PF-07304814 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial)

A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With COVID-19 (Trial H6: PF-07304814)

This study looks at the safety and effectiveness of PF-07304814 in treating COVID-19 in people who have been hospitalized with the infection. Participants in the study will be treated with either PF-07304814 plus current standard of care (SOC), or with placebo plus current SOC. This is ACTIV-3/TICO Treatment Trial H6.

Study Overview

• Status: Terminated
• Conditions: COVID-19
• Intervention / Treatment: Biological: Remdesivir; Drug: Placebo; Drug: PF-07304814

Detailed Description

This is a treatment trial of the ACTIV-3/TICO master protocol (NCT04501978) to evaluate the safety and efficacy of PF-07304814 in hospitalized patients infected with COVID-19.

This is a randomized, blinded, controlled sub-study of PF-07304814 plus current SOC against placebo plus current SOC. The placebo arm may be shared across other sub-studies of the ACTIV-3/TICO master protocol. When more than one drug is being tested at the same time, participants will be randomly allocated to treatments or placebo.

Randomization will be stratified by study site pharmacy and disease severity. There are 2 disease severity strata: participants without organ failure (severity stratum 1) and participants with organ failure (severity stratum 2).

An independent Data and Safety Monitoring Board (DSMB) will regularly review interim analyses and summarize safety and efficacy outcomes. The pace of enrollment with be initially restricted, and there will be an early review of safety data by the DSMB. At the outset of the trial, only participants in disease severity stratum 1 will be enrolled. This will continue until approximately 300 participants are enrolled and followed for 5 days. The exact number will vary according to the speed of enrollment and the timing of DSMB meetings. Prior to expanding enrollment to also include patients in disease severity stratum 2, safety will be evaluated and a pre-specified futility assessment by the DSMB will be carried out using 2 ordinal outcomes assessed at Day 5.

If PF-07304814 passes the futility assessment, enrollment of participants will be expanded, seamlessly and without any data unblinding, to include participants in disease severity stratum 2 as well as those in disease severity stratum 1. Future interim analyses will be based on the primary endpoint of sustained recovery and will use pre-specified guidelines to determine early evidence of benefit, harm, or futility for the investigational agent. Participants will be followed for 18 months following randomization.

This trial will be conducted in 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.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Aalborg Hospital (Site 625-005), Hobrovej 18
  • Aarhus N, Denmark, 8200
    • Aarhus Universitetshospital, Skejby (Site 625-002), Department of Infectious Diseases, Palle Juul-Hensens Boulevard 99
  • Copenhagen, Denmark, 2400
    • Bispebjerg Hospital (Site 625-013), Bispebjerg Bakke 23
  • Copenhagen Ø, Denmark, 2100
    • Righospitalet (Site 625-006), Blegdamsvej 9,
  • Herlev, Denmark, 2730
    • Herlev/Gentofte Hospital (Site 625-012), Medicinsk Afdeling, Herlev Ringvej 75
  • Hillerød, Denmark, 3400
    • Nordsjællands Hospital (Site 625-009), Dyrehavevej 29
  • Kolding, Denmark, 6000
    • Kolding Sygehus (Site 625-011), Medicinsk Afdeling, Sygehusvej 24
  • Odense, Denmark, 5000
    • Odense University Hospital (Site 625-004), Infektionsmedicinsk Forskningsenhed, J.B. Winsløwsgade 4
  • Roskilde, Denmark, 4000
    • Zealand University Hospital, Roskilde (Site 625-010), Sygehusvej 10
• United States
  • California
    • Chula Vista, California, United States, 91911
      • Velocity Chula Vista (Site 080-034), 752 Medical Center Ct., Ste. 304
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center (Site 208-002), 8700 Beverly Blvd.
    • Mather, California, United States, 95655
      • Sacramento VA Medical Center (Site 074-023), 10535 Hospital Way
    • Newport Beach, California, United States, 92663
      • Hoag Memorial Hospital Presbyterian (Site 080-026), One Hoag Drive
    • Palo Alto, California, United States, 94304
      • Palo Alto VAMC (Site 074-005), 3801 Miranda Avenue
    • Sacramento, California, United States, 95817
      • UC Davis Health (Site 203-004), 2315 Stockton Blvd.
    • San Diego, California, United States, 92161
      • VA San Diego Healthcare System (Site 074-016), 3350 La Jolla Village Drive
    • San Francisco, California, United States, 94121
      • San Francisco VAMC (Site 074-002), 4150 Clement St.
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health / St. Joseph Hospital (Site 204-003), 1400 Jackson Street
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • West Haven VA Medical Center (Site 025-007), 950 Campbell Avenue
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • MedStar Health Research Institute (Site 009-021), MedStar Washington Hospital Center, 110 Irving St., NW.
  • Florida
    • Bay Pines, Florida, United States, 33744
      • Bay Pines VAMC (Site 074-004), 10000 Bay Pines Blvd., Bldg. 100, Room 5B-104
    • Tampa, Florida, United States, 33602
      • Hillsborough County Health Department, University of South Florida (Site 032-001)
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Lutheran Medical Group (Site 301-010), 7916 W. Jefferson Boulevard
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation (Site 301-015), 1514 Jefferson Highway
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital (Site 202-002), 55 Fruit Street
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center (Site 202-001), 330 Brookline Ave.
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System, Henry Ford Hospital (Site 014-001), 2799 W. Grand Blvd.
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center/Mary Hitchcock Memorial Hospital (Site 301-024), One Medical Center Drive
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Hospital (Site 301-006), 2301 Erwin Road
  • Oregon
    • Portland, Oregon, United States, 97239
      • Portland VA Healthcare System (Site 074-024), 3710 SW. US Veterans Hospital Road
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital (Site 080-036), 593 Eddy Street
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hospital (Site 080-039), 164 Summit Ave.
  • South Carolina
    • Charleston, South Carolina, United States, 29401
      • Ralph H. Johnson VA Medical Center (Site 074-015), 109 Bee Street
    • Charleston, South Carolina, United States, 29425
      • MUSC Research Nexus Clinic (Site 210-002), 96 Jonathan Lucas St., CSB 214
    • Florence, South Carolina, United States, 29505
      • MUSC Health Florence Medical Center (Site 210-006), 805 Pamplico Highway
  • Texas
    • Dallas, Texas, United States, 75235
      • Parkland Health and Hospital Systems (Site 084-002), 5200 Harry Hines Blvd
    • Dallas, Texas, United States, 75235
      • UT Southwestern Medical Center (Site 084-001), 1936 Amelia Court, 2nd Floor
    • Dallas, Texas, United States, 75246
      • Baylor, Scott and White Health (Site 301-003), Baylor University Medical Center, 3500 Gaston Ave.
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Hospital (Site 211-002), 419 Wakara Way, Suite 207
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University (Site 301-023), One Medical Center Drive

