ACTIV-2: A Study for Outpatients With COVID-19

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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Adaptive Platform Treatment Trial for Outpatients With COVID-19 (Adapt Out COVID)

Conditions
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Covid19, Coronavirus

Intervention / Treatment
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* Biological: bamlanivimab 7000mg
* Biological: BRII-196+BRII-198
* Biological: AZD7442 (IV)
* Biological: AZD7442 (IM)
* Drug: SNG001
* Drug: Camostat
* Biological: BMS-986414 + BMS-986413
* Biological: SAB-185 (3,840 Units/kg)
* Biological: SAB-185 (10,240 Units/kg)
* Drug: CASIRIVIMAB + IMDEVIMAB
* Drug: Placebo for Bamlanivimab 7000mg
* Drug: Placebo for Bamlanivimab 700mg
* Drug: Placebo for BRII-196+BRII-198
* Drug: Placebo for SNG001
* Drug: Placebo for Camostat
* Drug: Placebo for SAB-185 (low dose)
* Drug: Placebo for BMS-986414 + BMS-986413
* Drug: Placebo for AZD7442 (IV)
* Drug: Placebo for AZD7442 (IM)
* Drug: Placebo for SAB-185 (high dose)
* Biological: bamlanivimab 700mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent. Documentation of laboratory-confirmed SARS-CoV-2 infection, as determined by a molecular (nucleic acid) or antigen test from any respiratory tract specimen (e.g. oropharyngeal, nasopharyngeal (NP), or nasal swab, or saliva) collected ≤240 hours (10 days) prior to study entry. Laboratory-confirmed SARS-CoV-2 infection outside the US must be conducted at a DAIDS-approved laboratory. Able to begin study treatment no later than 7 days from self-reported onset of COVID-19 related symptom(s) or measured fever, where the first day of symptoms is considered symptom day 0 and defined by the self-reported date of first reported sign/symptom from the following list: subjective fever or feeling feverish cough shortness of breath or difficulty breathing at rest or with activity sore throat body pain or muscle pain/aches fatigue headache chills nasal obstruction or congestion nasal discharge loss of taste or smell nausea or vomiting diarrhea temperature > 38°C (100.4°F) One or more of the following signs/symptoms within 24 hours of participating in the study: subjective fever or feeling feverish cough shortness of breath or difficulty breathing at rest or with activity sore throat body pain or muscle pain/aches fatigue headache chills nasal obstruction or congestion nasal discharge loss of taste or smell nausea or vomiting diarrhea temperature > 38°C (100.4°F) Oxygen levels of ≥92% obtained at rest (adjusted as needed for altitude) by study staff within 24 hours of study entry. For a potential participant who regularly receives chronic supplementary oxygen for an underlying lung condition, their oxygen saturation should be measured while on their standard home oxygen supplementation level. Participant must agree not to participate in another clinical trial for the treatment of COVID-19 or SARS-CoV-2 during the study period until hospitalization or 28 days after the start of the study, whichever occurs first. Meet the protocol definition of being at higher risk of progression to hospitalization or death (BRII-196/BRII-198). In Phase III, meeting the protocol definition of being at higher risk of progression to hospitalization or death (SNG001, SAB-185, BMS 986414+BMS 986413) For participants of reproductive potential, negative serum or urine pregnancy test within 48 hours prior to study entry by any clinic or laboratory that has a CLIA certification or its equivalent, or by a point of care (POC)/CLIA-waived test. Note: Participants not of reproductive potential are eligible without requiring the use of a contraceptive method (BRII-196/BRII-198. AZD7442 [IV], AZD7442 [IM], SNG001, Camostat, SAB-185, BMS 986414+BMS 986413). Participants that engage in sexual activity that may lead to pregnancy in their partner must agree to either remain abstinent or use male contraceptives. They are strongly advised to inform their non-pregnant sexual partners of reproductive potential to use effective contraceptives for 24 weeks after investigational product is administered. Participants with pregnant partners should use condoms during vaginal intercourse through 24 weeks after investigational agent administration. Participants should refrain from sperm donation for 24 weeks after investigational agent administration (BRII-196/BRII-198, AZD7442 [IV], AZD7442 [IM], SAB-185). Participants that engage in sexual activity that may lead to pregnancy in their partner must agree to either remain abstinent or use male contraceptives for 30 days after investigational agent administration. They are also strongly advised to inform their non-pregnant sexual partners of reproductive potential to sue effective contraceptives for 30 days after investigational agent is administered to the participant. Participants with pregnant partners should use condoms during vaginal intercourse through 30 days after last dose of investigational agent administration. Participants should refrain from sperm donation for 30 days after investigational agent administration (SNG001). Participants that engage in sexual activity that may lead to pregnancy in their partner must agree to either remain abstinent or use male contraceptives. They are also strongly advised to inform their non-regnant sexual partners of reproductive potential to use effective contraceptives from study entry through 90 days after study treatment. Participants with pregnant partners should use condoms during vaginal intercourse from study entry through 90 days after the last dose of the study treatment. Participants should refrain from sperm donation from study entry through 90 days after the last dose of study treatment (Camostat). If participating in sexual activity that could lead to pregnancy, participants who are of reproductive potential must agree to use effective contraception for 24 weeks after investigational agent is administered. This would include oral contraceptives, implanted contraceptives, implanted contraceptives, intrauterine devices, and barrier methods. If participating in sexual activity that could lead to pregnancy, participants who are of reproductive potential must agree to use highly effective contraception for 24 weeks after investigational agent is administered (AZD7442 [IV], AZD7442 [IM], SAB-185). If participating in sexual activity that could lead to pregnancy, participants who are of reproductive potential must agree to use effective contraception for 30 days after investigational agent is administered (SNG001). If participating in sexual activity that could lead to pregnancy, participants who are of reproductive potential must agree to use effective contraception for 90 days after the last dose of treatment (Camostat). If participating in sexual activity that could lead to pregnancy, participants who are of reproductive potential must agree to use highly effective contraception for at least 48 weeks after the investigational agent is administered (BMS 986414+BMS 986413). Exclusion Criteria: History of or current hospitalization for COVID-19. For the current SARS-CoV-2 infection, any positive SARS-CoV-2 nucleic acid or antigen tests from any respiratory tract specimen collected > 240 hours prior to study entry. Current need for hospitalization or immediate medical attention. Use of any prohibited medication listed in the protocol and/or use of systemic or inhaled steroids for the purpose of COVID-19 treatment (new or increased dose from chronic baseline) within 30 days prior to study. Receipt of convalescent COVID-19 plasma or other antibody-based anti-SARS-CoV-2 treatment or prophylaxis at any time prior to study entry. Receipt of other investigational treatments for SARS-CoV-2 any time before participating in the study (not including drugs approved and taken for other conditions/diseases or COVID-19 vaccines). Known allergy/sensitivity or hypersensitivity to study drug or placebo. Any condition requiring surgery up to 7 days before participating in the study, or that is considered life threatening up to 30 days before participating in the study. Currently pregnant or breastfeeding (BRII-196/BRII-198, AZD7442 [IV], AZD7442 [IM], SNG001, Camostat, SAB-185, BMS 986414+BMS 986413). In phase II, meeting the protocol definition of being at higher risk of progression to hospitalization or death (AZD7442 [IV], AZD7442 [IM], SNG001, Camostat, SAB-185, BMS 986414+BMS 986413). Inflammatory skin conditions that compromise the safety of intramuscular (IM) injections, or other overlying skin conditions or tattoos that would preclude the assessment of injection site reactions, per the discretion of the investigator (AZD7442 [IM]). Inflammatory skin conditions that compromise the safety of subcutaneous (SC) injections, or other overlying skin conditions or