Clinical trial NCT04434248: An Adaptive Study of Favipiravir Compared to Standard of Care in Hospitalized Patients With COVID-19
Official title: An Adaptive, Multicenter, Randomized, Open-label, Comparative Clinical Study to Assess Efficacy and Safety of Favipiravir in Hospitalized Patients With COVID-19
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: COVID-19
Keywords: SARS-CoV-2
2019-nCoV
Lead sponsor: Chromis LLC
Sponsor class: INDUSTRY
Collaborators: name: Chemical Diversity Research Institute
First posted: 2020-06-16
Enrollment: 330
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This is an adaptive, multicenter, open-label, randomized clinical study of Favipiravir versus standard of care (SOC) in hospitalized patients with moderate to severe COVID-19 pneumonia.
Primary purpose: TREATMENT

Brief summary: The study is Phase II/III and consists of pilot and pivotal stages. The objective of the pilot stage is to conduct a preliminary assessment of the efficacy and safety of Favipiravir, and to select the optimal dosing regimen to study during the pivotal stage. The objective of the pivotal stage is to assess the efficacy and safety of Favipiravir compared with the Standard of care (SOC) in hospitalized patients with moderate to severe COVID-19 pneumonia.

Detailed description: At the pilot stage: upon signing the informed consent form and screening, 60 eligible patients with polymerase chain reaction (PCR) confirmed COVID-19 pneumonia are randomized at a 1:1:1 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 Favipiravir 1800 mg BID on Day 1 followed by 800 mg BID on Days 2-14 (1800/800 mg), or SOC.

At the pivotal stage: additional 270 eligible patients are randomized at a 1:1 ratio to receive either Favipiravir (the dose regimen depends of the subject's weight) or SOC.

Eligibility criteria: Inclusion Criteria:

1. Signed Patient Information Sheet and Informed Consent form to participate in the study.
2. Men and women aged 18 years and older.
3. Patients hospitalized with a diagnosis of COVID-19.
4. The diagnosis of COVID-19 was confirmed by positive reverse transcription polymerase chain reaction (RT-PCR) test for SARS-CoV-2, performed no earlier than 7 days before hospitalization or at screening.
5. Moderate severity of COVID-19 with pneumonia with at least 1 of the following symptoms:

   * Fever above 38 °C;
   * Cough;
   * Shortness of breath during physical exertion;
   * C reactive protein (CRP) of blood serum \> 10 mg/l;
   * SpO2 \< 95%
6. The capability of oral drug administration.
7. The patients' consent to use adequate contraception methods during the study (condom with spermicide) and for 3 months following completion.

Exclusion Criteria:

1. Severe type of disease, with at least one of the following criteria:

   * Frequency of breath \> 35 per minute, which does not decrease after the body temperature drops to normal or subfebrile values;
   * Blood oxygen saturation (SpO2) \< 90% at rest;
   * Partial pressure of oxygen in arterial blood (PaO2) \< 60 mm Hg;
   * Oxygenation index (RaO2/FiO2) ≤ 200 mm Hg;
   * Partial pressure of CO2 in arterial blood (PaCO2) \< 60 mm Hg;
   * Septic shock.
2. Patients treated with lopinavir/ritonavir, ribavirin, arbidol, chloroquine, hydroxychloroquine, mefloquine, favipiravir within 7 days prior to screening.
3. Severe cardiovascular diseases currently or 6 months prior to randomization, including: New York Heart Association (NYHA) Class III or IV chronic heart failure, clinically significant ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation), unstable angina, myocardial infarction, heart and coronary vessel surgery, significant valvular heart disease, uncontrolled arterial hypertension with systolic blood pressure \> 180 mm Hg and diastolic blood pressure \> 110 mm Hg, pulmonary embolism or deep vein thrombosis.
4. Severe chronic renal impairment (GFR \< 30 ml / min) or continuous renal replacement therapy, hemodialysis or peritoneal dialysis.
5. A history of cirrhosis or an increase in alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) \> 5 times × upper limit of normal (ULN).
6. Severe diseases of the central nervous system, including seizures in history or conditions that may lead to their development; stroke or transient ischemic attack within 12 months prior to screening; head injuries or loss of consciousness within 12 months prior to screening; a brain tumor.
7. Significant uncontrolled concomitant disease, e.g. neurological, renal, hepatic, endocrinological or gastrointestinal disorder which according to the Investigator, could prevent the patient from participating in the study
8. Malignancies that require chemotherapy within 6 months prior to screening.
9. Known HIV infection
10. Hypersensitivity to any component of the study drug.
11. Participation in other clinical studies or taking other study drugs within 28 days prior to screening.
12. Pregnant or lactating women or women planning to get pregnant during the clinical study; women of child-bearing potential (including non-sterilized by surgical means and during the post-menopause period less than 2 years) who do not use adequate contraception methods.
13. Inability to read or write, unwillingness to understand and follow procedures of study protocol, as well as any other concomitant medical or serious mental conditions that make the patient unfit to participate in the study, limit the legality of obtaining informed consent or can affect patient's ability to participate in the study.

