Clinical trial NCT04817332
Conditions: Covid19
Sponsor: University of Dundee
Start date: 2020-06-05; Completion date: 2021-02-28
Enrollment: 406 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:
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.

Mortality from COVID-19 has been estimated at between 0.5% and 3.4% of infected patients and occurs most frequently because of the development of ARDS. In contrast to some, particularly bacterial pneumonias, where patients present with acute respiratory failure and sepsis, the dynamics of COVID-19 infection demonstrate a slow deterioration in oxygenation with the development of bilateral infiltrates in a high proportion of patients, consistent with the development of ARDS. Patients subsequently require mechanical ventilation.

Treatments that could prevent the requirement for mechanical ventilation or shorten the duration of intensive care unit stay by reducing the severity of ARDS are therefore the number 1 target for COVID-19 therapy.

Neutrophils in ARDS Neutrophil influx into the extravascular compartments of the lungs is a defining characteristic of ARDS. During ARDS, circulating neutrophils become primed, resulting in reduce deformability and retention within the pulmonary capillary bed. They then migrate across the endothelium through the interstitium and epithelium into the airways themselves. As neutrophils migrate they are activated and release oxidants, proteases and neutrophil extracellular traps. All of these processes are important in killing bacterial pathogens but in ARDS these processes become prolonged and excessive leading to progressive lung damage. Neutrophil elastase and other neutrophil proteases such as proteinase-3 and cathepsin-G cause tissue injury resulting in increased epithelial and endothelial permeability which leads to the influx of protein-rich alveolar oedema.

Mortality in ARDS correlates directly with the extent of neutrophilia in the lung. Both human clinical data and murine studies demonstrate a key role for neutrophils in ARDS. Neutrophil depletion in multiple models of ARDS including those induced by lipopolysaccharide, acid, ventilator lung injury, transfusion and other stimuli, reduces the severity of acute lung injury including endothelial-epithelial cell damage and capillary-alveolar permeability.

Neutrophil proteases and particularly neutrophil elastase are believed to be central to the neutrophil induced lung damage. Neutrophil elastase is a serine protease contained within primary neutrophil granules which is released in response to neutrophil activation or neutrophil extracellular trap formation. It is involved in the pathogenesis of multiple inflammatory diseases and therapeutic development of neutrophil elastase inhibitors for use in ARDS has been ongoing for many years. Neutrophil elastase is markedly elevated in human ARDS samples and the inhibition of neutrophil elastase has been demonstrated to reduce epithelial injury in multiple animal models of lung injury across multiple stimuli including lipopolysaccharide (LPS), bleomycin, ventilation, sepsis and many others. Neutrophil elastase is critical to the development of neutrophil extracellular traps, which are highly damaging webs of DNA studded with proteases and other neutrophil derived toxins. Neutrophil extracellular traps (NET) formation and the failure to clear NETs have been strongly implicated in the development and poor outcomes from ARDS. Inhibition of neutrophil elastase reduces the formation of NETs.

A challenge therapeutically has been how to inhibit neutrophil elastase since administration of competitive inhibitors either orally or through the inhaled route may not be sufficient to block elastase activity in the lung.

RATIONALE Neutrophil elastase, proteinase-3 and cathepsin-G are activated during neutrophil maturation in the bone marrow through dipeptidyl peptidase 1 (DPP1; also known as cathepsin C), which removes the N-terminal dipeptide sequence of neutrophil serine proteases allowing active enzymes to be packaged into granules prior to release of neutrophils into the circulation. Brensocatib (INS1007, formerly AZD7986) is an orally delivered selective, competitive, and reversible inhibitor of DPP1. Brensocatib has been shown to inhibit neutrophil serine protease activity in blood in both animal models and healthy volunteers.

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. Due to the need to replace the circulating pool of neutrophils with new neutrophils which are deficient in elastase, Brensocatib does not have its effect immediately, but rather over several days. Elastase concentrations were reduced at the first time point at day 14 in the phase 2 study, with very large reductions observed at the second time point at day 28.

In a cohort of 191 hospitalised COVID-19 patients with a completed outcome, the median time from illness onset to discharge was 22·0 days (IQR 18·0-25·0) and the median time to death was 18·5 days (15·0-22·0). Thirty-two patients (17%) required invasive mechanical ventilation and the median time from onset to mechanical ventilation was 14.5 days. The investigators hypothesise that the mechanism of action of Brensocatib to reduce protease activity will be more rapid in COVID-19 patients compared to bronchiectasis due to a more rapid turnover of neutrophils in acute illness. The objective is to test whether by reducing neutrophil protease activity in neutrophils the investigatorscan prevent or reverse the development of ARDS and thereby improve outcomes in individuals with COVID-19 infection.

Arms: arm 1: Brensocatib oral tablet, 25mg once per day for 28 days arm 2: Placebo oral tablet, 25mg once per day for 28 days
Interventions: intervention 1: Brensocatib intervention 2: Placebo
Intervention descriptions: intervention 1: Selective, competitive, and reversible inhibitor of DPP1 intervention 2: Matched placebo

Protocol documents:
Prot_000.pdf: 
HRA Template V1.2 March 2016 
STOP-COVID19 Protocol V9 19-01-21  
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 FULL/LONG TITLE OF THE TRIAL 
A randomised double-blind placebo-controlled trial of Brensocatib (INS1007) in patients with severe 
COVID-19  
SHORT TRIAL TITLE / ACRONYM 
STOP-COVID19: Superiority Trial Of Protease inhibition in COVID-19 
PROTOCOL VERSION NUMBER AND DATE 
V9 19-01-21 
This protocol has regard for the Health Research Authority (HRA) guidance and order of content V1.2 
March 2016 


 
 
 
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RESEARCH REFERENCE NUMBERS 
IRAS Number: 281986 
 
EudraCT Number: 2020-001643-13 
 
SPONSOR Number: 01.01.20 
ISRCTN Ref: ISRCTN30564012 
 
 
 
 
 
  
 
 


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SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator (CI) agrees to conduct the trial in compliance with the approved protocol and will adhere to 
the principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), 
amended regulations (SI 2006/1928) and any subsequent amendments of the clinical trial regulations, 
Good Clinical Practice (GCP) guidelines, the Sponsor’s (and any other relevant) SOPs, and other 
regulatory requirements as amended. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of the Sponsor. 
I also confirm that I will make the findings of the trial publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent account 
of the trial will be given; and that any discrepancies and serious breaches of GCP from the trial as 
planned in this protocol will be explained. 
For and on behalf of the Trial Sponsor: 
Signature:  
Date: 21/01/2021 
Name (please print): 
Patricia Burns 
Position: Senior Research Governance Manager 
Chief Investigator:    
Signature:   
Date: 19/01/2021 
Name: (please print): 
Prof. James Chalmers 
Statistician: 
Signature:  
Name: (please print): 
Position: …………………………. 


 
 
 
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1.
KEY TRIAL CONTACTS
Insert full details of the key trial contacts including the following 
Chief Investigator 
Prof. James Chalmers. Division of Cardiovascular Medicine, 
Level 5, Mailbox 12, Ninewells Hospital, Dundee, DD1 9SY, 
01382 383642 j.chalmers@dundee.ac.uk 
Trial Co-ordinator 
Margaret Band, Senior Trial Manager, Tayside Clinical Trials 
Unit, TASC, Residency Block, Level 3, Ninewells Hospital, 
Dundee, DD1 9SY  01382383097 m.band@dundee.ac.uk 
Sponsor 
University of Dundee & NHS Tayside 
Patricia Burns, Senior Research Governance Manager, 
Research & Development Office, TASC, Residency Block 
Level 3, George Pirie Way, Ninewells Hospital, Dundee DD1 
9SY, 01382 383297, TASCgovernance@dundee.ac.uk 
Funder(s) 
Insmed Inc, 700 US-206, Bridgewater Township, New Jersey, 
08807, USA 
Clinical Trials Unit 
Tayside Clinical Trials Unit, TASC, Residency Block, Level 3, 
Ninewells Hospital, Dundee, DD1 9SY 01382 383581, 
TCTU@dundee.ac.uk 
Key Protocol Contributors 
Data Management: Emma McKenzie, Clinical Trials 
Information Systems Manager, Tayside Clinical Trials Unit 
(TCTU), TAyside Medical Science Centre (TASC), School of 
Medicine, University of Dundee, 01382 383952 
E.J.McKenzie@dundee.ac.uk  
Statistician 
TBC 
Trials Pharmacist 
Shona Carson, Clinical Trials Pharmacy, Level 5, Ninewells 
Hospital, Dundee, DD1 9SY, 01382 632969, 
tay.clinicaltrials@nhs.scot 
Committees 
Data Monitoring Committee 
Oriol Sibila Vidal, Hospital Universitari de la Santa Creu i Sant 
Pau, Universitat Autónoma Barcelona, Barcelona, Spain 
osibila@clinic.cat 
Dr Aran Singanayagam, MRC Clinical Scientist and Honorary 
Consultant in Respiratory Medicine, Faculty of Medicine, 
Department of Infectious Diseases, Imperial College London, 
St Mary’s Hospital, Praed St, London, W2 1NY 
a.singanayagam@imperial.ac.uk
Prof Alex McConnachie, Professor of Clinical Trial 
Biostatistics, Robertson Centre for Biostatistics, University of 
Glasgow, Boyd Orr Building, Glasgow G12 8QQ 
Alex.McConnachie@glasgow.ac.uk  


 
 
 
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LIST OF CONTENTS 
 
FULL/LONG TITLE OF THE TRIAL .............................................................................................................. 1 
SHORT TRIAL TITLE / ACRONYM .............................................................................................................. 1 
PROTOCOL VERSION NUMBER AND DATE ............................................................................................. 1 
RESEARCH REFERENCE NUMBERS ........................................................................................................ 2 
SIGNATURE PAGE ...................................................................................................................................... 3 
LIST of CONTENTS ...................................................................................................................................... 6 
I. 
LIST OF ABBREVIATIONS ............................................................................................................. 10 
II. 
TRIAL SUMMARY ........................................................................................................................... 12 
III. 
FUNDING AND SUPPORT IN KIND .......................................................................................... 13 
IV. 
ROLE OF TRIAL SPONSOR AND FUNDER ............................................................................. 13 
V. 
ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITEES/GROUPS &    
INDIVIDUALS .......................................................................................................................................... 13 
VI. 
PROTOCOL CONTRIBUTORS .................................................................................................. 13 
VII. 
KEY WORDS: ............................................................................................................................. 14 
VIII. 
TRIAL FLOW CHART ................................................................................................................. 14 
1. 
BACKGROUND................................................................................................................................... 15 
2. 
RATIONALE ........................................................................................................................................ 16 
2.1. 
Assessment and Management of Risk ................................................................................... 18 
3. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS .............................................................. 18 
3.1. 
Primary objective ..................................................................................................................... 18 
3.2. 
Secondary objectives .............................................................................................................. 18 
3.3. 
Outcome measures/endpoints ................................................................................................ 18 
3.4. 
Primary endpoint/outcome ...................................................................................................... 18 
3.5. 
Secondary endpoints/outcomes .............................................................................................. 18 
3.6. 
Exploratory endpoints/outcomes ............................................................................................. 19 
3.7. 
Table of endpoints/outcomes .................................................................................................. 19 
4. 
TRIAL DESIGN ................................................................................................................................... 20 
5. 
TRIAL SETTING.................................................................................................................................. 21 
6. 
PARTICIPANT ELIGIBILITY CRITERIA ............................................................................................. 21 
6.1. 
Inclusion criteria ...................................................................................................................... 21 
6.2. 
Exclusion criteria ..................................................................................................................... 22 
6.3. 
Co-enrolment ........................................................................................................................... 22 


 
 
 
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7. 
TRIAL PROCEDURES ........................................................................................................................ 23 
7.1. 
Recruitment ............................................................................................................................. 23 
7.2. 
Payment .................................................................................................................................. 23 
7.3. 
Consent ................................................................................................................................... 23 
7.4. 
The randomisation scheme ..................................................................................................... 26 
7.5. 
Blinding .................................................................................................................................... 26 
7.6. 
Emergency Unblinding ............................................................................................................ 26 
7.7. 
Baseline data ........................................................................................................................... 26 
7.8. 
Trial assessments ................................................................................................................... 26 
7.9. 
Long term follow-up assessments ........................................................................................... 28 
7.10. 
Qualitative assessments ..................................................................................................... 28 
7.11. 
Withdrawal criteria ............................................................................................................... 29 
7.12. 
Storage and analysis of clinical samples ............................................................................ 29 
7.13. 
End of trial ........................................................................................................................... 29 
8. 
TRIAL TREATMENTS ......................................................................................................................... 30 
8.1. 
Name and description of investigational medicinal product (IMP) .......................................... 30 
8.2. 
Regulatory status of the drug .................................................................................................. 30 
8.3. 
Product Characteristics ........................................................................................................... 30 
8.4. 
Accountability Procedures ....................................................................................................... 31 
8.5. 
Preparation and labelling of Investigational Medicinal Product .............................................. 31 
8.6. 
Drug storage and supply ......................................................................................................... 31 
8.7. 
Dosage schedules ................................................................................................................... 31 
8.8. 
Dosage modifications .............................................................................................................. 31 
8.9. 
Known drug reactions and interaction with other therapies .................................................... 32 
8.10. 
Concomitant medication ...................................................................................................... 32 
8.11. 
Trial restrictions ................................................................................................................... 32 
8.12. 
Assessment of compliance with treatment .......................................................................... 32 
8.13. 
Name and description of each Non-Investigational Medicinal Product ............................... 33 
9. 
PHARMACOVIGILANCE .................................................................................................................... 33 
9.1. 
Definitions ................................................................................................................................ 33 
9.2. 
Operational definitions for (S)AEs ........................................................................................... 34 
9.3. 
Recording and reporting of SAEs, SARs AND SUSARs ........................................................ 34 
9.4. 
Reference Safety Information ................................................................................................. 35 
9.5. 
Responsibilities ....................................................................................................................... 35 
9.6. 
Notification of deaths ............................................................................................................... 36 


 
 
 
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9.7. 
Pregnancy reporting ................................................................................................................ 36 
9.8. 
Overdose ................................................................................................................................. 36 
9.9. 
Reporting urgent safety measures .......................................................................................... 36 
9.10. 
The type and duration of the follow-up of participants after adverse reactions (AR). ......... 36 
9.11. 
Development safety update reports .................................................................................... 37 
10. 
STATISTICS AND DATA ANALYSIS ............................................................................................. 37 
10.1. 
Sample size calculation ....................................................................................................... 37 
10.2. 
Statistical analysis plan ....................................................................................................... 39 
10.3. 
Subgroup analyses ............................................................................................................. 39 
10.4. 
Adjusted analysis ................................................................................................................ 39 
10.5. 
Interim analysis and criteria for the premature termination of the trial ................................ 39 
10.6. 
Economic evaluation ........................................................................................................... 40 
11. 
DATA MANAGEMENT .................................................................................................................... 40 
11.1. 
Data collection tools and source document identification ................................................... 40 
11.2. 
Access to Data .................................................................................................................... 41 
11.3. 
Archiving .............................................................................................................................. 41 
12. 
MONITORING, AUDIT & INSPECTION ......................................................................................... 41 
12.1. 
Monitoring ............................................................................................................................ 41 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..................................................................... 41 
13.1. 
Research Ethics Committee review & reports .................................................................... 41 
13.2. 
Peer review ......................................................................................................................... 42 
13.3. 
Public and Patient Involvement ........................................................................................... 42 
13.4. 
Regulatory Compliance ....................................................................................................... 42 
13.5. 
Protocol compliance ............................................................................................................ 42 
13.6. 
Notification of Serious Breaches to GCP and/or the protocol ............................................. 43 
13.7. 
Data protection and participant confidentiality .................................................................... 43 
13.8. 
Financial and other competing interests ............................................................................. 44 
13.9. 
Indemnity ............................................................................................................................. 44 
13.10. 
Amendments ....................................................................................................................... 44 
13.11. 
Post-trial care ...................................................................................................................... 44 
13.12. 
Access to the final trial dataset ........................................................................................... 44 
14. 
DISSEMINIATION POLICY ............................................................................................................. 45 
14.1. 
Dissemination policy ........................................................................................................... 45 
14.2. 
Authorship eligibility guidelines and any intended use of professional writers ................... 45 
15. 
REFERENCES ................................................................................................................................ 46 


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16.
APPENDICIES ................................................................................................................................ 49 
16.1. 
Appendix 1-Risk .................................................................................................................. 49 
16.2. 
Appendix 2 - Trial management / responsibilities ............................................................... 50 
16.3. 
Appendix 3 – Authorisation of participating sites ................................................................ 51 
16.4. 
Appendix 4 – Schedule of Procedures ................................................................................ 52 
16.5. 
Appendix 5 – Safety Reporting Flow Chart ......................................................................... 55 
16.6. 
Appendix 6 – Amendment History ....................................................................................... 56 


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I.
LIST OF ABBREVIATIONS
AE 
Adverse Event 
ALT       Alanine aminotransferase 
AR    
 Adverse Reaction 
ARDS     Acute Respiratory Distress Syndrome 
AST       aspartate aminotransferase 
CI 
Chief Investigator 
CNORIS   Clinical Negligence and Other Risks Insurance Scheme 
CoVs     Coronavirus 
CT         Computed Tomography 
CTA     Clinical Trial Authorisation 
CTIMP  Clinical Trial of Investigational Medicinal Product  
DMC 
Data Monitoring Committee 
DSUR Development Safety Update Report 
ECMO   Extracorporeal membrane oxygenation 
eCRF electronic Case Report Form 
eGFR    estimated Glomerular Filtration Rate 
GCP 
Good Clinical Practice 
HRA     Health Research Authority 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File (This forms part of the TMF) 
L    
 litre 
MHRA Medicines and Healthcare products Regulatory Agency 
NET       Neutrophil extracellular traps 
NEWS  National Early Warning Score 
NGT      Nasogastric tube 
NHS R&D   National Health Service Research & Development  
NP    
 Nasopharyngeal  
PCR      Polymerase Chain Reaction 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
PPE       Personal Protective Equipment 


 
 
 
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REC 
Research Ethics Committee 
RNA      Ribonucleic acid 
SAE 
Serious Adverse Event 
SAP       Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SARS   Severe Acute Respiratory Syndrome 
SpO2   peripheral capillary oxygen saturation 
SUSAR Suspected Unexpected Serious Adverse Reaction  
TCTU     Tayside Clinical Trials Unit 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TRuST    Tayside Randomisation System 
TSC 
Trial Steering Committee 
WHO     World Health Organisation 
 
 
 
  
 
 


 
 
