ACTIV-6: COVID-19 Study of Repurposed Medications - Arm D (Ivermectin 600)

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

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.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: Ivermectin; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1459
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Gilbert, Arizona, United States, 85298
      • Lamb Health, LLC
    • Mesa, Arizona, United States, 85203
      • First Care Medical Clinic
    • Peoria, Arizona, United States, 85382
      • Trident Health Center
  • California
    • Newport Beach, California, United States, 92663
      • Hoag Memorial Hospital Presbyterian
    • North Hollywood, California, United States, 91606
      • Assuta Family Medical Group APMC
    • Palo Alto, California, United States, 94304
      • Stanford
  • Colorado
    • Colorado Springs, Colorado, United States, 80917
      • Doctors Medical Group of Colorado Springs, P.C.
    • Colorado Springs, Colorado, United States, 80924
      • Pine Ridge Family Medicine Inc.
  • Connecticut
    • Stamford, Connecticut, United States, 06905
      • Tabitha B. Fortt, M.D., LLC
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • George Washington University Hospital
  • Florida
    • Deerfield Beach, Florida, United States, 33441
      • Arena Medical Group
    • Gainesville, Florida, United States, 32611
      • University of Florida Health
    • Gainesville, Florida, United States, 32606
      • Lupus Foundation of Gainesville
    • Jacksonville, Florida, United States, 32209
      • University of Florida-JAX-ASCENT
    • Jacksonville, Florida, United States, 32244
      • AMRON Vitality and Wellness Center, LLC
    • Lake Mary, Florida, United States, 32746
      • Sunshine Walk In Clinic
    • Lakeland, Florida, United States, 33805
      • Lakeland Regional Medical Center
    • Miami, Florida, United States, 33136
      • University of Miami
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital
    • Miami, Florida, United States, 33173
      • Well Pharma Medical Research
    • Palmetto Bay, Florida, United States, 33157
      • Innovation Clinical Trials Inc.
    • Plantation, Florida, United States, 33313
      • Lice Source Services Plantation
    • Saint Petersburg, Florida, United States, 33707
      • Premier Health
    • Tallahassee, Florida, United States, 32308
      • Tallahassee Memorial Hospital
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital
    • The Villages, Florida, United States, 32159
      • UF Health Precision Health Research
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Healthcare
    • College Park, Georgia, United States, 30349
      • Essential Medical Care, Inc.
    • Cordele, Georgia, United States, 31015
      • David Kavtaradze MD, Inc.
    • Douglasville, Georgia, United States, 30134
      • Elite Family Practice
    • Loganville, Georgia, United States, 30052
      • Christ the King Health Care, P.C.
    • Macon, Georgia, United States, 31201
      • Miller Family Practice, LLC
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60618
      • Olivo Wellness Medical Center
    • Evanston, Illinois, United States, 60201
      • Northshore Medical Group
    • Lake Zurich, Illinois, United States, 60047
      • Advanced Medical Care, Ltd
  • Indiana
    • Michigan City, Indiana, United States, 46360
      • Franciscan Health Michigan City
    • Mishawaka, Indiana, United States, 46545
      • Del Pilar Medical and Urgent Care
  • Kansas
    • Wichita, Kansas, United States, 67214
      • University of Kansas - Wichita
  • Kentucky
    • Central City, Kentucky, United States, 42330
      • A New Start II, LLC
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
    • New Orleans, Louisiana, United States, 70112
      • University Medical Center- New Orleans
  • Maryland
    • Baltimore, Maryland, United States, 21287-1900
      • Johns Hopkins Hospital
    • Rockville, Maryland, United States, 20855
      • Jadestone Clinical Research, LLC
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Lawrence, Massachusetts, United States, 01843
      • Health Quality Primary Care
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical School
  • Michigan
    • Dearborn, Michigan, United States, 48124
      • Ananda Medical Clinic
    • Detroit, Michigan, United States, 48202
      • GFC of Southeastern Michigan, PC
    • Detroit, Michigan, United States, 48206
      • Romancare Health Services
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • Essentia Health
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri - Columbia
  • Nevada
    • Henderson, Nevada, United States, 89052
      • Comprehensive Pain Management and Endocrinology
  • New Jersey
    • Bayonne, New Jersey, United States, 07002
      • Focus Clinical Research Solutions
    • Matawan, New Jersey, United States, 07747
      • Raritan Bay Primary Care & Cardiology Associates
    • Paterson, New Jersey, United States, 07514
      • G&S Medical Associates, LLC
    • Turnersville, New Jersey, United States, 08012
      • Mediversity Healthcare
  • New York
    • Clinton, New York, United States, 13323
      • Geriatrics and Medical Associates
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
    • Yonkers, New York, United States, 10701
      • Spinal Pain and Medical Rehab, PC
  • North Carolina
    • Clayton, North Carolina, United States, 27520
      • Vaidya MD PLLC
    • Dunn, North Carolina, United States, 28334
      • Maria Medical Center, PLLC
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Durham, North Carolina, United States, 27701
      • Duke Clinical Research Institute
    • Winston-Salem, North Carolina, United States, 27151
      • Wake Forest Baptist Health
  • Ohio
    • Canton, Ohio, United States, 44718
      • Diabetes and Endocrinology Assoc. of Stark County
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Montgomery, Ohio, United States, 45242
      • TriHealth, Inc
  • Oklahoma
    • Durant, Oklahoma, United States, 74701
      • The Heart and Medical Center
    • Hugo, Oklahoma, United States, 74743
      • Hugo Medical clinic
  • Pennsylvania
    • Morrisville, Pennsylvania, United States, 19067
      • Bucks County Clinical Research
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29403
      • Medical University of South Carolina
  • Tennessee
    • Franklin, Tennessee, United States, 37067
      • Clinical Trials Center of Middle TN
    • Hendersonville, Tennessee, United States, 37075
      • Rapha Family Wellness
    • Knoxville, Tennessee, United States, 37938
      • Medical Specialists of Knoxville
    • Nashville, Tennessee, United States, 37203
      • Vanderbilt University Medical Center
  • Texas
    • Allen, Texas, United States, 75013
      • Express Family Clinic
    • Edinburg, Texas, United States, 78539
      • DHR Health Institute for Research
    • El Paso, Texas, United States, 79905
      • Texas Tech University Health Sciences Center
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • Fort Worth, Texas, United States, 76107
      • Texas Health Physicians Group
    • Highlands, Texas, United States, 77562
      • Highlands Medical Associates, P.A.
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
    • Humble, Texas, United States, 77338
      • Family Practice Doctors P.A.
    • Irving, Texas, United States, 75039
      • Texas Health Physicians Group
    • Kingwood, Texas, United States, 77339
      • Kintex Group Texas LLC, DBA Activian Clinical Research
    • Pasadena, Texas, United States, 77504
      • University Diagnostics and Treatment Clinic
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
    • Sugar Land, Texas, United States, 77479
      • Jeremy W. Szeto, D.O., P.A.
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Completed Informed Consent
• Age ≥ 30 years old
• Confirmed SARS-CoV-2 infection (or reinfection) 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 (see Appendices)*

