Immune Modulators for Treating COVID-19

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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. The CVC arm of the study was closed to enrollment on 3-Sep-2021.

Official Title
-----------------
Randomized Master Protocol for Immune Modulators for Treating COVID-19

Conditions
-----------------
Covid19

Intervention / Treatment
-----------------
* Drug: Infliximab
* Drug: Abatacept
* Drug: Remdesivir
* Drug: cenicriviroc (closed to enrollment as of 3-Sep-2021)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Admitted to a hospital or awaiting admission in the ED with symptoms suggestive of COVID-19. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures. Subject (or legally authorized representative) understands and agrees to comply with planned study procedures. Male or non-pregnant female adults ≥18 years of age at time of enrollment. 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. 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. Women of childbearing potential must agree to either abstinence or use of at least one primary form of contraception not including hormonal contraception from the time of screening through Day 60. Agrees to not to participate in another interventional trial for the treatment of COVID-19 through Day 60. Exception 1: Participant may co-enroll in ACTIV-4 (ACTIV-4A and ACTIV-4C). Exception 2: Participants in ACTIV-2 who have been hospitalized may be enrolled in ACTIV-1 as long as ACTIV-2 study therapy has been discontinued. They will remain in ACTIV-2 follow-up. Exception 3: If participant is already participating in a COVID-19 vaccine trial but develops COVID-19 disease that requires hospitalization, participant is eligible for this study, assuming all other inclusion/exclusion criteria are met. Exclusion Criteria: ALT or AST >10 times the upper limit of normal. Estimated glomerular filtration rate (eGFR) <30 mL/min (including patients receiving hemodialysis or hemofiltration). Exception: Participants with an eGFR <30 mL/min may enroll as long as their renal insufficiency has been stable without renal replacement therapy for ≥1 month and they are not current candidates for renal replacement therapy. These participants will not receive remdesivir. Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L). Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 GI/L) Pregnancy or breast feeding. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours. Known allergy to any study medication. Received cytotoxic or biologictargeted immune-modulator treatments (such as anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], anti-IL-17, or T-cell or B-cell targeted therapies ([e.g., rituximab), tyrosine kinase], JAK inhibitors [including baricitinib,], TNF inhibitors, or interferon) within 4 weeks or 5 half-lives prior to screening., whichever is longer. 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 Exception 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 Exception 2: Infusion of convalescent plasma given for treatment of COVID-19 while on-study is also allowed. Exception 3: Monoclonal antibody therapy given for COVID-19 treatment at any time prior to enrollment is also allowed. BasedKnown or suspected history of untreated tuberculosis (TB). TB diagnosis may be suspected based on medical history and concomitant therapies that would suggest TB infection, have suspected clinical diagnosis of current active tuberculosis (TB) or, if. Participants are also excluded if they have known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required). Based on medical history and concomitant therapies that would suggest infection,Known or suspected serious, active bacterial, fungal, or viral (infection (excepting SARS-CoV-2 and including, but not limited to, active HBV, HCV, or HIV/AIDS). with the latter defined as a CD4 count <200 or an unsuppressed HIV viral load), or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product. Note: Broad-spectrum empiric antibiotic usage does not exclude participation. Have received any live vaccine (that is,or live attenuated) within 3 months before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note Exception: Use of prior non-live (inactivated) vaccinations is allowed for all participants, including any vaccine for COVID-19. Severe hepatic impairment (defined as liver cirrhosis Child stage C). CurrentKnown severe heart failure (New York Heart Association [NYHA] III-IV).) or new-onset left-systolic or global cardiac dysfunction in the setting of COVID-19. Exception: Right-sided heart dysfunction or pulmonary hypertension thought related to COVID-19 is permitted. In the Investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of Care + infliximab or matching placebo<br>infliximab (single dose IV 5mg/kg given on day 1) or matching placebo | Drug: Infliximab<br>* study drug or matching placebo<br>* Other names: remicade;Drug: Remdesivir<br>* Standard of Care<br>|
| Active Comparator: Standard of Care + abatacept or matching placebo<br>abatacept (single dose IV 10 mg/kg up to 1,000 mg given on day 1) or matching placebo | Drug: Abatacept<br>* study drug or matching placebo<br>* Other names: orencia;Drug: Remdesivir<br>* Standard of Care<br>|