 
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II. 
TRIAL SUMMARY 
 
Trial Title 
A randomised double-blind, placebo-controlled trial of Brensocatib 
(INS1007) in patients with severe COVID-19  
Internal ref. no. (or short title) 
STOP-COVID19: Superiority Trial Of Protease inhibition in COVID-
19  
Clinical Phase  
III 
Trial Design 
Multi-centre prospective, randomized placebo-controlled trial 
Trial Participants 
Patients presenting to hospital with PCR confirmed COVID-19 
(SARS-CoV-2 infection) 
Planned Sample Size 
400  
Treatment duration 
28 days 
Follow up duration 
29 days 
Planned Trial Period 
12 months 
 
Objectives 
Outcome Measures 
Primary 
 
To evaluate the efficacy of 
Brensocatib to improve clinical 
outcomes in COVID-19 up to 
day 29 
Clinical status on a 7-point 
ordinal scale 
Investigational Medicinal Product(s) 
Brensocatib (INS1007) 
Formulation, Dose, Route of 
Administration 
Oral tablet, 25mg once per day 
 
 
 


 
 
 
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III. 
FUNDING AND SUPPORT IN KIND 
FUNDER(S) 
Insmed Incorporated, 700 US Highway 
202/206, Bridgewater, NJ 08807, USA        
FINANCIAL AND NON FINANCIALSUPPORT GIVEN 
Supply of Investigational Medicinal Product (IMP) and 
placebo 
£672,306 
IV. 
ROLE OF TRIAL SPONSOR AND FUNDER 
The roles and responsibilities of the Sponsor and Funder will be detailed in the Clinical Research 
Agreement.  
V. 
ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITEES/GROUPS &    
INDIVIDUALS 
The trial will be coordinated by a Trial Management Group (TMG), consisting of the grant holders, 
including the CI, collaborators, statistician, research assistant, trial manager and research nurse where 
appropriate. Details of membership of the TMG will be held in the Trial Master File (TMF). The TMG will 
meet regularly to ensure all practical details of the trial are progressing well and working well and 
everyone within the trial understands them. Minutes of the TMG meetings will be maintained in the TMF. 
The functions of the Trial Steering Committee (TSC) will be undertaken by the TMG. No independent TSC 
will be convened for this trial. 
A Data Monitoring Committee (DMC) will be established to oversee the safety of trial participants. The 
terms of reference of the DMC are detailed in the DMC Charter and held in the TMF. Minutes of the DMC 
will be maintained in the TMF. 
The CI will be responsible for the conduct of the trial. Site delegate(s) will oversee the trial and will be 
accountable to the CI. A trial-specific Delegation Log will be prepared for the trial site, detailing the duties 
of each member of staff working on the trial. 
The trial will be conducted in accordance with the principles of GCP. 
In addition to Sponsorship approval, a favourable ethical opinion will be obtained from an appropriate 
NHS REC. Authorisation from the MHRA, and appropriate National Health Service Research & 
Development (NHS R&D) permissions will be obtained prior to commencement of the trial. 
VI. 
PROTOCOL CONTRIBUTORS 
Chief Investigator, Prof James Chalmers: Initial draft, review and final approval 
Co-investigator, Prof Jacob George: Review 
Senior Trial Manager, Margaret Band: Review 
Senior Research Statistician, Dr Mike Lonergan: Review 
Clinical Trial Pharmacist, Shona Carson: Review 
Clinical Trials Information Systems Manager, Dr Emma McKenzie: Review 


 
 
 
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VII. 
KEY WORDS: 
 
SARS-CoV-2, Coronavirus, COVID-19.  
VIII. 
TRIAL FLOW CHART 
 


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1.
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.1–3 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. We hypothesise that Brensocatib, by blocking damaging 
neutrophil proteases4, 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.5 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).1,6 
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.3 
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. 
Mortality from COVID-19 has been estimated at between 0.5% and 3.4% of infected patients and occurs 
most frequently because of the development of ARDS.8–10 In contrast to some, particularly bacterial 
pneumonias, where patients present with acute respiratory failure and sepsis, the dynamics of COVID-19 
infection demonstrate a slow deterioration in oxygenation with the development of bilateral infiltrates in a 
high proportion of patients, consistent with the development of ARDS.2 Patients subsequently require 
mechanical ventilation.  
Treatments that could prevent the requirement for mechanical ventilation or shorten the duration of 
intensive care unit stay by reducing the severity of ARDS are therefore the number 1 target for COVID-19 
therapy. 
Neutrophils in ARDS 
Neutrophil influx into the extravascular compartments of the lungs is a defining characteristic of ARDS.11 
During ARDS, circulating neutrophils become primed, resulting in reduce deformability and retention 
within the pulmonary capillary bed.11 They then migrate across the endothelium through the interstitium 
and epithelium into the airways themselves. As neutrophils migrate they are activated and release 
oxidants, proteases and neutrophil extracellular traps.12–14 All of these processes are important in killing 
bacterial pathogens but in ARDS these processes become prolonged and excessive leading to 
progressive lung damage. Neutrophil elastase and other neutrophil proteases such as proteinase-3 and 


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cathepsin-G cause tissue injury resulting in increased epithelial and endothelial permeability which leads 
to the influx of protein-rich alveolar oedema.11  
Mortality in ARDS correlates directly with the extent of neutrophilia in the lung.15 Both human clinical data 
and murine studies demonstrate a key role for neutrophils in ARDS.11,16–18 Neutrophil depletion in multiple 
models of ARDS including those induced by lipopolysaccharide, acid, ventilator lung injury, transfusion 
and other stimuli, reduces the severity of acute lung injury including endothelial-epithelial cell damage and 
capillary-alveolar permeability.19–22 
Neutrophil proteases and particularly neutrophil elastase are believed to be central to the neutrophil 
induced lung damage.17 Neutrophil elastase is a serine protease contained within primary neutrophil 
granules which is released in response to neutrophil activation or neutrophil extracellular trap formation.23 
It is involved in the pathogenesis of multiple inflammatory diseases and therapeutic development of 
neutrophil elastase inhibitors for use in ARDS has been ongoing for many years. Neutrophil elastase is 
markedly elevated in human ARDS samples16 and the inhibition of neutrophil elastase has been 
demonstrated to reduce epithelial injury in multiple animal models of lung injury across multiple stimuli 
including LPS, bleomycin, ventilation, sepsis and many others.17,24–27 Neutrophil elastase is critical to the 
development of neutrophil extracellular traps, which are highly damaging webs of DNA studded with 
proteases and other neutrophil derived toxins.12,28 Neutrophil extracellular traps (NET) formation and the 
failure to clear NETs have been strongly implicated in the development and poor outcomes from ARDS.18 
Inhibition of neutrophil elastase reduces the formation of NETs.12 
A challenge therapeutically has been how to inhibit neutrophil elastase since administration of competitive 
inhibitors either orally or through the inhaled route may not be sufficient to block elastase activity in the 
lung.29,30 
2.
RATIONALE
Neutrophil elastase, proteinase-3 and cathepsin-G are activated during neutrophil maturation in the bone 
marrow through dipeptidyl peptidase 1 (DPP1; also known as cathepsin C), which removes the N-terminal 
dipeptide sequence of neutrophil serine proteases allowing active enzymes to be  packaged into granules 
prior to release of neutrophils into the circulation.4 Brensocatib (INS1007, formerly AZD7986) is an orally 
delivered selective, competitive, and reversible inhibitor of DPP1. Brensocatib has been shown to inhibit 
neutrophil serine protease activity in blood in both animal models and healthy volunteers.4 
We 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. Due to the need to replace the circulating pool 
of neutrophils with new neutrophils which are deficient in elastase, Brensocatib does not have its effect 
immediately, but rather over several days. Elastase concentrations were reduced at the first time point at 
day 14 in the phase 2 study, with very large reductions observed at the second time point at day 28.   


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A.
Kaplan-Meier Plot for Time to First Exacerbation
Figure 1. Time to First Exacerbation and Number of Exacerbations (Intention-to-Treat Population). 
 Figure 2. Reductions in sputum neutrophil elastase 
In a cohort of 191 hospitalised COVID-19 patients with a completed outcome, the median time from 
illness onset to discharge was 22·0 days (IQR 18·0–25·0) and the median time to death was 18·5 days 
(15·0–22·0). Thirty-two patients (17%) required invasive mechanical ventilation and the median time from 
onset to mechanical ventilation was 14.5 days.2 Therefore endpoint assessments at day 15 and 29 are 


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proposed below. We hypothesise that the mechanism of action of Brensocatib to reduce protease activity 
will be more rapid in COVID-19 patients compared to bronchiectasis due to a more rapid turnover of 
neutrophils in acute illness. The objective is to test whether by reducing neutrophil protease activity in 
neutrophils we can prevent or reverse the development of ARDS and thereby improve outcomes in 
individuals with COVID-19 infection.  
2.1. Assessment and Management of Risk 
Importantly, despite the fact that bronchiectasis patients have chronic infection with bacteria such as 
Pseudomonas aeruginosa31, no increase in infections was seen in the phase 2 trial. It is therefore 
anticipated that Brensocatib is safe, even in patients with secondary bacterial infection, as Brensocatib 
does not impair other antimicrobial responses in contrast with other more potent immunosuppressive 
drugs such as steroids which are now in clinical trials for COVID-19. More than 50% of bronchiectasis 
exacerbations are viral32, and therefore the safety and efficacy demonstrated in the phase 2 
bronchiectasis study are considered encouraging to go forward to a study in COVID-19. 
A DMC will be convened to review unblinded data from the trial. The independent DMC will review 
adverse events, serious adverse events (SAEs) and laboratory data. The trial stopping criteria will be the 
discovery of an unexpected, significant, or unacceptable risk to the participants caused by treatment with 
the IMP as determined by the DMC.  
 This trial is categorised as: 
Type B = Somewhat higher than the risk of standard medical care 
See Appendix 1 
3.
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS
Hypothesis 
Treatment with Brensocatib in addition to standard care will be superior to standard care alone in 
achieving improved clinical status in patients initially hospitalised with COVID-19.  
3.1. Primary objective 
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 hospitalised with COVID-19. 
3.2. Secondary objectives 
See Section 3.7 
3.3. Outcome measures/endpoints 
See Section 3.7 
3.4. Primary endpoint/outcome 
See Section 3.7 
3.5. Secondary endpoints/outcomes 
See Section 3.7 


 
 
 
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3.6. Exploratory endpoints/outcomes  
See Section 3.7 
3.7. Table of endpoints/outcomes 
Objectives 
Outcome Measures  
Timepoint(s)  
Primary Objective 
Participant clinical status (on a 7-
point ordinal scale)  
In accordance with WHO 
recommendations the primary 
endpoint will be determined by a 
pilot trial of the first 100 
participants. 
 
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. 
Up to day 29 
 
Secondary Objectives 
Outcome Measures  
Timepoint(s)  
Evaluate the clinical efficacy of 
Brensocatib relative to standard 
care in adult patients hospitalised 
with COVID-19 
Clinical Severity 
Time to an improvement of one 
category from admission using 7-
point ordinal scale. 
Participant clinical status on 7-point 
ordinal scale  
Mean change in the 7-point ordinal 
scale  
 
Daily whilst hospitalised 
 
Days 3, 5, 8, 11, 15 and 29. .  
 
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. 
Change from baseline 
 
 
Daily whilst hospitalised 
 
Days 8, 15, 29 
Oxygenation: 
Oxygen free days  
Incidence and duration of new 
oxygen use during the trial 
 
1-29 days 
0-29 days 
 
Mechanical Ventilation: 
Ventilator free days  
 
1-29 days 


 
 
 
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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 
Evaluate the safety of the 
intervention through 28 days of 
follow-up as compared to the 
control arm 
 
Cumulative incidence of SAEs 
Discontinuation or temporary 
suspension of treatment 
Changes in white cell count, 
haemoglobin, platelets, creatinine, 
total bilirubin, ALT, and AST over 
time (hospitalised participants only) 
Adverse events of special interest- 
hyperkeratosis, infections and 
dental complications 
1-29 days 
1-29 days 
 
Days 0/1, 3, 5, 8, 11, 15, 29 
 
 
1-29 days 
Exploratory Objectives 
Outcome Measures  
Timepoint(s)  
Evaluate the virologic efficacy of 
Brensocatib  
 
Percent of participants with SARS-
CoV-2 detectable in 
nasopharyngeal (NP) sample (in 
hospital, Tayside only) 
Quantitative SARS-CoV-2 virus in 
NP samples. (Tayside only) 
Day 15 and day 29 
 
 
 
Day 15 and day 29 
 
*Neutrophil elastase and heparin 
binding protein measurement in 
blood (in hospital, Tayside only) 
*Neutrophil functional studies (NET 
formation, phagocytosis, elastase 
release, neutrophil proteomics- ( 
Tayside and Sheffield only) 
Days 1, 8, 15, 29 
 
 
Days 1, 15, 29 
Quality of life 
EQ-5D-5L administered via 
telephone (if at home) or in person 
if still in hospital 
Day 29 
*These analysis will be omitted in circumstances where there is no laboratory availability to process the 
samples in time, it is not possible to carry out analysis on stored samples.  
4. TRIAL DESIGN 
This is a multi-centre, randomised, double-blind, placebo-controlled, parallel group trial with two treatment 
arms, with 400 participants planned to be randomised  
The two treatment arms are as follows: 
1. Brensocatib 25mg once daily for 28 days 


 
 
 
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2. Placebo once daily for 28 days 
The use of these drugs, including a placebo comparator, is considered to be ethical, as there are no 
antiviral therapies for COVID-19, and UK and WHO guidance recommends that novel agents should only 
be evaluated in the context of a randomized clinical trial. Patients in both arms will therefore receive all 
other therapies required to manage their condition (standard of care) with the exception of other 
investigational products as described in section 6.2.  
Following trial completion or discontinuation, participants should be continued on standard of care. 
Randomisation will be stratified by  
1. Site 
2. Age: <65 years/≥65 years, as age has been shown to be a key risk factor for severe disease and 
mortality 
5. TRIAL SETTING 
This is a multi-centre trial recruiting from 15 NHS Trusts/Boards within UK, if required to fulfil recruitment 
more NHS Trusts/Boards will be added. Participants will be recruited from those presenting with 
symptoms of COVID-19 in an acute setting. This may include accident and emergency departments, 
COVID-19 treatment units and those admitted to secondary care for other reasons with COVID-19.  
6. PARTICIPANT ELIGIBILITY CRITERIA 
It is likely that the assessments to confirm eligibility will be carried out by the clinical team during routine 
care of patients being assessed for COVID-19. Where these assessments have been carried out by the 
clinical team the most recent of these results will be used to prevent duplication and further exposure of 
the trial staff to patients with COVID-19. 
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: 
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. 


 
 
 
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*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. 
6.2. 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 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 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. 
6.3. Co-enrolment 
Co-enrolment into COVID-19 CTIMPs will be described in individual agreements between STOP-
COVID19 and other trials. These agreements will be made available to recruiting sites. Where 
agreements are not in place for specific trials the site should contact the CI and co-enrolment will be 
decided on an individual participant basis. This decision will be documented in the participant’s medical 
record. 
Co-enrolment into COVID-19 non-CTIMP intervention trials will be allowed. 
Co-enrolment to other non-COVID-19 Clinical Trials of Investigational Medicinal Product (CTIMPs) will not 
be allowed. 
Enrolment in observational trials or studies will be allowed. 


 
 
 
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7. TRIAL PROCEDURES  
7.1. Recruitment 
400 male and female adults ≥16 years of age with COVID-19 who meet all eligibility criteria will be 
enrolled.  
Sites will be informed when the target of participants has been reached and will be instructed not to 
recruit any further participants. All participants already consented to take part at this point will go forward 
to randomisation and will be followed to the end of trial. 
It is anticipated that patients with COVID-19 will present to participating hospitals, and that no other 
efforts to recruit potential participants are needed. Recruitment efforts may also include dissemination of 
information about this trial to other medical professionals. 
7.1.1. Participant identification 
Identification of potentially eligible participants will be by a member of the trial staff delegated this role by 
the PI. The trial staff will identify patients admitted to COVID-19 assessment units and elsewhere in the 
hospital with a possible diagnosis of COVID-19.Screening 
The trial staff will access laboratory systems to screen patients with a possible diagnosis of COVID-19 for 
a positive SARS CoV PCR result. For patients with a positive SARS CoV PCR result the trial staff will 
check further inclusion criteria via medical records. Trial staff will work closely with the managing clinical 
teams who may also provide patient lists.   
7.1.2. Ineligible participants 
Anonymised information on participants who are not randomised for CONSORT reporting will include: 
• 
the reason not eligible for trial participation, or if they are eligible but declined 
Where participation in the trial has been discussed with the participant and the individual is found to be 
ineligible for trial participation, they will be thanked and the reasons for the ineligibility fully explained. 
Participants who meet one or more of the exclusion criteria will be withdrawn from the trial. The 
participant may be rescreened if their medical condition changes significantly. 
7.2. Payment  
No payment will be provided to participants as all assessments will be either carried out whilst already in 
hospital or over the phone after discharge. Participants in Tayside and Sheffield will receive travel 
expenses for attendance at the day 29 visit. 
7.3. Consent  
The Principal Investigator (PI) retains overall responsibility for the conduct of research at their site. This 
includes the taking of informed consent of participants at their site. They will ensure that any person 
delegated responsibility to participate in the informed consent process is duly authorised, trained and 
competent to participate according to the ethically approved protocol, principles of GCP and Declaration 
of Helsinki.  
Patients admitted to hospital with a possible diagnosis of COVID-19 will be provided with a participant 
information sheet (PIS) while in hospital. As the trial treatment should commence as soon as possible 


 
 
 
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after a diagnosis of COVID-19 has been confirmed, participants may have less than 24 hours to decide 
whether they wish to participate. 
Only trial staff experienced in consenting participants for CTIMPs will be delegated this role. The consent 
process will be completed face-to-face, and due to the infectious nature of COVID-19, only staff trained in 
the use of the appropriate personal protective equipment (PPE) will be delegated this role. Staff 
completing the consent process will wear the appropriate PPE and follow the hospital’s infection control 
measures for having contact with patients with COVID-19. 
Due to the highly infectious nature of COVID-19 the consenting process described below will be followed. 
Where a participant requests to speak with a physician from the trial team the consent process will not be 
completed until the participant has spoken to the physician and had all their questions answered to their 
satisfaction. 
The original Informed Consent Form (ICF) will be signed by the participant and staff receiving the 
consent. The original ICF will be photographed and a copy printed for filing in the ISF. The original ICF 
will remain with the participant and will be given to the participant or destroyed on discharge depending 
on local infection control policies. If the original ICF is destroyed a copy of the ICF should be given to the 
participant prior to discharge, or posted to them. Alternatively, the person taking the consent will have an 
envelope with a pro forma for the relevant information on it. The ICF is placed in the envelope by person 
taking consent prior to them leaving the room whilst the research staff hold the envelope outside. The 
information on the envelope is completed and the envelope stored securely. After 7 days the envelope 
will be opened and the ICF filed. A copy of the ICF should be given to the participant prior to discharge, or 
posted to them. 
For adults who lose capacity, their previous wishes will remain legally binding and this will remain valid 
unless the protocol changes significantly. If this occurs and further consent is required from a participant 
who has lost capacity, their legal representative will be asked for their consent, see below. In all cases the 
CI or delegate will consult with carers and take note of any signs of objection or distress from the 
participant – the participant will be withdrawn if they raise objection. Where appropriate, the participant 
will be withdrawn from any further research intervention and agreement will be sought from a carer to 
allow data collection. 
Adults with incapacity 
As patients requiring admission to hospital for treatment of COVID-19 are more likely to be older, there is 
likely to be a higher rate of co-morbid disease which may affect the patient’s ability to consent, e.g. 
dementia. With a symptom of high temperature being a feature of COVID-19 there may also be a 
proportion of patients experiencing delirium which could affect their capacity to give informed consent. It 
is felt that it is important to include these patients in the trial to give a representative sample of patients 
with COVID-19, especially as older patients and those with underlying medical conditions are likely to 
have poorer outcomes. Where patients are thought to lack the capacity to give informed consent, this will 
be sought from their legal representative. The participant’s treating clinician will make the decision as to 
whether the participant lacks capacity.  
In Scotland those who can act as legal representative are: 
• 
Personal legal representative i.e.  
o 
Adult's Welfare Guardian or Welfare Attorney, or if not appointed: 
o 
The adult's nearest relative, if neither are reasonably contactable: 
• 
Professional legal representative, i.e. a doctor responsible for the medical treatment of the adult if 
they are independent of the trial, or a person nominated by the healthcare provider. 


