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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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SARS-CoV-2 Infection, COVID-19

Intervention / Treatment
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* Drug: Molnupiravir 200 mg
* Drug: Molnupiravir 400 mg
* Drug: Molnupiravir 800 mg
* Drug: Placebo (PBO)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide informed consent prior to initiation of any study procedures. ≥18 years of age at Screening. Study treatment is expected to begin within ≤168 hours from first symptom onset. Ability to swallow pills. 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. 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). Agreed to not participate in another interventional clinical trial for the treatment of SARS-CoV-2 during the study period (28 days) unless hospitalized. Agreed to not obtain investigational medications outside of the molnupiravir study. Agreed to the sampling detailed in the schedule of evaluations and to comply with study requirements including contraception requirements. 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. 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: Need for hospitalization or immediate medical attention in the clinical opinion of the study investigator. Hemoglobin <10 g/dL in men and <9 g/dL in women. Platelet count <100,000/ µL or received a platelet transfusion within 5 days prior to enrollment. Was on dialysis or has an estimated glomerular filtration rate <30 mL/min/1.73 m^2 Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >3x upper limit normal (ULN). History of or current hospitalization for COVID-19. Note: Individuals hospitalized and then discharged, even if only hospitalized for 1 day, were excluded. History of kidney disease as evidenced by estimated creatinine clearance value <30 mL/min. 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. 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. Receipt of a SARS-CoV-2 vaccination prior to study entry. Known allergy/sensitivity or any hypersensitivity to components of molnupiravir, or its formulation. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. History of recent (within the past 3 months) hemorrhagic cerebrovascular accident) or major bleed. Presence of a condition, that in the opinion of the investigator, would place the subject at increased risk from study participation.

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Molnupiravir 200 mg<br>Molnupiravir 200 mg, twice daily (BID) for 5 days | Drug: Molnupiravir 200 mg<br>* Oral capsule of molnupiravir<br>|
| Experimental: Molnupiravir 400 mg<br>Molnupiravir 400 mg, twice daily (BID) for 5 days | Drug: Molnupiravir 400 mg<br>* Oral capsule of molnupiravir<br>|
| Experimental: Molnupiravir 800 mg<br>Molnupiravir 800 mg, twice daily (BID) for 5 days | Drug: Molnupiravir 800 mg<br>* Oral capsule of molnupiravir<br>|
| Placebo Comparator: Placebo (PBO) twice daily (BID) for 5 days<br> | Drug: Placebo (PBO)<br>* placebo oral capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Until First Non-detectable SARS-CoV-2 in Nasopharyngeal (NP) Swabs | 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 | 28 days | 
| Time to Clearance of SARS-CoV-2 in Nasopharyngeal Swabs | 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 | 28 days | 
| Number of Participants With Adverse Events (AEs) Grade 3 or Higher or Leading to Discontinuation of Study Treatment | 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. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Events (AEs), Grade 2 or Higher | Measure the safety and tolerability of EIDD-2801 by estimating the occurrence of Grade 2 or higher AE and drug related AEs. | 28 days |