A Randomised Double-blind Placebo-controlled Trial of Brensocatib (INS1007) in Patients With Severe COVID-19
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 406
- 试验地点
- 16
- 主要终点
- Comparison of Participant Clinical Status Between Treatment Arms
研究概览
简要总结
COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. There is currently no vaccine to prevent infection with SARS-CoV-2 and no therapeutic agent to treat COVID-19. This clinical trial is designed to evaluate the potential of Brensocatib (INS1007) as a novel host directed therapy for the treatment of adult patients hospitalized with COVID-19. The investigators hypothesise that Brensocatib, by blocking damaging neutrophil proteases, will reduce the incidence of acute lung injury and acute respiratory distress syndrome (ARDS) in patients with COVID-19, thereby resulting in improved clinical outcomes at day 15 and day 29, fewer days dependent on oxygen or mechanical ventilation, and shorter length of hospital stay.
High rates of patients requiring mechanical ventilation and overwhelming intensive care unit capacity has been the major issue contributing to excess deaths in Italy and Spain during the pandemic and is likely to be a major issue in other countries such as the United Kingdom in the coming weeks. Treatments that could prevent the requirement for mechanical ventilation or shorten the duration of ICU stay by reducing the severity of ARDS are therefore the number 1 target for COVID19 therapy.
The investigators recently conducted a large phase 2 study of Brensocatib in patients with bronchiectasis designed to test if treatment with Brensocatib could reduce infective exacerbations and reduce neutrophil elastase activity in the lung in bronchiectasis patients. The study met its primary endpoint of time to first exacerbation and key secondary endpoint of the frequency of exacerbations as well as showing marked reductions in neutrophil elastase concentrations in sputum.
Participants will be randomised to receive Brensocatib or placebo 25mg orally once daily for 28 days.
详细描述
BACKGROUND COVID-19 is a respiratory disease caused by a novel coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and causes substantial morbidity and mortality.This clinical trial is designed to evaluate the potential of Brensocatib as a novel host directed therapy for the treatment of adult patients hospitalised with COVID-19. The investigators hypothesise that Brensocatib, by blocking damaging neutrophil proteases, will reduce the incidence of acute lung injury and acute respiratory distress syndrome (ARDS) in patients with COVID-19, thereby resulting in improved clinical outcomes at day 15 and day 29, fewer days dependent on oxygen or mechanical ventilation, and shorter length of hospital stay.
Coronavirus (CoVs) are positive-sense single stranded enveloped Ribonucleic acid (RNA) viruses, many of which are commonly found in humans and cause mild symptoms. Over the past two decades, emerging pathogenic CoVs capable of causing life-threatening disease in humans and animals have been identified, namely severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and Middle Eastern respiratory syndrome coronavirus (MERS- CoV).
In December 2019, the Wuhan Municipal Health Committee (Wuhan, China) identified an outbreak of viral pneumonia cases of unknown cause.5 Coronavirus RNA was quickly identified in some of these patients. This novel coronavirus has been abbreviated as SARS-COV-2 and has 89% nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human SARS-CoV. This novel coronavirus has been designated SARS-CoV-2, and the disease caused by this virus has been designated COVID-19. Initial infections were travel associated with individuals having contact with Wuhan or other affected areas but the disease has now spread to affect hundreds of thousands of patients worldwide with widespread community transmission across the globe.
Outbreak forecasting and mathematical modelling suggest that these numbers will continue to rise.
Global efforts to evaluate novel antivirals and therapeutic strategies to treat COVID-19 have intensified but to date dexamethasone is the only therapy shown to reduce mortality in COVID-19 while repurposed antiviral drugs did not show clinical benefits in the World Health Organisation SOLIDARITY trial.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion criteria
- •Male or female
- •≥16 years of age
- •SARS-CoV-2 infection (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:
- •Radiographic infiltrates by imaging (e.g. chest x-ray, computed tomography (CT) scan) OR
- •Evidence of rales/crackles on physical examination OR
- •Peripheral capillary oxygen saturation (SpO2) ≤94% on room air prior to randomization OR
- •Requiring supplemental oxygen. OR
- •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 may occur up to 96 hours from onset of symptoms.
排除标准
- •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. estimated Glomerular Filtration Rate < 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 treatments 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 Chief Investigator.
- •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.
研究组 & 干预措施
Brensocatib
Brensocatib oral tablet, 25mg once per day for 28 days
干预措施: Brensocatib (Drug)
Placebo
Placebo oral tablet, 25mg once per day for 28 days
干预措施: Placebo (Drug)
结局指标
主要结局
Comparison of Participant Clinical Status Between Treatment Arms
时间窗: Up to 29 days
To determine the participant clinical status on a 7-point ordinal scale, minimum value 1, maximum value 7. Higher values indicate a worse outcome: 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 Extracorporeal membrane oxygenation (ECMO) 7. Death.
次要结局
- Incidence and Duration of New Oxygen Therapy Use During the Trial(0-29 days)
- Number of Mechanical Ventilator Free Days(1-29 days)
- Incidence and Duration of New Mechanical Ventilation Use During the Trial.(1-29 days)
- 28-day Mortality(Day 1 to 29)
- Cumulative Incidence of Serious Adverse Events (SAEs)(1-29 days)
- Discontinuation or Temporary Suspension of Treatment(1-29 days)
- Changes in Total Bilirubin (Umol/L) Over Time (Hospitalised Participants Only)(Day 29)
- Number of Oxygen Therapy Free Days(1-29 days)
- Changes in Aspartate Aminotransferase U/L Over Time (Hospitalised Participants Only)(Day 29)
- Improvement of One Category From Admission Using 7-point Ordinal Scale.(Day 29)
- Participant Clinical Status on 7-point Ordinal Scale(Day 15)
- Mean Change in the 7-point Ordinal Scale(Baseline to days 3, 5, 8, 11 and 29)
- Number of Participants Discharged or to a National Early Warning Score (NEWS) of Equal or Less Than 2 and Maintained for 24 Hours, Whichever Occurs First.(Up to 29 days)
- Change From Baseline of National Early Warning Score (NEWS).(Baseline to day 15)
- Duration of Hospitalisation (Days).(Duration between date of admission and discharge assessed up to 29 days.)
- Changes in Haemoglobin (g/L) Over Time (Hospitalised Participants Only)(Day 29)
- Changes in Platelets (x10^9/L) Over Time (Hospitalised Participants Only)(Day 29)
- Changes in Alanine Aminotransferase (U/L) Over Time (Hospitalised Participants Only)(Day 29)
- Changes in White Cell Count (x10^9/L) Over Time (Hospitalised Participants Only)(Day 29)
- Changes in Creatinine (Umol/L) Over Time (Hospitalised Participants Only)(Day 29)
- Adverse Events of Special Interest- Hyperkeratosis, Infections and Dental Complications(1-29 days)
研究者
James Chalmers
Professor of Respiratory Research
University of Dundee