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Safety, Tolerability and Efficacy of Molnupiravir (EIDD-2801) to Eliminate Infectious Virus Detection in Persons With COVID-19

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04405570
Recruitment Status : Completed
First Posted : May 28, 2020
Results First Posted : February 16, 2022
Last Update Posted : February 16, 2022
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Ridgeback Biotherapeutics, LP

Tracking Information
First Submitted Date  ICMJE May 26, 2020
First Posted Date  ICMJE May 28, 2020
Results First Submitted Date  ICMJE January 18, 2022
Results First Posted Date  ICMJE February 16, 2022
Last Update Posted Date February 16, 2022
Actual Study Start Date  ICMJE June 19, 2020
Actual Primary Completion Date February 21, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 14, 2022)
  • Number of Participants Until First Non-detectable SARS-CoV-2 in Nasopharyngeal (NP) Swabs [ Time Frame: 28 days ]
    The number of participants until first non-detectable SARS-CoV-2 in nasopharyngeal (NP) swabs will be estimated for each randomized arm (drug versus placebo), using Kaplan-Meier methods with a corresponding log-rank test. Non detectable defined as "a viral load below the limit of quantification
  • Time to Clearance of SARS-CoV-2 in Nasopharyngeal Swabs [ Time Frame: 28 days ]
    The distribution of days until first non-detectable SARS-CoV-2 in nasopharyngeal (NP) swabs will be estimated for each randomized arm (drug versus placebo), using Kaplan-Meier methods with a corresponding log-rank test. Non detectable defined as "a viral load below the limit of quantification
  • Number of Participants With Adverse Events (AEs) Grade 3 or Higher or Leading to Discontinuation of Study Treatment [ Time Frame: 28 days ]
    1) any AEs leading to early discontinuation of blinded treatment (active or placebo), 2) study drug-related discontinuation of treatment, 3) new grade 3 or higher AEs (not already present at baseline), and 4) study drug-related new grade 3 or higher AEs.
Original Primary Outcome Measures  ICMJE
 (submitted: May 26, 2020)
  • Virologic Efficacy [ Time Frame: 28 days ]
    The distribution of days until first non-detectable SARS-CoV-2 in nasopharyngeal (NP) swabs will be estimated for each randomized arm (drug versus placebo), using Kaplan-Meier methods with a corresponding stratified log-rank test (to account for the "early" versus "late" time from symptom onset randomization strata)
  • Number of Participants with any Adverse Events (AEs) as Assessed by Kaplan Meier Approach [ Time Frame: 28 days ]
    Measure the safety and tolerability of EIDD-2801 by estimating in the randomization arm the probability of 1) any adverse events (AEs) leading to early discontinuation of blinded treatment (active or placebo), 2) study drug-related discontinuation of treatment, 3) new grade 3 or higher AE (not already present at baseline), and 4) study drug-related new grade 3 or higher AE. The cumulative probability of each safety and each tolerability endpoint (4 endpoints) by using the Kaplan-Meier approach and stratified log-rank test.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 18, 2022)
Number of Participants With Any Adverse Events (AEs), Grade 2 or Higher [ Time Frame: 28 days ]
Measure the safety and tolerability of EIDD-2801 by estimating the occurrence of Grade 2 or higher AE and drug related AEs.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 26, 2020)
Number of Participants With any Adverse Events (AEs), Grade 2 or higher as Assessed by Kaplan Meier Approach [ Time Frame: 28 days ]
Measure the safety and tolerability of EIDD-2801 by estimating the occurrence of Grade 2 or higher AE and drug related AEs by using the Kaplan-Meier approach and stratified log-rank test.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability and Efficacy of Molnupiravir (EIDD-2801) to Eliminate Infectious Virus Detection in Persons With COVID-19
Official Title  ICMJE A Phase IIa Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability and Efficacy of EIDD-2801 to Eliminate SARS-CoV-2RNA Detection in Persons With COVID-19
Brief Summary This was a phase IIa, double-blind, placebo-controlled, randomized trial, designed to compare the safety, tolerability, and antiviral activity of EIDD-2801 (molnupiravir) versus placebo as measured by SARS-CoV-2 viral RNA detection in symptomatic adult outpatients with COVID-19.
Detailed Description

This was a phase IIa, double-blind, placebo-controlled, randomized trial, designed to compare the safety, tolerability, and antiviral activity of molnupiravir versus placebo as measured by SARS-CoV-2 viral RNA detection in symptomatic adult outpatients with COVID-19. The study was a multicenter trial that was conducted in the United States.