 
 
 
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In England and Wales those who can act as a legal representative are: 
• 
Personal legal representative, i.e. a person not connected with the conduct of the trial who is 
suitable to act as the legal representative by virtue of their relationship with the adult, and is 
available and willing to do so. If one is not available: 
• 
Professional legal representative, i.e. a doctor responsible for the medical treatment of the adult if 
they are independent of the study, or a person nominated by the healthcare provider. 
The PIS which the legal representative will receive will include: 
• 
That they are being asked to give consent on behalf of the incapacitated adult, 
• 
That they are free to decide whether they wish to make this decision or not, 
• 
That they are being asked to consider what the adult would want, and to set aside their own 
personal views when making this decision, 
• 
Sufficient information, in an understandable form, about the trial to ensure that they can make an 
informed decision. 
The participant themselves will also receive information, according to their capacity of understanding, 
about the trial and its risks and benefits.  
Where a participant regains their capacity to consent during the course of the trial, informed consent will 
be obtained. The participant will be given a PIS which explains what has happened so far and what their 
on-going consent is for. If a participant regains their capacity to consent after discharge from hospital but 
before the end of their involvement in the trial, the trial staff will discuss the trial with the participant on the 
phone and post a consent form for the participant to complete and return. A record of this will be detailed 
in the participant’s medical records. If a participant regains their capacity to consent but refused to give 
consent to continue in the trial, they will be asked if the data collected up to that point can be used. If 
refused, all data for that participant will be removed from analysis. This decision will be documented in the 
participant’s medical records. 
Eligibility for participation in the trial will be confirmed by the PI or medically qualified delegate. 
7.3.1. Additional consent provisions for collection and use of participant data and biological 
specimens in ancillary trials, if applicable 
Excess biological samples that are being taken for clinical reasons (Tayside only) and research samples 
taken (Tayside and Sheffield only) may be stored in research in labs at the University of Dundee for future 
research, including commercial research, if no longer required for clinical purposes. Specimens will be 
used for submission to ethically approved research tissue banks for future unspecified research held 
within Tayside and will be registered with NHS Tayside Tissue Bank. Future use of those specimens will 
be governed by the NHS Tayside Tissue Bank by a COVID-19 specific committee. 
Consent from participants will be gained for: 
• 
use of their data and specimens in future research unrelated to the clinical condition under trial  
• 
contact by trial staff for further ethically approved future research 
Where a participant subsequently rescinds their consent for this data, specimens and/or future contact, all 
data and specimens collected for these reasons will be destroyed. Any data collected to the point of 
withdrawal will be retained for reasons of public interest in the area of public health (Article 9(2)(i) GDPR). 
 
 


 
 
 
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7.4. The randomisation scheme  
Participants will be allocated to receive either Brensocatib (25mg once daily for 28 days) or placebo in 
addition to standard of care. Randomisation will be 1:1 intervention:placebo. Randomisation will be 
stratified by site and age: <65 years/≥65 years. 
7.4.1. Method of implementing the randomisation/allocation sequence 
After successful completion of screening the participant will be assessed for eligibility for randomization. 
This will be documented in the electronic Case Report Form (eCRF). 
Participants will be randomised by the PI or delegate to one of the two treatment regimens as noted in 
Section 8.1. 
The PI or delegate will use a centrally controlled web-based GCP compliant randomisation system, 
TRuST, run by the UKCRC registered Tayside Clinical Trials Unit (TCTU). TRuST is provided by the 
Health Informatics Centre, University of Dundee. TCTU use a validated randomisation program and will 
securely backup both the randomisation seed and the randomisation allocation. TRuST will provide an 
immediate allocation on screen and confirmation of allocation will be emailed to the site PI, person 
completing randomisation and clinical trials pharmacy. The trial manager, data manager and CI will 
receive treatment allocation emails for all participants at all sites. 
Access to be able to randomise a participant will only be given after completion of appropriate training. 
7.5. Blinding 
Double-blind, placebo-controlled Participants will be allocated via the randomisation system to receive 
either active treatment or matching placebo, see section 8.1 The active treatment/placebo will be 
packaged and labelled so as to not identify the contents. Trial staff and participants will be blind to the 
allocation received. The final unblinding of the treatment allocation will occur after the creation of a final 
locked database. 
7.6. Emergency Unblinding 
TCTU will provide each PI with a login to the interactive web-based randomisation system, Tayside 
Randomisation System (TRuST), for 24-hour emergency unblinding at their site only. The CI will also 
have access to unblind participants at all sites. The date, reason and result will be documented and 
signed by the person carrying out the unblinding. This will be stored in a sealed envelope in the ISF. 
Disclosure of the unblinding result will be to individuals involved in the participant’s care only. Where 
possible, the participant will remain in the trial and continue with the trial procedures. 
In addition, a paper copy of the allocation will be stored securely in NHS Tayside Clinical Trials 
Pharmacy. Unblinding will only be carried out where a physician considers that it is necessary for clinical 
safety. 
7.7. Baseline data 
Baseline data will be collected as per Schedule of Procedures, Appendix 4, and as described below, 
section 7.8. Only information directly related to the objectives and outcome measures detailed in the 
protocol shall be collected. 
7.8. Trial assessments 


 
 
 
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Trial assessments will be performed according to the Schedule of Procedures, Appendix 4.  
After informed consent, the following assessments will be reviewed to determine eligibility requirements 
as specified in the inclusion and exclusion criteria: 
• 
Focused medical history, taken from medical records, including the following information: 
o 
Approximate day of onset of COVID-19 symptoms 
o 
History of chronic medical conditions related to inclusion and exclusion criteria 
o 
Medication allergies 
o 
Review medications and therapies for this current illness  
• 
Review recent radiographic imaging (x-ray or CT scan) 
• 
Physical examination findings 
• 
SpO2 on air 
• 
Obtain blood for screening laboratory evaluations if not done in the preceding 72 hours: 
o 
ALT 
o 
AST 
o 
Creatinine 
o 
eGFR  
o 
Lymphocyte count 
Clinical screening laboratory evaluations will be performed locally by the site laboratory. The overall 
eligibility of the participant to participate in the trial will be assessed once all screening values are 
available. The screening process can be suspended prior to complete assessment at any time if 
exclusions are identified by the trial staff. Equally, if a patient qualifies for participation based on one 
inclusion criteria of severe, e.g requirement for supplemental oxygen, it is not necessary to perform a 
physical examination to confirm the presence of rales or crackles as the patient is already eligible. Trial 
participants who qualify will be immediately randomized. 
It is likely that the above assessments to confirm eligibility will be carried out by the clinical team during 
routine care of patients being assess for COVID-19. Where these assessments have been carried out by 
the clinical team in the preceding 72 hours, the most recent of these results will be used to prevent 
duplication and further exposure of the trial staff to patients with COVID-19. If any screening procedures 
have not been carried out in the previous 72 hours (96 hour for positive SARS-CoV-2 test) hours for these 
will be completed by the trial staff. Screening procedures will only be recorded/carried out after consent. 
For all baseline assessments and follow-up assessments, refer to Schedule of Procedures for procedures 
to be done, and details below for each assessment. 
Clinical Assessments 
It is expected that these clinical assessments will be carried out by the clinical team during routine clinical 
care and documented on a NEWS chart. Where the assessments have been carried out, the results of 
the assessment closest to 8am on the day will be used to prevent duplication and further exposure of the 
trial staff to patients with COVID-19. 
• 
Blood pressure and pulse, lying or seated 
• 
Tympanic temperature 
• 
SpO2  
• 
Record if SpO2 has been measured on air or oxygen concentration the participant was receiving. 
Ordinal Scale 
The ordinal scale is an assessment of the clinical status on a given trial day. Each day, the worst score 
for that day will be recorded. The scale is as follows: 


 
 
 
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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; 
7. Death. 
NEWS Score 
The NEWS score has demonstrated an ability to discriminate patients at risk of poor outcomes. (Smith, 
2016). This score is based on 7 clinical parameters. The NEWS2 Score is being used as an efficacy 
measure. 
This should be evaluated at the assessment recorded closest to 8am on a given trial day. These 
parameters can be obtained from the hospital chart.  
Exploratory assessment- viral shedding 
Where practical 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 
At the Tayside and Sheffield sites only, additional blood will be taken for isolation of peripheral blood 
neutrophils, as per outcome measures section 3.7.  
Exploratory assessment- quality of life 
The validated EQ-5D-5L quality of life tool will be administered to patients who are able to complete the 
questionnaire either in person (those still in hospital) or over the telephone (those at home) to determine 
the impact of treatment on quality of life. 
Clinical Evaluation 
As these participants are in-patients receiving care for COVID-19, they will be monitored as per clinical 
need. Where already obtained for clinical need the following blood results will be recorded at days 1, 3, 5, 
8, 11, 15, 29: 
• 
White cell count, haemoglobin, platelets, neutrophils, eosinophils, lymphocytes 
• 
creatinine, eGFR 
• 
AST and ALT 
Participants discharged home will not receive further safety assessments. It is not necessary to perform 
further blood tests on inpatients for the purposes of safety. Routine blood tests taken as part of routine 
clinical care will be used. If tests are not performed for clinical reasons they will be treated as missing 
data for analysis. 
7.9. Long term follow-up assessments 
Participants will receive long term clinical follow-up as deemed appropriate by local clinical teams. 
7.10. 
Qualitative assessments  
N/A 
 


 
 
 
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7.11. 
Withdrawal criteria  
Participants are free to withdraw at any time and are not obliged to give a reason(s). The CI, PI or 
delegate will make a reasonable effort to ascertain the reason(s), both for those who express their right to 
withdraw and for those lost to follow-up, while fully respecting the individual’s rights.  
The PI may withdraw a participant at any time if it felt to be in the best interest of the participant and 
treatment continuation would be detrimental to the participant’s wellbeing. In addition, the trial drug will be 
discontinued in the following circumstances: 
• 
Persistent adverse effects which are determined to be severe, persistent, treatment-related and 
not responsive to treatment 
• 
If an allergic reaction to trial drug occurs, the trial drug will be stopped and treatment will be 
initiated as appropriate 
• 
Absolute neutrophil count less than 1.0 x 109 cells per L at any time. 
A full explanation for discontinuation of trial drug will be provided to the participant. As the trial is being 
conducted on an intention to treat basis, if the participant has been randomised and given one or more 
dose of IMP, s/he will be asked to complete trial assessments as per the protocol, if the CI/PI considers it 
appropriate, to allow for an intention to treat analysis, but will be censored in the per-protocol analysis. 
Participants are free to refuse to do so. Withdrawn participants will not be prescribed trial drug. 
Those withdrawn, including those lost to follow-up, will be identified and a descriptive analysis of them 
provided, including the reasons for their loss, if known, and its relationship to treatment and outcome. 
7.12. 
Storage and analysis of clinical samples  
Storage and analysis of samples will only occur at the Tayside and Sheffield sites. The anonymisation, 
processing and storing of these specimens will be detailed in a local Laboratory Manual. 
Sheffield: 
• 
Will collect blood samples as per Schedule of Procedures, Appendix 4. 
• 
Neutrophil function studies will be carried out at the Sheffield site. 
• 
Blood will be processed and stored at Sheffield for later transfer to the Tayside laboratory for 
further analysis. Excess may be stored in the Tayside laboratory for future research use after trial 
results have been obtained. 
Tayside: 
• 
Will collect blood, sputum, endo-tracheal and nasal swab samples as per Schedule of 
Procedures, Appendix 4. 
• 
Will carry out analysis as per exploratory end points. 
• 
Preparations of blood, sputum and nasal swabs may be stored for future research use after trial 
results have been obtained.  
• 
Excess biological samples that are being taken for clinical reasons may be stored for future use if 
no longer required for clinical purposes 
7.13. 
End of trial 
The end of trial is defined as completion of day 29 assessments for last participant at all sites. The 
Sponsor and/or CI have the right at any time to terminate the trial for clinical or administrative reasons.  


 
 
 
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The end of the trial will be reported to the Sponsor, REC, MHRA and NHS R&D Office(s) within 90 days, 
or 15 days if the trial is terminated prematurely. The CI will ensure that any appropriate follow-up is 
arranged for all participants. 
A final clinical trial report will be submitted to the MHRA via EudraCT within 1 year of the end of the trial 
and will also be provided to the Sponsor and REC. 
8. TRIAL TREATMENTS 
8.1. Name and description of investigational medicinal product (IMP) 
 
Investigational Medicinal Product 
Dosage, form and strength 
Arm 1 
Brensocatib (INS1007) 
25mg once daily 
Arm 2 
Placebo 
25mg once daily 
 
Treatment is administered for 28 days in total.  
Tablets will be dispensed in bottles containing 35 tablets. Participants will be given the bottle allocated to 
them on discharge and instructed to take the tablets only for a total of 28 days. Written information, 
Participant Diary, will be given telling them when to stop taking their tablets. Participants will also be 
phoned on day 29 as per Schedule of Procedures, at this point they will be reminded that they should 
stop taking their tablets. 
8.2. Regulatory status of the drug 
No marketing authorisation  
8.3. Product Characteristics   
Brensocatib is a film-coated, oral tablet available in a dose strength of 25 mg. The tablets are round, 
biconvex, brown film-coated tablets. The tablets are an immediate-release dosage form with rapid 
dissolution characteristics under in vitro test conditions. Each tablet contains active ingredient 
Brensocatib and the following inactive US Pharmacopeia/National Formulary or European 
Pharmacopoeia compendia ingredients: microcrystalline cellulose, dibasic calcium phosphate dihydrate, 
sodium starch glycolate, silicon dioxide, and glyceryl behenate. The tablet is film coated with 
hypromellose, polyethyleneglycol, titanium dioxide, iron oxide red, iron oxide yellow, and iron oxide black. 
Matching Placebo 
The matching placebo tablet contains microcrystalline cellulose and sodium stearyl fumarate and is 
coated identically to Brensocatib tablets. 
8.3.1. Packaging and Labelling Information 
Brensocatib and matching placebo will be packed in individual high-density polyethylene bottles, labelled 
and stored as described below. 
Labels will be prepared in accordance with Good Manufacturing Practice Annex 13 requirements and 
local regulatory guidelines. The trial drug label on the bottle specifies the appropriate storage. 


 
 
 
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8.3.2. Storage  
All trial drug supplies must be stored in accordance with the label information. Until dispensed to the trial 
participants, the trial drugs will be stored at room temperature between 2°C and 30°C, at the sites in a 
securely locked, limited access storage area under appropriate storage conditions, accessible to 
authorized personnel only. 
8.4. Accountability Procedures 
All IMP will be supplied by Insmed Incorporated. Trial medication will be received by a delegated person 
at the trial site Clinical Trial Pharmacy, handled and stored safely and properly, and kept in a secured 
location as detailed in the IMP Management Plan. All trial clinical supplies will be dispensed only in 
accordance with the protocol.  
The PI or delegated trial staff will maintain an accurate record of the receipt and dispensing of the IMP in 
a drug accountability log. Monitoring of drug accountability will be performed as per Sponsor Monitoring 
Plan. Clinical staff will be asked to return all unused medications and packaging at the end of the trial or 
at the time of discontinuation of treatment. When discharged participants will be given a stamped 
addressed envelope to return unused IMP to trial staff. On return of the medicines, the trial staff will 
perform a check of returns and this will be recorded on the drug accountability log. Unused treatment will 
be disposed of by the Clinical Trial Pharmacy as per local Standard Operating Procedure. Non returned 
IMPs will be recorded by clinical trials pharmacy staff as per the IMP management plan. 
8.5. Preparation and labelling of Investigational Medicinal Product 
Preparation and labelling of trial medication will be performed by Insmed Inc. with annex 13-compliant 
labels. Trial medication will be supplied to Sharp Clinical Service (UK) Ltd who will act as Importer of 
Record for the Sponsor. Sharp will be responsible for distribution of trial medication to trial sites. 
8.6. Drug storage and supply 
Will be detailed in a trial IMP Management Plan. 
8.7. Dosage schedules 
Route of administration: oral. Where a participant is unable to take oral medication they will be excluded 
from the trial. If during the treatment phase a participant becomes unable to take oral medication their 
treatment will be given by nasogastric tube (NGT) where the participant has this in place for clinical 
reasons. After crushing, the tablet should be placed in water for 5-10 mins, after pushing through NGT, 
flush with 10 mL of water (or saline), and clamp NGT for 30 mins. 
Frequency of administration: once daily, before breakfast. On day of randomisation the first dose may be 
given up to 5pm, after that point the first dose should be given the following day before breakfast. The day 
of first dose received will be deemed to be day 1 of the trial. 
Missed doses: if a dose is missed this should be given within 10 hours of the missed dose.  
Maximum duration of treatment: 28 days. Where a participant misses a dose due to being unable to take 
oral medication, or for any other reason, the treatment duration will not be extended. 
8.8. Dosage modifications  
No changes to dosage or regimen will be made during the course of the trial 


 
 