tattoos that would preclude the assessment of infection site reactions, per the discretion of the investigator (BMS 986414+BMS 986413). History of coagulopathy which, in the opinion of the investigator, would preclude IM injection, or use of oral or injectable anticoagulants (protocol provides more information on prohibited medications) (AZD7442 [IM]). Use of or need for chronic supplemental oxygen (SNG001). Known severe liver disease prior to enrollment (defined as ALT or AST > 5 times upper limit of normal or end stage liver disease with Child-Pugh Class C or Child-Pugh-Turcotte score ≥ 10) (Camostat). Known severe kidney disease prior to enrollment (defined as estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m² or on renal-replacement therapy such as peritoneal dialysis or hemodialysis (Camostat) Other investigational drug protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bamlanivimab 7000 mg (Phase 2)<br>Administered by IV infusion. | Biological: bamlanivimab 7000mg<br>* Administered by single IV infusion. Participants are no longer being randomized to this intervention.<br>* Other names: LY3819253;|
| Placebo Comparator: Bamlanivimab 7000mg Placebo (Phase 2)<br>Administered by IV infusion | Drug: Placebo for Bamlanivimab 7000mg<br>* Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.<br>|
| Experimental: Bamlanivimab 700mg (Phase 2)<br>Administered by IV infusion | Biological: bamlanivimab 700mg<br>* Administered by single IV infusion. Participants are no longer being randomized to this intervention.<br>* Other names: LY3819253;|
| Placebo Comparator: Bamlanivimab 700mg Placebo (Phase 2)<br>Administered by IV infusion | Drug: Placebo for Bamlanivimab 700mg<br>* Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.<br>|
| Experimental: Bamlanivimab 700mg (Phase 3)<br>Administered by IV infusion | Biological: bamlanivimab 700mg<br>* Administered by single IV infusion. Participants are no longer being randomized to this intervention.<br>* Other names: LY3819253;|
| Experimental: BRII-196+BRII-198 (Pooled Phase 2/3)<br>Administered by IV infusion | Biological: BRII-196+BRII-198<br>* 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.<br>|
| Placebo Comparator: BRII-196+BRII-198 Placebo (Pooled Phase 2/3)<br>Administered by IV infusion | Drug: Placebo for BRII-196+BRII-198<br>* Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.<br>|
| Experimental: AZD7442 (IV) (Phase 2)<br>Administered by IV infusion | Biological: AZD7442 (IV)<br>* 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.<br>* Other names: AZD8895 + AZD1061;|
| Placebo Comparator: AZD7442 (IV) Pooled Placebo (Phase 2)<br>Administered by IV infusion; shared placebo includes AZD7442 (IM) placebo and placebo from other comparator arms in the study. | Drug: Placebo for AZD7442 (IV)<br>* Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.<br>|
| Experimental: AZD7442 (IM) (Phase 2)<br>Administered by IM injection | Biological: AZD7442 (IM)<br>* 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.<br>* Other names: AZD8895 + AZD1061;|
| Placebo Comparator: AZD7442 (IM) Pooled Placebo (Phase 2)<br>Administered by IM injection; shared placebo includes AZD7442 (IV) placebo and placebo from other comparator arms in the study. | Drug: Placebo for AZD7442 (IM)<br>* Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.<br>|
| Experimental: SNG001 (Phase 2)<br>Administered by inhalation | Drug: SNG001<br>* 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.<br>|
| Placebo Comparator: SNG001 Pooled Placebo (Phase 2)<br>Administered by inhalation; shared placebo includes placebo from other comparator arms in the study. | Drug: Placebo for SNG001<br>* 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.<br>|
| Experimental: Camostat (Phase 2)<br>Administered as oral tablets | Drug: Camostat<br>* 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.<br>* Other names: camostat mesylate;|
| Placebo Comparator: Camostat Pooled Placebo (Phase 2)<br>Administered as oral tablets; shared placebo includes placebo from other comparator arms in the study. | Drug: Placebo for Camostat<br>* 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.<br>|
| Experimental: SAB-185 (low dose) (Phase 2)<br>Administered by IV infusion | Biological: SAB-185 (3,840 Units/kg)<br>* Administered by IV infusion as single dose. Participants are no longer being randomized to this intervention.<br>* Other names: Anti-SARS-CoV-2 Human Immunoglobulin Intravenous (Tc bovine-derived);|