In this study, 204 participants were randomized and 202 received molnupiravir or placebo orally twice a day (BID) for 5 days. The study enrolled participants in 5 parts with each part evaluating molnupiravir doses of either 200 mg BID, 400 mg BID, or 800 mg BID. Doses were chosen based on emerging virology and safety data from this and ongoing studies. New dose groups were started after the selected dose had been studied for safety in a Phase 1 study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE SARS-CoV-2 Infection, COVID-19
Intervention  ICMJE
  • Drug: Molnupiravir 200 mg
    Oral capsule of molnupiravir
  • Drug: Molnupiravir 400 mg
    Oral capsule of molnupiravir
  • Drug: Molnupiravir 800 mg
    Oral capsule of molnupiravir
  • Drug: Placebo (PBO)
    placebo oral capsule
Study Arms  ICMJE
  • Experimental: Molnupiravir 200 mg
    Molnupiravir 200 mg, twice daily (BID) for 5 days
    Intervention: Drug: Molnupiravir 200 mg
  • Experimental: Molnupiravir 400 mg
    Molnupiravir 400 mg, twice daily (BID) for 5 days
    Intervention: Drug: Molnupiravir 400 mg
  • Experimental: Molnupiravir 800 mg
    Molnupiravir 800 mg, twice daily (BID) for 5 days
    Intervention: Drug: Molnupiravir 800 mg
  • Placebo Comparator: Placebo (PBO) twice daily (BID) for 5 days
    Intervention: Drug: Placebo (PBO)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 7, 2020)
204
Original Estimated Enrollment  ICMJE
 (submitted: May 26, 2020)
44
Actual Study Completion Date  ICMJE February 21, 2021
Actual Primary Completion Date February 21, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Able to provide informed consent prior to initiation of any study procedures.
  2. ≥18 years of age at Screening.
  3. Study treatment is expected to begin within ≤168 hours from first symptom onset.
  4. Ability to swallow pills.
  5. Documentation of confirmed active SARS-CoV-2 infection, as determined by a molecular or non-molecular ("rapid") test conducted at any clinic or laboratory that had a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent from a sample collected ≤96 hours prior to study entry.
  6. Was experiencing at least one of the following SARS-CoV-2 infection symptoms at the time of enrollment: fever (could be subjective including feeling feverish or having chills) OR signs/symptoms of respiratory illness (including but not limited to upper respiratory congestion, loss of sense of smell or taste, sore throat OR lower respiratory illness - cough, shortness of breath).
  7. Agreed to not participate in another interventional clinical trial for the treatment of SARS-CoV-2 during the study period (28 days) unless hospitalized.
  8. Agreed to not obtain investigational medications outside of the molnupiravir study.
  9. Agreed to the sampling detailed in the schedule of evaluations and to comply with study requirements including contraception requirements.
  10. A female participant was eligible to participate if she was not pregnant or breastfeeding and at least one of the following conditions applied:

    • Was not a woman of childbearing potential (WOCBP) OR
    • Was a WOCBP and using a contraceptive method that is highly effective (a low user dependency method OR a user-dependent method in combination with a barrier method), or was abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 2 of the study protocol during the intervention period and for at least 50 days after the last dose of study intervention. The investigator evaluated the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
    • A WOCBP must have had a negative highly sensitive pregnancy test (serum or urine) within 24 hours before the first dose of study intervention.
    • Additional requirements for pregnancy testing during and after study intervention were provided in the study protocol.
    • The investigator was responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
    • Contraceptive use by women was to be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    • Given the elevated risk of venous thrombotic events in patients hospitalized with COVID-19 (Benson et al, 2020; Spratt et al, 2020), estrogen-containing contraceptives could not be started to fulfill the contraceptive requirement of this study at any time during participant's participation. If contraceptives were interrupted as standard of care management of COVID-19 patients and resumed at a later time point, such as at hospital discharge, then abstinence was practiced for the defined period of back-up contraception per the contraceptive product labeling. After this period, contraceptive use had to adhere to the guidance in Appendix 2 of the study protocol.
  11. Male participants were eligible to participate if they agreed to the following during the intervention period and for at least 100 days after the last dose of study intervention:

    • Refrained from donating sperm

PLUS either:

  • Were abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agreed to remain abstinent.

OR

  • Had to agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause [Appendix 2 of the study protocol]) as detailed below:

    • Agreed to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who was not pregnant. Note: Men with a pregnant or breastfeeding partner had to agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
    • Contraceptive use by men was to be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

Exclusion Criteria:

  1. Need for hospitalization or immediate medical attention in the clinical opinion of the study investigator.
  2. Hemoglobin <10 g/dL in men and <9 g/dL in women.
  3. Platelet count <100,000/ µL or received a platelet transfusion within 5 days prior to enrollment.
  4. Was on dialysis or has an estimated glomerular filtration rate <30 mL/min/1.73 m^2
  5. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >3x upper limit normal (ULN).
  6. History of or current hospitalization for COVID-19. Note: Individuals hospitalized and then discharged, even if only hospitalized for 1 day, were excluded.
  7. History of kidney disease as evidenced by estimated creatinine clearance value <30 mL/min.
  8. History of significant liver disease in the opinion of the site investigator or active hepatitis B or active hepatitis C. Human immunodeficiency virus (HIV) that is advanced (CD4<200/mm^3) and/or on treatment with nucleos(t)ide analogues.
  9. Use of therapeutic interventions with possible anti-SARS-CoV-2 activity within 30 days prior to study entry, (e.g., remdesivir, lopinavir/ritonavir fixed dose combination, ribavirin, chloroquine, hydroxychloroquine, and convalescent plasma), or participation in a clinical trial involving any of these drugs whether for treatment or prophylaxis.
  10. Receipt of a SARS-CoV-2 vaccination prior to study entry.
  11. Known allergy/sensitivity or any hypersensitivity to components of molnupiravir, or its formulation.
  12. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
  13. History of recent (within the past 3 months) hemorrhagic cerebrovascular accident) or major bleed.
  14. Presence of a condition, that in the opinion of the investigator, would place the subject at increased risk from study participation.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04405570
Other Study ID Numbers  ICMJE EIDD-2801-2003
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: There is not a plan to make IPD available.
Responsible Party Ridgeback Biotherapeutics, LP
Study Sponsor  ICMJE Ridgeback Biotherapeutics, LP
Collaborators  ICMJE Merck Sharp & Dohme LLC
Investigators  ICMJE Not Provided
PRS Account Ridgeback Biotherapeutics, LP
Verification Date February 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP