ACTIV-6: COVID-19 Study of Repurposed Medications

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effectiveness of repurposed medications (study drug(s) in reducing symptoms of non-hospitalized participants with mild to moderate COVID-19. Participants will receive either study drug or placebo. They will self-report any new or worsening symptoms or medical events they may experience while taking study drug or placebo. This study is intended to be all remote with no in person visits, unless the study team feels it is in the best interest of a participant to see them in person. Prior and current drug arms are listed on clinicaltrials.gov and will be updated with the activation of any new drug arms. Each study arm will also have its own clinicaltrials.gov entry and will include Pro00107921 in the Unique Protocol ID. Pro00107921_A - Arm D (Ivermectin 400) - NCT05736861; Pro00107921_B - Arm B (Fluvoxamine) - NCT05890586; Pro00107921_C - Arm C (Fluticasone) - NCT05736874; Pro00107921_D - Arm D (Ivermectin 600) - NCT05894538; Pro00107921_E - Arm E (Fluvoxamine 100) - NCT05894564; Pro00107921_F - Arm F (Montelukast) - NCT05894577; Pro00107921_G - Arm G (Metformin) - NCT06042855.

Detailed Description
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel betacoronavirus that first emerged in December 2019 and has since caused a global pandemic unseen in almost a century with respect to the number of cases and overall mortality. The clinical disease related to SARS-CoV-2 is referred to as Coronavirus Disease 2019 (COVID-19). Over 2020, advances were made for treatment of COVID-19 and several vaccinations have received emergency use authorization for prevention of SARS-CoV-2 infections. However, the pandemic continues to evolve with new variants and surges of infections in different regions of the world, requiring an ongoing evidence-generating platform, in particular for the treatment of COVID-19 infection in the outpatient setting. This proposed platform protocol can serve as an evidence generating system for prioritized drugs repurposed from other indications with an established safety record and preliminary evidence of clinical efficacy for the treatment of COVID-19. The ultimate goal is to evaluate if repurposed medications can make participants feel better faster and reduce death and hospitalization. This platform protocol is designed to be flexible so that it is suitable for a wide range of settings within healthcare systems and in community settings where it can be integrated into routine COVID-19 testing programs and subsequent treatment plans. This platform protocol will enroll participants in an outpatient setting with a confirmed polymerase chain reaction (PCR) or antigen test for SARS-CoV-2. Participants will be randomized to study drugs or placebo based on the arms that are actively enrolling at the time of randomization. Study drugs may be added or removed according to adaptive design and/or emerging evidence. When there are multiple study drugs available, randomization will occur based on appropriateness of each drug for the participant as determined by the study protocol and investigator and participant equipoise. Each participant will be required to randomize to at least one study drug versus placebo. The probability of placebo to treatment will remain the same regardless of eligibility decisions. Eligible participants will be randomized (1:1), in a blinded fashion, to either the study drug arm or placebo arm in addition to standard of care. As additional study drugs are added, the randomization will be altered to leverage placebo data across arms. Participants will receive a complete supply study drug or placebo with the quantity depending on the study drug/placebo to which they are randomized. All study visits are designed to be remote. However, screening and enrollment may occur in-person at sites and unplanned study visits may occur in-person or remotely, as deemed appropriate by the site investigator for safety purposes. Participants will be asked to complete questionnaires and report safety events during the study. Participants will be prompted by the online system to report safety events and these will be reviewed and confirmed via medical records and site staff, as necessary.

