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STOP-COVID19: Superiority Trial Of Protease Inhibition in COVID-19 (STOP-COVID19)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04817332
Recruitment Status : Completed
First Posted : March 26, 2021
Last Update Posted : August 17, 2021
Sponsor:
Collaborators:
NHS Tayside
Insmed Incorporated
Information provided by (Responsible Party):
University of Dundee

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Covid19 Drug: Brensocatib Drug: Placebo Phase 3

Show Show detailed description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 406 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomised Double-blind Placebo-controlled Trial of Brensocatib (INS1007) in Patients With Severe COVID-19
Actual Study Start Date : June 5, 2020
Actual Primary Completion Date : February 28, 2021
Actual Study Completion Date : February 28, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Brensocatib
Brensocatib oral tablet, 25mg once per day for 28 days
Drug: Brensocatib
Selective, competitive, and reversible inhibitor of DPP1
Other Name: INS1007

Placebo Comparator: Placebo
Placebo oral tablet, 25mg once per day for 28 days
Drug: Placebo
Matched placebo




Primary Outcome Measures :
  1. Comparison of participant clinical status between treatment arms [ Time Frame: Up to 29 days ]

    To determine the participant clinical status on a 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 Extracorporeal membrane oxygenation (ECMO)
    7. Death.


Secondary Outcome Measures :
  1. Time to an improvement of one category from admission using 7-point ordinal scale. [ Time Frame: Up to 29 days ]
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: 7-point ordinal scale.

  2. Participant clinical status on 7-point ordinal scale [ Time Frame: Days 3, 5, 8, 11, 15 and 29 ]
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: 7-point ordinal scale.

  3. Mean change in the 7-point ordinal scale [ Time Frame: Baseline to days 3, 5, 8, 11, 15 and 29 ]
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: 7-point ordinal scale.

  4. Time to discharge or to a National Early Warning Score (NEWS) of ≤ 2 and maintained for 24 hours, whichever occurs first. [ Time Frame: Up to 29 days ]
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: National Early Warning Score

  5. Change from baseline of National Early Warning Score (NEWS) [ Time Frame: Days 8, 15, 29 ]
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: National Early Warning Score.Minimum value 0, maximum value 20. Higher scores mean worse outcome.

  6. Number of oxygen therapy free days [ Time Frame: 1-29 days ]
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: oxygenation

  7. Incidence and duration of new oxygen therapy use during the trial [ Time Frame: 0-29 days ]
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: oxygenation

  8. Number of mechanical ventilator free days [ Time Frame: 1-29 days ]
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: Mechanical ventilation

  9. Incidence and duration of new mechanical ventilation use during the trial. [ Time Frame: 1-29 days ]
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: Mechanical ventilation

  10. Duration of hospitalisation (days). [ Time Frame: Duration between date of admission and discharge assessed up to 29 days. ]
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: hospitalisation

  11. 28-day mortality [ Time Frame: Date of death up to 29 days ]
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: mortality

  12. Cumulative incidence of Serious Adverse Events (SAEs) [ Time Frame: 1-29 days ]
    Evaluation of the safety of the intervention through 29 days of follow-up as compared to the control arm

  13. Discontinuation or temporary suspension of treatment [ Time Frame: 1-29 days ]
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm

  14. Changes in white cell count (x10^9/L) over time (hospitalised participants only) [ Time Frame: Days 0/1, 3, 5, 8, 11, 15, 29 ]
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm

  15. Changes in haemoglobin (g/L) over time (hospitalised participants only) [ Time Frame: Days 0/1, 3, 5, 8, 11, 15, 29 ]
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm

  16. Changes in platelets (x10^9/L) over time (hospitalised participants only) [ Time Frame: Days 0/1, 3, 5, 8, 11, 15, 29 ]
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm

  17. Changes in creatinine (umol/L) over time (hospitalised participants only) [ Time Frame: Days 0/1, 3, 5, 8, 11, 15, 29 ]
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm

  18. Changes in total bilirubin (umol/L) over time (hospitalised participants only) [ Time Frame: Days 0/1, 3, 5, 8, 11, 15, 29 ]
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm

  19. Changes in Alanine Aminotransferase (U/L) over time (hospitalised participants only) [ Time Frame: Days 0/1, 3, 5, 8, 11, 15, 29 ]
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm

  20. Changes in Aspartate Aminotransferase U/L over time (hospitalised participants only) [ Time Frame: Days 0/1, 3, 5, 8, 11, 15, 29 ]
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm

  21. Adverse events of special interest- hyperkeratosis, infections and dental complications [ Time Frame: 1-29 days ]
    Evaluation of the safety of the intervention through 29 days of follow-up as compared to the control arm


Other Outcome Measures:
  1. Percent of participants with SARS-CoV-2 detectable in nasopharyngeal sample [ Time Frame: Day 15 and day 29 ]
    Evaluation of the virologic efficacy of Brensocatib

  2. Quantitative SARS-CoV-2 virus in nasopharyngeal samples. [ Time Frame: Day 15 and day 29 ]
    Evaluation of the virologic efficacy of Brensocatib

  3. Neutrophil elastase and heparin binding protein measurement in blood [ Time Frame: Days 1, 8, 15, 29 ]
    Evaluation of the virologic efficacy of Brensocatib

  4. Blood Neutrophil Elastase activity [ Time Frame: Days 1, 15, 29 ]
    Evaluation of the virologic efficacy of Brensocatib

  5. Neutrophil extracellular trap release [ Time Frame: Days 1, 15, 29 ]
    Evaluation of the virologic efficacy of Brensocatib

  6. Neutrophil surface protein expression analysis [ Time Frame: Days 1, 15, 29 ]
    Evaluation of the virologic efficacy of Brensocatib by flow cytometry- CD88, CXCR2, CD66b, CD11b, CD63)

  7. Neutrophil phagocytosis of FITC-labelled bacteria by flow cytometry [ Time Frame: Days 1, 15, 29 ]
    Evaluation of the virologic efficacy of Brensocatib by flow cytometry

  8. Quality of Life measured by EuroQol-5 dimensions-5 levels (EQ-5D-5L) [ Time Frame: Day 29 ]
    To evaluate patient reported outcome measures between the groups using EQ-5D-5L questionnaire. 5 dimensions score 0-20, higher score indicated worse outcome. Visual analog score 0-100, higher score indicates better outcome.



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

Inclusion Criteria:

6.1. 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.

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. 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.

-


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): NCT04817332


Locations
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United Kingdom
NHS Grampian
Aberdeen, United Kingdom
Royal United Hospitals Bath NHS Foundation Trust
Bath, United Kingdom
University Hospitals Birmingham NHS Foundation Trust
Birmingham, United Kingdom
Cardiff & Vale University Health Board
Cardiff, United Kingdom
NHS Tayside
Dundee, United Kingdom
NHS Fife
Dunfermline, United Kingdom
Frimley Health NHS Foundation Trust
Frimley, United Kingdom
Princess Alexandra Hospital NHS Trust
Harlow, United Kingdom
NHS Highland
Inverness, United Kingdom
NHS Forth Valley
Larbert, United Kingdom
University Hospitals of Leicester NHS Trust
Leicester, United Kingdom
Liverpool University Hospitals NHS Foundation Trust
Liverpool, United Kingdom
Portsmouth Hospitals NHS Trust
Portsmouth, United Kingdom
Sheffield Teaching Hospitals NHS Foundation Trust
Sheffield, United Kingdom
University Hospitals North Midlands NHS Trust
Stoke-on-Trent, United Kingdom
NHS Lanarkshire
Wishaw, United Kingdom
Sponsors and Collaborators
University of Dundee
NHS Tayside
Insmed Incorporated
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Responsible Party: University of Dundee
ClinicalTrials.gov Identifier: NCT04817332    
Other Study ID Numbers: 01.01.20
2020-001643-13 ( EudraCT Number )
281986 ( Other Identifier: IRAS )
First Posted: March 26, 2021    Key Record Dates
Last Update Posted: August 17, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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COVID-19
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases