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Pharmacokinetics and Bioequivalence of Molnupiravir, 200 mg Capsules and Lagevrio, 200 mg Capsules in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT05412173
Recruitment Status : Recruiting
First Posted : June 9, 2022
Last Update Posted : June 9, 2022
Sponsor:
Information provided by (Responsible Party):
Valenta Pharm JSC

Tracking Information
First Submitted Date  ICMJE June 6, 2022
First Posted Date  ICMJE June 9, 2022
Last Update Posted Date June 9, 2022
Actual Study Start Date  ICMJE April 1, 2022
Estimated Primary Completion Date December 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2022)
  • Pharmacokinetics - Cmax [ Time Frame: From 0 to 24 hours (Day 1-2 and Day 8-9) ]
    Maximum plasma concentration (Cmax) of β-D-N-4-hydroxycytidine (NHC)
  • Pharmacokinetics - tmax [ Time Frame: From 0 to 24 hours (Day 1-2 and Day 8-9) ]
    Time to reach Cmax (tmax) of NHC
  • Pharmacokinetics - AUC0-t [ Time Frame: From 0 to 24 hours (Day 1-2 and Day 8-9) ]
    Area under the plasma concentration-time curve from time 0 to t (AUC0-t) of NHC
  • Pharmacokinetics - AUC0-inf [ Time Frame: From 0 to 24 hours (Day 1-2 and Day 8-9) ]
    Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf) of NHC
  • Pharmacokinetics - AUCextr [ Time Frame: From 0 to 24 hours (Day 1-2 and Day 8-9) ]
    Extrapolated AUC of NHC, defined as (AUC0-inf - AUC0-t)/AUC0-inf
  • Pharmacokinetics - t1/2 [ Time Frame: From 0 to 24 hours (Day 1-2 and Day 8-9) ]
    Elimination half-life (t1/2) of NHC
  • Pharmacokinetics - kel [ Time Frame: From 0 to 24 hours (Day 1-2 and Day 8-9) ]
    Elimination constant (kel) of NHC
  • Pharmacokinetics - MRT [ Time Frame: From 0 to 24 hours (Day 1-2 and Day 8-9) ]
    Mean residence time (MRT) of NHC
  • Bioequivalence - ratio of Cmax [ Time Frame: From 0 to 24 hours (Day 1-2 and Day 8-9) ]
    Ratio of geometric mean Cmax for NHC after intake of R or T (with 90% confidence intervals)
  • Bioequivalence - ratio of AUC0-t [ Time Frame: From 0 to 24 hours (Day 1-2 and Day 8-9) ]
    Ratio of geometric mean AUC0-t for NHC after intake of R or T (with 90% confidence intervals)
  • Bioequivalence - ratio of AUC0-inf [ Time Frame: From 0 to 24 hours (Day 1-2 and Day 8-9) ]
    Ratio of geometric mean AUC0-inf for NHC after intake of R or T (with 90% confidence intervals)
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2022)
  • Safety and Tolerability: adverse event (AE) number and frequency [ Time Frame: From the screening (and signing informed consent form) to Day 14 of the study or to an early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Number and frequency of adverse events (AEs) or serious AEs (SAEs)
  • Safety and Tolerability: adverse event (AE) characteristics [ Time Frame: From the screening (and signing informed consent form) to Day 14 of the study or to an early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Description and severity of AEs or serious AEs (SAEs), concomitant therapy for AEs/SAEs, causal relationship, outcomes.
  • Safety and Tolerability: vital signs - systolic blood pressure (SBP) [ Time Frame: Screening, from Day 0 to Day 2, from Day 7 to Day 9, and/or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    SBP, mmHg
  • Safety and Tolerability: vital signs - diastolic blood pressure (DBP) [ Time Frame: Screening, from Day 0 to Day 2, from Day 7 to Day 9, and/or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    DBP, mmHg
  • Safety and Tolerability: vital signs - respiratory rate (RR) [ Time Frame: Screening, from Day 0 to Day 2, from Day 7 to Day 9, and/or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    RR, breaths per minute
  • Safety and Tolerability: vital signs - heart rate (HR) [ Time Frame: Screening, from Day 0 to Day 2, from Day 7 to Day 9, and/or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    HR, beats per minute
  • Safety and Tolerability: vital signs - body temperature [ Time Frame: Screening, from Day 0 to Day 2, from Day 7 to Day 9, and/or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Body temperature, centigrade scale
  • Safety and Tolerability: physical examination results [ Time Frame: Screening, from Day 0 to Day 2, from Day 7 to Day 9, and/or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Physical examination results
  • Safety and Tolerability: urinalysis - color [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Color of the urine
  • Safety and Tolerability: urinalysis - transparency [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Transparency of the urine
  • Safety and Tolerability: urinalysis - pH [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    pH of the urine
  • Safety and Tolerability: urinalysis - specific gravity [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Specific gravity of the urine
  • Safety and Tolerability: urinalysis - nitrites [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Nitrites in the urine (+/-)
  • Safety and Tolerability: urinalysis - protein [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Protein in the urine (g/L)
  • Safety and Tolerability: urinalysis - glucose [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Glucose in the urine (mmol/L)
  • Safety and Tolerability: urinalysis - ketones [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Ketones in the urine (mmol/L)
