferon (β1a), and standard of care.

On the 6th of August 2020, due to a review of the rationale and clinical evidence, the
Executive Group of the Steering Committee of the Solidarity trial recommended that a new arm
should be opened in the Solidarity trial, to evaluate the clinical efficacy of Acalabrutinib.

Simplicity of procedures: To facilitate collaboration even in hospitals that have become
overloaded, patient enrolment and randomisation (via the internet) and all other trial
procedures are greatly simplified, and no paperwork at all is required. Once a hospital has
obtained approval, electronic entry of patients who have given informed consent takes only a
few minutes. At the end of it, the randomly allocated treatment is displayed on the screen
and confirmed by electronic messaging.

Randomisation: Adults (age ≥18 years) recently hospitalised, or already in hospital, with
definite COVID and, in the view of the responsible doctor, no contra-indication to any of the
study drugs will be randomly allocated between

- Local standard of care alone, OR local standard of care plus one of

- Remdesivir (daily infusion for 10 days)

- Acalabrutinib (orally twice daily for 10 days)

- Interferon β1a(daily injection for 6 days).

Data reported before randomisation: Information is entered electronically on

- Country, hospital (from a list of approved hospitals) and randomising doctor

- Confirmation that informed consent has been obtained

- Patient identifiers, age and sex

- Patient characteristics (yes/no): current smoking, diabetes, heart disease, chronic lung
disease, chronic liver disease, asthma, HIV infection, active tuberculosis.

- COVID-19 severity at entry (yes/no): shortness of breath, being given oxygen, already on
a ventilator, and, if lungs imaged, major bilateral abnormality (infiltrations/patchy
shadowing)

- Whether any of the study drugs are currently NOT AVAILABLE at the hospital.

Exclusion from study entry: Patients will not be randomised if, in the view of the
randomising doctor, ANY of the AVAILABLE study drugs are contra-indicated (e.g., because of
patient characteristics, chronic liver or heart disease, or some concurrent medication).

Changing management of study patients: At all times the patient's medical team remains solely
responsible for decisions about that patient's care and safety. Hence, if the team decide
that deviation from the randomly allocated treatment arm is definitely necessary, this should
be done.

Follow-up: When patients die or are discharged, follow-up ceases and it is reported:

- Which study drugs were given (and for how many days)

- Whether ventilation or intensive care was received (and, if so, when it began)

- Date of discharge, or date and cause of death while still in hospital. If no report is
received within 6 weeks of study entry, an electronic reminder is sent.

Drug safety: Suspected unexpected serious adverse reactions that are life-threatening (e.g.,
Stevens-Johnson syndrome, anaphylaxis, aplastic anaemia, or anything comparably uncommon and
serious) must be reported within 24 hours of being diagnosed, without waiting for death or
discharge.

Major outcomes: The primary outcome is all-cause mortality, subdivided by severity of disease
at the time of randomisation. The major secondary outcomes are duration of hospital stay and
time to first receiving ventilation (or intensive care).

Data monitoring: A global Data and Safety Monitoring Committee will keep the accumulating
drug safety results and major outcome results under regular review.

Numbers entered: The larger the number entered the more accurate the results will be, but
numbers entered will depend on how the epidemic develops. If substantial numbers get
hospitalised in the participating centres, it may be possible to enter several thousand
hospitalised patients with relatively mild disease and a few thousand with severe disease,
but realistic, appropriate sample sizes could not be estimated at the start of the trial and
will depend on the evolution of the epidemic.

Heterogeneity between populations: If a study treatment does affect outcome, then this effect
could well differ between patients who had severe disease when randomised and those who had
less severe disease. It could also differ between younger and older patients, or between
patients in one or another country. If sufficient numbers are randomised, it may be possible
to obtain statistically reliable treatment comparisons within each of several different
countries or types of patient.

Adaptive design: The WHO may decide to add novel treatment arms while the trial is in
progress. Conversely, the WHO may decide to discontinue some treatment arms, especially if
the Global Data and Safety Monitoring Committee reports, based on interim analyses, that one
of the trial treatments definitely affects mortality.