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This is open-labe randomized multicenter comparative Phase III study conducted in 5 medical facilities. The objective of the study is to assess the efficacy and safety of Favipiravir compared with the Standard of care (SOC) in hospitalized patients with moderate COVID-19 pneumonia.
Upon signing the informed consent form and screening, 200 eligible patients with polymerase chain reaction (PCR) confirmed COVID-19 are randomized at a 1:1 ratio to receive either Favipiravir 1600 mg twice a day (BID) on Day 1 followed by 600 mg BID on Days 2-14 (1600/600 mg), or SOC. The course of treatment by Favipiravir is 14 days.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Favipiravir (Areplivir) | Experimental | Arm 1 (n=100) receives the study drug Areplivir film-coated tablets: on day 1 of therapy - 1600 mg (8 tablets) 2 times a day; on days 2-14 of treatment - 600 mg (3 tablets) 2 times a day. The drug is taken orally every 12 hours, swallowing whole tablet without chewing and washing down with a glass of water. The course of treatment is 14 days. The test drug is administered in hospital setting under supervision of a clinical investigator. The test drug is not handed over to the patient. |
|
| Standard of care | Active Comparator | Arm 2 (n=100) patients receive standard therapy prescribed in accordance with the recommended treatment regimens included in the Interim Guidelines for the prevention, diagnosis and treatment of new coronavirus infection (COVID-19) approved by the Russian Ministry of Health (but not Favipiravir) by decision of the investigator and taking into account the availability of drugs at the study site. Might include hydroxychloroquine (with or without azithromycin), chloroquine, lopinavir/ritonavir or other recommended schemes. Standard therapy is administered in hospital setting. Discharge of patients from a hospital is carried out in accordance with the local practice of the study site in compliance with the current sanitary and epidemiological regime. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Favipiravir | Drug | 200 mg coated tablets |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Rate of Clinical Status Improvement | Rate of clinical status improvement by categorical ordinal scale of clinical status improvement by 2 or more categories by Day 10 WHO Ordinal Scale for Clinical Improvement (WHO-OSCI), 0 - uninfected (There are no clinical and virological signs of infection), 8 - dead, higher scores mean a worse outcome | By Visit 3, approximately 10 days |
| Time to Clinical Improvement | Time (in days) to improvement in clinical status by WHO categorical ordinal scale of clinical status improvement. | 28 days |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of Viral Elimination by Day 10 | Percentage of patients with elimination (clearance) of COVID-19 according to PCR data by day 10 (negative PCR results). | 10 days |
| Time Before the End of Fever |
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Inclusion Criteria:
Signing and dating of the Informed Consent Form of the Patient Information Leaflet (PIL) by patients.
Men and women aged 18 to 80 years inclusive at the time of signing the Informed Consent Form in PIL.
No difficulty with oral medication (e.g. swallowing disorder).
Patient diagnosed with "Coronavirus infection caused by SARS-CoV-2 (confirmed)1, moderate severity form*" established in accordance with the Interim Guidelines of the Russian Ministry of Health for the prevention, diagnosis and treatment of a new coronavirus infection (COVID-19), (revision 6 of 28.04.2020).
*Moderate severity form: fever above 38 °C, BR above 22/min, dyspnea during exercise, pneumonia (confirmed by lung CT), SpO2 < 95%, C reactive protein (CRP) serum level above 10 mg/l.
Patient should be hospitalized no more than 48 hours before the start of the study therapy.
Positive PCR result for presence of SARS-CoV-2 RNA at screening phase (results obtained within 7 days prior to screening are appropriate).
