COVID-19
Conditions
Keywords
Favipiravir, Areplivir, COVID-19, SARS-CoV-2, 2019-nCoV
Brief summary
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.
Detailed description
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.
Interventions
DRUGFavipiravir
200 mg coated tablets
DRUGStandard 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.
Sponsors
Promomed, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Signing and dating of the Informed Consent Form of the Patient Information Leaflet (PIL) by patients. 2. Men and women aged 18 to 80 years inclusive at the time of signing the Informed Consent Form in PIL. 3. No difficulty with oral medication (e.g. swallowing disorder). 4. 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. 5. Patient should be hospitalized no more than 48 hours before the start of the study therapy. 6. Positive PCR result for presence of SARS-CoV-2 RNA at screening phase (results obtained within 7 days prior to screening are appropriate). 7. 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
1. Hypersensitivity to favipiravir and/or other components of the study drug. 2. Impossibility of CT procedure (for example, gypsum dressing or metal structures in the field of imaging). 3. The need to use drugs from the list of prohibited therapy. 4. Need for treatment in the intensive care unit. 5. Impaired liver function (AST and/or ALT ≥ 2 UNL and/or total bilirubin ≥ 1.5 UNL) at the time of screening. 6. Impaired kidney function (creatinine clearance according to Cockcroft-Gault formula less than 45 ml/min) at the time of screening. 7. Positive testing for HIV, syphilis, hepatitis B and/or C. 8. Chronic heart failure FC III-IV according to New York Heart Association (NYHA) functional classification. 9. Malabsorption syndrome or other clinically significant gastrointestinal disease that may affect absorption of the study drug (non-correctable vomiting, diarrhea, ulcerative colitis, and others). 10. Malignancies in the past medical history. 11. Alcohol, pharmacological and/or drug addiction in the past medical history and/or at the time of screening. 12. Schizophrenia, schizoaffective disorder, bipolar disorder, or other history of mental pathology or suspicion of their presence at the time of screening. 13. Severe, decompensated or unstable somatic diseases (any disease or condition that threaten the patient's life or impair the patient's prognosis, and also make it impossible for him/her to participate in the clinical study). 14. Any history data that the investigating physician believes could lead to complication in the interpretation of the study results or create an additional risk to the patient as a result of his/her participation in the study. 15. Patient's unwillingness or inability to comply with procedures of the Study Protocol (in the opinion of physician investigator). 16. Pregnant or nursing women or women planning pregnancy. 17. Participation in another clinical study for 3 months prior to inclusion in the study. 18. Other conditions that, according to the physician investigator, prevent the patient from being included in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinical Improvement | 28 days | Time (in days) to improvement in clinical status by WHO categorical ordinal scale of clinical status improvement. |
| Rate of Clinical Status Improvement | By Visit 3, approximately 10 days | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Level of Lung Damage According to CT | Days 15, 21, 28 | 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) |
| Rate of Transfer to the Intensive Care Unit | 28 Days | Percentage of patients transferred to intensive care unit (% of patients). |
| Rate of Viral Elimination by Day 10 | 10 days | Percentage of patients with elimination (clearance) of COVID-19 according to PCR data by day 10 (negative PCR results). |
| Rate of the Use of Mechanical Ventilation | 28 Days | Percentage of cases with mechanical lung ventilation (% of patients) |
| Mortality | 28 Days | Incidence of fatal cases (% of patients) |
| Rate of the Use of Non-invasive Lung Ventilation | 28 Days | Percentage of cases with non-invasive lung ventilation (% of patients). |
| Time Before the End of Fever | 28 days | Time (in days) before the end of fever (body temperature \< 37.2 ° C for 3 consecutive days without antipyretic medication). |
Countries
Russia
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 100 |
| 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. | 100 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | The need for prohibited therapy | 2 | 0 |
Baseline characteristics
| Characteristic | Standard of Care | Total | Favipiravir (Areplivir) |
|---|---|---|---|
| Age, Continuous | 49.98 years STANDARD_DEVIATION 13.06 | 49.68 years STANDARD_DEVIATION 13.09 | 49.38 years STANDARD_DEVIATION 13.18 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Russia | 100 participants | 200 participants | 100 participants |
| Sex: Female, Male Female | 54 Participants | 103 Participants | 49 Participants |
| Sex: Female, Male Male | 46 Participants | 97 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 100 | 0 / 100 |
| other Total, other adverse events | 25 / 100 | 28 / 100 |
| serious Total, serious adverse events | 3 / 100 | 0 / 100 |
Outcome results
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
Time frame: By Visit 3, approximately 10 days
Population: Intent-tо-treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Favipiravir (Areplivir) | Rate of Clinical Status Improvement | 27 Participants |
| Standard of Care | Rate of Clinical Status Improvement | 15 Participants |
Comparison: A comparative analysis of the rate of clinical status improvement by 2 or more categories. The difference in percentages between the AREPLIVIR arm and the standard therapy arm (pa-pb)p-value: 0.037295% CI: [-0.0004, 0.2367]Chi-squared
Primary
Time to Clinical Improvement
Time (in days) to improvement in clinical status by WHO categorical ordinal scale of clinical status improvement.