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria: Refer to the master protocol (NCT04501978)

Exclusion Criteria: Refer to the master protocol (NCT04501978)

Additional Exclusion Criteria:

1. Participants with moderate to severe hepatic impairment (i.e. Child-Pugh class B or C) or acute liver failure.
2. Participants receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450 (CYP) 3A4 (see Section H6.3.4).
3. Patients will be excluded if taking drugs which have a narrow therapeutic window that are substrates of CYP3A4, including but not limited to: astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, tacrolimus, and terfenadine.
4. Pregnant women
5. Nursing mothers
6. Women of child-bearing potential who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with men or practice appropriate contraception through 5 weeks of the study.
7. Men who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with women of child-bearing potential or to use barrier contraception through 5 weeks of the study.

8. Patients with a history of deep vein thrombosis or pulmonary thrombotic embolism*.

   • Prior to the initial futility assessment, which is performed when approximately 150 patients have been enrolled on PF-07304814 and 150 on placebo, patients with a history of deep vein thrombosis or pulmonary embolism will be excluded. These patients will be eligible for the trial if the initial futility assessment is passed by this agent, and if risk-benefit is favorable based on an assessment of available data that is reviewed by the independent DSMB. These data will include treatment comparisons of thromboembolic events and coagulation markers, and any additional data from studies carried out by Pfizer.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo plus SOC; Placebo administered by IV infusion; Remdesivir is provided to all study participants as SOC unless contraindicated for an individual patient; administered by IV infusion	Biological: Remdesivir; Antiviral agent; Other Names: Veklury; Drug: Placebo; Commercially available 0.9% sodium chloride solution
Experimental: PF-07304814 plus SOC; PF-07304814 250 mg per day for 5 days; administered as a constant rate IV infusion; Remdesivir is provided to all study participants as SOC unless contraindicated for an individual patient; administered by IV infusion	Biological: Remdesivir; Antiviral agent; Other Names: Veklury; Drug: PF-07304814; PF-07304814 is a phosphate ester prodrug of PF-00835231 (active moiety), a potent and selective inhibitor of the SARS-CoV-2 3CLpro.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Sustained Recovery	Sustained recovery defined as being discharged from the index hospitalization, followed by being alive and home for 14 consecutive days prior to Day 90.	Through Day 90
Number of Participants With an Ordinal Outcome on Day 5	Ordinal outcome with 7 mutually exclusive categories	Status on Day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Died From All Causes	All-cause mortality	Through Day 90
Number of Participants With a Safety Outcome Through Day 5	Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 5	Through Day 5
Number of Participants With a Safety Outcome Through Day 28	Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 28	Through Day 28
Number of Participants With a Safety Outcome Through Day 90	Death, SAE, clinical organ failure, serious infections through Day 90	Through Day 90

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Pfizer; University of Copenhagen; US Department of Veterans Affairs; Medical Research Council; University of Minnesota; AIDS Clinical Trials Group; Kirby Institute; Washington D.C. Veterans Affairs Medical Center; International Network for Strategic Initiatives in Global HIV Trials (INSIGHT); Prevention and Early Treatment of Acute Lung Injury; Cardiothoracic Surgical Trials Network
• Investigators: Principal Investigator: Jens Lundgren, Prof., INSIGHT Copenhagen International Coordinating Centre, Rigshospitalet, University of Copenhagen; Study Chair: James Neaton, Prof., INSIGHT Statistical and Data Management Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2021
• Primary Completion (Actual): April 6, 2022
• Study Completion (Actual): July 14, 2023

Study Registration Dates

• First Submitted: March 20, 2023
• First Submitted That Met QC Criteria: March 20, 2023
• First Posted (Actual): March 22, 2023

Study Record Updates

• Last Update Posted (Actual): February 9, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Coronavirus Infections; SARS-CoV-2; COVID 19; COVID-19; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; SARS Coronavirus; ACTIV-3; ACTIV3; TICO
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Remdesivir
• Other Study ID Numbers: 014/ACTIV-3/H6

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No