 
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8.9. Known drug reactions and interaction with other therapies 
Results of prior studies indicate that there was little or no effect of a strong CYP3A4/5 inhibitor 
(itraconazole) on the exposures of Brensocatib. However, co-administration of inhibitors of more than 1 
INS1007 elimination pathway (e.g. CYP3A4/5 with CYP2C8 and/or CYP2D6 inhibitors) should be 
cautioned as there is no information on the combined interaction potential. For this reason we have 
excluded patients taking strong CYP3A4/5 inhibitors with the exception of clarithromycin or other 
macrolide antibiotics. Macrolides were permitted in the phase 2 “Willow” trial of Brensocatib (INS1007)  
8.10. 
Concomitant medication 
Details of concomitant medications will be recorded on the trial eCRF on a concomitant medications form.  
8.11. 
Trial restrictions  
Participants should take their usual medication as well as any other medications prescribed for treatment 
of COVID-19 as directed by their clinical team. No concomitant medications will be stopped for trial 
enrolment purposes. 
Participants should not be prescribed Itraconazole, Ketoconazole, diltiazem, verapamil, phenytoin, 
rifampicinprotease/integrase inhibitors or non-nucleoside reverse transcriptase inhibitors whilst taking trial 
medication. The Liverpool HIV checker (https://www.hiv-druginteractions.org/checker) can be used to 
check for interactions. Simvastatin should be used as a surrogate for Brensocatib as it metabolised 
similarly by CYP 3A4. It will be a clinical decision by the PI as to whether trial drug or restricted drug is 
stopped. 
Females of childbearing potential and males must be willing to use a highly effective method of 
contraception (hormonal or barrier method of birth control; abstinence). Contraception should be 
continued until at least 30 days after final dose of IMP taken. Such methods include: 
• 
combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o 
oral 
o 
intravaginal 
o 
transdermal 
• 
progestogen-only hormonal contraception associated with inhibition of ovulation 
o 
oral 
o 
injectable 
o 
implantable  
• 
intrauterine device (IUD)  
• 
intrauterine hormone-releasing system ( IUS)  
• 
bilateral tubal occlusion  
• 
vasectomised partner  
• 
sexual abstinence 
8.12. 
Assessment of compliance with treatment  
Trial drug compliance will be assessed by trial staff in hospitalised participants by checking drug returns 
and medication record sheet. The PI or delegate will collect unused medication and packaging from the 
clinical team. Where participants are discharged from hospital during the treatment phase, returns will not 
be requested, trial staff will ask participants at the day 29 phone call how many tablets are remaining and 
this will be recorded on the accountability log. Trial drug compliance will be assessed from the information 
provided by the participant and the above medication checks 


 
 
 
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8.13. 
Name and description of each Non-Investigational Medicinal Product  
N/A 
9. PHARMACOVIGILANCE 
9.1. Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a medicinal product has 
been administered, including occurrences which are not necessarily caused by or 
related to that product. 
Adverse Reaction (AR) 
 
An untoward and unintended response in a participant to an IMP which is related to 
any dose administered to that participant. 
The phrase "response to an IMP" means that a causal relationship between a trial 
medication and an AE is at least a reasonable possibility, i.e. the relationship 
cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the 
Sponsor as having a reasonable suspected causal relationship to the trial 
medication qualify as ARs. It is important to note that this is entirely separate to the 
known side effects listed in the SmPC. It is specifically a temporal relationship 
between taking the drug, the half-life, and the time of the event or any valid 
alternative etiology that would explain the event. 
Serious Adverse Event 
(SAE) 
A SAE is any untoward medical occurrence that: 
• 
results in death 
• 
is life-threatening 
• 
requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
results in persistent or significant disability/incapacity 
• 
consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if they jeopardise 
the participant or require an intervention to prevent one of the above 
consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in 
which the participant was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more severe. 
Serious Adverse Reaction 
(SAR) 
An adverse event that is both serious and, in the opinion of the reporting 
Investigator, believed with reasonable probability to be due to one of the trial 
treatments, based on the information provided. 
Suspected Unexpected 
Serious Adverse Reaction 
(SUSAR) 
A SAR, the nature and severity of which is not consistent with the information about 
the medicinal product in question set out in the reference safety information. 
 
NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and “severe”, 
the following note of clarification is provided: “Severe” is often used to describe intensity of a specific 
event, which may be of relatively minor medical significance. “Seriousness” is the regulatory definition 
supplied above. 


 
 
 
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9.2. Operational definitions for (S)AEs  
Deterioration of the existing condition, COVID-19, with the exception of death, or known side-effects 
recorded as primary or secondary endpoints are not reported as (S)AEs or (S)ARs but are recorded 
separately. All events resulting in deaths will be reported as SAEs. 
The following events will be deemed as expected in participants with COVID-19 and will not be recorded 
as AEs: 
• 
cough 
• 
pyrexia 
• 
headache 
• 
tiredness 
• 
diarrhoea 
• 
aches and pains 
• 
nasal congestion 
• 
runny nose 
• 
sore throat 
• 
Anosmia 
• 
Loss of taste 
• 
deterioration in renal and or liver function and changes in full blood count parameters; these will 
be recorded as endpoints for the evaluation of safety of the IMP  
Anticipated AEs for the trial drug are be listed in the Reference Safety Information these would not be 
considered to be SUSARs unless the severity of the event was considered to be unexpected.  
All SAEs and SARs will be reported to sponsor, see section 9.3, with the exception of hospitalisation as 
this is recorded as an end point. 
9.3. Recording and reporting of SAEs, SARs AND SUSARs  
AEs will be recorded on the AE Log in the eCRF and will be assessed for severity and causality by the CI 
or PI. AEs occurring from the time a participant consents to join the trial until the participant’s day 29 will 
be recorded. An AE may be classified as a SAE or AR. An initial assessment of expectedness/listedness 
for SAEs will be conducted by the PI based on the Reference Safety Information (RSI).  
Participants discharged from hospital before the end of trial will be given a diary to record adverse events, 
this will be used as an aide memoire for them to report AEs at the telephone follow-up call. This diary will 
not be returned to the trial staff. 
The PI will make a clinical judgment as to whether or not an AE is of sufficient severity to require the 
participant’s discontinuation of treatment. A participant may also voluntarily discontinue treatment due to 
what he or she perceives as an intolerable AE. If either of these occurs, the participant should be given 
appropriate care under medical supervision until symptoms cease, or the condition becomes stable.  
AEs and SAEs will be followed up until recovered/recovered with sequelae/death or for 30 days after 
participant’s day 29 whichever happens first. SUSARS will be followed until resolution. 
The CI, PI or delegate will check the medical records for the occurrence of AEs and hospitalisations at 
every data collection point/telephone call during the trial. Serious AEs (SAEs) will be submitted on an 
SAE form to the Sponsor Pharmacovigilance Section Tay.pharmacovigilance@nhs.scot  within 24 hours 


 
 
 
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of becoming aware of the SAE. All SAEs need to be assessed and signed off by the PI or a delegated 
doctor within the 24hr reporting window. Site PIs will also notify the CI when submitting an SAE.  
The evaluation of expectedness will be made based on the knowledge of the reaction and the relevant 
safety information (RSI) in the Brensocatib Investigators Brochure (IB) (see section 9.4).The Sponsor will 
make the definitive assessment on expectedness for the purposes of SUSAR reporting. 
The Sponsor is responsible for reporting SUSARs to the UK competent authority, the MHRA, and the 
Research Ethics Committee (REC). Fatal or life threatening SUSARs will be reported within 7 days and 
non-fatal and non-life threatening SUSARs within 15 days. 
9.4. Reference Safety Information 
RSI is described in Section 6.6 of the IB. The RSI is used to assess the expectedness of events and will 
be checked by the CI for changes on the anniversary of the issue date of the CTA. Any change to the RSI 
for the IMP will be reviewed and if it changes significantly this may result in a substantial amendment to 
submit the updated IB. 
9.5. Responsibilities 
Principal Investigator (PI):  
• 
Checking medical records for AEs and ARs. 
• 
Using medical judgement in assigning seriousness, causality and whether the event/reaction was 
anticipated using the approved Reference Safety Information. 
• 
Confirmation of eligibility criteria 
Chief Investigator (CI) / delegate: 
• 
Clinical oversight of the safety of participants participating in the trial, including an ongoing review 
of the risk / benefit. 
• 
Using medical judgement in assigning the SAEs seriousness, causality and whether the event 
was anticipated (in line with the Reference Safety Information) where it has not been possible to 
obtain local medical assessment. 
• 
Review of specific SAEs and SARs in accordance with the trial risk assessment and protocol. 
• 
Assigning Medical Dictionary for Regulatory Activities (MedDRA) to all SAEs and SARs. 
• 
Preparing the clinical sections and final sign-off of the Development Safety Update Report 
(DSUR).  
• 
Central data collection and verification of AEs, ARs, SAEs, SARs and SUSARs according to the 
trial protocol onto a database.  
• 
Reporting safety information to the independent oversight committees identified for the trial 
(DMC). 
• 
Notifying PIs of SUSARs that occur within the trial. 
• 
Checking for (annually) and notifying PIs of updates to the Reference Safety Information for the 
trial. 
Sponsor:  
• 
Immediate review of all SUSARs.  
• 
Expedited reporting of SUSARs to the Competent Authority (MHRA in UK) and REC within 
required timelines. 


 
 
 
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• 
Preparing standard tables and other relevant information for the DSUR in collaboration with the 
CI and ensuring timely submission to the MHRA and REC. 
Data Monitoring Committee: 
In accordance with the Trial Terms of Reference for the DMC, periodically reviewing overall safety data to 
determine patterns and trends of events, or to identify safety issues, which would not be apparent on an 
individual case basis. The DMC will also advise on continuation/discontinuation of the trial at these 
reviews. 
9.6. Notification of deaths  
All deaths will be reported to the sponsor irrespective of whether the death is related to disease 
progression, the IMP, or an unrelated event. Reporting of deaths will follow the SAE reporting process 
and will be reported within 24 hours of the PI or delegate becoming aware of the death. 
9.7. Pregnancy reporting  
All pregnancies within the trial (either the trial participant or the participant’s partner, with participants 
consent) will be reported to the CI and the Sponsor using the relevant TASC Pregnancy Notification Form 
within 24 hours of notification. The TASC Pregnancy Notification Form will be submitted to the Sponsor 
Pharmacovigilance Section Tay.pharmacovigilance@nhs.scot  . The pregnancy will be followed up until 
the end of the pregnancy. If the trial participant is a male, informed consent for follow-up will be sought 
from his female partner. 
Pregnancy is not considered an AE unless a negative or consequential outcome is recorded for the 
mother or child/foetus. If the outcome meets the serious criteria, this would be considered an SAE 
9.8. Overdose  
An overdose will be defined as taking more than 50mg of trial medication in a 24-hour period.  
Whilst in hospital, the trial medication will be held and given to participants as per drug record by the 
clinical team. On discharge from hospital, participants will take home enough medication to complete 28 
days of treatment. 
An overdose itself is not an AE. However, if the overdose results in clinical signs and symptoms, it 
requires expedited reporting as if it is an SAE. In the case of an overdose, the PI or delegate should use 
clinical judgment in treating the overdose, and inform the Sponsor immediately.  
9.9. Reporting urgent safety measures  
The CI, PI or delegate will take appropriate immediate urgent safety measures in order to protect the 
participants against any immediate hazard to their health or safety. If any urgent safety measures are 
taken, the CI/Sponsor shall immediately and in any event no later than 3 days from the date the 
measures are taken, give written notice to the MHRA and the relevant REC of the measures taken and 
the circumstances giving rise to those measures.  
9.10. 
The type and duration of the follow-up of participants after adverse reactions (AR). 
Participants with unresolved ARs at end of trial will be followed up until 30 days after participant’s day 29. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be followed up until resolution. Any 


 
 
 
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SUSAR will be reported to the Sponsor irrespective of how long after IMP administration the reaction has 
occurred. 
9.11. 
Development safety update reports 
The DSUR will be prepared jointly by the Sponsor Pharmacovigilance Section and CI and submitted by 
the Sponsor to the MHRA on the anniversary of the date of Clinical Trial Authorisation (CTA). 
The DSUR and reports of SUSARs in the UK, with an HRA CTIMP Safety Report Form, will be sent to 
REC by the Sponsor Pharmacovigilance Section. Any other safety reports, for example, reports of a 
DMC, will be sent by the CI to REC, with a Safety Report Form, and to the Sponsor.  
10. STATISTICS AND DATA ANALYSIS 
10.1. 
Sample size calculation 
In accordance with the WHO multicentre adaptive trial design recommendations, this trial is intended to 
allow for adaptation of blinded confirmation or modification of the primary endpoint33. A brief summary is 
provided here. Details will be described in the interim evaluation analysis plan. 
Blinded endpoint confirmation or modification 
The current plan is to evaluate the primary endpoint up to day 29. Because there is uncertainty about the 
clinical course and potential different trajectories according to baseline disease severity, the day of the 
primary endpoint may be modified based on a blinded evaluation of various time points (e.g., days 7-29). 
[Posch, 2012] This will occur by a blinded evaluation by the statistician and trial steering committee 
without knowledge of treatment assignment.  
The primary outcome uses an ordinal severity scale with 7 categories. The null hypothesis being tested is 
whether the odds of improvement on the ordinal scale is the same for the placebo and experimental 
treatment arms (i.e., whether the common odds ratio differs from 1). 
The proportions of participants in the different categories of the ordinal scale at day 29 in the placebo and 
treatment arm assuming an odds ratio (OR) of 2 are given below. The odds ratio represents the odds of 
improvement in the ordinal scale for treatment relative to placebo control [Whitehead, 1993]  
Table 4 displays four scenarios considered for outcomes under placebo for sample size determination. 
There is significant uncertainty with these assumptions given the limited data available. 
Table 5 shows a range of sample sizes for odds ratios ranging from 1.5 to 2.5 for 85% power. For 90% 
power, increase the sample size by 17%. Table 6 displays the probabilities of being in different categories 
of the ordinal scale under an odds ratio of 2.  
Table 4: Four scenarios considered for outcomes under placebo for sample size determination 
Anticipated 
Severity Outcome 
outcome 
(%) 
Death 
2 
Hospitalised, on 
mechanical ventilation or ECMO 
1 


 
 
 
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Hospitalised, on non- invasive ventilation or 
high flow oxygen 
Devices 
2 
Hospitalised, requiring supplemental oxygen 
7 
Hospitalised, not requiring supplemental 
Oxygen 
8 
Not hospitalised, limitation on activities 
38 
Not hospitalised, no 
limitations on activities 
42 
 
Table 5. Sample size calculations for scenarios in Table 4 for a two-arm trial assuming 85% power 
and various true odds ratios. 
True odds ratio 
Total sample size 
1.5 
774 
1.75 
412 
2.0 
272 
2.25 
201 
2.5 
159 
 
Table 6. Treatment ordinal outcome proportions under odds ratio of 2 for scenario in 
Table 4 at day 15. 
Anticipated 
Severity Outcome 
Control  % 
Treatment % 
Death 
2 
1 
Hospitalised, on mechanical 
ventilation or ECMO 
 
1 
 
0.5 
Hospitalised, on non- invasive 
ventilation or high 
flow oxygen devices 
 
2 
 
1 
Hospitalised, requiring 
supplemental oxygen 
7 
3.8 
Hospitalised, not requiring 
supplemental oxygen 
8 
4.7 
Not hospitalised, limitation on 
activities 
38 
29.7 
Not hospitalised, no 
limitations on activities 
42 
59.2 
Note that columns may not sum to exactly 100 due to rounding errors. 


 
 
 
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Prior to the commencement of the trial, we took the anticipated WHO scenario and the odds ratio of 2 
which required enrolment of 272 participants. Allowing for a potential loss to follow-up of 9% (27 
participants) this meant we will required 300 participants (150 per arm) to achieve 85% power at 5% 
significance. This was subsequently reviewed as part of a pre-specified blinded sample size re-evaluation 
by an independent statistician. The results of this re-evaluation, using data for the primary endpoint 
available in December 2020 found that 300 patients enrolled would provide approximately 88% power to 
detect an odds ratio of 2.0. This, along with the results of other COVID-19 trials were reviewed by the 
Trial Steering Committee (TSC) and DMC who noted that other COVID-19 therapeutics had achieved 
odds ratios lower than 2.0 in the majority of cases. Based on this, the TSC and DMC recommended 
targeting an odds ratio of 1.75. At least 80% power for an odds ratio of 1.75 requires enrolment of a 
minimum of 360 patients with 400 patients provided approximately 85% power. A final sample size of 400 
subjects was therefore recommended by the TSC and subsequently approved by the DMC in December 
2020. Planned recruitment rate 
Recruitment is expected to be completed by the end of January 2021.  
10.2. 
Statistical analysis plan 
The primary analysis will be based on an intention-to-treat population, including participants randomized. 
Similarly, safety analyses will be based a modified intent-to-treat population consisting of all participants 
who were randomized. 
This is a controlled randomized trial testing a superiority hypothesis with a two-sided type I error rate of 
0.05. Secondary hypotheses have been ordered according to relative importance. These will be 
described according to the appropriate summary statistics (e.g., proportions for categorical data, means 
with 95% confidence intervals for continuous data, median for time-to-event data). 
A statistical analysis plan (SAP) will be prepared for analysis of primary and secondary outcomes and will 
include a plan for handling missing data. 
10.2.1. Summary of baseline data and flow of participants 
Detailed in SAP 
10.2.2. Primary outcome analysis 
Detailed in SAP 
10.2.3. Secondary outcome analysis 
Detailed in SAP 
10.3. 
Subgroup analyses 
Detailed in SAP 
10.4. 
Adjusted analysis 
Detailed in SAP 
10.5. 
Interim analysis and criteria for the premature termination of the trial 
For reasonable cause, the PI may terminate a participant’s participation in the trial prematurely. The 
Sponsor may decide to terminate the trial prematurely. If this occurs, written notification of the trial 


 
 
 
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termination is required to be sent to all the sites. Some conditions that may warrant trial termination 
include the following: 
 
• Discovery of an unexpected, significant, or unacceptable risk to the participants in the trial, 
• Decision on the part of the funder to suspend or discontinue development of the investigational product, 
• Decision by a regulatory authority or the Sponsor to stop the trial at any time, were applicable.  
 
If the trial is prematurely terminated, all participants who received a dose of any of the trial drugs and 
have not completed their trial period will be discontinued from the trial drug immediately; all the safety 
procedures required to be performed will be conducted. All discontinued participants will be followed up 
by a phone call 30 days after discontinuation for collection of AEs. The Sponsor will notify the appropriate 
Regulatory bodies in the respective countries regarding the reason for terminating the trial. 
 
