Pharmacokinetics, Safety and Efficacy Study of GP30341 (GEROPHARM, Russia) in Healthy Volunteers and Outpatients With COVID-19

Study Overview
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Brief Summary
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Pharmacokinetics, safety and efficacy study of GP30341, 200 mg capsules (GEROPHARM LLC, Russia) in healthy volunteers and patients with novel coronavirus infection 2019 (COVID-19) with a high risk of adverse outcome

Detailed Description
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Multicenter open two-stage study of pharmacokinetics, safety and efficacy of GP30341, 200 mg capsules (GEROPHARM LLC, Russia) involving healthy volunteers and patients with novel coronavirus infection 2019 (COVID-19) with a high risk of adverse outcome. I stage: An open non-comparative study of pharmacokinetics and safety of GP30341 studied at different dosing regimens with an escalation of the daily dose in healthy volunteers. II stage: Open randomized study efficacy and safety of GP30341, 200 mg capsules with active control - comparison with standard therapy - in patients with COVID-19 infection with a high risk of adverse outcome.

Official Title
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Multicenter Open Two-stage Study of Pharmacokinetics, Safety and Efficacy of GP30341, 200 mg Capsules (GEROPHARM LLC, Russia) in Healthy Volunteers and Outpatients With Novel Coronavirus Infection 2019 With a High Risk of Adverse Outcome

Conditions
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Safety Issues, Pharmacokinetics, Efficacy

Intervention / Treatment
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* Drug: GP30341 capsules 200 mg
* Drug: Standard therapy


