Drug studies often look at the effect one or two drugs have on a medical condition, and involve one company. There is currently an urgent need for one study to efficiently test multiple drugs from more than one company, in people who have tested positive for COVID-19 but who do not currently need hospitalization. This could help prevent disease progression to more serious symptoms and complications, and spread of COVID-19 in the community. This study looks at the safety and effectiveness of different drugs in treating COVID-19 in outpatients. In Phase II, participants in the study will be treated with either a study drug or with placebo. In protocol version 7.0, participants in Phase III of the study will be treated with either a study drug or active comparator drug. Participants assigned to the bamlanivimab agent/placebo arm and will have 28 days of intensive follow-up following study drug administration, followed by limited follow-up through 24 weeks in phase II and in phase III. All other investigational agents and their corresponding placebo arms will involve 28 days of intensive follow-up, followed by limited follow-up through 72 weeks in phase II and phase III. Additional study visits may be required, depending on the agent.
This is a master protocol to evaluate the safety and efficacy of multiple investigational agents aimed at modifying the host immune response to SARS-CoV-2 infection, or directly enhancing viral control in order to limit disease progression. The study includes both infused and non-infused agents and is a randomized controlled platform that allows agents to be added and dropped during the course of the study for efficient phase II and phase III testing of new agents within the same trial infrastructure. Version 7 of the protocol provided for blinded phase II evaluation of an investigational agent for superiority to placebo among participants at lower risk of progression to hospitalization or death, regardless of the mode of administration of the agent. Agents that graduate to phase III after initiation of the protocol version will be evaluated in persons at higher risk for progression to hospitalization or death for non-inferiority to an active comparator (monoclonal antibody cocktail of casirivimab plus imdevimab (REGEN-COV, Regeneron). This active comparator has been shown to be effective in this population in preventing hospitalization or death. When two or more agents are being evaluated in the same phase of the study, the trial design includes sharing of the control group (placebo in phase II and active comparator in phase III) for efficient evaluation of each agent. Investigational agents will be approved by the Trial Oversight Committee (TOC) for phase II evaluation based on the presence of in vitro data demonstrating promise as anti-SARS-CoV-2 therapeutics in pre-clinical testing, and for which there are suitable pharmacokinetics and safety data from phase I testing, or through clinical or research testing for a different indication, and agent availability. Investigational agents will be included in phase III evaluation based on agent entry criteria for phase III as outlined in the protocol (or by TOC approval based on data available outside ACTIV-2).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
4,044
Administered by single IV infusion. Participants are no longer being randomized to this intervention.
1000 mg (BRII-196)/1000 mg (BRII-198) combination therapy. Administered by consecutive IV infusions as single dose. Participants are no longer being randomized to this intervention.
300 mg AZD7442 (150 mg AZD8895 + 150 mg AZD1061). Administered by IV infusion as single dose. Participants are no longer being randomized to this intervention.
Administered intramuscularly as 2 separate injections sequentially (300 mg AZD8895 then 300 mg AZD1061) for one dose. Injections administered in the side of the thigh, one injection in each thigh. Participants are no longer being randomized to this intervention.
1.3 mL solution administered once daily for 14 days using Aerogen Ultra nebulizer (inhalation device). Participants are no longer being randomized to this intervention.
200 mg (2 x 100 mg) film-coated tablets administered orally every 6 hours for 7 days. Participants are no longer being randomized to this intervention.
Administered subcutaneously (SC) as 4 separate injections for one dose (two injections of C135-LS 200mg and two injections of C144-SL 200mg). Participants are no longer being randomized to this intervention.
Administered by IV infusion as single dose. Participants are no longer being randomized to this intervention.
Administered by IV infusion as single dose. Participants are no longer being randomized to this intervention.
600 mg casirivimab and 600 mg imdevimab, administered together as single IV infusion as one-time dose at study entry. Participants are no longer being randomized to this intervention.
Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.
Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.
Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.
Trisodium citrate dihydrate, di-sodium hydrogen-phosphate, sodium dihydrogen-phosphate dihydrate, racemic methionine (DL-methionine) and water. 1.3 mL solution administered once daily for 14 days using Aerogen Ultra nebulizer (inhalation device). Participants are no longer being randomized to this intervention.
200 mg (2 x 100 mg) film-coated tablets administered orally every 6 hours for 7 days. Participants are no longer being randomized to this intervention.
Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.
Administered SC as 4 separate injections for one dose. Participants are no longer being randomized to this intervention.
Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.
Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.
Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.
Administered by single IV infusion. Participants are no longer being randomized to this intervention.
Pinnacle Research Group (Site 1082), 321 E. 10th Street
Anniston, Alabama, United States
North Alabama Research Center LLC (Site 1194), 721 W. Market St., Ste. B
Athens, Alabama, United States
University of Alabama at Birmingham (Site 1005), 908 20th Street South
Birmingham, Alabama, United States
Cullman Clinical Trials (Site 1140), 501 Clark St. NE.
Cullman, Alabama, United States
Jasper Summit Research, LLC. (Site 1056), 1280 Summit
Jasper, Alabama, United States
COVID-19 Symptom Duration (Phase 2)
Bamlanivimab arms: Symptom duration=max. duration (days) across targeted symptoms including: feeling feverish, cough, shortness of breath/difficulty breathing at rest/with activity, sore throat, body pain/muscle pain/aches, fatigue, headache, chills, nasal obstruction/congestion, nasal discharge, nausea, vomiting, and diarrhea. Subjects who die on/before day 28 assigned symptom duration 29 days. No scale. Min. value: 0 Days, Max. Value 29 Days. Higher value=worse health condition. Non-Bamlanivimab arms: 13 symptoms (as for Bamlanivimab) scored daily as absent (score 0), mild (score 1), moderate (score 2) or severe (score 3). Symptom duration=time (days) from Day 0 (pre-treatment) to first of two consecutive days when all symptoms scored moderate/severe at Day 0 (pre-treatment) are scored mild/absent, AND all symptoms scored mild/absent at Day 0 (pre-treatment) are scored absent. No scale. Min. value: 0 Days, Max. Value 26 Days. Higher value=worse health condition.
Time frame: Up to Day 28
Quantification of SARS-CoV-2 RNA (Phase 2)
Bamlanivimab Agent arms: Measured as Detected or Undetected from staff-collected NP (nasopharyngeal) swabs. Lower Limit of Detection is 1.4 (log 10 copies/ml). Non-Bamlanivimab Agent arms: Measured as below Lower Limit of Quantification (LLoQ) or at/above LLoQ from staff-collected NP (nasopharyngeal) swabs. Lower Limit of Quantification is 2 (log 10 copies/ml). SNG001 and SNG001 Pooled Placebo arm each exclude 6 participants, due to unsuitable sample specimen conditions.
Time frame: Day 3
Quantification of SARS-CoV-2 RNA (Phase 2)
Bamlanivimab Agent arms: Measured as Detected or Undetected from staff-collected NP (nasopharyngeal) swabs. Lower Limit of Detection is 1.4 (log 10 copies/ml). Non-Bamlanivimab Agent arms: Measured as below Lower Limit of Quantification (LLoQ) or at/above LLoQ from staff-collected NP (nasopharyngeal) swabs. Lower Limit of Quantification is 2 (log 10 copies/ml).
Time frame: Day 7
Quantification of SARS-CoV-2 RNA (Phase 2)
Bamlanivimab Agent arms: Measured as Detected or Undetected from staff-collected NP (nasopharyngeal) swabs. Lower Limit of Detection is 1.4 (log 10 copies/ml). Non-Bamlanivimab Agent arms: Measured as below Lower Limit of Quantification (LLoQ) or at/above LLoQ from staff-collected NP (nasopharyngeal) swabs. Lower Limit of Quantification is 2 (log 10 copies/ml).
Time frame: Day 14
Number of Participants With New Adverse Event (AE) ≥ Grade 3 (Phase 2)
AE Severity: Adverse event Severity grading followed Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, which can be found on the DAIDS RSC website at: https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. * Grade 1 indicates a mild event * Grade 2 indicates a moderate event * Grade 3 indicates a severe event * Grade 4 indicates a potentially life-threatening event * Grade 5 indicates death
Time frame: Thru Day 28
Cumulative Incidence of Death Due to Any Cause or Hospitalization Due to Any Cause (Phase 3)
Hospitalization defined as ≥24 hours of acute care in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address medical needs of those with severe COVID-19. An event is defined as first occurrence of hospitalization/death (i.e. if subject has multiple hospitalizations, only the first hospitalization is counted as an event). Therefore, an event can only occur once for a subject. Results are presented as number of events.
Time frame: Thru Day 28
Proportion of Participants With New Adverse Event (AE) ≥ Grade 3 (Phase 3)
AE Severity: Adverse event Severity grading followed Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, which can be found on the DAIDS RSC website at: https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. * Grade 1 indicates a mild event * Grade 2 indicates a moderate event * Grade 3 indicates a severe event * Grade 4 indicates a potentially life-threatening event * Grade 5 indicates death
Time frame: Thru Day 28
COVID-19 Symptom Duration (Phase 3)
Bamlanivimab arm: Symptom duration=max. duration (days) across targeted symptoms including: feeling feverish, cough, shortness of breath/difficulty breathing at rest/with activity, sore throat, body pain/muscle pain/aches, fatigue, headache, chills, nasal obstruction/congestion, nasal discharge, nausea, vomiting, and diarrhea. Subjects who die on/before day 28 assigned symptom duration 29 days. No scale. Min. value: 0 Days, Max. Value 29 Days. Higher value=worse health condition. Non-Bamlanivimab arms: 13 symptoms (as for Bamlanivimab) scored daily as absent (score 0), mild (score 1), moderate (score 2) or severe (score 3). Symptom duration=time (days) from Day 0 (pre-treatment) to first of two consecutive days when all symptoms scored moderate/severe at Day 0 (pre-treatment) are scored mild/absent, AND all symptoms scored mild/absent at Day 0 (pre-treatment) are scored absent. No scale. Min. value: 0 Days, Max. Value 26 Days. Higher value=worse health condition.
Time frame: Thru Day 28
Quantification of SARS-CoV-2 RNA (Phase 3)
Measured as Detected or Undetected from staff-collected NP (nasopharyngeal) swabs. Lower Limit of Detection is 1.4 (log 10 copies/ml). Non-Bamlanivimab Agent arms: Measured as below Lower Limit of Quantification (LLoQ) or at/above LLoQ from staff-collected NP (nasopharyngeal) swabs. Lower Limit of Quantification is 2 (log 10 copies/ml).
Time frame: Day 3
Cumulative Incidence of Death From Any Cause or Hospitalization Due to Any Cause (Phase 2)
Hospitalization defined as ≥24 hours of acute care in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address medical needs of those with severe COVID-19. An event is defined as first occurrence of hospitalization/death (i.e. if subject has multiple hospitalizations, only the first hospitalization is counted as an event). Therefore, an event can only occur once for a subject. Results are presented as number of events.
Time frame: Thru Day 28
Cumulative Incidence of Death From Any Cause, or Hospitalization Due to Any Cause Related to COVID-19 (Phase 3)
Hospitalizations due to any cause deemed unrelated to COVID-19 are excluded. Hospitalization defined as ≥24 hours of acute care in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address medical needs of those with severe COVID-19. An event is defined as first occurrence of hospitalization/death (i.e. if subject has multiple hospitalizations, only the first hospitalization is counted as an event). Therefore, an event can only occur once for a subject. Results are presented as number of events.
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Absolute Clinical Research, LLC. (Site 1186), 7725 North 43rd Avenue, Ste. 211
Phoenix, Arizona, United States
University of Arizona (Site 1043), 1501 N. Campbell Ave., Rm. 6410
Tucson, Arizona, United States
Omnibus Clinical Research (Site 1253), 3340 W. Ball Road, Ste. I
Anaheim, California, United States
Franco A. Felizarta MD (Site 1174), 3535 San Dimas St.