Primary outcomes:
measure: Rate of viral elimination by Day 10 [pilot stage, dose selection]
timeFrame: 10 Days
measure: Time to viral elimination [pivotal stage]
timeFrame: 28 Days
measure: Time to clinical improvement [pivotal stage]
timeFrame: 28 Days
Secondary outcomes:
measure: Rate of viral elimination
timeFrame: Days 3, 5, 7, 9, and 11
measure: Time to normalization of clinical symptoms
timeFrame: 28 Days
measure: Duration of oxygen therapy
timeFrame: 28 Days
measure: Change in the level of lung damage according to CT
timeFrame: Days 15, 22, and 29
measure: Rate of transfer to the intensive care unit
timeFrame: 28 days
measure: Rate of the use of non-invasive lung ventilation
timeFrame: 28 days
measure: Rate of the use of mechanical ventilation
timeFrame: 28 days
measure: Mortality
timeFrame: 28 days
measure: Peak plasma concentration (Cmax)
timeFrame: Day 1
measure: Time to peak plasma concentration (Tmax)
timeFrame: Day 1
measure: Area under the plasma concentration versus time curve (AUC0-t)
timeFrame: 10 days
measure: Trough plasma concentration (Ctrough)
timeFrame: 10 days
Other outcomes:
Locations:
city: Makhachkala
country: Russian Federation
facility: Republican Clinical Hospital
city: Moscow
country: Russian Federation
facility: "K+31" Clinic
city: Moscow
country: Russian Federation
facility: "Khaven" Llc
city: Moscow
country: Russian Federation
facility: Central Clinical Hospital with Polyclinic
city: Moscow
country: Russian Federation
facility: Central Research Institute of Epidemiology
city: Moscow
country: Russian Federation
facility: City Clinical Hospital n.a. O.M. Filatov
city: Moscow
country: Russian Federation
facility: City Clinical Hospital named after S.S. Yudin
city: Moscow
country: Russian Federation
facility: City Clinical Hospital No. 24
city: Moscow
country: Russian Federation
facility: City Clinical Hospital No. 51
city: Moscow
country: Russian Federation
facility: First Moscow State Medical University n.a. I.M. Sechenov
city: Moscow
country: Russian Federation
facility: Moscow State University n.a. M. V. Lomonosov
city: Moscow
country: Russian Federation
facility: National Medical and Surgical Center named after N.I. Pirogov
city: Nizhny Novgorod
country: Russian Federation
facility: City Hospital № 33 of the Leninsky region of Nizhny Novgorod
city: Nizhny Novgorod
country: Russian Federation
facility: Infectious clinical hospital No.2 of Nizhny Novgorod
city: Ryazan
country: Russian Federation
facility: Ryazan State Medical University named after I.P. Pavlov
city: Saint Petersburg
country: Russian Federation
facility: Military Medical Academy named after S.M. Kirova
city: Saratov
country: Russian Federation
facility: Saratov State Medical University named after V.I. Razumovsky
city: Smolensk
country: Russian Federation
facility: Clinical hospital No.1
city: Tver
country: Russian Federation
facility: Regional Clinic Hospital
city: Ufa
country: Russian Federation
facility: Bashkir State Medical University
city: Yakutsk
country: Russian Federation
facility: Yakutsk City Clinical Hospital
city: Yaroslavl
country: Russian Federation
facility: Yaroslavl Regional Clinical Hospital for War Veterans
Study officials:
affiliation: Moscow State University n.a. M.V. Lomonosov
name: Elena Pavlikova, MD,PhD,Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Central Clinical Hospital with Polyclinic
name: Nikita Lomakin, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ivashchenko AA, Dmitriev KA, Vostokova NV, Azarova VN, Blinow AA, Egorova AN, Gordeev IG, Ilin AP, Karapetian RN, Kravchenko DV, Lomakin NV, Merkulova EA, Papazova NA, Pavlikova EP, Savchuk NP, Simakina EN, Sitdekov TA, Smolyarchuk EA, Tikhomolova EG, Yakubova EV, Ivachtchenko AV. AVIFAVIR for Treatment of Patients With Moderate Coronavirus Disease 2019 (COVID-19): Interim Results of a Phase II/III Multicenter Randomized Clinical Trial. Clin Infect Dis. 2021 Aug 2;73(3):531-534. doi: 10.1093/cid/ciaa1176.