| Active Comparator: Standard of Care + cenicriviroc or matching placebo (closed to enrollment as of 3-Sep-2021)<br>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 | Drug: Remdesivir<br>* Standard of Care<br>Drug: cenicriviroc (closed to enrollment as of 3-Sep-2021)<br>* study drug or matching placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Had Recovered by Day 28 | Time to recovery by day 28. The number of participants who have recovered by day 28. | Days 1-28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Status for Day 14 Using an 8 Point Ordinal Scale | 8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best) To determine a participant's clinical status using the ordinal scale their clinical status was collected at Day 15 assessing day 14. The scale used in this study is as follows (from worst to best): Death; Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplemental oxygen - requiring ongoing medical in-patient care (COVID-19 related or otherwise); Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical in-patient care; This would include those kept in hospital for quarantine/infection control/social reasons, awaiting bed in rehabilitation facility or homecare, etc. Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, | Day 14 | 
| Mortality Through 28 Days | mortality at day 28 | Day 1-28 | 
| Number of Participants With Clinical Status for Day 28 Using an 8 Point Ordinal Scale | 8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best) To determine a participant's clinical status using the ordinal scale their clinical status was collected at Day 29 assessing day 28. The scale used in this study is as follows (from worst to best): Death; Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplemental oxygen - requiring ongoing medical in-patient care (COVID-19 related or otherwise); Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical in-patient care; This would include those kept in hospital for quarantine/infection control/social reasons, awaiting bed in rehabilitation facility or homecare, etc. Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, | Day 28 | 
| Mortality Through 14 Days | mortality at day 14 | Day 1-14 | 
| Number of Participants Who Met a One Point Improvement in One Category From Day 0 (Baseline) to Day 28 Using an 8-point Ordinal Scale | 8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best). Number of people who met a 1 point improvement. The scale used in this study is as follows (from worst to best): Death; Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplemental oxygen - requiring ongoing medical in-patient care (COVID-19 related or otherwise); Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical in-patient care; This would include those kept in hospital for quarantine/infection control/social reasons, awaiting bed in rehabilitation facility or homecare, etc. Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities. | Day 1-day 28 | 
| Number of Participants Who Met a One Point Improvement in Two Categories From Day 0 (Baseline) to Day 28 Using an 8-point Ordinal Scale | 8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best). Number of people who met a two category improvement. The scale used in this study is as follows (from worst to best): Death; Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplemental oxygen - requiring ongoing medical in-patient care (COVID-19 related or otherwise); Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical in-patient care; This would include those kept in hospital for quarantine/infection control/social reasons, awaiting bed in rehabilitation facility or homecare, etc. Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities. | Day 1- day 28 | 
| Mean Change in the 8-point Ordinal Scale From Day 0 to Day 2 | 8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best) | Day 0 to day 2 | 
| Mean Change in the 8-point Ordinal Scale From Day 0 to Day 4 | 8 point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best) | Day 0 to day 4 | 
| Mean Change in the 8-point Ordinal Scale From Day 0 to Day 7 | 8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities=best) | Day 0 to day 7 | 
| Mean Change in the 8-point Ordinal Scale From Day 0 to Day 10 | 8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best) | Day 0 to day 10 | 
| Mean Change in the 8-point Ordinal Scale From Day 0 to Day 14 | 8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best) | Day 0 to day 14 | 
| Mean Change in the 8-point Ordinal Scale From Day 0 to Day 21 | 8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best) | Day 0 to day 21 | 
| Mean Change in the 8-point Ordinal Scale From Day 0 to Day 28 | 8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best) | Day 0 to day 28 | 
| Duration (Days) Alive and Free of Supplemental Oxygen | Days alive and free of supplemental oxygen | Day 1 to day 28 | 
| Number of Patients With New Supplemental Oxygen Use | Number of patients with new supplemental oxygen use | Day 1-day 28 | 
| Duration (Days) Alive and Free of Non-invasive Ventilation/ High Flow Oxygen | Days alive and free of non-invasive ventilation/ high flow oxygen | Day 1 to day 28 | 
| Number of Patients With New Non-invasive Ventilation/High Flow Oxygen Use | Number of patients with new non-invasive ventilation/high flow oxygen use | Day 1-day 28 | 
| Duration (Days) Alive and Free of Invasive Mechanical Ventilation or ECMO | Days alive and free of invasive mechanical ventilation or ECMO | Day 1 to day 28 | 
| Number of Patients With New Mechanical Ventilation or ECMO Use | Number of patients with new mechanical ventilation or ECMO use | Day 1 to day 28 | 
| Duration (Days) Alive and Out of the Hospital | Days alive and out of the hospital | Through day 28 | 
| Number of Patients With SAEs Through Day 28 | Cumulative Incidence of SAEs through day 28 | Day 28 | 
| Number of Patients With Grade 3 and 4 Adverse Events | Cumulative incidence of adverse events of grade 3 and 4 | Day 28 | 
| Number of Patients With Adverse Events Leading to Dose Modification | Number of patients with adverse events (serious and non serious) leading to dose modification | Day 1-28 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID19