Immune Modulators for Treating COVID-19
ACTIV-1 IM is a master protocol designed to evaluate multiple investigational agents for the treatment of moderately or severely ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The research objectives are to evaluate each agent with respect to speed of recovery, mortality, illness severity, and hospital resource utilization. Each agent will be evaluated as add-on therapy to the standard of care (SoC) in use at the local clinics, including remdesivir (provided). The SoC may change during the course of the study based on other research findings. Comparisons of the agents among themselves is not a research objective. The study population corresponds to moderately and severely ill patients infected with the coronavirus disease 2019 (COVID-19) virus. Recruitment will target patients already hospitalized for treatment of COVID-19 infection as well as patients being treated for COVID-19 infection in Emergency Departments while waiting to be admitted to the hospital. Patients both in and out of the ICU are included in the study population.
- Eligible Ages
- Over 18 Years
- Eligible Genders
- Accepts Healthy Volunteers
- Admitted to a hospital or awaiting admission in the ED with symptoms suggestive of COVID-19. 2. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures. 3. Subject (or legally authorized representative) understands and agrees to comply with planned study procedures. 4. Male or non-pregnant female adults ≥18 years of age at time of enrollment. 5. Has laboratory-confirmed (within 14 days prior to enrollment) SARS-CoV-2 infection as determined by PCR or other commercial or public health assay in any specimen. 6. Ongoing illness of any duration, and at least one of the following: - Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR - Blood oxygen saturation (SpO2) ≤94% on room air, OR - Requiring supplemental oxygen, OR - Requiring mechanical ventilation or ECMO. 7. Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through Day 60. 8. Agrees to not participate in another intervention trial for the treatment of COVID-19 through Day 60.
- ALT or AST >5 times the upper limit of normal. 2. Estimated glomerular filtration rate (eGFR) <30 mL/min (including patients receiving hemodialysis or hemofiltration). 3. Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L). 4. Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 GI/L) 5. Pregnancy or breast feeding. 6. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours. 7. Known Allergy to any study medication. 8. Received cytotoxic or biologic treatments (such as anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], IL-17, or T-cell or B-cell targeted therapies (e.g., rituximab), tyrosine kinase inhibitors including baricitinib, TNF inhibitors, or interferon within 4 weeks or 5 half-lives prior to screening. Steroid dependency defined as need for prednisone at a dose >10 mg (or equivalent) for >1 month within 2 weeks of screening is exclusionary. Note 1: Dexamethasone (at a dose of 6 mg per day for up to 10 days) is permitted for the treatment of COVID-19 in patients who are already mechanically ventilated and in patients who require supplemental oxygen at screening, but who are not mechanically ventilated in accordance with national guidelines. Note 2: Infusion of convalescent plasma is also allowed. 9. Based on medical history and concomitant therapies that would suggest infection, have suspected clinical diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required). 10. Based on medical history and concomitant therapies that would suggest infection, suspected serious, active bacterial, fungal, viral (including, but not limited to, active HBV, HCV, or HIV/AIDS). 11. Have received any live vaccine (that is, live attenuated) within 3 months before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-live (inactivated) vaccinations is allowed for all participants. 12. Severe hepatic impairment (defined as liver cirrhosis Child stage C). 13. Current severe heart failure (New York Heart Association [NYHA] III-IV). 14. In the Investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate.
- Phase 3
- Study Type
- Intervention Model
- Parallel Assignment
- Intervention Model Description
- ACTIV-1 IM builds upon findings and the model used for other network COVID studies. Including multiple therapeutic agents under a single protocol avoids duplication of effort in terms of infrastructure, trial governance, information systems (EDC, web-based randomization, etc.) and other aspects of study management. Implementation of the master protocol facilitates discontinuation of less promising agents and addition of possibly newly emergent agents that become available after the study begins, without stopping and starting the study itself for extended pauses. All test agents are evaluated as add-on therapies to the local SoC at each clinic. The master protocol design allows for the efficacy and safety of each agent to be determined based on comparisons with a pooled control group, consisting of patients receiving SoC plus placebo. Sharing control patients across all test agents substantially reduces the sample size requirements for the study.
- Primary Purpose
- Triple (Participant, Investigator, Outcomes Assessor)
- Masking Description
- Study Drug and Matching Placebo
Remdesivir + infliximab or matching placebo
|infliximab (single dose IV 5mg/kg given on day 1) or matching placebo||
Remdesivir + abatacept or matching placebo
|abatacept (single dose IV 10 mg/kg up to 1,000 mg given on day 1) or matching placebo||
Remdesivir + cenicriviroc or matching placebo
|cenicriviroc [tablet, Day 1/Loading Dose: 450 mg (300mg morning and 150mg evening) Day 2 - 29/Maintenance Dose: 300 mg (150 mg BID) through Day 29]. or matching placebo||
- Daniel Benjamin
Study ContactTheresa Jasion, MS
ACTIV-1 IM is a master protocol designed to evaluate immune modulators for the treatment of moderately or severely ill hospitalized patients infected with COVID-19. Trial participants will be assessed daily while hospitalized. If the participants are discharged from the hospital prior to Day 29, they will have follow-up study visits at Days 8, 11, 15, 22, and 29. For discharged participants, it is preferred that the Day 8, 11, 15, and 29 visits are in person to obtain safety laboratory tests and blood (serum/plasma) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the participant to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. The Day 60 assessment will be conducted by phone. The effectiveness of each therapeutic agent as add-on therapy to SoC plus remdesivir (provided) will be evaluated based on the primary endpoint of time to recovery by Day 29. The sample size requirements are based on the ability to detect a moderate improvement in time to recovery (3-4 fewer days) for each agent. A total of 788 recoveries are required for each comparison to provide approximately 85% power to detect a recovery rate ratio of 1.25. Assuming 73% of participants achieve recovery in 28 days, consistent with the ACTT-1 results, the total sample size to evaluate 1, 2, and 3 agents in ACTIV-1 IM is approximately 1080, 1620, and 2160, respectively. Because each agent is being compared to SoC with no between-agent comparisons, no multiplicity adjustments for multiple agents are planned.