The DMC will evaluate the results of the trial in an unblinded fashion for safety. Participant population 
The participant populations whose data will be participated to the trial analysis – both for the primary 
analysis and any applicable secondary analyses will be all-treated population, i.e. any participant 
randomised into the trial that received at least one dose of trial drug. Procedure(s) to account for missing 
or spurious data will be detailed in the SAP. 
The primary analysis will be based on the intention-to-treat principle. The extent of missing data will be 
examined and the reason for drop-out ascertained. Multiple imputation may be used to impute missing 
values if necessary and where assumptions for missing at random data are met. Where imputation is 
used, a sensitivity analysis will be conducted considering only cases without missing data. Complete case 
analysis where missing participants are excluded will be carried out as a secondary analysis.  
10.6. 
Economic evaluation 
No economic evaluation is planned.  
11. DATA MANAGEMENT  
11.1. 
Data collection tools and source document identification 
Medical records will be used as source data. The EQ-5D (interviewer administration) will be completed by 
the research staff and act as source data, the completed form will be filed in the medical notes. All trial 
data relevant to a participant’s general medical history will be recorded in the medical record. The medical 
record will be flagged to state that the patient is participating in the STOP-COVID19 trial. 
The PI or delegate will maintain source documents for each participant in the trial, consisting of hospital 
medical records containing demographic and medical information, laboratory data, electrocardiograms, 
trial questionnaires and the results of any other tests or assessments.  
An eCRF, using CASTOR Electronic Data Capture system, will be provided by TCTU. The trial system 
will be based on the protocol for the trial. Development and validation of the trial database and quality 
control will be done according to TCTU procedures.   
The eCRF will not collect more information than is required to meet the aims of the trial and to ensure the 
eligibility and safety of the participant. 
The PI may delegate eCRF completion but is responsible for completeness, plausibility and consistency 
of the eCRF. Delegated trial staff will enter the data required by the protocol into the eCRFs following 
training in the definitions and methods used in completing the eCRF. Any queries will be resolved by the 


 
 
 
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CI or delegated member of the trial team. On completion of data collection the PI must certify that the 
data entered into the eCRFs are complete and accurate. PI sign off of the eCRF will be embedded in the 
eCRF with the PI using their own login.  
Data verification and cleaning and extraction of data will be performed as per TCTU local procedures and 
detailed in the Data Management Plan.  
Data preservation and sharing will be in accordance with established procedures at the University of 
Dundee. General laboratory data methods and results will be documented in laboratory notebooks and 
then analysed and written up for publication for dissemination to the scientific community (Tayside only). 
All electronic data will be stored on secure University of Dundee or cloud-based servers which are have 
restricted access and have disaster recovery systems in place.  
11.2. 
Access to Data 
The CI, PIs and all institutions involved in the trial will permit trial related-monitoring, audits, REC review, 
and regulatory inspection. In the event of an audit, the CI will allow the Sponsor, representatives of the 
Sponsor or regulatory authorities direct access to all trial records and source documentation. 
11.3. 
Archiving 
Archiving of trial documents will be as detailed in the archiving plan, in compliance with Sponsor SOPs. 
All trial documentation, electronic and paper, will be kept for 25 years. Medical records will be maintained 
in compliance with local NHS policy on retention of medical records. The Sponsor will be responsible for 
archiving the Trial Master and Sponsor File, sites will be responsible for archiving local trial records 
including the Investigator Site File (ISF) and Pharmacy Site File.  
12. MONITORING, AUDIT & INSPECTION 
12.1. 
Monitoring 
A trial risk assessment will be carried out by the Sponsor prior to Sponsorship approval being granted. 
The Sponsor has determined the appropriate extent and nature of monitoring for the trial and will appoint 
appropriately qualified and trained monitors independent to the trial team. A Monitoring Plan will be 
developed by the sponsor based on the trial risk assessment which may include on site monitoring. The 
Monitoring Plan will be reviewed regularly using a risk-based approach and up-dated as required. The 
Monitoring Plan will detail the procedures and anticipated frequency of monitoring, processes reviewed. It 
is anticipated that due to the COVID-19 pandemic that monitoring will be completed remotely. Sites must 
have access to source data for purposes of remote monitoring and assist the Sponsor in monitoring of the 
trial. In recognition that source data may come from different sources at each site, sites shall ensure that 
a source data identification list is supplied to the Monitoring Team in advance of any monitoring review 
and ensure they have this data is available on the agreed date and time to facilitate the review  
13. ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Research Ethics Committee review & reports 
Before the start of the trial, approval will be sought from Scotland A REC (approved to review trials 
requiring ethical approval under the Adults with Incapacity (Scotland) Act 2000) for the trial protocol, ICF 
and other relevant documents, e.g. GP information letters 


 
 
 
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Substantial amendments that require review by REC will not be implemented until the REC grants a 
favourable opinion for the trial. 
All correspondence with the REC will be retained in the TMF.  
An annual progress report will be submitted to the REC within 30 days of the anniversary date on which 
the favourable opinion was given, and annually until the trial is declared ended. It is the CI’s responsibility 
to produce the annual reports as required.  
The CI will notify the REC of the end of the trial. If the trial is ended prematurely, the CI will notify the 
REC, including the reasons for the premature termination. Within one year after the end of the trial, the CI 
will submit a final report with the results, including any publications/abstracts, to the REC. 
A copy of all REC reports will be submitted to the Sponsor. 
13.2. 
Peer review 
This trial has been funded by Insmed Incorporated who have reviewed the grant application and the 
protocol has been reviewed and approved by the Sponsor Committee responsible for this. 
Resulting publications will be reviewed by the referees of the journal to which the paper will be submitted. 
13.3. 
Public and Patient Involvement 
Due to limited time in the development of the protocol, minimal public and patient involvement has been 
planned in the set-up phase. Lay person review of the PIS, ICF and diary has been completed by the 
Edinburgh Clinical Research Facility – Covid-19 Patient Public Involvement Advisory Group. Feedback 
from the group has been adopted throughout these documents. We will involve the European Lung 
Foundation, a European patient group, in dissemination of research results. 
13.4. 
Regulatory Compliance  
The trial will not commence until a CTA is obtained from the Medicines and Healthcare products 
Regulatory Agency (MHRA) and Favourable REC opinion. The protocol and trial conduct will comply with 
the Medicines for Human Use (Clinical Trials) Regulations 2004 and any relevant amendments 
Before any site can enrol participants into the trial, the CI, PI or delegate will ensure that appropriate 
approvals from participating organisations are in place.  
For any amendment to the trial, the CI, PI or delegate, in agreement with the sponsor, will submit 
information to the appropriate body in order for them to issue approval for the amendment. The CI, PI or 
delegate will work with sites (NHS R&D departments at sites as well as the trial delivery team) so they 
can put the necessary arrangements in place to implement the amendment to confirm their support for 
the trial as amended. 
13.5. 
Protocol compliance  
Prospective, planned deviations or waivers to the protocol are not allowed under the UK regulations on 
Clinical Trials and must not be used, e.g. it is not acceptable to enrol a participant if they do not meet the 
eligibility criteria or restrictions specified in the trial protocol. The CI will not implement deviations to the 
protocol except where necessary to eliminate an immediate hazard to trial participants. 
Accidental protocol breaches can happen at any time. They will be adequately documented on the 
relevant forms and reported to the CI and Sponsor using the TASC Breach Reporting and CAPA Form. In 


 
 
 
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the event that there is a breach of the protocol, the nature of and reasons for the breach will be recorded 
in the TMF and documented in the trial TASC Breach Report Log. Breaches from the protocol which are 
found to frequently recur are not acceptable, will require immediate action and could potentially be 
classified as a serious breach. 
13.6. 
Notification of Serious Breaches to GCP and/or the protocol  
A “serious breach” is a breach which is likely to effect to a significant degree – 
a) the safety or physical or mental integrity of the participants of the trial; or 
b) the scientific value of the trial 
The sponsor will be notified immediately of any case where the above definition applies during the trial 
conduct phase. The sponsor of a clinical trial will notify the licensing authority in writing of any serious 
breach of 
a) the conditions and principles of GCP in connection with that trial; or  
b) the protocol relating to that trial, as amended from time to time. 
 
If a serious breach of the protocol or GCP is suspected, this will be reported to the Sponsor immediately 
using the TASC Breach Reporting & CAPA Form and will be recorded in the eCRF and documented in 
the trial TASC Breach Report Log. 
If a breach necessitates a subsequent protocol amendment, this will be submitted to the Sponsor for 
approval and categorisation and then to the appropriate REC, MHRA and NHS R&D for review and 
approvals as appropriate. 
13.7. 
Data protection and participant confidentiality  
The CI and trial staff will comply with the requirements of the General Data Protection Regulation (EU) 
2016/679 (GDPR) and the UK Data Protection Act 2018 or any subsequent amendment or replacement 
thereof with regard to the collection, storage, processing and disclosure of personal data and will uphold 
the principles of GDPR in Article 5. 
The CI and trial staff will also adhere to the NHS Scotland Code of Practice on Protecting Participant 
Confidentiality or local equivalent.    
All trial records and data will be managed in a manner designed to maintain participant confidentiality. All 
records, electronic or paper, will be kept in a secure storage area with access limited to appropriate trial 
staff only. Computers used to collate data will have limited access measures via user names and 
passwords. Age, gender and ethnicity will be the only personal identifiable details held on CASTOR 
Electronic Data Capture system. 
Personal data or data concerning health will not be released without the existence of a legal basis for 
processing under Articles 6 and 9 of GDPR, such as official authority 6(1)e or substantial public interest 
9(2)g. The CI and trial staff will not disclose or use for any purpose other than performance of the trial, 
any data, record, or other unpublished, confidential information disclosed to those individuals for the 
purpose of the trial. Prior written agreement from the Sponsor will be required for the disclosure of any 
said confidential information to other parties. 
Access to collated participant data will be restricted to the CI and appropriate delegated trial staff.  
Where data requires to be transferred, an appropriate Data Transfer Agreement will be put in place. 


 
 
 
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Published results will not contain any personal data that could allow identification of individual 
participants. 
13.8. 
Financial and other competing interests  
The CI has received fees for consulting from the trial funder, Insmed Inc. and holds research grants from 
Insmed. Any conflict of interest declared by site staff shall be notified to the Sponsor and retained in the 
TMF. 
13.9. 
Indemnity 
The University of Dundee and Tayside Health Board are Co-Sponsoring the trial. 
Insurance. – The University of Dundee will obtain and hold Clinical Trials Insurance cover for legal 
liabilities arising from the trial. 
Tayside Health Board will maintain its membership of the Clinical Negligence and Other Risks Insurance 
Scheme (CNORIS) which covers the legal liability of Tayside in relation to the trial. 
Where the trial involves University of Dundee staff undertaking clinical research on NHS participants, 
such staff will hold honorary contracts with Tayside Health Board which means they will have cover under 
Tayside’s membership of the CNORIS scheme. 
Indemnity. The Co-Sponsors do not provide trial participants with indemnity in relation to participation in 
the Trial but have insurance for legal liability as described above. 
Where other Scottish Health Boards are participating as trial sites, those other Scottish Health Boards will 
maintain membership of CNORIS to cover their liability in relation to their conduct of the trial. 
Where other UK NHS organisations are participating as trial sites, those other UK NHS organisations will 
maintain membership of a scheme similar to CNORIS. 
13.10. Amendments  
Amendments to protocol will be conducted in compliance with Sponsor SOPs. The decision to amend the 
protocol will lie with the CI after consultation with the TMG, trial statistician and funder. The CI will seek 
Sponsor approval for any amendments to the Protocol or other approved trial documents. The Sponsor 
will decide whether an amendment is substantial or non-substantial. The CI will be responsible for 
submitting the amendment to the appropriate regulatory authorities and communicating amendments to 
sites. Amendments to the protocol or other trial documents will not be implemented without approval from 
the Sponsor and subsequent approval from the appropriate REC and/or MHRA, as appropriate, and NHS 
R&D Office(s). The amendment history will be detailed in an Amendment Log. 
13.11. Post-trial care 
As the trial treatment is for a 28 day treatment period only, and if used in clinical care would be a one-off 
treatment for COVID-19, no advantage is expected from continuing the trial treatment after the initial 28 
days. Trial treatment will not be made available to participants at the end of the trial. 
13.12. Access to the final trial dataset 
The CI and Trial Statistician will have access to the final trial dataset. Access to the final trial dataset to 
others will be approved by the CI. 


 
 
 
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14. DISSEMINIATION POLICY 
14.1. 
Dissemination policy 
Details of the trial and clinical trial final report will be published on the EudraCT database, the latter no 
later than 12 months after the end of trial, and will be available to the public via the EU Clinical Trial 
Register. The report will be made available to the Funder. The report can be used for publication and 
presentation at scientific meetings. Trial investigators have the right to publish orally or in writing the 
results of the trial. The criteria for authorship will follow the criteria of the International Committee of 
Medical Journal Editors.  
Publications will be reviewed according to the agreed contractual terms but will not restrict the general 
rights outlined above for the Investigators to publish the results of the trial.  
Summaries of results will also be made available to Investigators for dissemination within their clinical 
areas (where appropriate and according to their discretion). A newsletter giving a summary of the results 
of the trial will be made available to participants.  
14.2. 
Authorship eligibility guidelines and any intended use of professional writers 
The data arising from this trial resides with the trial team and ownership with the University of Dundee. 
The criteria for authorship will follow the criteria of the International Committee of Medical Journal Editors. 
On completion of the trial, the trial data will be analysed and tabulated, and a clinical trial final report will 
be prepared. The CI will be responsible for authorship of the final report. 
 
 


 
 
 
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15. REFERENCES 
1.  
Guan W-J, Ni Z-Y, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N 
Engl J Med. February 2020:10.1056/NEJMoa2002032. doi:10.1056/NEJMoa2002032 
2.  
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with 
COVID-19 in Wuhan, China: a retrospective cohort study. Lancet (London, England). March 
2020:S0140-6736(20)30566-3. doi:10.1016/S0140-6736(20)30566-3 
3.  
Ghinai I, McPherson TD, Hunter JC, et al. First known person-to-person transmission of severe 
acute respiratory syndrome  coronavirus 2 (SARS-CoV-2) in the USA. Lancet (London, England). 
March 2020. doi:10.1016/S0140-6736(20)30607-3 
4.  
Palmer R, Maenpaa J, Jauhiainen A, et al. Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a 
Sustained, Exposure-Dependent  Reduction in Neutrophil Elastase Activity in Healthy Subjects. 
Clin Pharmacol Ther. February 2018. doi:10.1002/cpt.1053 
5.  
Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 
2019. N Engl J Med. 2020;382(8):727-733. doi:10.1056/NEJMoa2001017 
6.  
Abo-Leyah H, Chalmers JD. Middle East respiratory syndrome: the need for better evidence in 
severe respiratory viral infections. Crit Care Med. 2015;43(6):1344-1346. 
doi:10.1097/CCM.0000000000001008 
7.  
Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe 
Covid-19. N Engl J Med. March 2020. doi:10.1056/NEJMoa2001282 
8.  
Ramanathan K, Antognini D, Combes A, et al. Planning and provision of ECMO services for 
severe ARDS during the COVID-19 pandemic  and other outbreaks of emerging infectious 
diseases. Lancet Respir Med. March 2020. doi:10.1016/S2213-2600(20)30121-1 
9.  
Deng Y, Liu W, Liu K, et al. Clinical characteristics of fatal and recovered cases of coronavirus 
disease 2019  (COVID-19) in Wuhan, China: a retrospective study. Chin Med J (Engl). March 
2020. doi:10.1097/CM9.0000000000000824 
10.  
Goh KJ, Choong MC, Cheong EH, et al. Rapid Progression to Acute Respiratory Distress 
Syndrome: Review of Current  Understanding of Critical Illness from COVID-19 Infection. Ann 
Acad Med Singapore. 2020;49(1):1-9. 
11.  
Zemans RL, Matthay MA. What drives neutrophils to the alveoli in ARDS? Thorax. 2017;72(1):1-3. 
doi:10.1136/thoraxjnl-2016-209170 
12.  
Toussaint M, Jackson DJ, Swieboda D, et al. Host DNA released by NETosis promotes rhinovirus-
induced type-2 allergic asthma exacerbation. Nat Med. 2017;23(6):681-691. doi:10.1038/nm.4332 
13.  
Porto BN, Stein RT. Neutrophil Extracellular Traps in Pulmonary Diseases: Too Much of a Good 
Thing? Front Immunol. 2016;7:311. doi:10.3389/fimmu.2016.00311 
14.  
Sjo P. Neutrophil elastase inhibitors: recent advances in the development of mechanism-based 
and nonelectrophilic inhibitors. Future Med Chem. 2012;4(5):651-660. doi:10.4155/fmc.12.17 
15.  
Steinberg KP, Milberg JA, Martin TR, Maunder RJ, Cockrill BA, Hudson LD. Evolution of 
bronchoalveolar cell populations in the adult respiratory distress  syndrome. Am J Respir Crit Care 
Med. 1994;150(1):113-122. doi:10.1164/ajrccm.150.1.8025736 
16.  
Donnelly SC, MacGregor I, Zamani A, et al. Plasma elastase levels and the development of the 


 
 
 
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adult respiratory distress  syndrome. Am J Respir Crit Care Med. 1995;151(5):1428-1433. 
doi:10.1164/ajrccm.151.5.7735596 
17.  
Fujino N, Kubo H, Suzuki T, et al. Administration of a specific inhibitor of neutrophil elastase 
attenuates pulmonary  fibrosis after acute lung injury in mice. Exp Lung Res. 2012;38(1):28-36. 
doi:10.3109/01902148.2011.633306 
18.  
Narasaraju T, Yang E, Samy RP, et al. Excessive neutrophils and neutrophil extracellular traps 
contribute to acute lung  injury of influenza pneumonitis. Am J Pathol. 2011;179(1):199-210. 
doi:10.1016/j.ajpath.2011.03.013 
19.  
Abraham E, Carmody A, Shenkar R, Arcaroli J. Neutrophils as early immunologic effectors in 
hemorrhage- or endotoxemia-induced  acute lung injury. Am J Physiol Lung Cell Mol Physiol. 
2000;279(6):L1137-45. doi:10.1152/ajplung.2000.279.6.L1137 
20.  
Kawano T, Mori S, Cybulsky M, et al. Effect of granulocyte depletion in a ventilated surfactant-
depleted lung. J Appl Physiol. 1987;62(1):27-33. doi:10.1152/jappl.1987.62.1.27 
21.  
Folkesson HG, Matthay MA, Hébert CA, Broaddus VC. Acid aspiration-induced lung injury in 
rabbits is mediated by  interleukin-8-dependent mechanisms. J Clin Invest. 1995;96(1):107-116. 
doi:10.1172/JCI118009 
22.  
Looney MR, Matthay MA. Animal models of transfusion-related acute lung injury. Crit Care Med. 
2006;34(5 Suppl):S132-6. doi:10.1097/01.CCM.0000214287.58444.2D 
23.  
Chalmers JD, Moffitt KL, Suarez-Cuartin G, et al. Neutrophil elastase activity is associated with 
exacerbations and lung function decline in bronchiectasis. Am J Respir Crit Care Med. 
2017;195(10). doi:10.1164/rccm.201605-1027OC 
24.  
Ginzberg HH, Cherapanov V, Dong Q, et al. Neutrophil-mediated epithelial injury during 
transmigration: role of elastase. Am J Physiol Gastrointest Liver Physiol. 2001;281(3):G705-17. 
doi:10.1152/ajpgi.2001.281.3.G705 
25.  
Hilgendorff A, Parai K, Ertsey R, et al. Neonatal mice genetically modified to express the elastase 
inhibitor elafin are  protected against the adverse effects of mechanical ventilation on lung growth. 
Am J Physiol Lung Cell Mol Physiol. 2012;303(3):L215-27. doi:10.1152/ajplung.00405.2011 
26.  
Kawabata K, Hagio T, Matsumoto S, et al. Delayed neutrophil elastase inhibition prevents 
subsequent progression of acute lung  injury induced by endotoxin inhalation in hamsters. Am J 
Respir Crit Care Med. 2000;161(6):2013-2018. doi:10.1164/ajrccm.161.6.9904047 
27.  
Tkalcevic J, Novelli M, Phylactides M, Iredale JP, Segal AW, Roes J. Impaired immunity and 
enhanced resistance to endotoxin in the absence of neutrophil  elastase and cathepsin G. 
Immunity. 2000;12(2):201-210. doi:10.1016/s1074-7613(00)80173-9 
28.  
Dicker AJ, Crichton ML, Pumphrey EG, et al. Neutrophil extracellular traps are associated with 
disease severity and microbiota diversity in patients with chronic obstructive pulmonary disease. J 
Allergy Clin Immunol. 2018;141(1). doi:10.1016/j.jaci.2017.04.022 
29.  
Stockley R, De Soyza A, Gunawardena K, et al. Phase II study of a neutrophil elastase inhibitor 
(AZD9668) in patients with bronchiectasis. Respir Med. 2013;107(4):524-533. 
doi:10.1016/j.rmed.2012.12.009 
30.  
Watz H, Pedersen F, Kirsten A, et al. Safety and tolerability of the NE inhibitor BAY 85-8501 in 
patients with non-CF bronchiectasis. Eur Respir J. 2016;48(suppl 60). 


 
 
 
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http://erj.ersjournals.com/content/48/suppl_60/PA4088.abstract. 
31.  
Araujo D, Shteinberg M, Aliberti S, et al. The independent contribution of Pseudomonas 
aeruginosa infection to long-term clinical outcomes in bronchiectasis. Eur Respir J. 2018;51(2). 
doi:10.1183/13993003.01953-2017 
32.  
Gao Y-H, Guan W-J, Xu G, et al. The role of viral infection in pulmonary exacerbations of 
bronchiectasis in adults: a prospective study. Chest. 2015;147(6):1635-1643. 
doi:10.1378/chest.14-1961 
33.      World Health Organisation, Master Protocol: A Multi-centre, Adaptive, Randomized, Double-Blind, 
Placebo-Controlled Clinical Trial of the Safety and Efficacy of Investigational Therapeutics for the 
Treatment of COVID-19 in Hospitalized Patients. 2020 
 
 
 


 
 
 
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16. APPENDICIES 
16.1. 
Appendix 1-Risk 
Risks associated with trial interventions 
 A ≡ Comparable to the risk of standard medical care 
 B ≡ Somewhat higher than the risk of standard medical care 
 C ≡ Markedly higher than the risk of standard medical care 
Justification: This is an investigational therapy but has been shown to be safe and well tolerated over a 6 
month period in over 200 patients with bronchiectasis. The treatment is therefore expected to represent a 
low risk of adverse effects for 28 days treatment.  
Undesirable effects are detailed in section 6.3 of the IB  
What are the key risks related to therapeutic 
interventions you plan to monitor in this trial? 
How will these risks be minimised? 
IMP/Intervention  
Body system/Hazard 
Activity 
Frequency 
Comments 
Increase in severity 
of infections 
Lung 
Close monitoring 
as clinically 
indicated 
 
Not expected in 
view of phase 2 
data 
Hyperkeratosis 
Skin 
Patients told to 
report 
Daily while in 
hospital 
Rare over 6 
months in phase 2 
Dental complications 
 
Teeth 
 
Patients told to 
report 
Daily while in 
hospital 
Not expected with 
short treatment 
duration 
Neutropenia 
Blood 
Regular blood 
tests  
as clinically 
indicated 
Not observed in 
phase 2 study. 
Outline any other processes that have been put in place to mitigate risks to participant safety (e.g. DMC, 
independent data review, etc.) 
Participant safety will be reviewed periodically by the DMC. 
An information sheet will be provided for clinical staff caring for the participant detailing dosing 
instructions and possible adverse effects. 
Outline any processes (e.g. IMP labelling +/- accountability +/- trial-specific temperature monitoring) that 
have been simplified based on the risk adapted approach.  
Nil 
 
 
 


 
 
 
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16.2. 
Appendix 2 - Trial management / responsibilities  
Responsibilities will be detailed the co-sponsorship and model trial agreements. 
16.2.1. Participant registration/randomisation procedure  
TCTU TRuST web-based randomisation system will be used: https://hicservices.dundee.ac.uk/TRuST/  
Sites will be provided with a randomisation guide detailing the web-based randomisation system process. 
Prior to recruitment individuals delegated this task and on completion of training will be given a username 
and password. 
16.2.2. Data management  
Data management will be overseen by TCTU Data Management Team (DMT). 
Local sites will be expected to enter data directly on to the eCRF Worksheets will be provided to facilitate 
this process but their use is not mandatory. Worksheets, where used, will not record source data and will 
not be used for monitoring purposes. 
All data from participants should be entered on the eCRF within 7 days of the last data collection point for 
that participant. 
Data queries will be generated by the DMT and emailed to sites, return of queries should be within 2 
weeks. 
16.2.3. Preparation and submission of amendments  
TCTU Trial Management Team will be responsible for working with the CI to submit any amendments. 
16.2.4. Preparation and submission of Annual Safety Report/Annual 
TCTU Trial Management Team will be responsible for liaising with the CI to submit REC annual reports. 
The Sponsor Pharmacovigilance Team will be responsible for liaising with the CI to submit Annual Safety 
Reports. 
16.2.5. Data protection/confidentiality  
The CI and trial staff will comply with the requirements of the EU General Data Protection Regulation and 
the Data Protection Act 2018 or any subsequent amendment or replacement thereof with regard to the 
collection, storage, processing and disclosure of personal data and will uphold the Principles of GDPR in 
Article 5. 
The CI and trial staff will also adhere to the NHS Scotland Code of Practice on Protecting Participant 
Confidentiality or local equivalent.    
16.2.6. Trial documentation and archiving  
Archiving trial site data will be the responsibility of individual sites. Payment for archiving will be provided 
as per site agreement. 
 


 
 
 
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16.3. 
Appendix 3 – Authorisation of participating sites  
16.3.1. Required documentation  
The following data should be made available to TCTU Trial Management Team prior to site initiation: 
• 
PI CV, signed and dated 
• 
PI GCP certificate 
• 
Protocol signature page, signed and dated by PI 
• 
Copy of signed Participating Site Agreement 
• 
Copy of R&D confirmation of capacity and capability 
The following data should be made available and held within the ISF/PSF prior to site initiation: 
• 
CV, signed and dated for all trial staff listed on Delegation Log 
• 
GCP certificate for all trial staff listed on Delegation Log 
16.3.2. Procedure for initiating/opening a new site  
Site Initiation will be carried out remotely due to COVID-19 pandemic. 
Site Initiation will be performed by Sponsor monitors and TCTU Trial Management Team. 
TCTU Trial Management Team will initiate release of trial drug to the site after R&D confirmation of 
capacity and capability. 
16.3.3. Principal Investigator responsibilities 
The PI’s legal responsibilities will be listed in the Participating Site Agreement a summary is given below: 
• 
Attendance at the initiation teleconference,  
• 
Training of new members of trial staff in the protocol and its procedures,  
• 
Ensuring that the ISF is accurately maintained,  
• 
Dissemination of important safety or trial related information to all stakeholders within their site 
• 
Safety reporting within the required timelines 
• 
Ensuring data entry to eCRF and responses to data clarification queries are completed within the 
required timelines. 
• 
Certify data entered on eCRF is correct and complete. 
• 
Ensuring any trial staff coming into contact with participants have the appropriate Personal 
Protective Equipment and training in its use. 
• 
Archiving of site trial data.


 
 
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16.4. 
Appendix 4 – Schedule of Procedures 
 
Screeningd 
 
 
Randomizationd 
 
 
 
 
Follow-up 
Assessments 
 
Follow-up 
assessments 
 
Follow-up 
Assessments 
 
Unscheduled 
Assessments 
 
Timeline 
Day 0 or 1 
 
Day 1 
Up to 24 hours 
after screening 
Daily whilst 
hospitalised  
Days 3, 5 &11 c 
(telephone call 
if at home) 
Day 8c 
(telephone 
call if at 
home) 
Day 15 c 
(telephone call 
if at home) 
Day 29 c 
(telephone call 
if at homeb) 
As Required in 
the event of AE 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
Check 
X 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Record Concomitant 
Medications 
X 
X 
 
 
X 
X 
X 
X 
Check Vital Signs*^ 
X 
X 
 
 
X∞ 
X∞ 
X∞ 
X 
ECG* 
X 
 
 
 
 
 
 
 
Full blood count*+ 
X 
 
 
X∞ 
X∞ 
X∞ 
X∞ 
 
Urea and electrolytes*+ 
X 
 
 
X∞ 
X∞ 
X∞ 
X∞ 
 
Liver function tests*+ 
X 
 
 
X∞ 
X∞ 
X∞ 
X∞ 
 
SARS CoV-2 PCR*  
X 
 
 
 
 
 
 
 
Record SARS CoV-2 PCR 
results, only if done for 
clinical reasons 
 
 
 
X 
X 
X 
X 
 
Nasal swab for SARS CoV-2 
PCR* (Tayside only) 
 
 
 
 
 
X∞ 
X 
 
Research Blood Sample * 
(Tayside and Sheffield only) 
 
X 
 
 
X∞ 
X∞ 
X 
X 
Sputum sample for storage if 
available*+ (Tayside only) 
 
X 
 
 
X∞ 
X∞ 
X 
 
Endotracheal aspirate 
sample for storage if 
available*+a (Tayside only) 
 
 
 
 
X∞ 
X∞ 
X∞ 
 
Clinical status on 7 point 
scale 
X 
X 
X 
X 
X 
X 
X 
X 
NEWS recording* 
X 
X 
X 
X∞ 
X∞ 
X∞ 
X∞ 
 


 
 
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STOP-COVID19 Protocol V9 19-01-21                                                Page 53 of 57 
 
Screeningd 
 
 
Randomizationd 
 
 
 
 
Follow-up 
Assessments 
 
Follow-up 
assessments 
 
Follow-up 
Assessments 
 
Unscheduled 
Assessments 
 
Timeline 
Day 0 or 1 
 
Day 1 
Up to 24 hours 
after screening 
Daily whilst 
hospitalised  
Days 3, 5 &11 c 
(telephone call 
if at home) 
Day 8c 
(telephone 
call if at 
home) 
Day 15 c 
(telephone call 
if at home) 
Day 29 c 
(telephone call 
if at homeb) 
As Required in 
the event of AE 
EQ-5D questionnaire 
 
 
 
 
 
 
X 
 
Record supplemental 
oxygen* 
X 
X 
 
 
X∞ 
X∞ 
X∞ 
X 
Record CT scan results, only 
if done for clinical reasons 
X 
X 
X 
X∞ 
X∞ 
X∞ 
X∞ 
X∞ 
Pregnancy Testing (urine or 
blood) If Applicable 
X 
 
 
 
 
 
 
 
Record Adverse Events  
 
X 
X 
X 
X 
X 
X 
X 
Randomisation 
 
X 
 
 
 
 
 
 
Dispense Trial Drugs 
 
X 
 
 
 
 
 
 
Drug Return And 
Compliance Check 
 
 
 
 
 
 
X 
 
^ Vital Signs: Blood Pressure, pulse, temperature, oxygen saturation 
*indicates procedures that will be performed by the clinical team as part of routine care but results will be recorded and included in the eCRF. If not 
performed by the clinical team, but clinically indicated, the research team may assist in this being performed but all processes will avoid 
duplication and exposure to potentially infected participants.  
+Excess biological samples that are being taken for clinical reasons may be stored for future use if no longer required for clinical purposes 
(Tayside only). 
a For those participants who are intubated. 
∞These assessments will not be completed if the participant has been discharged from hospital. 
b For the Tayside and Sheffield site only, the day 29 assessments will be carried out face-to-face either at a NHS facility or at the participant’s 
home. Home visits will only be carried out if no one in the household has symptoms of COVID-19.  
cResearch blood samples (Tayside and Sheffield only) and, once discharged, assessments may be completed within +/- 1 day 
dScreening and randomisation may occur on the same day if all eligibility criteria are met. Day of first dose of IMP will be considered as day 1 for 
the calculation of follow up assessments. 


 
 
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16.5. 
Appendix 5 – Safety Reporting Flow Chart  
Activity 
Responsibility 
Timing 
Comments 
Review medical 
records for evidence 
of AEs whilst in 
hospital or ask 
participant if 
discharged. 
Trial staff 
Days 3, 5, 8, 11, 15, 29 
 
Recorded on eCRF system. Where Trial 
Staff are not available on these specific 
days this should be completed asap.  
Review of recorded 
AEs for causality 
and seriousness 
PI (or 
delegate) 
Within 24 hour of 
recording 
Recorded on eCRF and/or medical 
records. 
Reporting SAEs - All 
SAEs need to be 
assessed and 
signed off by the PI 
or delegated doctor. 
PI (or 
delegate) 
Within 24 hours of 
becoming aware of SAE 
SAE form: 
https://www.ahspartnership.org.uk/tasc/for-
researchers/sops/safety-and-
pharmacovigilance 
Reported to: 
Tay.pharmacovigilance@nhs.scot 
j.chalmers@dundee.ac.uk 
Reviewing of SAEs 
Sponsor 
Within 24 hours of 
receiving SAE form 
 
Reporting of 
SUSARs to MHRA 
Sponsor 
Within 7 days if life 
threating or fatal. 
Within 15 days for others  
 
 
 
 
 


 
 
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16.6. 
Appendix 6 – Amendment History 
Amendment 
No. 
Protocol 
version 
no. 
Date 
issued 
Author(s) 
of 
changes 
Details of changes made 
N/A prior to 
full approval 
2 
04-05-20 
M Band/J 
Chalmers 
Requested by MHRA: 
Inclusion criteria to include hospitalised participants. 
Contraception to be used for 30 days after last dose of 
IMP. 
AM02 
3 
20-05-20 
M Band/J 
Chalmers 
Removal of the requirement for Caldicott Guardian 
approval for research staff to identify potential 
participants. Conforms to advice from Confidentiality 
Advisory Group and Public Benefit and Privacy Panel. 
Additional guidance on handling Informed Consent 
Form with COVID-19 patients. 
Minor clarifications to protocol. 
AM04 
4 
30-06-20 
M Band/J 
Chalmers 
Inclusion criteria to include clinically suspected COVID-
19. 
Exclusion criteria to exclude currently taking phenytoin 
or rifampicin 
Clarification of co-enrolment. 
Clarification of handling ICF 
Addition of visit instead of phone call for participants at 
day 29 (Tayside only). 
Itraconazole, Ketoconazole, diltiazem, verapamil, 
phenytoin or rifampicin added as trial restrictions 
Minor clarifications to protocol. 
AM07 
5 
03-07-20 
M Band/J 
Chalmers 
Update of consent process to reflect process 
requested by and confirmed with REC for AM05 
approval 
Addition of Sheffield to take research bloods 
Clarification that day 1 of trial will be day of first dose of 
IMP 
AM09 
6 
19-08-20 
M Band/J 
Chalmers 
Update eligibility with criteria for hospitalisation 
timelines 
Update eligibility with excluded medications 
Update on trial restrictions – excluded medications 
 


 
 
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Removal of long-term follow-up 
Clarification on IMP accountability procedures for 
discharged participants, 
Clarification on safety reporting flow chart 
Addition of recording SARS CoV-2 PCR results when 
done for clinical reasons 
AM12 
7 
10-10-20 
M Band/J 
Chalmers 
3.7 Exploratory blood analysis omitted if no lab 
capacity 
16.4 Clarification that research samples taken on Day 
29 for Tayside & Sheffield 
AM13 
8 
12-12-20 
M Band/J 
Chalmers 
I Addition of Key Contacts 
1 Update to background with current scientific 
knowledge 
6.2 Exclusion criteria changed to: Current treatments 
with potent Cyp3A4 inducers/inhibitors (e.g 
Itraconazole, Ketoconazole, diltiazem, verapamil, 
phenytoin or rifampicin) 
7.1 & 10.2 Recruitment to continue beyond 300, final 
recruitment target will be confirmed after the evaluation 
of the power calculation 
9.3 & 16.5 Clarification of SAE reporting process 
10.1 Update to blinded endpoint confirmation process. 
AM14 
9 
 
M Band/J 
Chalmers 
Update to sample size and justification of change 
 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
  
 
 
 
 
 
STOP-COVID19 
SAP version 2 STOP COVID-19 
05-04-2021 
Page 1 of 46 
 
 
 
 
Statistical Analysis Plan  
TRIAL FULL TITLE 
A randomised double-blind placebo-controlled trial of 
Brensocatib (INS1007) in patients with severe COVID-19 
SAP VERSION 
V2.0 
REC Number 
20/SS/0057 
Sponsor R&D Number 
01.01.20 
SAP VERSION DATE 
05.04.2021 
TRIAL STATISTICIAN 
Thenmalar Vadiveloo 
TRIAL CHIEF 
INVESTIGATOR 
Prof. James Chalmers 
SAP AUTHOR 
Prof Graeme MacLennan, Thenmalar Vadiveloo  
ISRCTN Number 
ISRCTN30564012 
Protocol Version 
9.0 
 


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SAP version 2 STOP COVID-19 
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Page 2 of 46 
 
Signatures 
By signing this document I am confirming that I have read and approve the Statistical 
Analysis Plan (SAP) for the trial. 
Chief Investigator 
Signature 
 
Date 
James Chalmers 
 
 
05/04/2021 
 
 
 
 
Graeme MacLennan 
 
Trial Statistician                Signature 
 
05/04/2021 
 
Date 


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Page 3 of 46 
 
1 Table of Contents 
1 
Table of Contents ............................................................................................. 3 
2 
Abbreviations and Definitions ........................................................................... 6 
3 
Introduction ...................................................................................................... 6 
3.1 
Preface ....................................................................................................... 6 
3.2 
Purpose of the analyses .............................................................................. 6 
4 
Study Objectives and Endpoints ........................................................................ 7 
4.1 
Study Objectives ......................................................................................... 7 
4.2 
Endpoints ................................................................................................... 7 
4.3 
Derived variables ........................................................................................ 8 
5 
Study Methods .................................................................................................. 9 
5.1 
General Study Design and Plan ................................................................... 9 
5.2 
Inclusion-Exclusion Criteria and General Study Population ....................... 10 
5.2.1 
Inclusion criteria ................................................................................ 10 
5.2.2 
Exclusion criteria ................................................................................ 11 
5.2.3 
Co-enrolment .................................................................................... 11 
5.3 
Randomisation and Blinding ..................................................................... 12 
5.4 
Study Variables ......................................................................................... 13 
6 
Sample Size .................................................................................................... 17 
7 
General Considerations ................................................................................... 20 
7.1 
Timing of Analyses ................................................................................... 20 
7.2 
Analysis Populations ................................................................................. 20 
7.2.1 
Full Analysis Population ..................................................................... 20 
7.2.2 
Per Protocol Population ...................................................................... 20 
7.2.3 
Preliminary analysis population .......................................................... 20 
7.2.4 
Safety Population ............................................................................... 20 
7.3 
Covariates and Subgroups ........................................................................ 20 
7.4 
Missing Data ............................................................................................ 21 


