Safety, Tolerability and Efficacy of Molnupiravir (EIDD-2801) to Eliminate Infectious Virus Detection in Persons With COVID-19
Condition: SARS-CoV-2 Infection, COVID-19
MeSH terms: COVID-19
Intervention: Molnupiravir 200 mg; Molnupiravir 400 mg; Molnupiravir 800 mg; Placebo (PBO)
Intervention description: Oral capsule of molnupiravir; Oral capsule of molnupiravir; Oral capsule of molnupiravir; placebo oral capsule
Intervention MeSH terms: Molnupiravir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 204.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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.