An Adaptive Study of Favipiravir Compared to Standard of Care in Hospitalized Patients With COVID-19

Phase 2

• Conditions: COVID-19
• Interventions: Drug: Standard of Care; Drug: Favipiravir

• Registration Number: NCT04434248
• Lead Sponsor: Chromis LLC

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.

Study Timeline

• Study Start: 2020-04-23
• Status Verified: 2020-06
• Study First Submitted: 2020-06-13
• Study First Submitted QC: 2020-06-15
• Last Update Submitted: 2020-06-15
• Study First Posted: 2020-06-16
• Last Update Posted: 2020-06-16
• Primary Completion: 2020-07
• Study Completion: 2020-07

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 330

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Standard of care (pilot stage)	Standard of Care	Based on approved clinical recommendations for treatment of COVID-19 in the Russian Federation (but not Favipiravir). Might include hydroxychloroquine, chloroquine, lopinavir/ritonavir or other recommended schemes.
Standard of care (pivotal stage)	Standard of Care	Based on approved clinical recommendations for treatment of COVID-19 in the Russian Federation (but not Favipiravir). Might include hydroxychloroquine, chloroquine, lopinavir/ritonavir or other recommended schemes.
Favipiravir, lower dose (pilot stage)	Favipiravir	1600mg BID on the 1st day followed by 600mg BID for 13 days
Favipiravir, higher dose (pilot stage)	Favipiravir	1800mg BID on the 1st day followed by 800mg BID for 13 days
Favipiravir, selected dose (pivotal stage)	Favipiravir	The dose will be selected based on pilot study results.

Primary Outcome Measures

Name	Time	Method
Rate of viral elimination by Day 10 [pilot stage, dose selection]	10 Days	Percent of patients with undetectable SARS-CoV-2 RNA level on Day 10
Time to viral elimination [pivotal stage]	28 Days	Median time to reach undetectable SARS-CoV-2 RNA level
Time to clinical improvement [pivotal stage]	28 Days	Median time reach clinical improvement (2 points of the Ordinal Scale for Clinical Improvement) or discharge from the hospital

Secondary Outcome Measures

Name	Time	Method
Duration of oxygen therapy	28 Days	Mean duration of oxygen therapy \[days\]
Rate of viral elimination	Days 3, 5, 7, 9, and 11	Percent of patients with undetectable SARS-CoV-2 RNA level
Rate of transfer to the intensive care unit	28 days	Percent of patients transferred to the intensive care unit \[% of patients\]
Area under the plasma concentration versus time curve (AUC0-t)	10 days	Determination of AUC0-t \[ng\*h/ml\]
Time to normalization of clinical symptoms	28 Days	Median time \[days\] to reach normal levels of clinical indicators (body temperature, SpO2, breathing rate)
Change in the level of lung damage according to CT	Days 15, 22, and 29	Change of lung damage level according to CT comparing to baseline \[% of patients\]
Rate of the use of non-invasive lung ventilation	28 days	Percent of patients undergoing non-invasive lung ventilation \[% of patients\]
Mortality	28 days	Percent of patients died within 28-days period \[% of patients\]
Time to peak plasma concentration (Tmax)	Day 1	Determination of Tmax \[h\]
Trough plasma concentration (Ctrough)	10 days	Determination of Ctrough \[ng/ml\]
Rate of the use of mechanical ventilation	28 days	Percent of patients undergoing mechanical ventilation \[% of patients\]
Peak plasma concentration (Cmax)	Day 1	Determination of Cmax \[ng/ml\]

Trial Locations

Locations (22)

Yakutsk City Clinical Hospital; 🇷🇺 Yakutsk, Russian Federation

Moscow State University n.a. M. V. Lomonosov; 🇷🇺 Moscow, Russian Federation

Infectious clinical hospital No.2 of Nizhny Novgorod; 🇷🇺 Nizhny Novgorod, Russian Federation

Clinical hospital No.1; 🇷🇺 Smolensk, Russian Federation

Bashkir State Medical University; 🇷🇺 Ufa, Russian Federation

Ryazan State Medical University named after I.P. Pavlov; 🇷🇺 Ryazan, Russian Federation

Military Medical Academy named after S.M. Kirova; 🇷🇺 Saint Petersburg, Russian Federation

Regional Clinic Hospital; 🇷🇺 Tver, Russian Federation

Saratov State Medical University named after V.I. Razumovsky; 🇷🇺 Saratov, Russian Federation

Yaroslavl Regional Clinical Hospital for War Veterans; 🇷🇺 Yaroslavl, Russian Federation

"K+31" Clinic; 🇷🇺 Moscow, Russian Federation

"Khaven" Llc; 🇷🇺 Moscow, Russian Federation

Republican Clinical Hospital; 🇷🇺 Makhachkala, Russian Federation

Central Clinical Hospital with Polyclinic; 🇷🇺 Moscow, Russian Federation

Central Research Institute of Epidemiology; 🇷🇺 Moscow, Russian Federation

City Clinical Hospital n.a. O.M. Filatov; 🇷🇺 Moscow, Russian Federation

City Clinical Hospital named after S.S. Yudin; 🇷🇺 Moscow, Russian Federation

City Clinical Hospital No. 51; 🇷🇺 Moscow, Russian Federation

City Clinical Hospital No. 24; 🇷🇺 Moscow, Russian Federation

First Moscow State Medical University n.a. I.M. Sechenov; 🇷🇺 Moscow, Russian Federation

City Hospital № 33 of the Leninsky region of Nizhny Novgorod; 🇷🇺 Nizhny Novgorod, Russian Federation

National Medical and Surgical Center named after N.I. Pirogov; 🇷🇺 Moscow, Russian Federation