  • Safety and Tolerability: urinalysis - urobilinogen [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Urobilinogen in the urine (mmol/L)
  • Safety and Tolerability: urinalysis - bilirubin [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Bilirubin in the urine (+/-)
  • Safety and Tolerability: urinalysis (microscopy) - red blood cells [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Red blood cells in the urine (number in sight)
  • Safety and Tolerability: urinalysis (microscopy) - white blood cells [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    White blood cells in the urine (number in sight)
  • Safety and Tolerability: urinalysis (microscopy) - cylinders (except hyaline) [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Cylinders (except hyaline) in the urine (number in sight)
  • Safety and Tolerability: urinalysis (microscopy) - bacteria [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Bacteria in the urine (number in sight)
  • Safety and Tolerability: complete blood count - hemoglobin [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Hemoglobin, g/dL
  • Safety and Tolerability: complete blood count - red blood cells [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Red blood cells, 10^6/uL
  • Safety and Tolerability: complete blood count - hematocrit [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Hematocrit, %
  • Safety and Tolerability: complete blood count - platelets [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Platelets, 10^3/uL
  • Safety and Tolerability: complete blood count - white blood cells [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    White blood cells, 10^3/uL
  • Safety and Tolerability: complete blood count - erythrocyte sedimentation rate [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Erythrocyte sedimentation rate, mm per hour
  • Safety and Tolerability: complete blood count - neutrophils [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Neutrophils, %
  • Safety and Tolerability: complete blood count - lymphocytes [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Lymphocytes, %
  • Safety and Tolerability: complete blood count - eosinophils [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Eosinophils, %
  • Safety and Tolerability: complete blood count - monocytes [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Monocytes, %
  • Safety and Tolerability: complete blood count - basophils [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Basophils, %
  • Safety and Tolerability: blood test results - total protein [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Total protein in blood serum, g/L
  • Safety and Tolerability: blood test results - creatinine [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Creatinine in blood serum, umol/L
  • Safety and Tolerability: blood test results - urea [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Urea in blood serum, mmol/L
  • Safety and Tolerability: blood test results - glucose [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Glucose in blood serum, mmol/L
  • Safety and Tolerability: blood test results - total bilirubin [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Total bilirubin in blood serum, umol/L
  • Safety and Tolerability: blood test results - direct bilirubin [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Direct bilirubin in blood serum, umol/L
  • Safety and Tolerability: blood test results - total cholesterol [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Total cholesterol in blood serum, mmol/L
  • Safety and Tolerability: blood test results - triglycerides [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    Triglycerides in blood serum, mmol/L
  • Safety and Tolerability: blood test results - alanine transaminase (ALT) [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    ALT in blood serum, U/L
  • Safety and Tolerability: blood test results - aspartate transaminase (AST) [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    AST in blood serum, U/L
  • Safety and Tolerability: blood test results - alkaline phosphatase (ALP) [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    ALP in blood serum, U/L
  • Safety and Tolerability: 12-lead electrocardiogram (ECG) - heart rate [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: heart rate (beats per minute)
  • Safety and Tolerability: 12-lead electrocardiogram (ECG) - PQ interval [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: PQ interval (ms)
  • Safety and Tolerability: 12-lead electrocardiogram (ECG) - QRS complex [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: QRS complex (ms)
  • Safety and Tolerability: 12-lead electrocardiogram (ECG) - corrected QT interval (QTc) [ Time Frame: Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) ]
    12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: QTc (ms)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacokinetics and Bioequivalence of Molnupiravir, 200 mg Capsules and Lagevrio, 200 mg Capsules in Healthy Volunteers
Official Title  ICMJE A Randomized, Open-label, Cross-over Adaptive Study of the Comparative Pharmacokinetics and Bioequivalence of the Drugs Molnupiravir, Capsules, 200 mg and Lagevrio, Capsules, 200 mg in Healthy Volunteers at Fasted Conditions
Brief Summary

