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] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051905 |
E.1.2 | Term | Coronavirus infection |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
The overall objective of the study is to evaluate the clinical efficacy of Brensocatib compared to placebo on top of standard care in adult patients hospitalized with COVID-19 |
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E.2.2 | Secondary objectives of the trial |
Evaluate the safety of the intervention through 28 days of follow-up as compared to the control arm Quality of life |
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E.2.3 | Trial contains a sub-study | No |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The following will be carried out at the Tayside site only. Exploratory assessment- viral shedding Where practical in a substudy at the Tayside site only, nasal swabs will be obtained on day 15 and day 29 to evaluate viral clearance by PCR. Exploratory assessment- neutrophil studies In a substudy at the Tayside site only, additional blood will be taken for isolation of peripheral blood neutrophils to examine neutrophil serine protease activity.
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E.3 | Principal inclusion criteria |
• Male or female • ≥16 years of age • SARS-CoV-2infection (clinically suspected+ or laboratory confirmed*). • Admitted to hospital as in-patient less than 96 hours prior to randomisation^ • Illness of any duration, and at least one of the following: o Radiographic infiltrates by imaging (e.g. chest x-ray, computed tomography (CT) scan) OR o Evidence of rales/crackles on physical examination OR o Peripheral capillary oxygen saturation (SpO2) ≤94% on room air prior to randomization OR o Requiring supplemental oxygen. OR o Lymphocyte count <1 x 109 cells per litre (L) • Participant (or legally authorized representative) provides written informed consent • Able to take oral medication • Participant (or legally authorised representative) understands and agrees to comply with planned trial procedures. *Laboratory-confirmed: SARS-CoV-2 infection as determined by polymerase chain reaction (PCR), or other commercial or public health assay in any specimen < 96 hours prior to randomization. +Clinically suspected: in general, SARS-CoV-2 infection should be suspected when a patient presents with (i) typical symptoms (e.g. influenza-like illness with fever and muscle pain, or respiratory illness with cough and shortness of breath); and (ii) compatible chest X-ray findings (consolidation or ground-glass shadowing); and (iii) alternative causes have been considered unlikely or excluded (e.g. heart failure, influenza). However, the diagnosis remains a clinical one based on the opinion of the managing doctor ^Where a patient has been admitted to hospital for a non COVID-19 reason and develops COVID-19 symptoms whilst an in-patient, randomisation my occur up to 96 hours from onset of symptoms.
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E.4 | Principal exclusion criteria |
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 5 times the upper limit of normal, result within 72 hours of randomization (the result closest to randomization should be used if several results are available). • History of severe liver disease • Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR < 30), result within 72 hours of randomization (the result closest to randomization should be used if several results are available) • Absolute neutrophil count less than 1.0 x 109 cells per L within 72 hours of randomization (the result closest to randomization should be used if several results are available) • Current treatment with potent Cyp3A4 inducers/inhibitors (e.g Itraconazole, Ketoconazole, diltiazem, verapamil, phenytoin or rifampicin) • HIV treatments - current treatment with protease/integrase inhibitors or non-nucleoside reverse transcriptase inhibitors* • Pregnant or breast feeding. • Anticipated transfer to another hospital which is not a trial site within 24 hours. • Allergy to Brensocatib • Use of any investigational drug within five times of the elimination half-life after the last trial dose or within 30 days, whichever is longer. Co-enrolment with COVID-19 trials is allowed as per co-enrolment agreements and/or individual decision by the CI. Women of child-bearing potential must be willing to have pregnancy testing prior to trial entry. *The Liverpool HIV checker (https://www.hiv-druginteractions.org/checker) should be used to check for any HIV drug interactions. Simvastatin could be used as a surrogate for Brensocatib as it metabolised similarly by CYP 3A4 pathway.
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E.5 End points |
E.5.1 | Primary end point(s) |
Clinical status on 7-point ordinal scale: 1. Not hospitalised, no limitations on activities 2. Not hospitalised, limitation on activities; 3. Hospitalised, not requiring supplemental oxygen; 4. Hospitalised, requiring supplemental oxygen; 5. Hospitalised, on non-invasive ventilation or high flow oxygen devices; 6. Hospitalised, on invasive mechanical ventilation or ECMO (Extracorporeal membrane oxygenation) 7. Death.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Clinical Severity Time to an improvement of one category from admission using 7-point ordinal scale. Daily whilst hospitalised Participant clinical status on 7-point ordinal scale Days 3, 5, 8, 11, 15 and 29. Mean change in the 7-point ordinal scale Baseline to days 3, 5, 8, 11, 15 and 29.
National Early Warning Score (NEWS): Time to discharge or to a NEWS of ≤ 2 and maintained for 24 hours, whichever occurs first. Daily whilst in hospital. Change from baseline Days 8, 15, 29
Oxygenation: Oxygen free days 1-29 days Incidence and duration of new oxygen use during the trial 1-29 days
Mechanical Ventilation: Ventilator free days 1-29 days Incidence and duration of new mechanical ventilation use during the trial. 1-29 days
Hospitalisation: Duration of hospitalisation (days). Date of admission and discharge
Mortality: 28-day mortality Date of death
Cumulative incidence of serious Adverse events (SAEs) 1-29 days Discontinuation or temporary suspension of treatment 1-29 days Changes in white cell count, haemoglobin, platelets, creatinine, total bilirubin, ALT, and AST over time (hospitalised participants only) Days 0/1, 3, 5, 8, 11, 15, 29 Adverse events of special interest- hyperkeratosis, infections and dental complications 1-29 days
EQ-5D-5L administered via telephone (if at home) or in person if still in hospital Day 29
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
E.8.5 | The trial involves multiple Member States | No |
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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Last day 29 for last participant |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 20 |