Adaptive Platform Treatment Trial for Outpatients With COVID-19 (Adapt Out COVID)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 4,044
- 试验地点
- 252
- 主要终点
- COVID-19 Symptom Duration (Phase 2)
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Unblinded data will be provided to the Data and Safety Monitoring Board for interim analyses. Unblinded Day 28 data will also be provided to a small group of people from the company who owns the investigational agent, to assist the company in deciding if the agent should move into phase 3 evaluation; or in choosing a dose of their agent to move into phase 3 evaluation.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •shortness of breath or difficulty breathing at rest or with activity
- •sore throat
- •body pain or muscle pain/aches
- •nasal obstruction or congestion
- •nasal discharge
- •loss of taste or smell
- •nausea or vomiting
- •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
- •shortness of breath or difficulty breathing at rest or with activity
- •sore throat
- •body pain or muscle pain/aches
- •nasal obstruction or congestion
- •nasal discharge
- •loss of taste or smell
- •nausea or vomiting
- •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-
- •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).
排除标准
- •History of or current hospitalization for COVID-
- •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.
研究组 & 干预措施
Camostat (Phase 2)
Administered as oral tablets
干预措施: Camostat (Drug)
Bamlanivimab 7000 mg (Phase 2)
Administered by IV infusion.
干预措施: bamlanivimab 7000mg (Biological)
Bamlanivimab 7000mg Placebo (Phase 2)
Administered by IV infusion
干预措施: Placebo for Bamlanivimab 7000mg (Drug)
Bamlanivimab 700mg (Phase 2)
Administered by IV infusion
干预措施: bamlanivimab 700mg (Biological)
Bamlanivimab 700mg Placebo (Phase 2)
Administered by IV infusion
干预措施: Placebo for Bamlanivimab 700mg (Drug)
Bamlanivimab 700mg (Phase 3)
Administered by IV infusion
干预措施: bamlanivimab 700mg (Biological)
BRII-196+BRII-198 (Pooled Phase 2/3)
Administered by IV infusion
干预措施: BRII-196+BRII-198 (Biological)
BRII-196+BRII-198 Placebo (Pooled Phase 2/3)
Administered by IV infusion
干预措施: Placebo for BRII-196+BRII-198 (Drug)
AZD7442 (IV) (Phase 2)
Administered by IV infusion
干预措施: AZD7442 (IV) (Biological)
AZD7442 (IV) Pooled Placebo (Phase 2)
Administered by IV infusion; shared placebo includes AZD7442 (IM) placebo and placebo from other comparator arms in the study.
干预措施: Placebo for AZD7442 (IV) (Drug)
AZD7442 (IM) (Phase 2)
Administered by IM injection
干预措施: AZD7442 (IM) (Biological)
AZD7442 (IM) Pooled Placebo (Phase 2)
Administered by IM injection; shared placebo includes AZD7442 (IV) placebo and placebo from other comparator arms in the study.
干预措施: Placebo for AZD7442 (IM) (Drug)
SNG001 (Phase 2)
Administered by inhalation
干预措施: SNG001 (Drug)
SNG001 Pooled Placebo (Phase 2)
Administered by inhalation; shared placebo includes placebo from other comparator arms in the study.
干预措施: Placebo for SNG001 (Drug)
Camostat Pooled Placebo (Phase 2)
Administered as oral tablets; shared placebo includes placebo from other comparator arms in the study.
干预措施: Placebo for Camostat (Drug)
SAB-185 (low dose) (Phase 2)
Administered by IV infusion
干预措施: SAB-185 (3,840 Units/kg) (Biological)
SAB-185 (low dose) Pooled Placebo (Phase 2)
Administered by IV infusion; includes SAB-185 (high dose) placebo and placebo from other comparator arms in the study.
干预措施: Placebo for SAB-185 (low dose) (Drug)
SAB-185 (low dose) (Phase 3) Non-OMICRON population
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.
干预措施: SAB-185 (3,840 Units/kg) (Biological)
Casirivimab and Imdevimab (Phase 3) Non-OMICRON population
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.
干预措施: CASIRIVIMAB + IMDEVIMAB (Drug)
SAB-185 (high dose) (Phase 2)
Administered by IV infusion
干预措施: SAB-185 (10,240 Units/kg) (Biological)
SAB-185 (high dose) Pooled Placebo (Phase 2)
Administered by IV infusion; includes SAB-185 (low dose) placebo and placebo from other comparator arms in the study.
干预措施: Placebo for SAB-185 (high dose) (Drug)
BMS 986414+BMS 986413 (Phase 2)
Administered as subcutaneous (SC) injections
干预措施: BMS-986414 + BMS-986413 (Biological)
BMS 986414+BMS 986413 Pooled Placebo (Phase 2)
Administered as subcutaneous (SC) injections; shared placebo includes placebo from other comparator arms in the study.
干预措施: Placebo for BMS-986414 + BMS-986413 (Drug)
SAB-185 (low dose) (Phase 3) OMICRON population
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.
干预措施: SAB-185 (3,840 Units/kg) (Biological)
Casirivimab and Imdevimab (Phase 3) OMICRON population
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.
干预措施: CASIRIVIMAB + IMDEVIMAB (Drug)
结局指标
主要结局
COVID-19 Symptom Duration (Phase 2)
时间窗: Up to Day 28
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.
Number of Participants With New Adverse Event (AE) ≥ Grade 3 (Phase 2)
时间窗: Thru Day 28
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
Quantification of SARS-CoV-2 RNA (Phase 2)
时间窗: Day 14
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).
Cumulative Incidence of Death Due to Any Cause or Hospitalization Due to Any Cause (Phase 3)
时间窗: Thru Day 28
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.
Proportion of Participants With New Adverse Event (AE) ≥ Grade 3 (Phase 3)
时间窗: Thru Day 28
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
次要结局
- COVID-19 Symptom Duration (Phase 3)(Thru Day 28)
- Quantification of SARS-CoV-2 RNA (Phase 3)(Day 3)
- Cumulative Incidence of Death From Any Cause or Hospitalization Due to Any Cause (Phase 2)(Thru Day 28)
- Proportion of Participants With New Adverse Event (AE) ≥ Grade 3 (Phases 2 and 3)(Thru Week 24)
- Cumulative Incidence of Death From Any Cause, or Hospitalization Due to Any Cause Related to COVID-19 (Phase 3)(Thru Day 28)
- Level of SARS-CoV-2 RNA From NP Swabs (Phase 2)(Thru Day 14)
- Level of SARS-CoV-2 RNA From NP Swabs (Phase 3)(Day 3)
- Duration of Targeted Clinical COVID-19 Symptoms (Phases 2 and 3)(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 72)
- Oxygen Saturation Level (Phases 2 and 3)(Thru Day 28)
- COVID-19 Symptom Severity Ranking (Phases 2 and 3)(From Day 0 thru Day 28)
- Proportion of Participants With ≥1 Worsening Symptom of COVID-19 (Phases 2 and 3)(Thru Day 28)
- Time to Self-reported Return to Usual Health (a) (Phases 2 and 3)(Thru Day 28)
- AUC of SARS-CoV-2 RNA From Site-collected NP Swabs (Phase 2)(Thru Day 14)
- Proportion of Participants With New Adverse Event (AE) ≥ Grade 2 (Phases 2 and 3)(Thru Week 24)
- Time to Self-reported Return to Usual Health (b) (Phases 2 and 3)(Thru Day 28)