The study aimed for:

  1. Comparative evaluation of the safety of the drug Molnupiravir, capsules, 200 mg (JSC "Valenta Pharm", Russia), and Lagevrio, capsules, 200 mg (Merck Sharp & Dohme (UK) Limited, UK), based on the analysis of adverse events (AEs);
  2. Comparative assessment of pharmacokinetic parameters and bioequivalence of the drug Molnupiravir, capsules, 200 mg (Valenta Pharm JSC, Russia), and Lagevrio, capsules, 200 mg (Merck Sharp & Dohme (UK) Limited, UK), in healthy volunteers in fasted conditions.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE
  • Viral Infection
  • COVID-19
Intervention  ICMJE Drug: Molnupiravir
A single dose of R or T drug in each of 2 periods of the study in fasted conditions
Study Arms  ICMJE
  • RT-sequence
    The volunteers will take 1 capsule (200 mg) of Lagevrio (R), 200 mg capsules (Merck Sharp & Dohme (UK) Limited, UK) in Period 1, and 1 capsule (200 mg) of Molnupiravir (T), 200 mg capsules (Valenta Pharm, Russia) in Period 2.
    Intervention: Drug: Molnupiravir
  • TR-sequence
    The volunteers will take 1 capsule (200 mg) of the drug Molnupiravir (T), capsules, 200 mg (Valenta Pharm JSC, Russia) in Period 1, and 1 capsule (200 mg) of the drug Lagevrio (R), capsules, 200 mg (Merck Sharp & Dohme (UK) Limited, UK) in Period 2.
    Intervention: Drug: Molnupiravir
Publications * Not Provided

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 6, 2022)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2023
Estimated Primary Completion Date December 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Presence of written consent of the volunteer to participate in the study in accordance with applicable law.
  2. Healthy male and female caucasian volunteers aged 18 to 45 years (inclusive).
  3. Verified diagnosis "healthy": no deviations from the reference values of the data of standard clinical, laboratory and instrumental methods of examination.
  4. Systolic blood pressure (SBP) in the range of 110-130 mmHg; diastolic blood pressure (DBP) is 60-85 mmHg).
  5. 60-90 bpm at rest for heart rate (HR).
  6. 16-20 breaths/min for respiratory rate (RR).
  7. 35.5 to 36.9°C for body temperature.
  8. Body mass index (BMI) within the range of 18.5 ≤ BMI ≤ 30 kg/m2 with a body weight not less than 45 kg for female and not less than 55 kg for male volunteers.
  9. The consent of the volunteer (including the partner) to use adequate methods of contraception during the study and 30 days after its completion; for female volunteers - negative blood/urine test result for β-chorionic gonadotropin.
  10. Volunteers must behave adequately, coherent speech must be observed.