Patient's consent to use reliable contraceptive methods throughout the study and within 1 month for women and 3 months for men after its completion. Persons eligible for participation in the study: - Women who have a negative pregnancy test and use the following contraceptives: barrier method (condom or occlusive cap (diaphragm or cervical/vaulted cap)) or double barrier method of contraception (condom or occlusive cap (diaphragm or cervical/vaulted cap) plus spermicide (foam/gel/film/cream/suppository)). Women incapable of childbearing may also participate in the study (with past history of: hysterectomy, tubal ligation, infertility, menopause more than 1 year) or men with preserved reproductive function who use barrier contraceptives, as well as men with infertility or vasectomy in the past medical history.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Dmitriy Pushkar | Moscow State Clinical Hospital №50 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| State Clinical Hospital №50 | Moscow | Russia | ||||
| Regional Clinic Hospital of Ryazan |
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The study will randomize 200 patients. Given the possible non-inclusion of patients at the screening stage, the maximum number of patients to sign the Informed Consent Form in the Patient Information Leaflet and to participate in screening can be no more than 210 people.
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| ID | Title | Description |
|---|---|---|
| FG000 | Favipiravir (Areplivir) | Arm 1 (n=100) receives the study drug Areplivir film-coated tablets: on day 1 of therapy - 1600 mg (8 tablets) 2 times a day; on days 2-14 of treatment - 600 mg (3 tablets) 2 times a day. The drug is taken orally every 12 hours, swallowing whole tablet without chewing and washing down with a glass of water. The course of treatment is 14 days. The test drug is administered in hospital setting under supervision of a clinical investigator. The test drug is not handed over to the patient. Favipiravir: 200 mg coated tablets |
| FG001 | Standard of Care | Arm 2 (n=100) patients receive standard therapy prescribed in accordance with the recommended treatment regimens included in the Interim Guidelines for the prevention, diagnosis and treatment of new coronavirus infection (COVID-19) approved by the Russian Ministry of Health (but not Favipiravir) by decision of the investigator and taking into account the availability of drugs at the study site. Might include hydroxychloroquine (with or without azithromycin), chloroquine, lopinavir/ritonavir or other recommended schemes. Standard therapy is administered in hospital setting. Discharge of patients from a hospital is carried out in accordance with the local practice of the study site in compliance with the current sanitary and epidemiological regime. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Favipiravir (Areplivir) | Arm 1 (n=100) receives the study drug Areplivir film-coated tablets: on day 1 of therapy - 1600 mg (8 tablets) 2 times a day; on days 2-14 of treatment - 600 mg (3 tablets) 2 times a day. The drug is taken orally every 12 hours, swallowing whole tablet without chewing and washing down with a glass of water. The course of treatment is 14 days. The test drug is administered in hospital setting under supervision of a clinical investigator. The test drug is not handed over to the patient. Favipiravir: 200 mg coated tablets |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Rate of Clinical Status Improvement | Rate of clinical status improvement by categorical ordinal scale of clinical status improvement by 2 or more categories by Day 10 WHO Ordinal Scale for Clinical Improvement (WHO-OSCI), 0 - uninfected (There are no clinical and virological signs of infection), 8 - dead, higher scores mean a worse outcome | Intent-tо-treat population | Posted | Count of Participants | Participants | By Visit 3, approximately 10 days |
|
Safety assessment was carried out: up to 30 days for each patient and during the entire period of the study as a whole. Safety population: patients who have received at least one dose of the study drug and for whom there is an assessment of condition and/or AE for at least one time point after administration.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Favipiravir (Areplivir) | Arm 1 (n=100) receives the study drug Areplivir film-coated tablets: on day 1 of therapy - 1600 mg (8 tablets) 2 times a day; on days 2-14 of treatment - 600 mg (3 tablets) 2 times a day. The drug is taken orally every 12 hours, swallowing whole tablet without chewing and washing down with a glass of water. The course of treatment is 14 days. The test drug is administered in hospital setting under supervision of a clinical investigator. The test drug is not handed over to the patient. Favipiravir: 200 mg coated tablets |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment | According to investigators, the causal relationship with the study drug was estimated as "unrelated", SAE was associated with the presence of concomitant diseases, i.e. type 2 diabetes mellitus, obesity, and hyperthyroidism. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Increased alanine aminotransferase activity | Hepatobiliary disorders | MedDRA | Systematic Assessment | According to investigators, the causal relationship with the study drug was estimated as "unrelated" in 22.2% |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Academician Dmitry Pushkar | A.I. Yevdokimov Moscow State University of Medicine and Dentistry of the Ministry of Healthcare of the Russian Federation | +7495-609-67-00 | dmitry.pushkar@gmail.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 10, 2020 | Oct 11, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| C462182 | favipiravir |
| D059039 | Standard of Care |
| ID | Term |
|---|---|
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |
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| Standard of care | Drug | Drug: Standard of Care Standard of Care will be prescribed in accordance with the recommended treatment regimens presented in the Russian guidelines for the prevention, diagnosis and treatment of COVID-19 according to the decision of the Investigator. Other Name: Hydroxychloroquine, chloroquine, lopinavir/ritonavir, etc. |
|
Time (in days) before the end of fever (body temperature < 37.2 ° C for 3 consecutive days without antipyretic medication).
| 28 days |
| Change in the Level of Lung Damage According to CT | Assessment of lung injury (degree of damage by "empirical" visual scale and % of patients) according to CT data comparing to baseline. The number of patients in whom by the end of therapy there was an improvement in the condition of the lungs (a decrease in the volume of the lesion according to CT) | Days 15, 21, 28 |
| Rate of Transfer to the Intensive Care Unit | Percentage of patients transferred to intensive care unit (% of patients). | 28 Days |
| Rate of the Use of Non-invasive Lung Ventilation | Percentage of cases with non-invasive lung ventilation (% of patients). | 28 Days |
| Rate of the Use of Mechanical Ventilation | Percentage of cases with mechanical lung ventilation (% of patients) | 28 Days |
| Mortality | Incidence of fatal cases (% of patients) | 28 Days |
| Ryazan |
| Russia |
| City Hospital N40 of Kurortny District | Saint Petersburg | Russia |
| Medical institute Ogarev Mordovia State university | Saransk | Russia |
| Smolensk clinical hospital №1 | Smolensk | Russia |
| Protocol Violation |
|
| BG001 | Standard of Care | Arm 2 (n=100) patients receive standard therapy prescribed in accordance with the recommended treatment regimens included in the Interim Guidelines for the prevention, diagnosis and treatment of new coronavirus infection (COVID-19) approved by the Russian Ministry of Health (but not Favipiravir) by decision of the investigator and taking into account the availability of drugs at the study site. Might include hydroxychloroquine (with or without azithromycin), chloroquine, lopinavir/ritonavir or other recommended schemes. Standard therapy is administered in hospital setting. Discharge of patients from a hospital is carried out in accordance with the local practice of the study site in compliance with the current sanitary and epidemiological regime. Standard of care: Drug: Standard of Care Standard of Care will be prescribed in accordance with the recommended treatment regimens presented in the Russian guidelines for the prevention, diagnosis and treatment of COVID-19 according to the decision of the Investigator. Other Name: Hydroxychloroquine, chloroquine, lopinavir/ritonavir, etc. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Standard of Care | Arm 2 (n=100) patients receive standard therapy prescribed in accordance with the recommended treatment regimens included in the Interim Guidelines for the prevention, diagnosis and treatment of new coronavirus infection (COVID-19) approved by the Russian Ministry of Health (but not Favipiravir) by decision of the investigator and taking into account the availability of drugs at the study site. Might include hydroxychloroquine (with or without azithromycin), chloroquine, lopinavir/ritonavir or other recommended schemes. Standard therapy is administered in hospital setting. Discharge of patients from a hospital is carried out in accordance with the local practice of the study site in compliance with the current sanitary and epidemiological regime. |
|
|
|
| Primary | Time to Clinical Improvement | Time (in days) to improvement in clinical status by WHO categorical ordinal scale of clinical status improvement. | patients who received at least one dose of the drug in the study and for whom there is data for at least one visit after the baseline | Posted | Median | Inter-Quartile Range | days | 28 days |
|
|
|
|
| Secondary | Rate of Viral Elimination by Day 10 | Percentage of patients with elimination (clearance) of COVID-19 according to PCR data by day 10 (negative PCR results). | patients who received at least one dose of the drug in the study and for whom there is data for at least one visit after the baseline | Posted | Count of Participants | Participants | 10 days |
|
|
|
|
| Secondary | Time Before the End of Fever | Time (in days) before the end of fever (body temperature < 37.2 ° C for 3 consecutive days without antipyretic medication). | patients who received at least one dose of the drug in the study and for whom there is data for at least one visit after the baseline | Posted | Median | Inter-Quartile Range | days | 28 days |
