Early Intervention in COVID-19: Favipiravir Verses Standard Care (PIONEER)

A Randomised Controlled Trial of Early Intervention in Patients HospItalised With COVID-19: Favipiravir and StaNdard Care vErsEs Standard CaRe

Currently we do not know how best to treat patients infected with COVID-19. This study is looking at whether randomising participants to either favipiravir or to usual care, can help patients with suspected or proven COVID-19 infection.

Study Overview

• Status: Completed
• Conditions: Coronavirus Infection
• Intervention / Treatment: Drug: Favipiravir; Other: Standard of care management

Detailed Description

A prospective, randomised, open label study of the combined use of favipiravir and standard clinical care verses standard clinical care alone.

A computer-based software will randomise participants 1:1 to either receive favipiravir and standard medical care or standard medical care alone. The allocated medical regime will commence for 10 days.

Research blood, sputum nose swab and urine samples will be collected at baseline, as well as between day 5 and 10, and between day 14 and 28 to enable comparative analyses.

A COVID-19 antibody test will also be performed 14-28 days after randomisation. In the event of clinically indicated bronchoscopy taking place within 28 days of consent then additional bronchoscopy washing and brushing samples and paired blood sample will be taken for research purposes If a participant is discharged before one of the latter time points, they will be required to return to hospital (provided they are well enough) for the collection of repeat samples.

Participants will be closely monitored whilst taking the study medications. Participants will study exit at subject death or 28 days post-randomisation.

• Study Type: Interventional
• Enrollment (Actual): 502
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Porto Alegre, Brazil
    • Grupo Hospitalar Conceição
  • Rio De Janeiro, Brazil
    • Fundação Oswaldo Cruz - Instituto Nacional de Infectologia Evandro Chagas (Fiocruz/INI)
• Mexico
  • Mexico City, Mexico
    • Instituto Nacional de Ciencias Medicas y Nutricion, Salvador Zubiran
• United Kingdom
  • Hull, United Kingdom
    • Hull University Teaching Hospitals NHS Trust - Castle Hill Hospital
  • London, United Kingdom
    • Chelsea And Westminster Hospital
  • London, United Kingdom
    • West Middlesex University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult participants: Signed informed consent
2. New admission to hospital for period expected to last ≥ 1 night

3. Suspected or confirmed COVID-19 infection

   Patients are suspected of COVID-19 infection if they have the following:

   · Influenza like illness (fever ≥37.8°C and at least one of the following respiratory symptoms, which must be of acute onset: persistent cough, hoarseness, nasal discharge or congestion, shortness of breath, sore throat, wheezing or sneezing).

   And

   · Finding from either a chest x-ray or CT suggestive of Covid-19 infection

   And

   · Alternative causes are considered unlikely

4. For women to be eligible to enter and participate in the study they should be: of non-child-bearing

   • potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or,
   • or of child-bearing potential have a negative pregnancy test at screening and agrees to remain sexually abstinent or use a method of contraception with a failure rate of < 1% per year as indicated in Appendix B during the treatment and for a period of 7 days after the last dose. Hormonal contraceptive methods must be supplemented by a barrier method.
5. Men who are sexually active must use an adequate method of contraception as listed in Appendix B, for a period of at least 7 days after the last dose

Exclusion Criteria:

1. Pregnant or breast feeding, due to potential teratogenicity
2. Hepatic impairment - (AST or ALT > 3.5 x upper limit of normal)
3. Presently enrolled in an interventional drug study
4. Unable to take medication via the oral or nasogastric route
5. Known sensitivity Favipiravir

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Favipiravir & Standard of Care; Favipiravir: Day 1 1800mg twice per day, Days 2-10 800mg twice per day	Drug: Favipiravir; Anti-viral; Other Names: Avigan; Other: Standard of care management; Standard of care management for COVID-19
OTHER: Standard of care; No trial intervention	Other: Standard of care management; Standard of care management for COVID-19

