Favipiravir +/- Nitazoxanide: Early Antivirals Combination Therapy in COVID-19

NCT04918927 | Completed Phase 2 DMC

• 1 other identifier: 2021-785-018
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease. The plan is to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and IMSS beneficiaries. Participants with or without symptomatic COVID-19 or tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease.

Conditions

Covid19

Outcome Measures

Primary Outcomes (1)

• Upper respiratory tract viral load at Day 5.

  Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy

  Day 5 from randomisation

Secondary Outcomes (20)

• Percentage of participants with undetectable upper respiratory tract viral load after 5 days of therapy

  Day 5 from randomisation

• Proportion of participants with undetectable stool viral load after 7 days of therapy and 14 days post-randomisation.

  Day 7 and Day 14 from randomization

• Rate of decrease in upper respiratory tract viral load during 7 days of therapy.

  From day of randomisation to day 7

• Duration of fever following commencement of medication

  From day of randomisation to day 7

• Proportion of participants with hepatotoxicity after 7day of therapy and 14 days post-randomisation.

  Day 7 and day 14 from randomisation.

Study Arms (2)

Arm 1: Favipiravir + Nitazoxanide

EXPERIMENTAL

Oral Favipiravir 1800 mg twice daily on Day 1, followed by 400 mg four (4) times daily from Day 2 to Day 7 PLUS Nitazoxanide at 1000 mg twice daily on Day 1 followed by 500 mg four (4) times daily from Day 2 to Day 7

Drug: Favipiravir; Drug: Nitazoxanide

Arm 2: Favipiravir + Nitazoxanide placebo

EXPERIMENTAL

Oral favipiravir, 1800 mg twice daily on Day 1, followed by 400 mg four (4) times daily from Day 2 to Day 7 PLUS Nitazoxanide matched placebo at 1000 mg twice daily on Day 1 followed by 500 mg four (4) times daily from Day 2 to Day 7.

Drug: Favipiravir; Other: Nitazoxanide Placebo

Interventions

Favipiravir DRUG

Oral Favipiravir 1800 mg twice daily on Day 1, followed by 400 mg four (4) times daily from Day 2 to Day 7

Arm 1: Favipiravir + Nitazoxanide; Arm 2: Favipiravir + Nitazoxanide placebo

Nitazoxanide DRUG

Nitazoxanide at 1000 mg twice daily on Day 1 followed by 500 mg four (4) times daily from Day 2 to Day 7

Also known as: Daxon

Arm 1: Favipiravir + Nitazoxanide

Nitazoxanide Placebo OTHER

Nitazoxanide matched placebo at 1000 mg twice daily on Day 1 followed by 500 mg four (4) times daily from Day 2 to Day 7.

Also known as: Daxon Placebo

Arm 2: Favipiravir + Nitazoxanide placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Health workers, their household members and, IMSS beneficiaries with the following:
• Symptoms compatible with COVID-19 disease (Fever \>37.8oC on at least one occasion AND either cough and/ or anosmia) within the first 5 days of symptom onset (date/time of enrolment must be within the first 5 days of symptom onset)
• OR ANY symptoms compatible with COVID-19 disease (may include, but are not limited to fever, cough, shortness of breath, malaise, myalgia, headache, coryza) and tested positive for SARS-CoV-2 within the first 7 days of symptom onset (date/time of enrolment must be within the first 7 days of symptom onset)
• OR no symptoms but tested positive for SARS-CoV-2 within the last 48 hours (date/time of test must be within 48 hours of enrolment)
• Male or female aged 18 years to 70 years old inclusive at screening
• Willing and able to take daily saliva samples
• Able to provide full informed consent and willing to comply with trial-related procedures

You may not qualify if:

• Known hypersensitivity to any of the active ingredients or excipients in favipiravir, and in nitazoxanide and matched placebo
• Chronic liver disease at screening (known cirrhosis of any aetiology, chronic hepatitis (e.g. autoimmune, viral, steatohepatitis), cholangitis or any known elevation of liver aminotransferases with AST or ALT \> 3 X ULN)\*
• Chronic kidney disease (stage 3 or beyond) at screening: eGFR \< 60 ml/min/1.73m2\*
• HIV infection, if untreated, detectable viral load or on protease inhibitor therapy
• Any clinical condition which the investigator considers would make the participant unsuitable for the trial
• Concomitant medications known to interact with favipiravir, and with nitazoxanide and matched placebo, and carry risk of toxicity for the participant (See Appendix 4)
• Current severe illness requiring hospitalisation
• Pregnancy and/ or breastfeeding
• Eligible female participants of childbearing potential and male participants with a partner of childbearing potential not willing to use highly effective contraceptive measures during the trial and within the time point specified following last trial treatment dose.
• Participants enrolled in any other interventional drug or vaccine trial (co-enrolment in observational studies is acceptable).
• Considering the importance of early treatment of COVID-19 to impact viral load, the absence of chronic liver/ kidney disease will be confirmed verbally by the participant during pre- screening and Screening/Baseline visit. Safety blood samples will be collected at Screening/Baseline visit (Day 1) and test results will be examined as soon as they become available within 24 hours.

Sponsors & Collaborators

• Coordinación de Investigación en Salud, Mexico: lead
• University College, London: collaborator
• Centro de Investigacion y Estudios Avanzados del Instituto Politecnico Nacional (CINVESTAV): collaborator
• Universidad Autonoma de Guadalajara: collaborator
• Siegfried Rhein S.A. de C.V.: collaborator
• Strides Pharma Science Limited: collaborator
• Hakken Enterprise: collaborator

Study Sites (1)

Hospital de Infectología "Daniel Méndez Hernández" del Centro Médico Nacional La Raza

Mexico City, Azcapotzalco, 02290, Mexico

Location

Related Publications (1)

• Smith T, Hoyo-Vadillo C, Adom AA, Favari-Perozzi L, Gastine S, Dehbi HM, Villegas-Lara B, Mateos E, Gonzalez YSP, Navarro-Gualito MD, Cruz-Carbajal AS, Cortes-Vazquez MA, Bekker-Mendez C, Aguirre-Alvarado C, Aguirre-Gil G, Delgado-Pastelin L, Owen A, Lowe D, Standing J, Escobedo J. Favipiravir and/or nitazoxanide: a randomized, double-blind, 2x2 design, placebo-controlled trial of early therapy in COVID-19 in health workers, their household members, and patients treated at IMSS (FANTAZE). Trials. 2022 Jul 22;23(1):583. doi: 10.1186/s13063-022-06533-0.

  PMID: 35869526 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

favipiravir; nitazoxanide

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Jorge Escobedo, Dr.

  Instituto Mexicano del Seguro Social

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Double-blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of the Epidemiology Clinical Research Unit

Model Details: Phase IIA randomised, double-blind, placebo-controlled, interventional trial.

Study Record Dates

• First Submitted: June 4, 2021
• First Posted: June 9, 2021
• Study Start: October 12, 2021
• Primary Completion: March 21, 2023
• Study Completion: March 21, 2023
• Last Updated: March 24, 2023

Record last verified: 2023-03

Locations

ME (1)