Bakersfield, California, United States
Clearview Medical Research LLC. (Site 1251), 2714 Hidaway Ave., Ste. 103
Canyon Country, California, United States
...and 242 more locations
Time frame: Thru Day 28
Level of SARS-CoV-2 RNA From NP Swabs (Phase 2)
Measured from staff-collected NP swabs
Time frame: Thru Day 14
Level of SARS-CoV-2 RNA From NP Swabs (Phase 3)
Measured from staff-collected NP swabs
Time frame: Day 3
Duration of Targeted Clinical COVID-19 Symptoms (Phases 2 and 3)
Duration defined as the number of days from start of investigational agent to the first of four consecutive days when all symptoms scored as absent. Targeted symptoms are: Feeling feverish; cough, shortness of breath or difficulty breathing; sore throat; body pain or muscle pain/aches; fatigue (low energy); headache, chills, nasal obstruction or congestion (stuffy nose); nasal discharge (runny nose); nausea or vomiting; and diarrhea. Each symptom is scored daily by the participant as absent (score 0), mild (1), moderate (2) or severe (3)
Time frame: Thru Day 28
COVID-19 Symptom Severity Ranking (Phases 2 and 3)
Symptoms scored daily as absent (score 0), mild (score 1), moderate (score 2) or severe (score 3). Symptoms: feeling feverish, cough, shortness of breath/difficulty breathing at rest/with activity, sore throat, body pain/muscle pain/aches, fatigue, headache, chills, nasal obstruction/congestion, nasal discharge, nausea, vomiting, and diarrhea. Subjects alive and never hospitalized through Day 28: Symptom Severity Ranking=subject-specific AUC (area under curve) joining daily total symptom score associated with COVID-19 disease, over time (through Day 28, counting Day 0 as first day), calculated by trapezoidal rule and rescaled for time by dividing by the total number of trapezoids. Subjects who died within Day 28: Assigned severity score 42; Subjects alive but remaining hospitalized at Day 28: Assigned severity score 41; Subjects alive but no longer hospitalized at Day 28: Assigned severity score 40. Calculated Severity Score=scale of 0 to 42. Higher value=worse health condition.
Time frame: From Day 0 thru Day 28
Proportion of Participants With ≥1 Worsening Symptom of COVID-19 (Phases 2 and 3)
Progression of one or more COVID-19-associated symptoms to a worse status than recorded in study diary at study entry, prior to start of investigational product or placebo
Time frame: Thru Day 28
Time to Self-reported Return to Usual Health (a) (Phases 2 and 3)
Defined as the number of days from start of investigational treatment until the first of two consecutive days that a participant reported return to usual (pre-COVID-19) health as recorded in a participant's study diary. Not analyzed for Bamlanivimab Phase 2 and Phase 3 arms.
Time frame: Thru Day 28
Cumulative Incidence of Death Due to Any Cause or Hospitalization Due to Any Cause (Phases 2 and 3)
Hospitalization defined as ≥24 hours of acute care in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address medical needs of those with severe COVID-19. An event is defined as first occurrence of hospitalization/death (i.e. if subject has multiple hospitalizations, only the first hospitalization is counted as an event). Therefore, an event can only occur once for a subject. Results are presented as number of events.
Time frame: Day 0 thru Week 24
Cumulative Incidence of Death Due to Any Cause or Hospitalization Due to Any Cause (Phases 2 and 3)
Not applicable to Bamlanivimab arms as these were only 24 week-long studies. Hospitalization defined as ≥24 hours of acute care in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address medical needs of those with severe COVID-19. An event is defined as first occurrence of hospitalization/death (i.e. if subject has multiple hospitalizations, only the first hospitalization is counted as an event). Therefore, an event can only occur once for a subject. Results are presented as number of events.
Time frame: Day 0 thru Week 72
Oxygen Saturation Level (Phases 2 and 3)
Measured by pulse oximeter and categorized as \<96% versus ≥96%. Analysis not performed for Bamlanivimab arms.
Time frame: Thru Day 28
AUC of SARS-CoV-2 RNA From Site-collected NP Swabs (Phase 2)
Measured by area under the curve (AUC) and above assay lower limit of quantification of quantitative SARS-CoV-2 RNA over time. Not analyzed for Bamlanivimab arms.
Time frame: Thru Day 14
Proportion of Participants With New Adverse Event (AE) ≥ Grade 2 (Phases 2 and 3)
Time frame: Thru Day 28
Proportion of Participants With New Adverse Event (AE) ≥ Grade 2 (Phases 2 and 3)
Time frame: Thru Week 24
Proportion of Participants With New Adverse Event (AE) ≥ Grade 3 (Phases 2 and 3)
Time frame: Thru Week 24
Time to Self-reported Return to Usual Health (b) (Phases 2 and 3)
Defined as the number of days from start of investigational treatment until the first of four consecutive days that a participant reported return to usual (pre-COVID-19) health as recorded in a participant's study diary. Not collected for Bamlanivimab Phase 2 and Phase 3 arms.
Time frame: Thru Day 28