Clinical Study To Evaluate The Performance And Safety Of Favipiravir in COVID-19

A Multi-center, Randomized, Double-blind, Placebo-controlled, Phase III Clinical Study Evaluating the Efficacy and Safety of Favipiravir in the Treatment of Patients With COVID-19-Moderate Type

This study evaluates treatment with Favipiravir combined with supportive care for adult patients with COVID-19-moderate type.

Study Overview

• Status: Unknown
• Conditions: COVID-19
• Intervention / Treatment: Drug: Favipiravir; Other: Placebo

Detailed Description

This is a double-blind, placebo controlled, multicenter study that evaluates the performance and safety of the Favipiravir combined with supportive care for adult patients with COVID-19-moderate type.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Milano, Italy, 20157
    • ASST Fatebenefratelli Sacco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Voluntarily participating in the clinical study; fully understanding and being fully informed of the study and having signed the Informed Consent Form (ICF); willingness and capability to complete all the study procedures;
2. Age 18-75 years (inclusive) at the time of signing ICF;

3. Being confirmed with COVID-19-Moderate type according to Competent Authority and Italian Ministry of Health guidelines and to the recommendations reported in Appendix 1 to the present protocol. Based on comprehensive analysis and judgement taking into account both the epidemiological history and clinical manifestations, the diagnosis is to be confirmed for suspected cases/clinically diagnosed cases with all of the following etiological evidences:

   • Positivity in RT-PCR 2019-nCov test on respiratory tract specimens;
   • High homology with known gene sequence of 2019-nCov in viral gene sequencing on respiratory tract specimens; Note: The above criterion would be subject to any update of the Competent Authority and Italian Ministry of Health guidelines and to the recommendations reported in Appendix 1 to the present protocol. In case any new etiologically detection methods/criteria or any new detectable specimens become available after confirmed diagnosis, the new methods or new specimens may or may not be used at the discretion of the investigator.

   Note: Sputum specimen is preferred for RT-PCR test of 2019-nCov nucleic acid; the specific type of respiratory tract specimen (e.g., nasopharyngeal swabs, sputum, lower respiratory tract secretions) is to be selected based on the conditions of the local laboratory.

   The type of specimen and detection method for 2019-nCov should remain consistent for the same subject receiving study treatment.

4. Chest imaging (CT as first option or X-ray if CT not possible)-documented pneumonia; if CT cannot be performed, Pneumonia confirmed by X-ray may be used. The method of chest imaging pneumonia diagnosis must be consistent all through the study period.
5. Patients with pyrexia (axillary ≥37℃ or oral ≥37.5℃, or axillary or rectal≥38℃) or either respiratory rate >24/min and <30/min or cough; For not hospitalized patients, the Investigator should maintain the detection method consistent all through the study period. In addition, the Investigator should maintain the data collection and quality compliant with GCP requirements.
6. The interval between symptoms onset and randomization is no more than 10 days; symptoms onset is primarily based on pyrexia, and can be based on cough or other related symptoms for patients without experiencing pyrexia following onset;

7. For female subjects: evidence of post-menopause, or, for pre-menopause subjects, negative pre-treatment serum or urine pregnancy test. Menopause is defined as amenorrhea for at least 12 months without other medical cause, with the following age-specific requirements:

   • For female subjects aged <50 years: menopause for at least 12 months following withdrawal of exogenous hormonal therapy, with LH or FSH within the post-menopausal ranges, or having undergone any contraceptive surgery (bilateral oophorectomy or hysterectomy);
   • For female subjects aged ≥50 years: menopause for at least 12 months following withdrawal of exogenous hormonal therapy, or having undergone radiotherapy-induced oophorectomy with amenorrhea>1 year, or having undergone chemotherapy-induced menopause with amenorrhea>1 year, or having undergone any contraceptive surgery (bilateral oophorectomy or hysterectomy).
8. Eligible subjects of child-bearing age (male or female) must agree to take effective contraceptive measures (including hormonal contraception, barrier methods or abstinence) with his/her partner during the study period and for at least 7 days following the last study treatment;
9. Not participating in any other interventional drug clinical studies before completion of the present study.

Exclusion Criteria:

1. Where, in the opinion of the investigator, participation in this study will not be in the best interest of the subject, or any other circumstances that prevent the subject from participating in the study safely;
2. Refractory nausea, vomiting, or chronic gastrointestinal disorders, inability to swallow the study drug or having undergone extensive bowel resection which may affect adequate absorption of Favipiravir;
3. Severe liver disease: underlying liver cirrhosis or alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevated over 5 times the ULN;
4. Gout/history of gout or hyperuricemia (above the ULN);
5. Oxygen saturation (SPO2)≤93% or arterial oxygen partial pressure (PaO2)/ fraction of inspired O2 (FiO2)≤300 mmHg;
6. Known allergy or hypersensitivity to Favipiravir;
7. Known severe renal impairment [creatinine clearance (CcCl) <30 mL/min] or having received continuous renal replacement therapy, hemodialysis or peritoneal dialysis; CcCl is to be calculated by the following Cockcroft-Gault formula only when the serum creatinine is>1.5×ULN
8. Possibility of the subject being transferred to a non-study hospital within 72h;
9. Pregnant or lactating women;
10. Having used Favipiravir or participated in any other interventional drug clinical study within 30 days prior to first dose of study drug.