Exclusion Criteria:

  1. A history of allergy;
  2. A history of drug intolerance to the active and/or excipients in the study drugs;
  3. Chronic diseases of the kidneys, liver, gastrointestinal tract (GIT), cardiovascular, lymphatic, respiratory, nervous, endocrine, musculoskeletal, genitourinary and immune systems, as well as skin, blood and vision;
  4. History of gastrointestinal surgery (except appendectomy at least 1 year prior to screening);
  5. Diseases/conditions that in the opinion of the investigator may affect the absorption, distribution, metabolism or excretion of the study drugs (drugs);
  6. Acute infectious disease less than 4 weeks prior to screening;
  7. Taking medications that significantly affect hemodynamics and medications that affect liver function (barbiturates, omeprazole, cimetidine, etc.) less than 2 months prior to screening;
  8. Regularly taking a medicines less than 2 weeks before screening and taking a single medicine less than 7 days before screening;
  9. Donating blood or plasma less than 3 months before screening;
  10. Use of hormonal contraceptives (in women) less than 2 months before screening;
  11. The use of depot injections of any drug less than 3 months before screening;
  12. Pregnancy or lactation; positive blood/urine β-CGH test for women with preserved reproductive potential;
  13. Women of preserved reproductive potential with a history of unprotected intercourse within 30 days prior to study drug administration with an unsterilized partner;
  14. Participation in another clinical trial less than 3 months prior to screening or concurrently with the present study;
  15. Taking more than 10 units of alcohol (1 unit of alcohol is equivalent to 330 mL of beer, 150 mL of wine or 40 mL of spirits) in the week in the last month before inclusion in the study or anamnestic evidence of alcoholism, drug addiction, drug abuse;
  16. Smoking more than 10 cigarettes per day currently, or a history of smoking the specified number of cigarettes during the 6 months prior to screening; disagreement to abstain from smoking for the duration of the hospital stay;
  17. Positive blood tests for antibodies to human immunodeficiency virus (HIV) 1 and 2, antibodies to Treponema pallidum antigens, hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus antigens, rapid tests of biomaterial (nasopharyngeal and/or oropharyngeal swab) for Severe Acute Respiratory Syndrome Coronavirus 2 antigen (SARS-CoV-2), Coronavirus Disease 2019 (COVID-19);
  18. Clinically significant abnormalities on the electrocardiogram (ECG);
  19. Positive urinalysis for narcotics and potent drugs;
  20. Positive test for the content of alcohol vapor in exhaled air.
  21. Scheduling an inpatient stay during the study period, for any reason other than hospitalization required by this protocol.
  22. Inability to meet the requirements of the protocol, perform the procedures prescribed in the protocol, follow the diet, activity regimen.
  23. Other conditions that, in the opinion of the Investigator, preclude inclusion of the volunteer in the study or may result in early withdrawal of the volunteer from the study, including fasting or a special diet (e.g. vegetarian, vegan, limited table salt) or a special lifestyle (night work, extreme physical activity).

Withdrawal criteria:

  1. A volunteer withdraws from further participation in the study;
  2. Failure of the volunteer to comply with the rules of participation in the study (skipping study procedures, independent use of drugs prohibited in the study, violation of dietary and lifestyle restrictions, etc.);
  3. Occurrence of causes/occurrence during the study of situations that threaten the safety of the volunteer (e.g., hypersensitivity reactions, etc.);
  4. Volunteers selected for the study in violation of the inclusion/inclusion criteria;
  5. Volunteer's development of severe adverse event during the study;
  6. Missing 2 or more consecutive blood samples or 3 or more blood samples during the same Study Period.
  7. Occurrence of vomiting/diarrhea within 6 hours of study drug administration;
  8. Positive urine test for narcotics and drugs;
  9. Positive breath alcohol vapor test.
  10. Positive pregnancy test in women;
  11. Positive test for COVID-19;
  12. The occurrence in the course of the study of other reasons that prevent the study according to the protocol.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Listed Location Countries  ICMJE Russian Federation
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05412173
Other Study ID Numbers  ICMJE MOL-05-02-2021
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Current Responsible Party Valenta Pharm JSC
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Valenta Pharm JSC
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Valenta Pharm JSC
Verification Date June 2022

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