| Placebo Comparator: SAB-185 (low dose) Pooled Placebo (Phase 2)<br>Administered by IV infusion; includes SAB-185 (high dose) placebo and placebo from other comparator arms in the study. | Drug: Placebo for SAB-185 (low dose)<br>* Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.<br>|
| Experimental: SAB-185 (low dose) (Phase 3) Non-OMICRON population<br>Administered by IV infusion. The Non-Omicron subpopulation enrolled under Protocol Version 7 was defined as all participants enrolled under Protocol Version 7 excluding those in the Omicron subpopulation. Omicron/Non-Omicron subpopulation definitions were updated in Version 10.0 of the Primary SAP to be based on the timing of emergence of the Omicron variant within the study population as follows: Variant information from any sample (i.e., not just from samples obtained on day 0) could be used to assign a participant to the Omicron or non-Omicron Subpopulations. For participants without variant information, those randomized under Protocol Version 7.0 on or after December 15, 2021 would be assigned to the Omicron Subpopulation, and those randomized on or before December 14, 2021 would be assigned to the Non-Omicron Subpopulation. | Biological: SAB-185 (3,840 Units/kg)<br>* Administered by IV infusion as single dose. Participants are no longer being randomized to this intervention.<br>* Other names: Anti-SARS-CoV-2 Human Immunoglobulin Intravenous (Tc bovine-derived);|
| Active Comparator: Casirivimab and Imdevimab (Phase 3) Non-OMICRON population<br>Administered by IV infusion. The Non-Omicron subpopulation enrolled under Protocol Version 7 was defined as all participants enrolled under Protocol Version 7 excluding those in the Omicron subpopulation. Omicron/Non-Omicron subpopulation definitions were updated in Version 10.0 of the Primary SAP to be based on the timing of emergence of the Omicron variant within the study population as follows: Variant information from any sample (i.e., not just from samples obtained on day 0) could be used to assign a participant to the Omicron or non-Omicron Subpopulations. For participants without variant information, those randomized under Protocol Version 7.0 on or after December 15, 2021 would be assigned to the Omicron Subpopulation, and those randomized on or before December 14, 2021 would be assigned to the Non-Omicron Subpopulation. | Drug: CASIRIVIMAB + IMDEVIMAB<br>* 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.<br>* Other names: REGN-COV2;|
| Experimental: SAB-185 (high dose) (Phase 2)<br>Administered by IV infusion | Biological: SAB-185 (10,240 Units/kg)<br>* Administered by IV infusion as single dose. Participants are no longer being randomized to this intervention.<br>* Other names: Anti-SARS-CoV-2 Human Immunoglobulin Intravenous (Tc bovine-derived);|
| Placebo Comparator: SAB-185 (high dose) Pooled Placebo (Phase 2)<br>Administered by IV infusion; includes SAB-185 (low dose) placebo and placebo from other comparator arms in the study. | Drug: Placebo for SAB-185 (high dose)<br>* Commercially available 0.9% sodium chloride solution. Participants are no longer being randomized to this intervention.<br>|
| Experimental: BMS 986414+BMS 986413 (Phase 2)<br>Administered as subcutaneous (SC) injections | Biological: BMS-986414 + BMS-986413<br>* 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.<br>* Other names: C135-LS + C144-LS;|
| Placebo Comparator: BMS 986414+BMS 986413 Pooled Placebo (Phase 2)<br>Administered as subcutaneous (SC) injections; shared placebo includes placebo from other comparator arms in the study. | Drug: Placebo for BMS-986414 + BMS-986413<br>* Administered SC as 4 separate injections for one dose. Participants are no longer being randomized to this intervention.<br>|
