A Multi-center,Randomized,Double-blind,Placebo-controlled,Phase 3 Study Evaluating Favipiravir in Treatment of COVID19

COVID-19 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04425460
• Other study ID #: HS216C17(MRCT)
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: June 2020
• Est. completion date: September 2020

Study information

• Verified date: May 2020
• Source: Zhejiang Hisun Pharmaceutical Co. Ltd.
• Contact: Dionisio Barattini, MD Europe, Opera CRO
• Phone: +40774012684
• Email: barattini[@]operacro.ro
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multi-center, randomized, double-blind, placebo-controlled, phase III clinical study to evaluate the efficacy of Favipiravir combined with supportive care for adult patients with COVID-19-Moderate type.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 256
• Est. completion date: September 2020
• Est. primary completion date: August 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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 Ministry of Health and respective country guidelines and recommendations reported in Appendix 1 (a, b, c, d) 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 or 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.

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 tympanic 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 through 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 (it is strongly recommended that the interval between symptoms onset and randomization should not exceed 5 days);

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 3 months (in male) and 1 month (in female)following the last study treatment; in addition:

1. For female participants of childbearing potential only highly effective methods (failure rate < 1 %) plus one barrier method is allowed throughout the period of relevant systemic exposure with Favipiravir. Double barrier methods alone are not considered as highly effective. Additionally, pregnancy testing at baseline only is not deemed sufficient and must be repeated more frequently, at least if clinical signs of pregnancy occur and at follow-up / end of study.

2. male participants, if vasectomized or not, must wear a condom each time having heterosexual intercourse throughout the period of relevant systemic exposure with Favipiravir (as it is distributed to seminal fluid).

3. male participant must be instructed not to have intercourse with pregnant women throughout the period of relevant systemic exposure with Favipiravir.

4. For further details on contraception in clinical trials, please refer to the CTFG guidance: https://www.hma.eu/fileadmin/dateien/Human_Medicines/01- About_HMA/Working_Groups/CTFG/2014_09_HM A_CTFG_Contraception.pd

9. Not participating in any other 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 or any of its excipients, or to placebo excipients

7. Known severe renal impairment [creatinine clearance (CrCl) <30 mL/min] or having received continuous renal replacement therapy, hemodialysis or peritoneal dialysis;

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 or having received treatments with other Investigational Medicinal Products (IMPs) or previous therapies within two weeks or five times the half-life of the drug, whichever is longer, must lead to exclusion

11. Persons, who were placed in an institution due to official or legal orders should be excluded

12. Persons, who are dependent on the sponsor, the investigator or the trial site, meaning that the voluntary nature of their consent is no longer guaranteed, must be excluded from participation

Related Conditions & MeSH terms

• COVID-19

Intervention

Drug:
• Favipiravir
Favipiravir combined with supportive care recommended in the current National/Local guidelines. Favipiravir dosage and method of administration: Day 1 1800 mg x2; Day 2 up to a maximum of 14 days 600 mg x 3

Other:
• Placebo
Placebo combined with supportive care recommended in the current National/Local guidelines. Placebo dosage and method of administration: Day 1 1800 mg x2; Day 2 up to a maximum of 14 days 600 mg x 3

Locations

Country	Name	City	State
China	Peking University First Hospital	Beijing	Xicheng District
China	The First Affiliated Hospital of Zhejiang University School of Medicine	Hangzhou	Shangcheng District
Germany	Department of Internal Medicine Pneumology and infectious diseases Neukölln Clinic	Berlin
Germany	Medical clinic and polyclinic IV Hospital of the University of Munich	München
Romania	National Institute of Infectious Diseases "Prof.Dr.Matei Bals"	Bucharest	Ilfov
Romania	Infectious Diseases Hospital Cluj-Napoca	Cluj-Napoca	Cluj
Romania	"Dr.Victor Babes" Infectious Diseases and Pneumoftiziology Clinical Hospital Timisoara	Timisoara	Timis
Romania	"Dr.Victor Babes" Infectious Diseases and Pneumoftiziology Clinical Hospital Timisoara	Timisoara	Timis
Romania	Dr.Victor Babes Infectious Diseases and Pneumoftiziology Clinical Hospital Timisoara	Timisoara	Timis
Romania	Emergency County Hospital "Pius Brinzeu"Timisoara	Timisoara	Timis

Sponsors (2)

Lead Sponsor	Collaborator
Zhejiang Hisun Pharmaceutical Co. Ltd.	Opera CRO, a TIGERMED Group Company

Countries where clinical trial is conducted

China,  Germany,  Romania, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 72h.; Criteria for normalization or relief: Pyrexia (body temperature): axillary =37?,or oral=37.5?,or rectal or tympanic; =38?; Respiratory rate: =24/min without oxygen inhalation; SPO2: >94% without oxygen inhalation; Cough: Subject-perceived improvement or resolution of cough.	28 days
Secondary	Negativity in RT-PCR nucleic acid test	Time from randomization to negativity in RT-PCR nucleic acid test for 2019-nCov within 28 days of randomization;	28 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Rate of auxiliary oxygen therapy or non-invasive ventilation	Rate of auxiliary oxygen therapy or non-invasive ventilation within 28 days of randomization;	28 days
Secondary	ICU admission rate within 28 days of randomization	ICU admission rate within 28 days of randomization (except patients already enrolled in ICU which respect eligibility criteria);	28 days
Secondary	All-cause mortality within 28 days of randomization.	All-cause mortality within 28 days of randomization.	28 days