Official Title
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ACTIV-6: COVID-19 Outpatient Randomized Trial to Evaluate Efficacy of Repurposed Medications

Conditions
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Covid19

Intervention / Treatment
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* Drug: Ivermectin
* Drug: Fluvoxamine
* Drug: Fluticasone
* Other: Placebo
* Drug: Montelukast
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Eligibility for overall study are listed below. There may be additional appendix-specific criteria. Inclusion Criteria: Completed Informed Consent Age ≥ 30 years old Confirmed SARS-CoV-2 infection by any authorized or approved polymerase chain reaction (PCR) or antigen test collected within 10 days of screening Two or more current symptoms of acute infection for ≤7 days. Symptoms include the following: fatigue, dyspnea, fever, cough, nausea, vomiting, diarrhea, body aches, chills, headache, sore throat, nasal symptoms, new loss of sense of taste or smell Exclusion Criteria: Current or recent (within 10 days of screening) hospitalization for COVID-19 infection Current or planned participation in another interventional trial to treat COVID-19, at the discretion of the study principal investigator (PI) Current or recent use (within the last 14 days) of study drug or study drug/device combination Known allergy/sensitivity or any hypersensitivity to components of the study drug or placebo Known contraindication(s) to study drug including prohibited concomitant medications Previous or current enrollment in the ACTIV-6 trial

Ages Eligible for Study
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Minimum Age: 30 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
Interventional Model Description: Double-Blind, Placebo-Controlled, Randomized Trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - Ivermectin 400<br>Ivermectin - 7-mg tablets Participant will be instructed to take a pre-specified number of tablets for 3 consecutive days based on their weight for a daily dose of approximately 300-400 µg/kg. | Drug: Ivermectin<br>* Each participant will receive a sufficient quantity of 7-mg tablets to be taken as directed based on their weight. The tablets are white, round, biconvex tablets with 123 over the scoring on one side. All packaging will be labeled to indicate that the product is for investigational use.<br>* Other names: Ivermectin Tablets;|
| Placebo Comparator: Arm A - Placebo<br>Placebo - appearance and size matched to active study drug. Participant will be instructed to take a pre-specified number of tablets for 3 consecutive days based on their weight, matched to active study drug dosing. | Other: Placebo<br>* Each study arm will contain a placebo comparator. Placebo will look similar to study drug and will be administered via the same route of administration and dose. However, placebo will be an inactive substance, containing no study drug.<br>|
| Experimental: Arm B - Fluvoxamine<br>Fluvoxamine will be self-administered orally by each participant at a dose of 50 mg twice a day for 10 days. | Drug: Fluvoxamine<br>* Fluvoxamine is a round golden 50 mg tablet that is scored on both sides - one side has APO and the other side has F50 with a partial bisect. All packaging will be labeled to indicate that the product is for investigational use, administered at a dose of 50 mg, twice daily for 10 days.<br>* Other names: Fluvoxamine Maleate Tablets;|
| Placebo Comparator: Arm B- Placebo<br>Placebo - appearance and size matched to active study drug. Placebo will be self-administered orally by each participant twice a day for 10 days. | Other: Placebo<br>* Each study arm will contain a placebo comparator. Placebo will look similar to study drug and will be administered via the same route of administration and dose. However, placebo will be an inactive substance, containing no study drug.<br>|
| Experimental: Arm C - Fluticasone<br>Fluticasone is a self-administered inhaled drug. Participants will self-administer 200 µg (1 blister) of fluticasone once daily for 14 days. After inhaler activation, the powder within the blister is exposed and the participant inhales the study drug through the mouthpiece. | Drug: Fluticasone<br>* Fluticasone furoate is an inhaled powder drug product composed of fluticasone furoate. It is a synthetic trifluorinated corticosteroid that is insoluble in water. Fluticasone furoate is a white powder and will be provided in a two tone grey inhaler with a mouthpiece cover and separate foil blister strips. The inhaler will be packaged in a moisture-protective foil tray with a desiccant and a peelable lid.All packaging will be labeled to indicate that the product is for investigational use. Participants will self-administer 200 µg (1 blister) of fluticasone furoate once daily for 14 days.<br>* Other names: Fluticasone Furoate;|