Participation Criteria
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Eligibility Criteria
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Stage 1 Inclusion Criteria: Signed informed consent to participate in the study. Males with a verified diagnosis healthy according to the data of standard clinical, laboratory and instrumental examination methods. Age 18-45 years old inclusive. Body mass index 18.5 - 30 kg/m2. Agree to use an adequate method of contraception (double barrier method) during the entire period of participation in the study and for 3 weeks after its completion. Consent to all restrictions imposed during the study. Citizenship of the Russian Federation. Exclusion Criteria: Burdened allergic history, drug intolerance. Hypersensitivity to heparin, molnupiravir and any of the excipients of the study drug. Any acute and chronic diseases, incl. but not limited to: diseases of the cardiovascular, bronchopulmonary, neuroendocrine systems, as well as diseases of the gastrointestinal tract (including diseases of the colon), liver, kidneys, blood; positive test results for hepatitis C (antibodies) or hepatitis B (surface antigen), HIV (antibodies to HIV-1/2), syphilis (antibodies to Treponema pallidum). Deviations from normal values of heart rate (60-89), SBP (90-130 mm Hg), DBP (60-89 mm Hg), NPV (12-20), body temperature (35.7 - 37.0 °C). ECG Deviations, according to a specialist, during screening. laboratory tests results deviations from the normal values. Hard-to-reach veins of the upper extremities, vein thrombosis, thrombophlebitis in a family history of close relatives, compromised veins due to frequent previous venipunctures. Surgical interventions on the gastrointestinal tract (with the exception of appendectomy) in history. Acute infectious diseases less than 4 weeks prior to screening. Presence of at least one of the epidemic signs: return from overseas travel 14 days prior to screening and no test results for SARS-CoV-2 RNA or SARS-CoV-2 antigen; close contact in the last 14 days prior to screening with a person under observation for COVID-19 who subsequently fell ill; close contact in the past 14 days prior to screening with individuals who have laboratory-confirmed case of COVID-19; Occupational contacts in the past 14 days prior to screening with individuals who have a suspected or confirmed case of COVID-I9. Regular intake of any medications, including vitamins, herbal preparations, and dietary supplements, less than 2 weeks before screening. Significant blood loss (more than 450 ml of blood or plasma) within 3 months prior to screening, due to, including, but not limited to, blood donation, blood loss during advanced surgery or trauma. Drinking alcohol in quantities exceeding 10 units per week (on average) (1 unit of alcohol is equivalent to 500 ml of beer, 200 ml of dry wine or 50 ml of strong alcoholic drinks) or anamnestic information about alcoholism, drug addiction, abuse of strong drugs. Positive test results for alcohol, drug use and the use of strong drugs. Nicotine addiction (regular tobacco use, including smoking of all types of electronic cigarettes, hookahs, snuff, etc. less than 6 months prior to screening). Participation in a clinical trial of any drugs (including experimental drugs) or experimental medical devices for 3 months or 5 half-lives prior to Screening, whichever is longer. Dehydration due to diarrhea, vomiting, or other cause within the last 24 hours prior to screening. Any diet (eg vegetarian, fasting, etc.) or lifestyle (including night work and extreme physical activity such as heavy lifting) that may interfere with the study. Taking drugs that have a pronounced effect on hemodynamics, liver function, etc. (barbiturates, omeprazole, cimetidine, etc.) less than 30 days before screening. Mental diseases, history of epilepsy, seizures. Volunteers who are obviously or likely, in the opinion of the investigator, unable to understand and evaluate the information on this study as part of the informed consent process, in particular regarding expected risks and possible discomfort. Stage2: Inclusion Criteria: Signed informed consent to participate in the study. Male and female patients aged ≥18 years at the time of providing informed consent. Laboratory confirmation of COVID-19 infection ≤5 days prior to randomization1, defined as a positive RT-PCR test for SARS-CoV-2 RNA and/or a positive antigen test for SARS-CoV-2 in a nasal swab. Clinical onset of COVID-19 infection (as ≥1 symptom consistent with COVID-19) ≤5 days prior to randomization. Presence of ≥1 symptom consistent with COVID-19 at time of randomization3. Mild to moderate COVID-19 infection with ≥1 risk factor for adverse outcome. WHO (World Health Organization) Clinical Progression Scale score ≥3 at screening 6. Consent and ability to take oral medications. Agree to use reliable contraceptive measures throughout the study and for 3 weeks after - Negative pregnancy test in women capable of childbearing. Consent and ability to comply with the Protocol's procedures, prohibitions and restrictions. Exclusion Criteria: Hypersensitivity or intolerance reactions to any of the components of the test drug or the proposed standard therapy drugs according to the anamnesis. Vaccination to prevent COVID-19 within 6 months prior to screening or planning vaccination during the study period. Vaccination with any vaccine within 4 weeks prior to screening. Use of drugs from the list of prohibited therapy (section 5.3.3 of the Study Protocol) in the anamnesis or their planned use during the study period. Past infection with COVID-19 within 6 months prior to screening. Current hospitalization or, in the opinion of the Investigator, expected hospitalization within 48 hours after randomization. Dysfunction of organs that affect the absorption and metabolism of the test drug, which include, but are not limited to the following: diseases of the gastrointestinal tract, which, in the opinion of the researcher, may interfere with the absorption of the contents of the capsules; Kidney Disease Outcomes Quality Initiative (KDOQI) stage 4 or 5 chronic kidney disease; Signs of significant uncontrolled comorbidity, such as disorders of the nervous, respiratory, cardiovascular, kidney, liver, endocrine, or gastrointestinal tract, that persist at the time of screening and, in the opinion of the Investigator, significantly increase the risk of adverse outcome and preclude participation patient in the study. Acute pancreatitis or exacerbation of chronic pancreatitis ≤3 months prior to randomization. Severe immunodeficiency states, which include, but are not limited to, the following: HIV infection, syphilis; chemotherapy within 5 weeks prior to screening; absolute number of neutrophils in blood <500/mm3; history of hematopoietic stem cell transplantation. Signs of severe or extremely severe COVID-19 infection at the time of screening and randomization. Heart rate less than 50 beats per minute at rest at screening. Platelet count <100,000/µl or platelet transfusion within 5 days prior to randomization12. Pregnancy or lactation in women. Alcoholism or alcohol consumption in excess of: for men: 14 units per week (on average); for women: 7 units per week (on average). Addiction and/or substance abuse. Participation in other clinical trials within 28 days prior to screening, or planned participation during the period of this study.

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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Accepts Healthy Volunteers