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7.5 
Interim Analyses and Data Monitoring ...................................................... 21 
7.5.1 
Planned Schedule of Interim Analyses ................................................. 21 
7.5.2 
Scope of Adaptations ......................................................................... 21 
7.5.3 
Stopping Rules ................................................................................... 21 
7.5.4 
Adjustment of Confidence Intervals and p-values ............................... 22 
7.5.5 
Documentation of Interim Reports...................................................... 22 
7.6 
Preliminary analysis .................................................................................. 23 
7.7 
Multi-centre Studies ................................................................................. 23 
7.8 
Multiple Testing ....................................................................................... 23 
8 
Summary of Study Data ................................................................................... 24 
8.1 
Subject Disposition ................................................................................... 24 
8.2 
Protocol Deviations .................................................................................. 24 
8.3 
Demographic and Baseline Variables ........................................................ 24 
8.3.1 
Other Baseline Characteristics ............................................................ 25 
8.4 
Treatment Compliance ............................................................................. 25 
8.5 
Loss to follow-up ..................................................................................... 25 
9 
Efficacy Analyses ............................................................................................ 26 
9.1 
Primary Efficacy Analysis .......................................................................... 26 
9.2 
Secondary Efficacy Analyses ..................................................................... 26 
9.2.1 
Time to clinical improvement (1 category) .......................................... 26 
9.2.2 
Clinical status at Day 3, 5, 8, 11, 15, 29 ............................................. 26 
9.2.3 
Change in 7-point scale ..................................................................... 26 
9.2.4 
Time to discharge or to a NEWS of ≤2 ................................................ 26 
9.2.5 
Change in NEWS from baseline to days 8, 15 and 29 .......................... 27 
9.2.6 
No of days free from oxygen .............................................................. 27 
9.2.7 
Duration of new oxygen used ............................................................. 27 
9.2.8 
Number of patients receiving new mechanical ventilation ................... 27 
9.2.9 
No of days free from ventilation ......................................................... 27 


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9.2.10 
Duration of new ventilation used ..................................................... 27 
9.2.11 
Duration of hospital stay – days ...................................................... 27 
9.2.12 
28-day mortality ............................................................................. 27 
9.3 
Exploratory Efficacy Analyses ................................................................... 28 
10 
Safety Analyses ............................................................................................ 28 
10.1 Extent of Exposure ................................................................................... 28 
10.2 Adverse Events ......................................................................................... 29 
10.3 Deaths, Serious Adverse Events and other Significant Adverse Events ....... 29 
10.4 Pregnancies .............................................................................................. 29 
10.5 Clinical Laboratory Evaluations ................................................................. 29 
10.6 Other Safety Measures .............................................................................. 29 
11 
Other Analyses ............................................................................................ 29 
11.1 Quality of Life (EQ-5D-5L) ........................................................................ 30 
12 
Reporting Conventions ................................................................................ 30 
13 
Technical Details ......................................................................................... 30 
14 
Summary of Changes to the Protocol ........................................................... 30 
15 
References ................................................................................................... 30 
16 
Listing of Tables, Listings and Figures ......................................................... 31 
 


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2 Abbreviations and Definitions 
 
AE 
Adverse Event 
CRF 
Case Report Form 
IMP 
Investigational Medical Product 
SAP 
Statistical Analysis Plan 
3 Introduction 
3.1 Preface 
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. We 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.  
 
3.2 Purpose of the analyses 
These analyses will assess the efficacy and safety of Brensocatib in comparison with 
placebo and will be included in the clinical study report. 


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4 Study Objectives and Endpoints 
4.1 Study Objectives 
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 hospitalised with 
COVID-19. 
4.2 Endpoints 
Primary outcome 
The primary outcome is participant clinical status (on a 7-point ordinal scale) at day 
29.  
Secondary outcome 
Clinical severity: 
1. Time to an improvement of one category from admission to day 29 using 7-
point ordinal scale 
2. Clinical status on 7-point ordinal at days 3, 5, 8, 11, 15 and 29 
3. Change on 7-point ordinal from baseline to day 15 
4. Proportion of participants showing improvement on 7-point ordinal scale at 
day 15 
5. Mean change in the 7-point ordinal scale from baseline (day 1) to days 3, 5, 
8, 11, 15 and 29. 
National Early Warning Score (NEWS): 
1. Time to discharge or to a NEWS of ≤ 2 and maintained for 24 hours, whichever 
occurs first. 
2. Change from baseline to days 3, 5, 8, 11, 15 and 29 
Oxygenation: 
1. Oxygen free days 
2. Incidence and duration of new oxygen use during the trial 
Mechanical ventilation: 
1. Ventilation free days 
2. Incidence and duration of new mechanical ventilation use during the trial 
Hospitalisation: 
Duration of hospitalisation (days) 


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Mortality: 
29 day mortality 
 
Safety of the intervention: 
1. Cumulative incidence of serious adverse events (SAEs) from day 1 to 29. 
2. Discontinuation or temporary suspension of treatment from days 1 to 28. 
Quality of life 
1. EQ-5D-5L at day 29  
4.3 Derived variables 
The primary endpoint is an assessment of the clinical status on a given trial day using 
a 7-point ordinal scale. Each day, the worse score for will be recorded. The scale is 
as follows: 
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; 
7. Death. 
The NEWS score is based on 7 clinical parameters: 
1. Respiration rate (per minute) 
2. SpO2 Scale 1(%) 
3. Air or Oxygen 
4. Systolic blood pressure (mmHg) 
5. Pulse (per minute) 
6. Consciousness 
7. Temperature (oC) 
 


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5 Study Methods 
5.1 General Study Design and Plan 
(ICH E3;9) 
This is a multi-centre, randomised, double blind, placebo controlled, parallel group 
trial with two treatment arms, with 400 participants planned to be randomised  
The two treatment arms are as follows: 
1. Brensocatib 25mg once daily for 28 days 
2. Placebo once daily for 28 days 
Following trial completion or discontinuation, participants should be continued on 
standard of care. 
Randomisation will be stratified by  
1. Site 
2. Age: <65 years/≥65 years  
The proposed primary outcome assessed on a 7-point ordinal scale at day 28. 
 
 
 


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5.2 Inclusion-Exclusion Criteria and General Study Population 
It is likely that the assessments to confirm eligibility will be carried out by the clinical 
team during routine care of patients being assessed for COVID-19. Where these 
assessments have been carried out by the clinical team the most recent of these 
results will be used to prevent duplication and further exposure of the trial staff to 
patients with COVID-19. 
5.2.1 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: 
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 


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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. 
5.2.2 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 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 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. 
5.2.3 Co-enrolment 


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Co-enrolment into COVID-19 CTIMPs will be described in individual agreements 
between STOP-COVID19 and other trials. These agreements will be made available to 
recruiting sites. Where agreements are not in place for specific trials the site should 
contact the CI and co-enrolment will be decided on an individual participant basis. 
This decision will be documented in the participant’s medical record. 
Co-enrolment into COVID-19 non-CTIMP intervention trials will be allowed. 
Co-enrolment to other non-COVID-19 Clinical Trials of Investigational Medicinal 
Product (CTIMPs) will not be allowed. 
Enrolment in observational trials or studies will be allowed. 
Enrolment in observational trials will not be an exclusion to participation. 
Co-enrolment in another CTIMP is not acceptable 
5.3 Randomisation and Blinding 
Participants will be allocated to receive either Brensocatib (25mg once daily for 28 
days) or placebo in addition to standard of care. Randomisation will be 1:1 
intervention:placebo. Randomisation will be stratified by site and age: <65 years/≥65 
years. Randomisation will be done centrally using a web-based validated 
randomisation program provided by Tayside Clinical Trials Unit. The trial is doubled-
blind, participants and trial staff are blind to allocation, unblinding will take place 
after database lockdown. Emergency unblinding procedures are described in section 
7.6 of the protocol.  
 
 
 
 


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5.4 Study Variables 
Table 1: Study variables 
 
Screeningd 
 
 
Randomizationd 
 
 
 
 
Follow-up 
Assessment
s 
 
Follow-up 
assessments 
 
Follow-up 
Assessments 
 
Unscheduled 
Assessments 
 
Timeline 
Day 0 or 1 
 
Day 1 
Up to 24 hours 
after screening 
Daily 
whilst 
hospitalise
d  
Days 3, 5 &11 
c 
(telephone call 
if at home) 
Day 8c 
(telephone 
call if at 
home) 
Day 15 c 
(telephone 
call if at 
home) 
Day 29 c 
(telephone 
call if at 
homeb) 
As Required in 
the event of AE 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria Check 
X 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Record Concomitant 
Medications 
X 
X 
 
 
X 
X 
X 
X 
Check Vital Signs*^ 
X 
X 
 
 
X∞ 
X∞ 
X∞ 
X 
ECG* 
X 
 
 
 
 
 
 
 
Full blood count*+ 
X 
 
 
X∞ 
X∞ 
X∞ 
X∞ 
 
Urea and electrolytes*+ 
X 
 
 
X∞ 
X∞ 
X∞ 
X∞ 
 
Liver function tests*+ 
X 
 
 
X∞ 
X∞ 
X∞ 
X∞ 
 
SARS CoV-2 PCR*  
X 
 
 
 
 
 
 
 
Record SARS CoV-2 PCR 
results, only if done for 
clinical reasons 
 
 
 
X 
X 
X 
X 
 


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Screeningd 
 
 
Randomizationd 
 
 
 
 
Follow-up 
Assessment
s 
 
Follow-up 
assessments 
 
Follow-up 
Assessments 
 
Unscheduled 
Assessments 
 
Timeline 
Day 0 or 1 
 
Day 1 
Up to 24 hours 
after screening 
Daily 
whilst 
hospitalise
d  
Days 3, 5 &11 
c 
(telephone call 
if at home) 
Day 8c 
(telephone 
call if at 
home) 
Day 15 c 
(telephone 
call if at 
home) 
Day 29 c 
(telephone 
call if at 
homeb) 
As Required in 
the event of AE 
Nasal swab for SARS CoV-
2 PCR* (Tayside only) 
 
 
 
 
 
X∞ 
X 
 
Research Blood Sample * 
(Tayside and Sheffield 
only) 
 
X 
 
 
X∞ 
X∞ 
X 
X 
Sputum sample for 
storage if available*+ 
(Tayside only) 
 
X 
 
 
X∞ 
X∞ 
X 
 
Endotracheal aspirate 
sample for storage if 
available*+a (Tayside only) 
 
 
 
 
X∞ 
X∞ 
X∞ 
 
Clinical status on 7 point 
scale 
X 
X 
X 
X 
X 
X 
X 
X 
NEWS recording* 
X 
X 
X 
X∞ 
X∞ 
X∞ 
X∞ 
 
EQ-5D questionnaire 
 
 
 
 
 
 
X 
 
Record supplemental 
oxygen* 
X 
X 
 
 
X∞ 
X∞ 
X∞ 
X 
Record CT scan results, 
only if done for clinical 
reasons 
X 
X 
X 
X∞ 
X∞ 
X∞ 
X∞ 
X∞ 


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Screeningd 
 
 
Randomizationd 
 
 
 
 
Follow-up 
Assessment
s 
 
Follow-up 
assessments 
 
Follow-up 
Assessments 
 
Unscheduled 
Assessments 
 
Timeline 
Day 0 or 1 
 
Day 1 
Up to 24 hours 
after screening 
Daily 
whilst 
hospitalise
d  
Days 3, 5 &11 
c 
(telephone call 
if at home) 
Day 8c 
(telephone 
call if at 
home) 
Day 15 c 
(telephone 
call if at 
home) 
Day 29 c 
(telephone 
call if at 
homeb) 
As Required in 
the event of AE 
Pregnancy Testing (urine 
or blood) If Applicable 
X 
 
 
 
 
 
 
 
Record Adverse Events  
 
X 
X 
X 
X 
X 
X 
X 
Randomisation 
 
X 
 
 
 
 
 
 
Dispense Trial Drugs 
 
X 
 
 
 
 
 
 
Drug Return And 
Compliance Check 
 
 
 
 
 
 
X 
 
^ Vital Signs: Blood Pressure, pulse, temperature, oxygen saturation 
*indicates procedures that will be performed by the clinical team as part of routine care but results will be recorded and included in the eCRF. 
If not performed by the clinical team, but clinically indicated, the research team may assist in this being performed but all processes will avoid 
duplication and exposure to potentially infected participants.  
+Excess biological samples that are being taken for clinical reasons may be stored for future use if no longer required for clinical purposes 
(Tayside only). 
a For those participants who are intubated. 
∞These assessments will not be completed if the participant has been discharged from hospital. 
b For the Tayside and Sheffield site only, the day 29 assessments will be carried out face-to-face either at a NHS facility or at the participant’s 
home. Home visits will only be carried out if no one in the household has symptoms of COVID-19.  
cResearch blood samples (Tayside and Sheffield only) and, once discharged, assessments may be completed within +/- 1 day 


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dScreening and randomisation may occur on the same day if all eligibility criteria are met. Day of first dose of IMP will be considered as day 1 
for the calculation of follow up assessments. 


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6 Sample Size  
(ICH E3; 9.7.2. ICH E9; 3.5) 
In accordance with the WHO multicentre adaptive trial design recommendations, this 
trial is intended to allow for adaptation of blinded confirmation or modification of the 
primary endpoint.1 
Blinded endpoint confirmation or modification 
The trial was originally designed with the option of modifying the primary endpoint. 
However, decision was made to retain the original primary outcome. 
The primary outcome uses an ordinal severity scale with 7 categories. The null 
hypothesis being tested is whether the odds of improvement on the ordinal scale is 
the same for the placebo and experimental treatment arms (i.e., whether the common 
odds ratio differs from 1). 
The proportions of participants in the different categories of the ordinal scale at day 
28 in the placebo and treatment arm assuming an odds ratio (OR) of 2 are given 
below. The odds ratio represents the odds of improvement in the ordinal scale for 
treatment relative to placebo control.2 
Table 2 displays four scenarios considered for outcomes under placebo for sample 
size determination. There is significant uncertainty with these assumptions given the 
limited data available. 
Table 3 shows a range of sample sizes for odds ratios ranging from 1.5 to 2.5 for 
85% power. For 90% power, increase the sample size by 17%. Table 4 displays an 
anticipated scenario for the primary outcome of the ordinal scale under an odds ratio 
of 2.  


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Table 2: anticipated scenario for the primary outcome  
Anticipated 
Severity Outcome 
outcome 
(%) 
Death 
2 
Hospitalised, on mechanical ventilation or ECMO 
1 
Hospitalised, on non- invasive ventilation or high flow oxygen 
Devices 
2 
Hospitalised, requiring supplemental oxygen 
7 
Hospitalised, not requiring supplemental Oxygen 
8 
Not hospitalised, limitation on activities 
38 
Not hospitalised, no limitations on activities 
42 
 
Table 3. Sample size calculations for scenarios in Table 2 for a two-arm trial 
assuming 85% power and various true odds ratios. 
True odds ratio Total sample 
size 
1.5 
774 
1.75 
412 
2.0 
272 
2.25 
201 
2.5 
159 
 
Table 4. Treatment ordinal outcome proportions under odds ratio of 2 
for scenario in Table 4 at day 15. 
Anticipated 
Severity Outcome 
Control  % 
Treatment % 
Death 
2 
1 
Hospitalised, on mechanical ventilation or ECMO 
1 
0.5 


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Hospitalised, on non- invasive ventilation or high 
flow oxygen devices 
 
2 
 
1 
Hospitalised, requiring supplemental oxygen 
7 
3.8 
Hospitalised, not requiring supplemental oxygen 
8 
4.7 
Not hospitalised, limitation on activities 
38 
29.7 
Not hospitalised, no limitations on activities 
42 
59.2 
*Note that columns may not sum to exactly 100 due to rounding errors. 
Prior to the commencement of the trial, we took the anticipated WHO scenario and 
the odds ratio of 2 which required enrolment of 272 participants. Allowing for a 
potential loss to follow-up of 9% (27 participants) this meant we will required 300 
participants (150 per arm) to achieve 85% power at 5% significance. This was 
subsequently reviewed as part of a pre-specified blinded sample size re-evaluation 
by an independent statistician. The results of this re-evaluation, using data for the 
primary endpoint available in December 2020 found that 300 patients enrolled would 
provide approximately 88% power to detect an odds ratio of 2.0. This, along with the 
results of other COVID-19 trials were reviewed by the Trial Steering Committee (TSC) 
and DMC who noted that other COVID-19 therapeutics had achieved odds ratios 
lower than 2.0 in the majority of cases. Based on this, the TSC and DMC recommended 
targeting an odds ratio of 1.75. At least 80% power for an odds ratio of 1.75 requires 
enrolment of a minimum of 360 patients with 400 patients provided approximately 
85% power. A final sample size of 400 subjects was therefore recommended by the 
TSC and subsequently approved by the DMC in December 2020 (Appendix 1). 