| Placebo Comparator: Arm C - Placebo<br>Placebo is a self-administered by inhalation. Participants will self-administer 1 blister of placebo once daily for 14 days. After inhaler activation, the powder within the blister is exposed and the participant inhales the placebo through the mouthpiece. | Other: Placebo<br>* Each study arm will contain a placebo comparator. Placebo will look similar to study drug and will be administered via the same route of administration and dose. However, placebo will be an inactive substance, containing no study drug.<br>|
| Experimental: Arm D - Ivermectin 600<br>Ivermectin - 7-mg tablets Participant will be instructed to take a pre-specified number of tablets for 6 consecutive days based on their weight for a daily dose of approximately 400-600 µg/kg. | Drug: Ivermectin<br>* Each participant will receive a sufficient quantity of 7-mg tablets to be taken as directed based on their weight. The tablets are white, round, biconvex tablets with 123 over the scoring on one side. All packaging will be labeled to indicate that the product is for investigational use.<br>* Other names: Ivermectin Tablets;|
| Placebo Comparator: Arm D - Placebo<br>Placebo - appearance and size matched to active study drug. Participant will be instructed to take a pre-specified number of tablets for 6 consecutive days based on their weight, matched to active study drug dosing. | Other: Placebo<br>* Each study arm will contain a placebo comparator. Placebo will look similar to study drug and will be administered via the same route of administration and dose. However, placebo will be an inactive substance, containing no study drug.<br>|
| Experimental: Arm E - Fluvoxamine 100<br>Fluvoxamine will be self-administered orally by each participant at a dose of 50 mg twice a day for 1 day, followed by a dose of 100 mg twice a day for 12 days. | Drug: Fluvoxamine<br>* Fluvoxamine is a round golden 50 mg tablet that is scored on both sides - one side has APO and the other side has F50 with a partial bisect. All packaging will be labeled to indicate that the product is for investigational use, administered at a dose of 50 mg, twice daily for 10 days.<br>* Other names: Fluvoxamine Maleate Tablets;|
| Placebo Comparator: Arm E - Placebo<br>Placebo - appearance and size matched to active study drug. Placebo will be self-administered orally by each participant, with number of tablets matched to active study drug dosing. | Other: Placebo<br>* Each study arm will contain a placebo comparator. Placebo will look similar to study drug and will be administered via the same route of administration and dose. However, placebo will be an inactive substance, containing no study drug.<br>|
| Experimental: Arm F - Montelukast<br>Montelukast will be self-administered orally by each participant at a dose of 10 mg once a day for 14 days. | Drug: Montelukast<br>* Montelukast sodium is a white to off-white powder. The 10 mg montelukast tablets are beige, rounded square-shaped, biconvex, film-coated tablets. Each tablet contains 10.4 mg of montelukast sodium, which is equivalent to 10 mg montelukast. All packaging will be labeled to indicate that the product is for investigational use.<br>|
| Placebo Comparator: Arm F - Placebo<br>Placebo - appearance and size matched to active study drug. Placebo will be self-administered orally by each participant, with number of tablets matched to active study drug dosing. | Other: Placebo<br>* Each study arm will contain a placebo comparator. Placebo will look similar to study drug and will be administered via the same route of administration and dose. However, placebo will be an inactive substance, containing no study drug.<br>|
| Experimental: Arm G - Metformin<br>Metformin IR tablets will be self-administered orally according to the following dosing schedule: 500 mg on Day 1; 500 mg in the morning and 500 mg in the evening on Day 2 through Day 5; and 500 mg in the morning and 2 x 500 mg (a total of 1000 mg) in the evening on Day 6 through Day 14. | Drug: Metformin<br>* Metformin IR tablets contain the active metformin hydrochloride and inactive ingredients including povidone and magnesium stearate. Commercially available metformin 500 mg tablets will be provided.<br>|
