| Protocol No: | ECCT/21/06/01 | Date of Protocol: | 22-12-2020 |
| Study Title: | ACTIV-2/A5401 "Adaptive Platform Treatment Trial for Outpatients with COVID-19" (Adapt Out COVID)_ |
| Study Objectives: |
1.1 Co-Primary Objectives
1.1.1 Phases II and III: To evaluate safety of the investigational agent.
1.1.2 Phase II: To determine efficacy of the investigational agent to reduce the duration of COVID-19 symptoms through study day 28.
1.1.3 Phase II: To determine the efficacy of the investigational agent to increase the proportion of participants with nasopharyngeal (NP) SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) at study days 3, 7, 14, and 28.
1.1.4 Phase III for infused agents only: To determine if the investigational agent will prevent the composite endpoint of either hospitalization or death through study day 28. Hospitalization is 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 during the COVID-19 pandemic.
1.2 Secondary Objectives
1.2.1 Phases II and III: To determine whether the investigational agent reduces a COVID-19 Severity Ranking scale based on COVID-19-associated symptom burden (severity and duration), hospitalization, and death, through study day 28.
1.2.2 Phase II and III: To determine whether the investigational agent reduces the progression of COVID-19-associated symptoms.
1.2.3 Phases II and III: To determine if the investigational agent reduces levels of SARS-CoV-2 RNA in nasal swabs.
1.2.4 Phase II: To determine the pharmacokinetics of the investigational agent.
1.2.5 Phase II: To evaluate differences in SARS-CoV-2 RNA levels in NP swabs between the investigational agent versus placebo and among subgroups of the population and risk groups defined by age and comorbidities.
1.2.6 Phase II: To determine efficacy of the investigational agent to obtain pulse oximetry measurement of ≥96% through day 28.
1.2.7 Phase III: To evaluate differences in symptom duration between the investigational agent versus placebo among subgroups of the population, and risk groups defined by age and comorbidities.
1.2.8 Phase III: To determine if the investigational agent will prevent the compositeendpoint of either hospitalization or death through study week 24.
1.3 Exploratory Objectives
1.3.1 Phases II and III: To explore the impact of the investigational agent on participant-reported rates of SARS-CoV-2 positivity of household contacts.
1.3.2 Phases II and III: To explore if baseline and follow-up hematology, chemistry, coagulation, viral, and inflammatory biomarkers are associated with clinical and virologic outcomes in relation to investigational agent use.
1.3.3 Phases II and III: To explore possible predictors of outcomes across the study population, notably sex, time from symptom onset to start of investigational agent, race/ethnicity, and risk groups defined by age and comorbidities.
1.3.4 Phases II and III: To explore if the investigational agent changes the hospital course once a participant requires hospitalization.
1.3.5 Phases II and III: To explore and develop a model for the interrelationships between virologic outcomes, clinical symptoms, hospitalization, and death in each study group.
1.3.6 Phases II and III: To explore the relationship between exposure to the investigational agent and SARS-CoV-2 innate, humoral or cellular response, including anti-drug antibodies, as appropriate per investigational agent.
1.3.7 Phases II and III: To explore baseline and emergent viral resistance to the investigational agent.
1.3.8 Phases II and III: To explore the association between viral genotypes and phenotypes, and clinical outcomes and response to agents.
1.3.9 Phases II and III: To explore the association between host genetics and clinical outcomes and response to agents.
1.3.10 Phases II and III: To explore relationships between dose and concentration of investigational agent with virology, symptoms, and oxygenation.
1.3.11 Phases II and III: To explore the association between zinc and vitamin D levels and clinical outcomes and response to agents.
1.3.12 Phase II: To explore the impact of investigational agents on levels of SARS-CoV-2 RNA in the blood.
1.3.13 Phase II: To explore if levels of SARS-CoV-2 RNA in self-collected nasal swabs correlate with levels of SARS-CoV-2 RNA in site-collected NP swabs.
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| Laymans Summary: | novel pneumonia emerged in Wuhan, China, in December 2019. The virus is closely related to SARS-CoV-1, which caused an outbreak in 2003, and has been named SARS-CoV-2. The human disease caused by SARS-CoV-2 is called COVID-19. There is no clinically proven antiviral treatment for SARS-CoV-2 infection in the outpatient setting. New agents are becoming available that may be useful for the treatment of non-hospitalized persons with COVID-19. Before they can be clinically deployed, they will need to be evaluated quickly in ambulatory persons in a rigorous clinical trial, as will be achieved through ACTIV-2/A5401, the Adapt Out COVID Trial. The goal of this study is to rapidly evaluate therapies in the outpatient setting, to prevent disease progression, and reduce serious complications of COVID-19 and transmission. An investigational agent that has shown effects on clinical symptoms, hospitalization, death, oxygenation, and/or viral shedding and has an acceptable safety profile will be considered by the Trial Oversight Committee (TOC) for graduation to phase III evaluation. This is the phase within which the MUCRC will participate. |
| Abstract of Study: |
DESIGN
Adapt Out COVID is a master protocol to evaluate the safety and efficacy of investigational agents for the treatment of symptomatic non-hospitalized adults with COVID-19.
