STOP-COVID19: Superiority Trial Of Protease Inhibition in COVID-19
Condition: Covid19
MeSH terms: COVID-19
Intervention: Brensocatib; Placebo
Intervention description: Selective, competitive, and reversible inhibitor of DPP1; Matched placebo
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 406.0
Sex: All
Minimum age: 16 Years
Healthy volunteers: No

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.
    

Eligibility 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.

        -