Interventions

In three substudies, three therapeutic agents will be evaluated as an add-on therapy to SoC.

These agents are:

Infliximab (Remicade)
Abatacept (Orencia)
Cenicriviroc

Participants will be randomly assigned to receive either SoC plus one of the test agents or SoC plus placebo. Randomization will proceed in two stages. At the first stage, each participant will be assigned to one of the sub-studies with equal probability. At the second stage, each participant will be assigned to either the test agent or its matching placebo in an n:1 ratio, where n = the number of substudies currently active in the master protocol and for which the patient is eligible to receive. With three agents and SoC, for example, this procedure results in a randomization ratio of 1:1:1:1 if the patient is eligible to receive all three agents.

Inclusion of a placebo for each agent enables masking of study participants and clinical personnel to treatment assignment at the second stage. Data from patients receiving SoC plus placebo will be pooled across agents for comparative analyses and hypothesis testing.

If there are supply limitations on any product, the sub-study containing that product, or its matching placebo will be temporarily closed to enrollment.

The initial SoC may include remdesivir in accordance with local or national guidelines, based on the results of the ACTT-1 study. Participants will receive remdesivir according to the FDA-approved package insert as follows:

For participants not already receiving remdesivir, remdesivir will be administered as a 200 mg intravenous (IV) loading dose on Day 1, followed by a 100 mg once-daily IV maintenance dose.

Participants who have already been receiving remdesivir as SoC prior to Day 1 will continue to receive a 100 mg once-daily IV maintenance dose up to a total of 10 days (inclusive of the days of treatment prior to Day 1).

Duration of SoC therapy:

Remdesivir IV component – up to 10 days while hospitalized (see Section 6.1.2), per FDA package insert.
Other SoC as determined by the treating site in accordance with local or national guidelines

For the Remicade/placebo component:

Remicade/placebo will be administered as a single dose of 5 mg/kg (IV) on Day 1 in addition to SoC. The administration window will be within 24 hours of randomization. Infusion of Remicade/placebo and remdesivir should not be given concurrently in order not to confound attribution of possible infusion reactions or hypersensitivity events.

Duration of therapy:

Remicade/placebo IV component – single dose on Day 1.

For the abatacept/placebo component, the dose of abatacept/placebo will be 10 mg/kg with a maximum dose of 1000 mg. Study medication will be administered in a fixed volume of 100 mL at a constant infusion rate over approximately 30 minutes. The IV line must be flushed with 25 mL of NS solution at the end of the infusion. The administration window will be within 24 hours of randomization.

Infusion of abatacept/placebo and remdesivir should not be given concurrently in order not to confound attribution of possible infusion reactions or hypersensitivity events.

Duration of therapy:

Abatacept/placebo IV component – single infusion on Day 1.

For the Cenicriviroc (CVC)/placebo component, treatment will be administered to participants while hospitalized as in-patients and will continue whether or not the patient is discharged from the hospital for a total 28-day course. CVC/placebo should be administered twice daily at approximately 12-hour intervals with food and at approximately the same time each day (±2 hours). Patients may receive a larger dose (450 mg total) for their first day of treatment as a loading dose administered as a morning dose of 300 mg and an evening dose of 150 mg. The administration window will be within 24 hours of randomization. Any dose that is delayed may be given later that calendar day. Any dose that is missed (not given that calendar day) is not made up.

Duration of therapy:

CVC/placebo (Oral) – BID x 28 days (i.e., up to Day 29 of study), including while hospitalized and post-discharge.