| Experimental: SAB-185 (low dose) (Phase 3) OMICRON population<br>Administered by IV infusion The Omicron subpopulation enrolled under Protocol v.7 was defined as (1) all participants randomized under Protocol v.7 infected with the Omicron variant as identified on sequencing of NP sample obtained on day 0, plus (2) all participants randomized under Protocol v.7 on/after December 26, 2021, who do not have variant information available from sample obtained on day 0. Definitions were updated in Primary SAP v10.0 to be based on timing of emergence of Omicron variant within the study population as follows: Variant information from any sample (i.e. not just from samples obtained on day 0) could be used to assign a participant to the Omicron or non-Omicron Subpopulations. For participants without variant information, those randomized under Protocol v7 on or after December 15, 2021 would be assigned to the Omicron Subpopulation, and those randomized on or before December 14, 2021 would be assigned to the Non-Omicron Subpopulation. | Biological: SAB-185 (3,840 Units/kg)<br>* Administered by IV infusion as single dose. Participants are no longer being randomized to this intervention.<br>* Other names: Anti-SARS-CoV-2 Human Immunoglobulin Intravenous (Tc bovine-derived);|
| Active Comparator: Casirivimab and Imdevimab (Phase 3) OMICRON population<br>Administered by IV infusion The Omicron subpopulation enrolled under Protocol v.7 was defined as (1) all participants randomized under Protocol v.7 infected with the Omicron variant as identified on sequencing of NP sample obtained on day 0, plus (2) all participants randomized under Protocol v.7 on/after December 26, 2021, who do not have variant information available from sample obtained on day 0. Definitions were updated in Primary SAP v10.0 to be based on timing of emergence of Omicron variant within the study population as follows: Variant information from any sample (i.e. not just from samples obtained on day 0) could be used to assign a participant to the Omicron or non-Omicron Subpopulations. For participants without variant information, those randomized under Protocol v7 on or after December 15, 2021 would be assigned to the Omicron Subpopulation, and those randomized on or before December 14, 2021 would be assigned to the Non-Omicron Subpopulation. | Drug: CASIRIVIMAB + IMDEVIMAB<br>* 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.<br>* Other names: REGN-COV2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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). | 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). | Day 14 | 
| Proportion 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 | 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 | 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 | Thru Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| COVID-19 Symptom Duration (Phase 3) | Duration defined as the number of days from start of investigational agent to the first of two consecutive days when any symptoms scored as moderate or severe as study entry (pre-treatment) are scored as mild or absent; and any symptoms scored as mild or absent at study entry are scored as absent, AND any symptoms scored as mile or absent at study entry (pre-treatment) are 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) | Thru Day 28 | 
| Quantification of SARS-CoV-2 RNA (Phase 3) | Measured as quantification (<LLoQ versus ≥LLoQ ) from staff-collected NP (nasopharyngeal) swabs | 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 | 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 | Thru Day 28 | 
| Level of SARS-CoV-2 RNA From NP Swabs (Phase 2) | Measured from staff-collected NP swabs | Thru Day 14 | 
| Level of SARS-CoV-2 RNA From NP Swabs (Phase 3) | Measured from staff-collected NP swabs | 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) | 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. | 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 | 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 | Thru Day 28 | 
| Cumulative Incidence of Death Due to Any Cause or Hospitalization Due to Any Cause (Phases 2 and 3) |  | Day 0 thru Week 24 | 
| Cumulative Incidence of Death Due to Any Cause or Hospitalization Due to Any Cause (Phases 2 and 3) |  | Day 0 thru Week 72 | 
| Oxygen Saturation Level (Phases 2 and 3) | Measured by pulse oximeter and categorized as <96% versus ≥96% | 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 | Thru Day 14 | 
| Incidence of New Adverse Event (AE) ≥ Grade 2 (Phases 2 and 3) |  | Thru Day 28 | 
| Incidence of New Adverse Event (AE) ≥ Grade 2 (Phases 2 and 3) |  | Thru Week 24 | 
| Incidence of New Adverse Event (AE) ≥ Grade 3 (Phases 2 and 3) |  | 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 | Thru Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Coronavirus, COVID 19, Coronaviridae Infections, Coronavirus Infections, RNA Virus Infections, Virus Diseases, Nidovirales Infections, SARS-CoV-2, SARS Coronavirus, ACTIV-2, ACTIV2