| Placebo Comparator: Arm G - Placebo<br>Placebo - appearance and size matched to active study drug. Placebo will be self-administered orally by each participant, with number of tablets matched to active study drug dosing. | Other: Placebo<br>* Each study arm will contain a placebo comparator. Placebo will look similar to study drug and will be administered via the same route of administration and dose. However, placebo will be an inactive substance, containing no study drug.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to sustained recovery in Days | Time to sustained recovery was the number of days between receipt of study drug and the third of 3 consecutive days without symptoms. Participants who died, by definition, did not recover regardless of reported symptom freedom. The reported summary is the median survival time. The overall effect of each study drug versus matching placebo will be quantified using one of these two primary endpoints, which will be defined and documented per study drug appendix prior to the initial IA: clinical events (hospitalization or death) or time to recovery. The other will be evaluated as a secondary endpoint. | Up to 28 days | 
| Number of Participants With Hospitalization or Death | The overall effect of each study drug versus matching placebo will be quantified using one of these two primary endpoints, which will be defined and documented per study drug appendix prior to the initial IA: clinical events (hospitalization or death) or time to recovery. The other will be evaluated as a secondary endpoint. | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to sustained recovery in Days | (If not evaluated as primary endpoint for the given study drug appendix) Time to sustained recovery was the number of days between receipt of study drug and the third of 3 consecutive days without symptoms. Participants who died, by definition, did not recover regardless of reported symptom freedom. The reported summary is the median survival time. The overall effect of each study drug versus matching placebo will be quantified using one of these two primary endpoints, which will be defined and documented per study drug appendix prior to the initial IA: clinical events (hospitalization or death) or time to recovery. The other will be evaluated as a secondary endpoint. | Up to 28 days | 
| Number of Participants With Hospitalization or Death | (If not evaluated as primary endpoint for the given study drug appendix) | Up to 28 days | 
| Number of Participants With Mortality |  | Up to 28 days | 
| Time to mortality | Time to mortality was the number of days between drug receipt and death. | Up to 28 days | 
| Number of Participants With Hospitalization, Urgent Care, Emergency Room Visit, or Death |  | Up to 28 days | 
| Number of Participants at Each Score on the COVID Clinical Progression Scale at Day 7. | COVID Clinical Progression Scale is a scale of 0 to 8 where 0 = No clinical or virological evidence of infection, 1 = No limitation of activities, 2 = Limitation of activities, 3 = Hospitalized, no oxygen therapy, 4 = Hospitalized, on oxygen by mask or nasal prongs, 5 = Hospitalized, on non-invasive ventilation or high-flow oxygen, 6 = Hospitalized, on intubation and mechanical ventilation, 7 = Hospitalized, on ventilation + additional organ support (pressors, RRT, ECMO), 8 = Death. | Day 7 | 
| Number of Participants at Each Score on the COVID Clinical Progression Scale at Day 14. | COVID Clinical Progression Scale is a scale of 0 to 8 where 0 = No clinical or virological evidence of infection, 1 = No limitation of activities, 2 = Limitation of activities, 3 = Hospitalized, no oxygen therapy, 4 = Hospitalized, on oxygen by mask or nasal prongs, 5 = Hospitalized, on non-invasive ventilation or high-flow oxygen, 6 = Hospitalized, on intubation and mechanical ventilation, 7 = Hospitalized, on ventilation + additional organ support (pressors, RRT, ECMO), 8 = Death. | Day 14 | 
| Number of Participants at Each Score on the COVID Clinical Progression Scale at Day 28. | COVID Clinical Progression Scale is a scale of 0 to 8 where 0 = No clinical or virological evidence of infection, 1 = No limitation of activities, 2 = Limitation of activities, 3 = Hospitalized, no oxygen therapy, 4 = Hospitalized, on oxygen by mask or nasal prongs, 5 = Hospitalized, on non-invasive ventilation or high-flow oxygen, 6 = Hospitalized, on intubation and mechanical ventilation, 7 = Hospitalized, on ventilation + additional organ support (pressors, RRT, ECMO), 8 = Death. | Day 28 | 
| Quality of Life (QOL) as measured by the PROMIS-29 - Physical Function | The PROMIS-29 (Patient-Reported Outcomes Measurement Information System) consists of seven health domains with four 5-level items associated with each and a pain intensity assessment using a 0-10 numeric rank. The seven health domains include physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance. Raw score ranges from 4-20, where a higher score correlates to better outcome for physical function. | Day 7, 14, 28, 90, 120, and 180 | 
