NCT04817332: STOP-COVID19

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

Completed Phase 3 Results posted Last updated 22 August 2023

What this trial tests

Phase 3 trial testing Brensocatib in Covid19 in 406 participants. Completed in 28 February 2021.

Timeline

5 June 2020

Primary endpoint
28 February 2021

28 February 2021

Quick facts

Lead sponsor	University of Dundee
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	406
Start date	5 June 2020
Primary completion	28 February 2021
Estimated completion	28 February 2021
Sites	16 locations across United Kingdom

Drugs / interventions tested

• Brensocatib (BRENSOCATIB) — full drug profile →
• Placebo

Conditions studied

• Covid19 — all drugs for Covid19 →

Sponsor

University of Dundee

Who can join

16 and older, any sex, with Covid19. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Comparison of Participant Clinical Status Between Treatment Arms Primary · 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.

Not hospitalized, no limitations on activities

Group	Value	95% CI
Brensocatib	28
Placebo	40

Not hospitalized, limitations on activities

Group	Value	95% CI
Brensocatib	112
Placebo	129

Hospitalized, not requiring supplemental oxygen

Group	Value	95% CI
Brensocatib	7
Placebo	11

Hospitalized, requiring supplemental oxygen

Group	Value	95% CI
Brensocatib	6
Placebo	1

Hospitalized, on non-invasive ventilation or high flow oxygen devices

Group	Value	95% CI
Brensocatib	0
Placebo	1

Hospitalized, on invasive mechanical ventilation or ECMO

Group	Value	95% CI
Brensocatib	5
Placebo	6

Death

Group	Value	95% CI
Brensocatib	29
Placebo	23

Improvement of One Category From Admission Using 7-point Ordinal Scale. Secondary · Day 29

Evaluation of the clinical efficacy of Brensocatib relative to standard care: 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, limitations 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

Group	Value	95% CI
Brensocatib	159
Placebo	186

Participant Clinical Status on 7-point Ordinal Scale Secondary · Day 15

Evaluation of the clinical efficacy of Brensocatib relative to standard care: 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, limitations 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

Not hospitalised, no limitations on activities

Group	Value	95% CI
Brensocatib	22
Placebo	26

Not hospitalised, limitations on activities

Group	Value	95% CI
Brensocatib	103
Placebo	124

Hospitalised, not requiring supplemental oxygen

Group	Value	95% CI
Brensocatib	12
Placebo	19

Hospitalised, requiring supplemental oxygen

Group	Value	95% CI
Brensocatib	16
Placebo	13

Hospitalised, on non-invasive ventilation or high flow oxygen devices

Group	Value	95% CI
Brensocatib	3
Placebo	5

Hospitalised, on invasive mechanical ventilation or ECMO

Group	Value	95% CI
Brensocatib	9
Placebo	6

Death

Group	Value	95% CI
Brensocatib	20
Placebo	18

Missing

Group	Value	95% CI
Brensocatib	5
Placebo	3

Mean Change in the 7-point Ordinal Scale Secondary · Baseline to days 3, 5, 8, 11 and 29

Evaluation of the clinical efficacy of Brensocatib relative to standard care: 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, limitations 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

Baseline to day 29

Group	Value	95% CI
Brensocatib	1.0	± 2.0
Placebo	1.3	± 2.0

Baseline to day 15

Group	Value	95% CI
Brensocatib	1.0	± 1.8
Placebo	1.2	± 1.6

Baseline to day 11

Group	Value	95% CI
Brensocatib	0.9	± 1.6
Placebo	1.1	± 1.5

Baseline to day 8

Group	Value	95% CI
Brensocatib	0.7	± 1.5
Placebo	0.9	± 1.0

Baseline to day 5

Group	Value	95% CI
Brensocatib	0.5	± 1.1
Placebo	0.5	± 1.1

Baseline to day 3

Group	Value	95% CI
Brensocatib	0.2	± 0.8
Placebo	0.2	± 0.9

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. Secondary · Up to 29 days

Evaluation of the clinical efficacy of Brensocatib relative to standard care: National Early Warning Score (NEWS). NEWS is a system that scores 6 physiological parameters (respiration rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or new-onset confusion, temperature) to give an aggerate score. Minimum score is 1, maximum score is 20.. Higher scores indicate worsening clinical outcomes.

