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Early Intervention in COVID-19: Favipiravir Verses HydroxycholorquiNe & Azithromycin & Zinc vErsEs Standard CaRe (PIONEER)

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ClinicalTrials.gov Identifier: NCT04373733
Recruitment Status : Recruiting
First Posted : May 4, 2020
Last Update Posted : June 25, 2020
Sponsor:
Collaborators:
NEAT ID Foundation
FUJIFILM Toyama Chemical Co., Ltd.
Imperial College London
Universitaire Ziekenhuizen Leuven
Information provided by (Responsible Party):
Chelsea and Westminster NHS Foundation Trust

Brief Summary:
Currently we do not know how best to treat patients infected with COVID-19. This study is looking at whether randomising participants to either a combination of azithromycin, hydroxychloroquine and zinc or favipiravir, alongside usual care, can help patients with suspected or proven COVID-19 infection.

Condition or disease Intervention/treatment Phase
Coronavirus Infection Drug: Favipiravir Drug: Hydroxychloroquine Drug: Azithromycin Drug: Zinc Sulfate Other: Standard of care management Phase 3

Detailed Description:

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

A computer-based software will randomise participants 1:1:1 to either receive; hydroxychloroquine, azithromycin and zinc and standard medical care; 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 450 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Open-label parallel group randomised control trial. Two trial treatment arms and one standard of care comparator arm.
Masking: None (Open Label)
Masking Description: Open label
Primary Purpose: Treatment
Official Title: A Randomised Controlled Trial of Early Intervention in Patients HospItalised With COVID-19: Favipiravir Verses HydroxycholorquiNe & Azithromycin & Zinc vErsEs Standard CaRe
Actual Study Start Date : May 1, 2020
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : March 31, 2021


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 Name: Avigan

Other: Standard of care management
Standard of care management for COVID-19

Experimental: Hydroxychloroquine, azithromycin, zinc & standard of Care
Hydroxychloroquine: Day 1 400mg twice per day, Days 2-10 200mg twice per day; Azithromycin: Day 1-3 250mg once per day; Zinc-sulfate: Days 1-10 125mg twice per day;
Drug: Hydroxychloroquine
Quinoline
Other Name: Plaquenil

Drug: Azithromycin
Macrolide antibiotic

Drug: Zinc Sulfate
Essential mineral
Other Name: Zinc

Other: Standard of care management
Standard of care management for COVID-19

Standard of care
No trial intervention
Other: Standard of care management
Standard of care management for COVID-19




Primary Outcome Measures :
  1. Time to improvement by two points on a seven-category ordinal scale [ Time Frame: Up to 28 days from randomisation ]

    Time from randomisation to clinical improvement by two points on a seven-category ordinal scale:

    1. Not hospitalised with resumption of normal activities
    2. Not hospitalised, but unable to resume normal
    3. Hospitalised, not requiring supplemental oxygen
    4. Hospitalised, requiring supplemental oxygen
    5. Hospitalised, requiring nasal high-flow oxygen therapy, non-invasive mechanical ventilation or both
    6. Hospitalised, requiring ECMO (Extra-corporal membrane oxygenation), invasive mechanical ventilation or both
    7. Death


Secondary Outcome Measures :
  1. Clinical status on a seven-category ordinal scale (Day 7) [ Time Frame: Day 7 from randomisation ]
    Clinical status of patients at given on the seven-category ordinal scale (see primary endpoint for scale)

  2. Clinical status on a seven-category ordinal scale (Day 14) [ Time Frame: Day 14 from randomisation ]
    Clinical status of patients at given on the seven-category ordinal scale (see primary endpoint for scale)

  3. Overall survival [ Time Frame: 28 days from randomisation ]
    Survival of patients to end of study

  4. Time to improvement by two points on the NEWS score [ Time Frame: Up to 28 days from randomisation ]
    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

  5. Time to improvement by two points on the NEWS element score for temperature [ Time Frame: Up to 28 days from randomisation ]
    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

  6. Time to improvement by two points on the NEWS element score for heartrate [ Time Frame: Up to 28 days from randomisation ]
    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

  7. Time to improvement by two points on the NEWS element score for respiratory rate [ Time Frame: Up to 28 days from randomisation ]
    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

  8. Time to improvement by two points on the NEWS element score for oxygen saturation. [ Time Frame: Up to 28 days from randomisation ]
    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

  9. Admission to intensive care [ Time Frame: Up to 28 days from randomisation ]
    Frequency of admission of patients to intensive care

  10. Requirement for mechanical ventilation [ Time Frame: Up to 28 days from randomisation ]
    Frequency of requirement to administer mechanical ventilation to patients

  11. Requirement for non-invasive ventilation, continuous positive airways pressure or high-flow oxygen [ Time Frame: Up to 28 days from randomisation ]
    Frequency of requirement to administer non-invasive ventilation, continuous positive airways pressure or high-flow oxygen to patients

  12. Incidence of bacterial or fungal infection [ Time Frame: Up to 28 days from randomisation ]
    Frequency of culture-confirmed bacterial or fungal infection in patients

  13. Incidence of adverse events not directly caused by COVID-19 infection. [ Time Frame: Up to 28 days from randomisation. ]
    Frequency and severity of adverse events in patients not directly attributed by clinicians to COVID-19 infection.


Other Outcome Measures:
  1. Readmission to inpatient care [ Time Frame: Up to 28 days from randomisation ]
    Frequency of readmission to inpatient care of patients discharged from hospital.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. Renal impairment - (eGFR <10ml/ minute)
  4. Known history of retinopathy
  5. Known history of G6PD deficiency
  6. Known history of Myasthenia gravis
  7. QT-prolongation (>450ms in males or >470ms in females, calculated as per investigators discretion)
  8. Presently enrolled in an interventional drug study or on hydroxychloroquine or azithromycin for other therapeutic reasons
  9. Unable to take medication via the oral or nasogastric route
  10. Immunocompromised patients (see Appendix C)
  11. Known sensitivity to Azithromycin (or other macrolide drugs), hydroxychloroquine, zinc or favipiravir

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04373733


Contacts
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Contact: Research Delivery Operations Manager 020 3315 6825 research.development@chewest.nhs.uk

Locations
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United Kingdom
Chelsea and Westminster Hospital Recruiting
London, United Kingdom
Contact: Research Delivery Operations Manager    020 3315 6825    research.development@chelwest.nhs.uk   
Principal Investigator: Pallav Shah         
West Middlesex University Hospital Recruiting
London, United Kingdom
Contact: Research Delivery Operations Manager    020 3315 6825    research.development@chelwest.nhs.uk   
Principal Investigator: Bobby Mann         
Sponsors and Collaborators
Chelsea and Westminster NHS Foundation Trust
NEAT ID Foundation
FUJIFILM Toyama Chemical Co., Ltd.
Imperial College London
Universitaire Ziekenhuizen Leuven
Investigators
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Principal Investigator: Pallav Shah Chelsea and Westminster NHS Foundation Trust
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Responsible Party: Chelsea and Westminster NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT04373733    
Other Study ID Numbers: CW002
2020-001449-38 ( EudraCT Number )
First Posted: May 4, 2020    Key Record Dates
Last Update Posted: June 25, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
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.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Chelsea and Westminster NHS Foundation Trust:
COVID-19
Coronavirus
Additional relevant MeSH terms:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Zinc
Azithromycin
Hydroxychloroquine
Zinc Sulfate
Anti-Bacterial Agents
Anti-Infective Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents
Trace Elements
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Astringents
Dermatologic Agents