E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051905 |
E.1.2 | Term | Coronavirus infection |
E.1.2 | System Organ Class | 100000004862 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether early intervention with either a combination of hydroxychloroquine, azithromycin and zinc or favipirivir improves time to significant improvement in clinical status. |
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E.2.2 | Secondary objectives of the trial |
To assess whether early intervention with Favipiravir or the combination of Hydroxychloroquine, Zinc and Azithromycin improves mortality in patients with COVID-19 infection
To determine whether early intervention with Favipiravir or the combination of Hydroxychloroquine, Zinc and Azithromycin reduces resource utilisation in patients with COVID-19 infection
To explore whether early intervention with Favipiravir or the combination of Hydroxychloroquine, Zinc and Azithromycin attenuates the excessive inflammatory cytokine response in patients with COVID-19 infection
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
he participant may enter the study if the following apply: 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 one of 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). · Acute respiratory distress syndrome · Radiological evidence of pneumonia 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
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E.4 | Principal exclusion criteria |
The participant may not enter the study if ANY of the following apply: 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 (>430ms in males or >450ms 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 NB See Section 9.1 for dose reduction guidance for patients with eGFR <50ml/ minute
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to clinical improvement (post randomisation) by two points on a seven-category ordinal scale or live discharge from the hospital, whichever comes first The 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
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Data for assessment of primary endpoint will be collected until discharge from inpatient care, 28 day from enrolment or death. |
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E.5.2 | Secondary end point(s) |
1. Clinical status as assessed with the seven-category ordinal scale at day 7 and day 14 (post- randomisation)(19) 2. Change in clinical status as assessed with the seven-category ordinal scale at day 7 and day 14 (post- randomisation) relative to baseline(19) 3. All-cause in-hospital mortality 4. Time to clinical response defined as: Time to hospital discharge OR Time to NEWS2 (National Early Warning Score 2) of ≤ 2, maintained for 24 hours(20) 5. Time to substantial clinical response as defined as: Time to hospital discharge or Time to NEWS2 (National Early Warning Score 2) of ≤ 3, maintained for 24 hours(20) 6. Time to clinical response (temperature, heartrate, respiratory rate, oxygen saturations) 7. Number of participants requiring intensive care admission 8. Duration of intensive care admission 9. Number of participants requiring mechanical ventilation 10. Duration of mechanical ventilation 11. Number of participants requiring non-invasive ventilation, continuous positive airways pressure or high-flow oxygen via (Optiflo ®, Airvo system or equivalent) 12. Percentage of progression in supplemental oxygen requirement at day 7 13. Inflammatory serum makers at day 7 to 10, relative to baseline 14. Number of participants readmitted to hospital (all-cause) 15. Proportion of patients with bacterial or fungal infection 16. Changes in host cytokine profiles at post randomisation time points relative to baseline
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Data and samples will be collected from recruitment to discharge from inpatient care, 28 days from enrolment or death in order to assess the secondary endpoints. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Current UK standard of care for COVID-19 infection |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 1 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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All randomised participants are to be followed up until death, or 28 days post-randomisation (whichever is sooner). The day the final subject reaches one of these three milestones will be end of study.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 19 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 19 |