ACTIV-3b: Therapeutics for Severely Ill Inpatients With COVID-19

This study looks at the safety and effectiveness of different drugs in treating COVID-19 in people who have been hospitalized with the infection and who have acute respiratory failure. Participants in the study will be treated with either a study drug plus current standard of care (SOC), or with placebo plus current SOC.

This is a master protocol to evaluate the safety and efficacy of investigational agents aimed at improving outcomes for patients with acute respiratory failure related to COVID-19.

Trials within this protocol will be adaptive, randomized, blinded and initially placebo-controlled. Participants will receive standard of care (SOC) treatment as part of the protocol. If an investigational agent shows superiority over placebo, SOC for the study of future investigational agents may be modified accordingly.

The international trials within this protocol will be conducted in up to several hundred clinical sites. Participating sites are affiliated with networks funded by the United States National Institutes of Health (NIH) and the US Department of Veterans Affairs.

The protocol is for a phase III platform study that allows investigational drugs to be added and dropped during the course of the study. This allows for efficient testing of new drugs against control within the same trial infrastructure. When more than one agent is being tested concurrently, participants may be randomly allocated across agents (as well as between the agent and its placebo) so the same control group can be shared, when feasible. In some situations, a factorial design may be used to study multiple agents.

Participants will be followed for 90 days following randomization for the primary endpoint and most secondary endpoints. Selected secondary endpoints will be measured at 180 days.

This study is planned to provide 80% power to detect an odds ratio of 1.5 for improvement in recovery status at Day 90 for an investigational agent versus placebo with use of the ordinal outcome. The planned sample size is 640 participants (320 per group) for each investigational agent/placebo. Sample size may be re-estimated before enrollment is complete based on an assessment of whether the pooled proportions of the outcome are still consistent with adequate power for the hypothesized difference measured by the odds ratio.

Randomization will be stratified by study site pharmacy and by receipt of invasive mechanical ventilation, or ECMO at enrollment. Other agent-specific stratification factors may be considered.

Investigational agents suitable for testing in the inpatient setting will be prioritized based on in vitro data, preclinical data, phase I pharmacokinetic and safety data, and clinical data from completed and ongoing trials. In some cases, a vanguard cohort/initial pilot phase may be incorporated into the trial.

An independent Data and Safety Monitoring Board (DSMB) will review interim safety and efficacy data at least monthly. Pre-specified guidelines will be established to recommend early stopping of the trial for evidence of harm or substantial efficacy. The DSMB may recommend discontinuation of an investigational agent if the risks are judged to outweigh the benefits.

Eligibility Criteria:
Inclusion Criteria:

* Signed informed consent.
* Requiring admission to hospital for acute medical care (not for purely public health or quarantine purposes).
* Current respiratory failure (i.e. receipt of high-flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation, or ECMO (extracorporeal membrane oxygenation) used to treat acute hypoxemic respiratory failure).
* SARS-CoV-2 (COVID-19) infection, documented by a nucleic acid test (NAT) or equivalent testing with most recent rest within 14 days prior to randomization.
* Respiratory failure is believed to be due to SARS-CoV-2 pneumonia.

Exclusion Criteria:

* Known allergy to investigational agent or vehicle.
* More than 4 days since initiation of support for respiratory failure.
* Chronic/home mechanical ventilation (invasive or non-invasive) for chronic lung or neuromuscular disease (non-invasive ventilation used solely for sleep-disordered breathing is not an exclusion).
* Moribund patient (i.e. not expected to survive 24 hours).
* Active use of "comfort care" or other hospice-equivalent standard of care.
* Expected inability to participate in study procedures.
* In the opinion of the investigator, any condition for which, participation would not be in the best interest of the participant or that could limit protocol-specified assessments.
* Previous enrollment in TESICO

Agent-specific exclusion criteria

* Prior receipt of any dose of remdesivir during present illness (remdesivir agent).
* GFR (glomerular filtration rate) \< 30 ml/min and not receiving dialysis (remdesivir agent).
* ALT (alanine aminotransferase) or AST (aspartate aminotransferase) \> 10 times upper limit of normal (remdesivir agent).
* Unwillingness to commit to avoid sex that may result in pregnancy for at least 7 days after completion of remdesivir vs. placebo (remdesivir agent).
* Refractory hypotension (aviptadil agent).
* Severe diarrhea (Aviptadil agent).
* Current C. difficile infection (aviptadil agent).
* Pregnancy or current breast-feeding (aviptadil agent).
* End-stage liver disease (aviptadil agent).