Group	Value	95% CI
Brensocatib	172
Placebo	195

Change From Baseline of National Early Warning Score (NEWS). Secondary · Baseline to day 15

Evaluation of the clinical efficacy of Brensocatib relative to standard care: National Early Warning Score. NEWS is a system that scores 6 physiological parameters (respiration rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or new-onset confusion, temperature) to give an aggerate score. Minimum score is 1, maximum score is 20.. Higher scores indicate worsening clinical outcomes.

-11

Group	Value	95% CI
Brensocatib	1
Placebo	0

-9

Group	Value	95% CI
Brensocatib	2
Placebo	0

-8

Group	Value	95% CI
Brensocatib	0
Placebo	1

-7

Group	Value	95% CI
Brensocatib	1
Placebo	0

-6

Group	Value	95% CI
Brensocatib	0
Placebo	2

-5

Group	Value	95% CI
Brensocatib	1
Placebo	0

-4

Group	Value	95% CI
Brensocatib	1
Placebo	3

-3

Group	Value	95% CI
Brensocatib	4
Placebo	1

Number of Oxygen Therapy Free Days Secondary · 1-29 days

Evaluation of the clinical efficacy of Brensocatib relative to standard care: oxygenation

Group	Value	95% CI
Brensocatib	24	11 – 27
Placebo	24.5	17 – 27

Incidence and Duration of New Oxygen Therapy Use During the Trial Secondary · 0-29 days

Evaluation of the clinical efficacy of Brensocatib relative to standard care: oxygenation

Group	Value	95% CI
Brensocatib	0	0 – 2
Placebo	0	0 – 1

Number of Mechanical Ventilator Free Days Secondary · 1-29 days

Evaluation of the clinical efficacy of Brensocatib relative to standard care: Mechanical ventilation

Group	Value	95% CI
Brensocatib	28	22 – 28
Placebo	28	26 – 28

Incidence and Duration of New Mechanical Ventilation Use During the Trial. Secondary · 1-29 days

Evaluation of the clinical efficacy of Brensocatib relative to standard care: Mechanical ventilation

Group	Value	95% CI
Brensocatib	0	0 – 0
Placebo	0	0 – 0

Duration of Hospitalisation (Days). Secondary · Duration between date of admission and discharge assessed up to 29 days.

Evaluation of the clinical efficacy of Brensocatib relative to standard care: hospitalisation

Group	Value	95% CI
Brensocatib	8.4	± 8.3
Placebo	8.2	± 8.3

28-day Mortality Secondary · Day 1 to 29

Evaluation of the clinical efficacy of Brensocatib relative to standard care: mortality. Survival analysis was used to compare 28-day mortality between the treatment arms. Participants who did not die were censored on the last study day. Those who withdrew or were loss to follow-up and their day 29 status was unknown were censored at the date of loss to follow-up/withdrawal. Other participants were censored 28 days from randomisation in study time.