Time frame: 28 days
Population: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Favipiravir (Areplivir) | Time to Clinical Improvement | 8 days |
| Standard of Care | Time to Clinical Improvement | 12 days |
Comparison: Comparative analysis of time to clinical status improvement by categorical ordinal clinical improvement scale between the AREPLIVIR arm and the standard therapy armp-value: <0.0001Log Rank
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)
Time frame: Days 15, 21, 28
Population: 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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Favipiravir (Areplivir) | Change in the Level of Lung Damage According to CT | 60 Participants |
| Standard of Care | Change in the Level of Lung Damage According to CT | 40 Participants |
p-value: 0.1953Chi-squared
Secondary
Mortality
Incidence of fatal cases (% of patients)
Time frame: 28 Days
Population: the number of patients who died
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Favipiravir (Areplivir) | Mortality | 0 Participants |
| Standard of Care | Mortality | 0 Participants |
Secondary
Rate of the Use of Mechanical Ventilation
Percentage of cases with mechanical lung ventilation (% of patients)
Time frame: 28 Days
Population: the number of patients who required mechanical lung ventilation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Favipiravir (Areplivir) | Rate of the Use of Mechanical Ventilation | 0 Participants |
| Standard of Care | Rate of the Use of Mechanical Ventilation | 0 Participants |
Secondary
Rate of the Use of Non-invasive Lung Ventilation
Percentage of cases with non-invasive lung ventilation (% of patients).
Time frame: 28 Days
Population: the number of patients who required non-invasive lung ventilation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Favipiravir (Areplivir) | Rate of the Use of Non-invasive Lung Ventilation | 0 Participants |
| Standard of Care | Rate of the Use of Non-invasive Lung Ventilation | 0 Participants |
Secondary
Rate of Transfer to the Intensive Care Unit
Percentage of patients transferred to intensive care unit (% of patients).
Time frame: 28 Days
Population: the number of patients who required transfer to the intensive care unit
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Favipiravir (Areplivir) | Rate of Transfer to the Intensive Care Unit | 0 Participants |
| Standard of Care | Rate of Transfer to the Intensive Care Unit | 0 Participants |
p-value: 0.4975Chi-squared
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).
Time frame: 10 days
Population: 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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Favipiravir (Areplivir) | Rate of Viral Elimination by Day 10 | 98 Participants |
| Standard of Care | Rate of Viral Elimination by Day 10 | 79 Participants |
p-value: 0.00016Chi-squared
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).
Time frame: 28 days
Population: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Favipiravir (Areplivir) | Time Before the End of Fever | 4 days |
| Standard of Care | Time Before the End of Fever | 5 days |
p-value: 0.052Log Rank
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)
Time frame: 10 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Favipiravir (Areplivir) | Amount of Patients Without Any Clinical Signs of Disease by the Completion of Therapy (Category 0 According to a WHO Categorical Ordinal Scale) | 44 Participants |
| Standard of Care | Amount of Patients Without Any Clinical Signs of Disease by the Completion of Therapy (Category 0 According to a WHO Categorical Ordinal Scale) | 10 Participants |
Post Hoc
A Number of Patients With Fever Reduction Below 37.2 ° C by the 3rd Day of Therapy
Time frame: 3 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Favipiravir (Areplivir) | A Number of Patients With Fever Reduction Below 37.2 ° C by the 3rd Day of Therapy | 60 Participants |
| Standard of Care | A Number of Patients With Fever Reduction Below 37.2 ° C by the 3rd Day of Therapy | 37 Participants |
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)
Time frame: 10 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Favipiravir (Areplivir) | The Number of Patients Achieved a Category Lower Than or Equal to 2 on the WHO Clinical Improvement Scale (They Were Discharged From Hospital) | 90 Participants |
| Standard of Care | The Number of Patients Achieved a Category Lower Than or Equal to 2 on the WHO Clinical Improvement Scale (They Were Discharged From Hospital) | 67 Participants |