The trial is a randomized, blinded, controlled adaptive platform that allows agents to be added and dropped during the course of the study for efficient testing of new agents against placebo within the same trial infrastructure. When two or more new agents are being tested concurrently, the same placebo will be used, if feasible.
The protocol will be amended when information becomes available from within or outside of the trial indicating that further randomization to a placebo is inappropriate.
Version 3 of the protocol will introduce agents that do not require an intravenous infusion (non-infused agents). Thus, the trial will include both infused and non-infused agents. For infused agents, enrollment will be restricted to participants at higher risk of progression to severe COVID-19. Non-infused agents will be open to participants at both “higher” and “lower” risk of progression to severe COVID-19.
For infused agents, the study begins with a phase II evaluation, followed by a transition into a larger phase III evaluation for promising agents. The phase III evaluation is a continuation of the phase II trial for agents that meet study-defined criteria for further evaluation and for which sufficient investigational agent is available. An infused agent may also enter directly into phase III evaluation based on Trial Oversight Committee (TOC) assessments.
For non-infused agents, the same phase II study will be undertaken as for infused agents. However, the design of the phase III evaluation for non-infused agents will be developed in a subsequent version of the protocol. Once developed, non-infused agents may also enter directly into phase III base don TOC assessments.
REGIMEN
Investigational agents will be selected by the 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.
DURATION
28 days of intensive follow-up, followed by limited follow-up through 24 weeks. Study visits may be required after week 24, depending on the agent. Details are listed in the agent-specific protocol appendix and consents.
STRATIFICATION
Randomization in both phase II and phase III will be stratified by time from symptom onset (≤5 days versus >5 days). Randomization for non-infused agents will also be stratified by risk of progression to severe COVID-19 (“higher” versus “lower”).
POPULATION
Outpatient adults (≥18 years) with a documented positive SARS-CoV-2 molecular test (antigen or nucleic acid) from a sample collected ≤240 hours (10 days) prior to study entry and with ≤10 days of symptoms of COVID-19 at study entry, plus the presence of select symptoms within 24 hours prior to study entry.
Participants eligible for infused agents will have at least one of the following factors for “higher” risk of progression to severe COVID-19:
• age 60 years and older
• any age with at least one of the following conditions (self-report is acceptable):
o current smoker (any inhaled nicotine product)
o exogenous or endogenous immunosuppression defined as any of the following:
HIV infection with CD4 count <200 cells/mm3
receiving corticosteroids equivalent to prednisone ≥20mg daily for at least 14 consecutive days within 30 days prior to study entry
treatment with biologics (e.g., infliximab, abalizumab, ustekinumab, etc.), immunomodulators (e.g., methotrexate, 6MP, azathioprine, etc.), or cancer chemotherapy within 90 days prior to study entry
o chronic lung disease or asthma requiring daily prescribed therapy
o obesity (body mass index [BMI] >35; may be based on self-report of height and weight)
o hypertension, with at least one medication recommended or prescribed
o cardiovascular disease defined as history of any of the following: myocardial infarction, stroke, transient ischemic attack, heart failure, angina with prescribed nitroglycerin, coronary artery bypass grafts, percutaneous coronary intervention (PCI), carotid endarterectomy, and aortic bypass
o diabetes mellitus
o chronic kidney disease requiring hemodialysis or peritoneal dialysis
o history of cirrhosis
o active cancer, other than localized skin cancer
For non-infused agents, participants may be at “higher” or “lower” risk for progression to severe COVID-19.
SAMPLE SIZE
Approximately 110 participants per investigational agent (and 110 on placebo) in the phase II evaluation. For infused agents, approximately 421 participants per investigational agent (and 421 on placebo), in the phase III evaluation (including those enrolled in phase II). The sample size for Phase III for non-infused agents will be included in a subsequent version of the protocol.
OUTCOME MEASURES
The primary outcome measures in the phase II evaluation will be duration of symptoms, SARS-CoV-2 RNA below lower limit of quantification by nasopharyngeal (NP) swabs, and safety.
For infused agents, determination of whether an agent in phase II will continue to be evaluated in phase III will be made after the last participant randomized to that agent or placebo completes their day 28 phase II visit. If continued in phase III, data collected from participants enrolled in phase II will be included in the phase III evaluation. The fully powered phase III trial will evaluate the efficacy of each selected investigational infused agent compared to placebo to prevent hospitalization and death in non-hospitalized adults with COVID-19.
A subsequent version of the protocol will include a new phase III evaluation of non-infused agents in a broad outpatient population with COVID-19, which will, with the primary outcome, likely be based on a symptom duration outcome measure.
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