Additional Appendix-Level Exclusion Criteria:

• End-stage renal disease on renal replacement therapy
• Liver failure or decompensated cirrhosis
• Current or planned use of the following drugs during the study, listed by drug class:
• Antiarrhythmic/antihypertensive drug class: quinidine, amiodarone, diltiazem, spironolactone, verapamil
• Antibiotic-macrolides drug class: clarithromycin, erythromycin
• Antifungal drug class: itraconazole, ketoconazole
• Immunosuppressant drug class: cyclosporine, tacrolimus
• Anti-HIV drug class: indinavir, ritonavir
• Nursing mothers
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm D - Ivermectin 600; 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; 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.; Other Names: Ivermectin Tablets
Placebo Comparator: Arm D - Placebo; 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; 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.

What is the study measuring?

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.	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Hospitalization or Death		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
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
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
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
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
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
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
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
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
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. Measure of dispersion is 95% credible interval.	Up to 14 days

Collaborators and Investigators

• Sponsor: Susanna Naggie, MD
• Collaborators: Vanderbilt University Medical Center; National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Susanna Naggie, MD, Duke Clinical Research Institute; Principal Investigator: Adrian Hernandez, MD, Duke Clinical Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2022
• Primary Completion (Actual): August 29, 2022
• Study Completion (Actual): October 30, 2022

Study Registration Dates

• First Submitted: June 6, 2023
• First Submitted That Met QC Criteria: June 6, 2023
• First Posted (Actual): June 8, 2023

Study Record Updates

• Last Update Posted (Estimated): November 3, 2023
• Last Update Submitted That Met QC Criteria: October 18, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; Outcomes; Placebo; ivermectin; ACTIV; Duke University Health System; Duke Clinical Research Institute; ACTIV 6
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Anti-Infective Agents; Antiparasitic Agents; Ivermectin
• Other Study ID Numbers: Pro00107921_D; 3U24TR001608-05W1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will share this data after it has been de-identified. We will share data beginning around 6 months after publication and for up to 36 months afterward. Access will only be shared with those who have obtained prior IRB approval to be able to access this data.
• IPD Sharing Time Frame: Up to 36 months after publication
• IPD Sharing Access Criteria: Interested investigators will need to seek prior IRB approval before access to any data is granted.
• IPD Sharing Supporting Information Type: SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No