Group	Value	95% CI
Brensocatib	29
Placebo	23

Adverse events — posted to ClinicalTrials.gov

Time frame: 29 days. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Brensocatib

Serious: 40/192 (21%)

Deaths: 29/192

Placebo

Serious: 35/214 (16%)

Deaths: 23/214

Serious adverse events (11 terms)

Reaction	System	Brensocatib	Placebo
Infections	Infections and infestations	—	—
Respiratory disorders	Respiratory, thoracic and mediastinal disorders	—	—
Nervous system disorders	Nervous system disorders	—	—
Gastrointestinal disorders	Gastrointestinal disorders	—	—
Psychiatric disorders	Psychiatric disorders	—	—
Skin disorders	Skin and subcutaneous tissue disorders	—	—
Cardiac disorders	Cardiac disorders	—	—
General disorders	General disorders	—	—
Neoplasms	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Renal and urinary disorders	Renal and urinary disorders	—	—
Vascular disorders	Vascular disorders	—	—

Other adverse events (113 terms — click to expand)

Reaction	System	Brensocatib	Placebo
Rash	Skin and subcutaneous tissue disorders	—	—
Dizziness	Nervous system disorders	—	—
Chest pain	General disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Oral candidiasis	Infections and infestations	—	—
Chest discomfort	General disorders	—	—
Peripheral swelling	General disorders	—	—
Hiccups	Respiratory, thoracic and mediastinal disorders	—	—
Insomnia	Psychiatric disorders	—	—
Alanine aminotransferase increased	Investigations	—	—
Palpitations	Cardiac disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Headache	Nervous system disorders	—	—
Vision blurred	Eye disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Dry mouth	Gastrointestinal disorders	—	—
Mouth ulceration	Skin and subcutaneous tissue disorders	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Pollakiuria	Renal and urinary disorders	—	—
Respiratory tract infection	Infections and infestations	—	—
Vulvovaginal candidiasis	Infections and infestations	—	—
Chronic lymphocytic leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Peripheral ischaemia	Vascular disorders	—	—
Cold sweat	General disorders	—	—
Swelling face	General disorders	—	—
Oedema peripheral	General disorders	—	—
Extravasation	General disorders	—	—
Malaise	General disorders	—	—
Feeling hot	General disorders	—	—
Pneumothorax	Respiratory, thoracic and mediastinal disorders	—	—

Most-reported serious reactions: Infections, Respiratory disorders, Nervous system disorders, Gastrointestinal disorders, Psychiatric disorders, Skin disorders, Cardiac disorders, General disorders.

Data from ClinicalTrials.gov NCT04817332 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment.
   Drożdżal S, Rosik J, Lechowicz K, Machaj F, et al · · 2021 · cited 186× · PMID 34991982 · DOI 10.1016/j.drup.2021.100794
2. Neutrophils in COVID-19: Not Innocent Bystanders.
   McKenna E, Wubben R, Isaza-Correa JM, Melo AM, et al · · 2022 · cited 76× · PMID 35720378 · DOI 10.3389/fimmu.2022.864387
3. Small molecules in the treatment of COVID-19.
   Lei S, Chen X, Wu J, Duan X, et al · · 2022 · cited 74× · PMID 36464706 · DOI 10.1038/s41392-022-01249-8
4. Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza.
   Cambier S, Metzemaekers M, de Carvalho AC, Nooyens A, et al · · 2022 · cited 50× · PMID 34793331 · DOI 10.1172/jci.insight.155055
5. Neutrophils as emerging protagonists and targets in chronic inflammatory diseases.
   Rawat K, Shrivastava A. · · 2022 · cited 35× · PMID 36289077 · DOI 10.1007/s00011-022-01627-6
6. On the Origin of Neutrophil Extracellular Traps in COVID-19.
   Pastorek M, Dúbrava M, Celec P. · · 2022 · cited 25× · PMID 35359960 · DOI 10.3389/fimmu.2022.821007
7. Targeting Cathepsin C in PR3-ANCA Vasculitis.
   Jerke U, Eulenberg-Gustavus C, Rousselle A, Nicklin P, et al · · 2022 · cited 25× · PMID 35292437 · DOI 10.1681/asn.2021081112
8. Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the protein kinase C inhibitor ruboxistaurin.
   Dowey R, Cole J, Thompson AAR, Hull RC, et al · · 2022 · cited 19× · PMID 35382002 · DOI 10.1183/23120541.00596-2021