Note: Considering that COVID-19 requires immediate treatment, absence of severe hepatic/renal disorders (e.g., cirrhosis, long-term dialysis) in the medical record can be used as an evidence for eligibility determination. It is recommended that hepatic function and creatinine be examined whenever possible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Favipiravir; Experimental: Favipiravir Dosage and method of administration: Day 1: 1800mg, BID; Day 2 and thereafter: 600mg, TID, for a maximum of 14 days. Where the subject has experienced an adverse event related to liver injury of grade≥3 (NCI CTCAE v5.0), the dose is to be reduced to 600mg BID. It is at the discretion of the investigator whether or not to perform dose reduction based on how the subject is benefiting from study treatment. The subject should be discontinued from treatment if he/she re-experiences any adverse event related to liver injury of grade≥3 after dose reduction.	Drug: Favipiravir; Dosage and method of administration: Day 1: 1800mg, BID; Day 2 and thereafter: 600mg, TID, for a maximum of 14 days. Where the subject has experienced an adverse event related to liver injury of grade≥3 (NCI CTCAE v5.0), the dose is to be reduced to 600mg BID. It is at the discretion of the investigator whether or not to perform dose reduction based on how the subject is benefiting from study treatment. The subject should be discontinued from treatment if he/she re-experiences any adverse event related to liver injury of grade≥3 after dose reduction
Placebo Comparator: Placebo; Comparator: Placebo Dosage and method of administration: Day 1: 1800mg, BID; Day 2 and thereafter: 600mg, TID, for a maximum of 14 days. Where the subject has experienced an adverse event related to liver injury of grade≥3 (NCI CTCAE v5.0), the dose is to be reduced to 600mg BID. It is at the discretion of the investigator whether or not to perform dose reduction based on how the subject is benefiting from study treatment. The subject should be discontinued from treatment if he/she re-experiences any adverse event related to liver injury of grade≥3 after dose reduction	Other: Placebo; Dosage and method of administration: Day 1: 1800mg, BID; Day 2 and thereafter: 600mg, TID, for a maximum of 14 days. Where the subject has experienced an adverse event related to liver injury of grade≥3 (NCI CTCAE v5.0), the dose is to be reduced to 600mg BID. It is at the discretion of the investigator whether or not to perform dose reduction based on how the subject is benefiting from study treatment. The subject should be discontinued from treatment if he/she re-experiences any adverse event related to liver injury of grade≥3 after dose reduction

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from randomization to clinical recovery	The duration from start of treatment (Favipiravir or placebo) to normalization of pyrexia, respiratory rate and SPO2 and relief of cough (where there are relevant abnormal symptoms at enrolment) that is maintained for at least 72 hours.	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from randomization to negativity in RT-PCR nucleic acid test	1. Time from randomization to negativity in RT-PCR nucleic acid test for 2019-nCov within 28 days of randomization;	28 days
Incidence of deterioration/aggravation of pneumonia	Incidence of deterioration/aggravation of pneumonia (defined as SPO2≤93% or PaO2/FiO2 ≤300 mmHg or distressed RR≥30/min without oxygen inhalation and requiring oxygen therapy or more advanced breath support) within 28 days of randomization;	28 days
Time from randomization to resolution of pyrexia	Time from randomization to resolution of pyrexia (defined the same as for the primary efficacy variable; applicable to subjects with pyrexia at enrolment) within 28 days of randomization;	28 days
Time from randomization to relief of cough	Time from randomization to relief of cough (defined the same as for the primary efficacy variable; applicable to subjects with cough at enrolment) within 28 days of randomization; It is recommended that the severity of cough be graded as per NCI-CTCAE v5.0: Mild: Requires non-prescription treatment;; Moderate: Requires medication treatment; limits instrumental activities of daily living;; Severe: Limits self-care activities of daily living	28 days
Time from randomization to relief of dyspnoea	Time from randomization to relief of dyspnoea (defined as subject-perceived improvement or resolution of dyspnoea; applicable to subjects with dyspnoea at enrolment) within 28 days of randomization;	28 days
Rate of auxiliary oxygen therapy	6. Rate of auxiliary oxygen therapy or non-invasive ventilation within 28 days of randomization	28 days
ICU admission rate	ICU admission rate within 28 days of randomization	28 days
Mortality	All-cause mortality within 28 days of randomization	28 days

Collaborators and Investigators

• Sponsor: Giuliano Rizzardini
• Investigators: Principal Investigator: Giuliano Rizzardini, Md, ASST Fatebenefratelli Sacco

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2020
• Primary Completion (Anticipated): July 1, 2020
• Study Completion (Anticipated): July 1, 2020

Study Registration Dates

• First Submitted: April 3, 2020
• First Submitted That Met QC Criteria: April 3, 2020
• First Posted (Actual): April 7, 2020

Study Record Updates

• Last Update Posted (Actual): April 8, 2020
• Last Update Submitted That Met QC Criteria: April 7, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: COVID-19
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Anti-Infective Agents; Antiviral Agents; Favipiravir
• Other Study ID Numbers: HS216C17-PHASE III

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No