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
Interventional Model Description: two-stage study: 1 stage - two-period escalating dose study involved two sequential cohorts of 6 healthy volunteers. 2 stage - randomized comparative study with hypothesis of superior efficacy in parallel groups.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GP30341 capsules 200 mg<br>4 capsules containing 200 mg of molnupiravir p.o. twice a day during 5 days (daily dose 1600 mg) in combination with Standard therapy in accordance with the current version of the guidelines for the prevention, diagnosis and treatment of a new coronavirus infection 2019 (COVID-19). | Drug: GP30341 capsules 200 mg<br>* orall take of capsules twice a day<br>* Other names: molnupiravir;|
| Active Comparator: Standart therapy<br>Standard therapy in accordance with the current version of the guidelines for the prevention, diagnosis and treatment of a new coronavirus infection 2019 (COVID-19). | Drug: Standard therapy<br>* Standard medicines for treatment of a new coronavirus infection 2019 (COVID-19).<br>* Other names: COVID-19 therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-t | Total area under the curve concentration of the active metabolite of the active substance - time in the time interval from 0 (the moment of taking the drug) to the collection of the last blood sample with the determined concentration of the active substance at the time point t. | cohort N1 - 10 min, 10 min, 20 min, 30 min, 45 min, 1h, 1h 15 min, 1.5h, 2h, 2.5h, 4 h, 5h, 6h , 8h, 10h, 12h, 24h; Cohort N2 -10 min, 30 min, 1h, 2h, 12h, 12.5 h, 13 h, 14 h, 24 h, 36 h | 
| Cmax | maximum concentration of the active metabolite of the active substance in the blood plasma of volunteers during the observation period. | cohort N1 - 10 min, 10 min, 20 min, 30 min, 45 min, 1h, 1h 15 min, 1.5h, 2h, 2.5h, 4 h, 5h, 6h , 8h, 10h, 12h, 24h; Cohort N2 -10 min, 30 min, 1h, 2h, 12h, 12.5 h, 13 h, 14 h, 24 h, 36 h | 
| tmax | time to reach the maximum concentration (Cmax) of the active metabolite of the active substance in the blood plasma of volunteers. | cohort N1 - 10 min, 10 min, 20 min, 30 min, 45 min, 1h, 1h 15 min, 1.5h, 2h, 2.5h, 4 h, 5h, 6h , 8h, 10h, 12h, 24h; Cohort N2 -10 min, 30 min, 1h, 2h, 12h, 12.5 h, 13 h, 14 h, 24 h, 36 h | 
| t1/2 | half-life of the active metabolite of the active substance. | 0-24h | 
| λz | rate constant of elimination of the active metabolite of the active substance. | cohort N1 - 10 min, 10 min, 20 min, 30 min, 45 min, 1h, 1h 15 min, 1.5h, 2h, 2.5h, 4 h, 5h, 6h , 8h, 10h, 12h, 24h; Cohort N2 -10 min, 30 min, 1h, 2h, 12h, 12.5 h, 13 h, 14 h, 24 h, 36 h | 
| AUC0-∞ | total area under the curve concentration of the active metabolite of the active substance - time in the time interval from 0 (the moment of taking the drug) to infinity. | cohort N1 - 10 min, 10 min, 20 min, 30 min, 45 min, 1h, 1h 15 min, 1.5h, 2h, 2.5h, 4 h, 5h, 6h , 8h, 10h, 12h, 24h; Cohort N2 -10 min, 30 min, 1h, 2h, 12h, 12.5 h, 13 h, 14 h, 24 h, 36 h | 
| Frequency of COVID-19 progression on Day 14 | Frequency of COVID-19 progression to a more severe severity compared to baseline on Day 14 | day 14 from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients hospitalized or dying within 28±2 days of randomization. | Proportion of patients hospitalized or dying from any cause within 28±2 days of randomization. | 0-30 days from randomization | 
| Proportion of patients with a score of more than 3 on the WHO Clinical Progression Scale on Day of end of therapy, Day 10 and Day 14. | Proportion of patients with a score of more than 3 on the WHO (World Health Organization) Clinical Progression Scale on Day of end of therapy, Day 10 and Day 14. | 0-14 days from randomization | 
| Time to clinical improvement in the form of a persistent reduction in the number of symptoms characteristic of COVID-19 infection by one or more within 28 ± 2 days from randomization. | Time to clinical improvement in the form of a persistent reduction in the number of symptoms characteristic of COVID-19 infection by one or more within 28 ± 2 days from randomization. | 0-30 days from randomization | 
| Time to clinical progression in the form of (whichever is sooner) a persistent increase in the number of symptoms characteristic of COVID-19 infection by one or more, hospitalization or death from any cause within 28±2 days from randomization. | Time to clinical progression in the form of (whichever is sooner) a persistent increase in the number of symptoms characteristic of COVID-19 infection by one or more, hospitalization or death from any cause within 28±2 days from randomization. | 0-30 days from randomization | 
| Proportion of patients with a positive nasal swab test for SARS-CoV-2 on Days 3, Day of end of therapy, 10, 14, 28±2 from randomization. | roportion of patients with a positive nasal swab test for SARS-CoV-2 on Days 3, Day of end of therapy, 10, 14, 28±2 from randomization. | 0-30 days from randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Molnupiravir, COVID-19, SARS-CoV-2