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from randomisation to a sustained clinical improvement (maintained for 24 hours) by two points on a seven-category ordinal scale or to discharge, whichever occurs first	Time from randomisation to a sustained clinical improvement (maintained for 24 hours) by two points on a seven-category ordinal scale or to discharge, whichever occurs first The seven-category ordinal scale is : Not hospitalised with resumption of normal activities; Not hospitalised, but unable to resume normal; Hospitalised, not requiring supplemental oxygen; Hospitalised, requiring supplemental oxygen; Hospitalised, requiring nasal high-flow oxygen therapy, non-invasive mechanical ventilation or both; Hospitalised, requiring ECMO (Extra-corporal membrane oxygenation), invasive mechanical ventilation or both; Death	Up to 28 days from randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical status on a seven-category ordinal scale (Day 7)	Clinical status of patients at given on the seven-category ordinal scale (see primary endpoint for scale)	Day 7 from randomisation
Clinical status on a seven-category ordinal scale (Day 14)	Clinical status of patients at given on the seven-category ordinal scale (see primary endpoint for scale)	Day 14 from randomisation
Overall survival	Survival of patients to end of study	28 days from randomisation
Time to improvement by two points on the NEWS score	Time from randomisation to improvement by two points on the NEWS score of patient condition, if maintained for 24 hours. For details of NEWS score see https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2	Up to 28 days from randomisation
Time to improvement by two points on the NEWS element score for temperature	Time from randomisation to improvement by two points on the NEWS element score for temperature, if maintained for 24 hours. For details of NEWS score see https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2	Up to 28 days from randomisation
Time to improvement by two points on the NEWS element score for heartrate	Time from randomisation to improvement by two points on the NEWS element score for heartrate, if maintained for 24 hours. For details of NEWS score see https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2	Up to 28 days from randomisation
Time to improvement by two points on the NEWS element score for respiratory rate	Time from randomisation to improvement by two points on the NEWS element score for respiratory rate, if maintained for 24 hours. For details of NEWS score see https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2	Up to 28 days from randomisation
Time to improvement by two points on the NEWS element score for oxygen saturation.	Time from randomisation to improvement by two points on the NEWS element score for oxygen saturation, if maintained for 24 hours. For details of NEWS score see https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2	Up to 28 days from randomisation
Admission to intensive care	Frequency of admission of patients to intensive care	Up to 28 days from randomisation
Requirement for mechanical ventilation	Frequency of requirement to administer mechanical ventilation to patients	Up to 28 days from randomisation
Requirement for non-invasive ventilation, continuous positive airways pressure or high-flow oxygen	Frequency of requirement to administer non-invasive ventilation, continuous positive airways pressure or high-flow oxygen to patients	Up to 28 days from randomisation
Incidence of bacterial or fungal infection	Frequency of culture-confirmed bacterial or fungal infection in patients	Up to 28 days from randomisation
Incidence of adverse events not directly caused by COVID-19 infection.	Frequency and severity of adverse events in patients not directly attributed by clinicians to COVID-19 infection.	Up to 28 days from randomisation.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Readmission to inpatient care	Frequency of readmission to inpatient care of patients discharged from hospital.	Up to 28 days from randomisation

Collaborators and Investigators

• Sponsor: Chelsea and Westminster NHS Foundation Trust
• Collaborators: Imperial College London; NEAT ID Foundation; FUJIFILM Toyama Chemical Co., Ltd.
• Investigators: Principal Investigator: Pallav Shah, Chelsea and Westminster NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2020
• Primary Completion (ACTUAL): June 25, 2021
• Study Completion (ACTUAL): June 25, 2021

Study Registration Dates

• First Submitted: May 1, 2020
• First Submitted That Met QC Criteria: May 1, 2020
• First Posted (ACTUAL): May 4, 2020

Study Record Updates

• Last Update Posted (ACTUAL): November 18, 2021
• Last Update Submitted That Met QC Criteria: November 17, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Coronavirus; COVID-19
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Coronavirus Infections; Anti-Infective Agents; Antiviral Agents; Favipiravir
• Other Study ID Numbers: CW002; 2020-001449-38 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Research team wishes to enable any meta-analyses of COVID-19 trials making appropriate requests. No plan to share IPD has been made at this time.

Drug and device information, study documents

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