| Quality of Life (QOL) as measured by the PROMIS-29 - Fatigue | The PROMIS-29 (Patient-Reported Outcomes Measurement Information System) consists of seven health domains with four 5-level items associated with each and a pain intensity assessment using a 0-10 numeric rank. The seven health domains include physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance. Raw score ranges from 4-20, where a lower score correlates to better outcome for fatigue. | Day 7, 14, 28, 90, 120, and 180 | 
| Quality of Life (QOL) as measured by the PROMIS-29 - Pain | The PROMIS-29 (Patient-Reported Outcomes Measurement Information System) consists of seven health domains with four 5-level items associated with each and a pain intensity assessment using a 0-10 numeric rank. The seven health domains include physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance. Raw score ranges from 4-20, where a lower score correlates to better outcome for pain. | Day 7, 14, 28, 90, 120, and 180 | 
| Quality of Life (QOL) as measured by the PROMIS-29 - Depression | The PROMIS-29 (Patient-Reported Outcomes Measurement Information System) consists of seven health domain with four 5-level items associated with each and a pain intensity assessment using a 0-10 numeric rank. The seven health domains include physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance. Raw score ranges from 4-20, where a lower score correlates to better outcome for depression. | Day 7, 14, 28, 90, 120, and 180 | 
| Quality of Life (QOL) as measured by the PROMIS-29 - Anxiety | The PROMIS-29 (Patient-Reported Outcomes Measurement Information System) consists of seven health domains with four 5-level items associated with each and a pain intensity assessment using a 0-10 numeric rank. The seven health domains include physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance. Raw score ranges from 4-20 where a lower score correlates to better outcome for anxiety. | Day 7, 14, 28, 90, 120, and 180 | 
| Quality of Life (QOL) as measured by the PROMIS-29 - Social | The PROMIS-29 (Patient-Reported Outcomes Measurement Information System) consists of seven health domains with four 5-level items associated with each and a pain intensity assessment using a 0-10 numeric rank. The seven health domains include physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance. Raw score ranges from 4-20 where a higher score correlates to better outcome for social roles and activities. | Day 7, 14, 28, 90, 120, and 180 | 
| Quality of Life (QOL) as measured by the PROMIS-29 - Sleep | The PROMIS-29 (Patient-Reported Outcomes Measurement Information System) consists of seven health domains with four 5-level items associated with each and a pain intensity assessment using a 0-10 numeric rank. The seven health domains include physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance. Raw score ranges from 4-20 where a lower score correlates to better outcome for sleep. | Day 7, 14, 28, 90, 120, and 180 | 
| Time Unwell in Days as Measured by the Symptom and Clinical Event Scale | The symptom and clinical event scale is a daily measurement that combines the global symptom burden scale with clinical events hospitalization and mortality. (No symptoms, mild symptoms, moderate symptoms, severe symptoms, hospitalized, deceased). Time unwell was the portion of follow-up (in days) that a participant was symptomatic, hospitalized, or deceased. The quantity is estimated from a Bayesian longitudinal ordinal regression model with covariate adjustment and weakly informative priors. | Up to 14 days | 
| Mean Days Benefit as Measured by the Symptom and Clinical Event Scale | The symptom and clinical event scale is a daily measurement that combines the global symptom burden scale with clinical events hospitalization and mortality. (No symptoms, mild symptoms, moderate symptoms, severe symptoms, hospitalized, deceased). The cumulative benefit of treatment A is the probability of experiencing a better outcome on treatment A compared to treatment B, summed over the days of follow-up. The difference between the cumulative benefit of treatment A and the cumulative benefit of treatment B is known as the difference in days benefit. Measure of dispersion is 95% credible interval. | Up to 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2, COVID-19, ivermectin, Placebo, Duke University Health System, Outcomes, Duke Clinical Research Institute, fluticasone, fluvoxamine, ACTIV 6, ACTIV, montelukast, metformin