|
|
|
|
| Secondary | Change in the Level of Lung Damage According to CT | Assessment of lung injury (degree of damage by "empirical" visual scale and % of patients) according to CT data comparing to baseline. The number of patients in whom by the end of therapy there was an improvement in the condition of the lungs (a decrease in the volume of the lesion according to CT) | The number of patients in whom by the end of therapy there was an improvement in the condition of the lungs (a decrease in the volume of the lesion according to CT) | Posted | Count of Participants | Participants | Days 15, 21, 28 |
|
|
|
|
| Secondary | Rate of Transfer to the Intensive Care Unit | Percentage of patients transferred to intensive care unit (% of patients). | the number of patients who required transfer to the intensive care unit | Posted | Count of Participants | Participants | 28 Days |
|
|
|
|
| Secondary | Rate of the Use of Non-invasive Lung Ventilation | Percentage of cases with non-invasive lung ventilation (% of patients). | the number of patients who required non-invasive lung ventilation | Posted | Count of Participants | Participants | 28 Days |
|
|
|
| Secondary | Rate of the Use of Mechanical Ventilation | Percentage of cases with mechanical lung ventilation (% of patients) | the number of patients who required mechanical lung ventilation | Posted | Count of Participants | Participants | 28 Days |
|
|
|
| Secondary | Mortality | Incidence of fatal cases (% of patients) | the number of patients who died | Posted | Count of Participants | Participants | 28 Days |
|
|
|
| Post-Hoc | Amount of Patients Without Any Clinical Signs of Disease by the Completion of Therapy (Category 0 According to a WHO Categorical Ordinal Scale) | Posted | Count of Participants | Participants | 10 days |
|
|
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| Post-Hoc | The Number of Patients Achieved a Category Lower Than or Equal to 2 on the WHO Clinical Improvement Scale (They Were Discharged From Hospital) | Posted | Count of Participants | Participants | 10 days |
|
|
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| Post-Hoc | A Number of Patients With Fever Reduction Below 37.2 ° C by the 3rd Day of Therapy | Posted | Count of Participants | Participants | 3 days |
|
|
|
| 0 |
| 100 |
| 3 |
| 100 |
| 25 |
| 100 |
| EG001 | Standard of Care | Arm 2 (n=100) patients receive standard therapy prescribed in accordance with the recommended treatment regimens included in the Interim Guidelines for the prevention, diagnosis and treatment of new coronavirus infection (COVID-19) approved by the Russian Ministry of Health (but not Favipiravir) by decision of the investigator and taking into account the availability of drugs at the study site. Might include hydroxychloroquine (with or without azithromycin), chloroquine, lopinavir/ritonavir or other recommended schemes. Standard therapy is administered in hospital setting. Discharge of patients from a hospital is carried out in accordance with the local practice of the study site in compliance with the current sanitary and epidemiological regime. | 0 | 100 | 0 | 100 | 28 | 100 |
|
| Multiple organ failure syndrome | General disorders | MedDRA | Systematic Assessment | According to investigators, the causal relationship with the study drug was estimated as "unrelated", SAE was associated with the presence of concomitant diseases, i.e. type 2 diabetes mellitus, obesity, and hyperthyroidism. |
|
| Aortic valve stenosis | Cardiac disorders | MedDRA | Systematic Assessment | According to investigators, the causal relationship with the study drug was estimated as "doubtful", SAE was associated with the presence of concomitant diseases, i.e. type 2 diabetes mellitus, obesity, and hyperthyroidism. |
|
|
| Increased aspartate aminotransferase activity | Hepatobiliary disorders | MedDRA | Systematic Assessment | According to investigators, the causal relationship with the study drug / standard therapy was estimated as "unrelated" in 69.2% /61.5% |
|
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| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |