Aviptadil for Severely Ill Inpatients With COVID-19 (An ACTIV-3b/TESICO Treatment Trial)

This is a treatment trial of the ACTIV-3b/TESICO master protocol (NCT04843761) to evaluate the safety and efficacy of Aviptadil at improving outcomes for patients with acute respiratory failure related to COVID-19.

This protocol will be adaptive, randomized, blinded and initially placebo-controlled. Participants will receive standard of care (SOC) treatment as part of the protocol.

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 3 study.

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 Aviptadil versus placebo with use of the ordinal outcome. The planned sample size is 320 participants. 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 (extracorporeal membrane oxygenation) at enrollment. Other agent-specific stratification factors may be considered.

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.

• Aviptadil (Biological), also known as Vasoactive Intestinal Peptide, VIP: Administered by IV infusion over 12 hours per day for 3 days. The Day 1 infusion rate is 50 pmol/kg/hr, the Day 2 infusion rate is 100 pmol/kg/hr, and the Day 3 infusion rate is 150 pmol/kg/hr.
• Aviptadil Placebo (Biological): Commercially available 0.9% sodium chloride solution. Administered by IV infusion over 12 hours per day for 3 days.
• Corticosteroid (Drug): In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.

Primary outcomes

• Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 [Status on Day 90]: The primary outcome was a 6-category ordinal outcome defining the participant's status at Day 90: (1) at home (defined as the type of residence before hospitalization) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalized but either on supplemental oxygen or not at home, (5) hospitalized or in hospice care, or (6) dead.

Secondary outcomes

• Number of Participants Who Died Through Day 90 [Through Day 90]
• Number of Participants With a Safety Outcome Through Day 5 [Through Day 5]: Composite safety outcome of a serious adverse event, Grade 3/4 adverse event, organ failure/serious infection, or death through Day 5
• Number of Participants With a Safety Outcome Through Day 28 [Through Day 28]: Composite safety outcome of a serious adverse event, Grade 3/4 adverse event, organ failure/serious infection, or death through Day 28
• Number of Participants Who Died Through Day 180 [Through Day 180]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

Refer to the master protocol (NCT04843761)

Exclusion Criteria:

Refer to the master protocol (NCT04843761)

Additional Exclusion Criteria:

* Refractory hypotension
* Severe diarrhea
* Current C. difficile infection
* Pregnancy or current breast-feeding
* End-stage liver disease

Participant flow

Outcome results

• Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 (Primary), Count of participants, Participants: Aviptadil + SOC 36; Placebo + SOC 31 (p 0.54)
• Number of Participants Who Died Through Day 90 (Secondary), Count of participants, Participants: Aviptadil + SOC 86; Placebo + SOC 83 (p 0.78)
• Number of Participants With a Safety Outcome Through Day 5 (Secondary), Count of participants, Participants: Aviptadil + SOC 146; Placebo + SOC 129 (p 0.10)
• Number of Participants With a Safety Outcome Through Day 28 (Secondary), Count of participants, Participants: Aviptadil + SOC 181; Placebo + SOC 172 (p 0.15)
• Number of Participants Who Died Through Day 180 (Secondary), Count of participants, Participants: Aviptadil + SOC 90; Placebo + SOC 86 (p 0.71)

Adverse events

Time frame: All-cause mortality collected through Day 180 Serious adverse events collected through Day 90 Other adverse events (not serious): Combined reporting of infusion reactions on Study days 0, 1, and 2 AND any other Adverse Events through Study Day 28.

Serious adverse events by term

Other adverse events by term

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• Study Protocol: Aviptadil (H1) (PDF, 2022-03-08)
• Study Protocol: Remdesivir (H2) (PDF, 2021-04-01)
• Study Protocol: Master (PDF, 2022-03-08)
• Study Protocol: Overview of Study Documents (PDF, 2025-08-05)
• Statistical Analysis Plan: Addendum (PDF, 2022-05-01)
• Statistical Analysis Plan: Main (PDF, 2021-08-05)
• Informed Consent Form (PDF, 2022-03-08)

• Samuel Brown, MD, Principal investigator, Intermountain Medical Center/University of Utah
• Prof. James Neaton, Study chair, INSIGHT Statistical and Coordinating Centre, University of Minnesota