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7 General Considerations 
7.1 Timing of Analyses 
The final analysis will be conducted following last patient last visit assuming that at 
least 400 patients have been enrolled.  
7.2 Analysis Populations 
(ICH E3; 9.7.1, 11.4.2.5. ICH E9; 5.2) 
7.2.1 Full Analysis Population 
The primary analysis will be based on the intention-to-treat principle, which will 
include all participants who are randomised and received at least one dose of 
randomised therapy. 
7.2.2 Per Protocol Population 
Per-protocol (PP) analyses restricted to participants who completed the trial or died 
without a major protocol violation/deviation.   
7.2.3 Preliminary analysis population 
Includes all subjects in the full analysis population with complete endpoint data 
available as of 5/4/2021 for preliminary analysis on an unlocked database. 
7.2.4 Safety Population 
Safety analyses will be based a modified intent-to-treat population consisting of all 
participants who were randomised and received at least one dose of randomised 
therapy. 
7.3 Covariates and Subgroups 
(ICH E3; 9.7.1, 11.4.2.1. ICH E9; 5.7) 
7.3.1 Covariates 
The primary analysis will be adjusted for the stratification variables (site and age). 
Baseline ordinal scale will be included if considered necessary.    
7.3.2 Subgroups 
The primary endpoint will be analysed for the following participant subgroups: 
1. Age (years): (a) <65 years and (b) ≥ 65 


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2. Sex at birth: (a) Male and (b) Female 
3. Symptom duration (days): (a) <10 and (b) ≥10 
4. Baseline 7-point ordinal scale: (a) 3, (b) 4 and (c) 5 
5. Co-enrolment into RECOVERY: (a) Yes and (b) No 
6. Co-treatment with dexamethasone: (a) Yes and (b) No (if a meaningful 
number if patients did not receive dexamethasone) 
  
7.4 Missing Data 
(ICH E3; 9.7.1, 11.4.2.2. ICH E9;5.3. EMA Guideline on Missing Data in Confirmatory 
Clinical Trials) 
All reasonable efforts will be taken to minimise loss to follow-up, which is expected 
to be minimal as data collection for primary and secondary outcomes using trial-
specific eCRFs is combined with linkage to routine clinical data on study outcomes. 
The number and percentage of participants with follow-up information at day 29 
after the randomisation will be reported. For all participants who were discharged 
and alive but have missing clinical status, a clinical status scale of 2 (Not hospitalised, 
limitation on activities) will be applied. 
7.5 Interim Analyses and Data Monitoring 
(ICH E3; 9.7.1, 11.4.2.3. ICH E9; 4.1, FDA Feb 2010 “Guidance for Industry Adaptive 
Design Clinical Trials for Drugs and Biologics”) 
7.5.1 Planned Schedule of Interim Analyses 
No planned interim analysis but DMC has the rights to request for one. 
7.5.2 Scope of Adaptations 
No planned interim analysis. 
7.5.3 Stopping Rules 
For reasonable cause, the PI may terminate a participant’s participation in the trial 
prematurely. The Sponsor may decide to terminate the trial prematurely. If this 
occurs, written notification of the trial termination is required to be sent to all the 
sites. Some conditions that may warrant trial termination include the following: 


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• Discovery of an unexpected, significant, or unacceptable risk to the participants in 
the trial, 
• Decision on the part of the funder to suspend or discontinue development of the 
investigational product, 
• Decision by a regulatory authority or the Sponsor to stop the trial at any time, were 
applicable. 
If the trial is prematurely terminated, all participants who received a dose of any of 
the trial drugs and have not completed their trial period will be discontinued from 
the trial drug immediately; all the safety procedures required to be performed will be 
conducted. All discontinued participants will be followed up by a phone call 30 days 
after discontinuation for collection of AEs. The Sponsor will notify the appropriate 
Regulatory bodies in the respective countries regarding the reason for terminating 
the trial. 
The DMC will evaluate the results of the trial in an unblinded fashion for safety. The 
DMC will also determine the adequacy of the assumptions in table 4 with regard to 
the proportion of patients experiencing the endpoints in the ordinary scale at day 29 
on blinded data after at least 100 participants have been recruited. Following this 
interim evaluation the DMC may make the following recommendations to the TMG: 
1- To continue the trial without modifications 
2- To continue the trial with a modification of the sample size 
3- To continue the trial with a change in the primary endpoint 
4- To terminate the trial due to a low likelihood of achieving statistically significant 
results (futility) 
7.5.4 Adjustment of Confidence Intervals and p-values 
No planned interim analysis and adjustment of confidence intervals and p-values. 
7.5.5 Documentation of Interim Reports 
Snapshots of the data available at each interim report to the DMC and/or TSC will 
be preserved. All documentation of analysis plans, programming code and 
reporting provided at each interim will be preserved.  


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7.6 Preliminary analysis 
An analysis for preliminary efficacy and safety will be performed on an unlocked 
database using the full analysis population. The preliminary analysis will focus on 
the primary endpoints and a limited number of key secondary endpoints plus 
safety. The endpoints to be evaluated in the preliminary analysis are as follows: 
Primary endpoint:  Clinical Status on the WHO ordinal scale at day 29 
Key secondary endpoints: Time to improvement on the ordinal scale, proportion of 
patients requiring mechanical ventilation, mortality, duration of hospitalization 
Safety: Proportion of patients with one or more adverse events, proportion of 
patients with serious adverse events 
Virologic efficacy of Brensocatib: Neutrophil elastase measurement in blood by 
treatment arm. 
7.7 Multi-centre Studies 
(ICH E3;9.7.1, 11.4.2.4. ICH E9; 3.2) 
This is a multi-centre trial recruiting from 15 NHS Trusts/Boards within UK, if 
required to fulfil recruitment more NHS Trusts/Boards will be added. 
Centre will be treated as random effect in the mixed ordinal logistic regression 
model and analysis of secondary outcomes.  
7.8 Multiple Testing 
(ICH E3; 9.7.1, 11.4.2.5. ICH E9; 2.2.5) 
Due allowance for multiple testing will be made in the interpretation of the results: 
the larger the number of events on which a comparison is based and the more 
extreme the P-value after any allowance has been made for the nature of the 
particular comparison (i.e. primary or secondary; pre-specified or exploratory), the 
more reliable the comparison and, hence, the more definite any finding will be 
considered. 95% confidence intervals will be presented for the main comparisons. 


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8 Summary of Study Data 
All continuous variables will be summarised using the following descriptive statistics: 
n (non-missing sample size), mean, standard deviation, median, maximum and 
minimum or median for non-normally distributed data with their interquartile range. 
The frequency and percentages (based on the non-missing sample size) of observed 
levels will be reported for all categorical measures. All summary tables will be 
structured with a column for each treatment in the order (Control, Experimental) and 
will be annotated with the total population size relevant to that table/treatment, 
including any missing observations. 
8.1 Subject Disposition 
The summary statistics will be produced in accordance with section 8. 
8.2 Protocol Deviations 
Prospective, planned deviations or waivers to the protocol are not allowed under the 
UK regulations on Clinical Trials and must not be used, e.g. it is not acceptable to 
enrol a participant if they do not meet the eligibility criteria or restrictions specified 
in the trial protocol. The CI will not implement deviations to the protocol except where 
necessary to eliminate an immediate hazard to trial participants. 
8.3 Demographic and Baseline Variables 
Subject demographic data and baseline characteristics ((eg, sex, race/ethnicity, age 
and co-morbidities)) will be summarized by treatment group and overall using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for 
continuous data and by the number and percentage of participants for categorical 
data.  
Age group (< 65 and ≥ 65) will be summarized by treatment group and overall. 


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8.3.1 Other Baseline Characteristics 
The following baseline disease characteristics will be summarized by treatment 
group and overall using descriptive statistics: 
• 
Clinical status (7-point ordinal scale) 
• 
Severity of illness 
• 
Participants with confirmed SARS-CoV-2 PCR test and those treated as 
clinically suspected who never had a positive swab 
8.4 Treatment Compliance 
Trial drug compliance will be assessed by trial staff in hospitalised participants by 
checking drug returns and medication record sheet. The PI or delegate will collect 
unused medication and packaging from the clinical team. Where participants are 
discharged from hospital during the treatment phase, returns will not be requested, 
trial staff will ask participants at the day 29 phone call how many tablets are 
remaining and this will be recorded on the accountability log. Trial drug compliance 
will be assessed from the information provided by the participant and the above 
medication checks. For patients that attended for day 29 visits, medications will be 
returned and unused medication counted and documented.  
8.5 Loss to follow-up 
All reasonable efforts will be taken to minimise loss to follow-up, which is expected 
to be minimal as data collection for primary and secondary outcomes using trial-
specific eCRFs is combined with linkage to routine clinical data on study outcomes. 
The number and percentage of participants with follow-up information at day 29 
after the randomisation will be reported.  


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9 Efficacy Analyses 
9.1 Primary Efficacy Analysis 
The primary endpoint will be analysed using a mixed ordinal logistic regression, 
assuming proportional odds ratios adjusted for age and sites as a random effect. The 
odds ratio, 95% confidence interval and p-value for comparing treatments will be 
provided. The assumption of odds proportionality will be assessed using Brant Test3 
of Parallel Regression Assumption. If the test indicate that proportional odds 
assumption is violated, the model will be run as a generalised ordered logistic model. 
9.2 Secondary Efficacy Analyses 
9.2.1 Time to clinical improvement (1 category) 
The endpoint will be analysed with a time-to-event framework. Cox models will be 
used, and the survivor function will be estimated. The hazard ratio and 95% 
confidence interval will be provided. Participants without the endpoint being analysed 
will be censored on the day of the last non-missing ordinal scale assessment. The 
model will adjust for age and sites. Kaplan-Meier estimates for the time to event will 
also be plotted. 
9.2.2 Clinical status at Day 3, 5, 8, 11, 15, 29 
The number and percentage of participants in each clinical status category for day 
3, 5, 8, 11, 15 and 29 will be summarized by treatment group. In addition, stacked 
bar charts by study day will be produced by treatment group using the definition 
specified in Section 4.3. 
9.2.3 Change in 7-point scale 
Change in ordinal scale at specific time points will be summarized by proportions 
(e.g., proportion who have a 1-, 2-, 3-, or 4-point improvement or 1-, 2-, 3-, 4-
point worsening). Mean changes from baseline to days 3, 5, 8, 11, 15 and 29 will be 
reported. 
9.2.4 Time to discharge or to a NEWS of ≤2 
The endpoint will be analysed with a time-to-event framework. Cox models will be 
used, and the survivor function will be estimated. The hazard ratio and 95% 
confidence interval will be provided. Participants without the endpoint being analysed 
will be censored on the day of the last non-missing ordinal scale assessment. The 


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model will adjust for age and sites. Kaplan-Meier estimates for the time to event will 
also be plotted. 
9.2.5 Change in NEWS from baseline to days 8, 15 and 29 
Change in NEWS at specific time points will be summarized by proportions (e.g., 
proportion who have a 1-, 2-, 3-, or 4-point improvement or 1-, 2-, 3-, 4-point 
worsening). Mean changes from baseline to days 8, 15 and 29 will be reported. 
9.2.6 No of days free from oxygen 
Number of days free from oxygen support will be compared between the treatment 
arms using the negative binomial regression with time in ICU as the offset. Number 
of days will be calculated as the number of days free from oxygen support reported 
on the 7-point ordinal scale eCRF. 
9.2.7 Duration of new oxygen used 
Duration of new oxygen used will be calculated and will be compared between the 
treatment arms using the negative binomial regression with time in ICU as the 
offset.  
9.2.8 Number of patients receiving new mechanical ventilation 
The number and percentage of participants who received new mechanical ventilation 
will be presented. Comparison between the treatment arms will be performed using 
a Fisher’s Exact test.  
9.2.9 No of days free from ventilation 
Number of days free from ventilation will be compared between the treatment arms 
using negative binomial regression with time in ICU as the offset.  
9.2.10  Duration of new ventilation used 
Duration of new ventilation used will be calculated and will be compared between the 
treatment arms using negative binomial regression with time in ICU as the offset.  
9.2.11 Duration of hospital stay – days 
Duration of hospitalization will be calculated only for participants who are discharged 
alive on or prior to Day 29 and will be compared between the treatment arms using 
negative binomial regression. 
 
9.2.12  28-day mortality 


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All-cause mortality will be estimated using the Kaplan-Meier product limit method 
with all available data. The treatment arms will be compared using the log-rank test, 
and hazard ratios and 95% confidence intervals will be provided. Participants who did 
not die will be censored on the last study day. 
9.3 Exploratory Efficacy Analyses 
The virologic efficacy of Brensocatib will be evaluated. 
1. The percentage of participants with SARS-CoV-2 detectable in nasopharyngeal 
(NP) sample (in hospital, Tayside only) 
2. Quantitative SARS-CoV-2 virus in NP samples (Tayside only) 
3. *Neutrophil elastase and heparin binding protein measurement in blood (in 
hospital, Tayside only) 
4. *Neutrophil functional studies (NET formation, phagocytosis, elastase release, 
neutrophil proteomics- (Tayside and Sheffield only) 
*These analysis will be omitted in circumstances where there is no laboratory availability to 
process the samples in time, it is not possible to carry out analysis on stored samples.  
10 Safety Analyses 
Safety endpoints include cumulative incidence of SAEs, discontinuation or temporary 
suspension of treatment, changes in white cell count, haemoglobin, platelets, 
creatinine, total bilirubin, ALT and AST over time. Adverse events of special interest; 
hyperkeratosis (skin), infection, and dental complications will be reported. These 
events will be analysed univariately. The proportion of participants who had adverse 
events will compared between both the groups using Poisson regression. Adverse 
events leading to premature discontinuation from the study intervention and serious 
AEs will be presented either in a table or a listing. 
10.1 Extent of Exposure 
The summary statistics will be produced in accordance with section 8. 
 
 


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10.2 Adverse Events 
For the calculation of incidence of adverse events (i.e., on a per subject basis), each 
subject will only be counted once and any repetitions of adverse events within a 
subject will be ignored; the denominator will be the number of subjects in the Treated 
population. All adverse events reported will be included in the summaries and 
analyses.  Adverse events incidences will be reported by System Organ Class and 
Preferred Term.  
10.3 Deaths, Serious Adverse Events and other Significant Adverse 
Events 
Listings of death and other serious adverse events will be presented. 
10.4 Pregnancies 
For any subjects in the Treated population who become pregnant during the study, 
every attempt will be made to follow these subjects to completion of pregnancy to 
document the outcome, including information regarding any complications with 
pregnancy and/or delivery. 
10.5 Clinical Laboratory Evaluations 
 Clinical safety laboratory adverse events are collected Day 0/1, 3, 5, 8, 11 and Day 
15 and 29 if able to return to clinic or still hospitalized. Parameters evaluated include 
white blood cell count, platelet, haemoglobin concentration, creatinine, total 
bilirubin, ALT and AST. Laboratory safety parameters will be graded according to the 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, version 2.1 (July 2017). The distribution of Grade 3 and 4 chemistry and 
haematology laboratory results by time point and treatment group will be presented.  
Descriptive statistics including mean, median, standard deviation, maximum, and 
minimum values and change from baseline by time point, for all and each chemistry 
and haematology laboratory parameter will be summarized by treatment arm.  
10.6 Other Safety Measures 
Not applicable 
 
11 Other Analyses 


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11.1 Quality of Life (EQ-5D-5L) 
This will be compared at Day 29. Standard measure specific algorithms will be used 
to derive scores from and handle missing data in the QoL questionnaires. A mixed 
model will be used in the analysis. 
12 Reporting Conventions 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values less than 
0.0005 will be reported as “0.999”. The mean, standard deviation, and other statistics 
will be reported to1 decimal place greater than the original data. The minimum and 
maximum will use the same number of decimal places as the original data. 
Proportions will be presented as 2 decimal places; values greater than zero but < 
0.5% will be presented as “99. Estimated parameters, not on the same scale as raw 
observations (e.g. regression coefficients) will be reported to 3 significant figures 
13 Technical Details 
STATA version 16 will be used to analyse all the data and to generate all tables, 
figures and listings. 
14 Summary of Changes to the Protocol 
There are no changes to report. 
15 References 
1. World Health Organisation, Master Protocol: A Multi-centre, Adaptive, 
Randomized, Double-Blind, Placebo-Controlled Clinical Trial of the Safety and 
Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in 
Hospitalized Patients. 2020 
2. Whitehead, J. (1993), Sample size calculations for ordered categorical data. 
Statist. Med., 12: 2257-2271. 
3. Brant R. Assessing proportionality in the proportional odds model for ordinal 
logistic regression. Biometrics. 1990 Dec;46(4):1171-8. PMID: 2085632.


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16  Listing of Tables, Listings and Figures 
 
Table 1: Stratification variables 
 
Variable  
Brensocatib  
N = 
Placebo 
N = 
Age – n (%) 
 
 
 
<65 
 
 
 
>=65 
 
 
Sites – n (%) 
 
 
 
 
Table 2: Demographic 
 
Variable  
Brensocatib  
N = 
Placebo 
N = 
Age (mean SD)  
Gender – n (%) 
 
 
 
Male 
 
 
 
Female 
 
 
Ethnicity – n (%) 
 
 
 
English/ Welsh/ Scottish/ Northern Irish/ British 
 
 
 
Irish 
Gypsy or Irish Traveller 
Any other White background 
White and Black Caribbean 
White and Black African 
White and Asian 
Any other Mixed/ Multiple ethnic background 
Indian 
Pakistani 
Bangladeshi 
Chinese 
Any other Asian background 
African 
Caribbean 
Any other Black/ African/ Caribbean background 
Arab 
 
 


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Any other ethnic group 
Unknown 
Living status – n (%) 
 
 
 
Own home (on own or with others) 
 
 
 
Sheltered housing 
 
 
 
Care home (nursing or residential) 
 
 
 
Prison 
 
 
 
Other 
Comorbidities 
a. Chronic Neutropenia 
b. Chronic cardiac disease, including 
congenital heart disease 
c. Hypertension 
d. COPD 
e. Chronic pulmonary disease (not COPD or 
asthma) 
f. Asthma (physician diagnosed) 
g. Chronic kidney disease (eGFR less than 44 
ml/min, on dialysis or previous 
transplant) 
h. Moderate or severe liver disease 
i. Mild liver disease 
j. Chronic neurological disorder 
k. Malignant neoplasm 
l. Chronic hematologic disease 
m. AIDS / HIV 
n. Obesity  
o. Diabetes with complications 
p. Diabetes without complications 
q. Rheumatologic disorder 
r. Dementia 
s. Malnutrition 
 
 
 
 
 
Table 3: Severity of the patient population 
 
 
Brensocatib 
Placebo 


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N = 
N = 
Radiographic infiltrates by imaging (e.g. chest x-ray, 
computed tomography (CT) scan) 
 
 
Evidence of rales/crackles on physical examination 
 
 
Peripheral capillary oxygen saturation (SpO2) less 
than or equal to 94% on room air prior to 
randomization 
 
 
Requiring supplemental oxygen 
 
 
Lymphocyte count less than 1 x 10^9 cells per litre 
(L) 
 
 
 
Table 4: SARS-COV—2 PCR test 
 
 
Brensocatib 
N = 
Placebo 
N = 
Confirmed positive SARS CoV-2 PCR test 
 
 
Clinically suspected without a positive 
swab 
 
 
 


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Table 5: Clinical status at randomisation 
 
 
 
 
Brensocatib  
N = 
Placebo 
N = 
7-point ordinal scale 
 
Not hospitalised, no limitations on activities 
 
 
 
Not hospitalised, limitation on activities; 
 
 
 
Hospitalised, not requiring supplemental oxygen; 
 
 
 
Hospitalised, requiring supplemental oxygen; 
 
 
 
Hospitalised, on non-invasive ventilation or high 
flow oxygen devices; 
 
 
 
Hospitalised, on invasive mechanical ventilation or 
ECMO (Extracorporeal membrane oxygenation) 
 
 
 
Death. 
 
 
 
 
 
 
NEWS Score, mean (SD) 
 
 
 
Table 6: Primary outcome: Clinical status at day 29 according to treatment Group. 
 
 
 
Brensocatib  
N = 
Placebo 
N = 
Effect estimate (95% 
CI) 
Clinical status at day 29 on the 7-point 
ordinal scale — no. of patients (%) 
 
 
 
 
Not hospitalised, no limitations on 
activities 
 
 
 
 
Not 
hospitalised, 
limitation 
on 
activities 
 
 
 
 
Hospitalised, 
not 
requiring 
supplemental oxygen 
 
 
 
 
Hospitalised, requiring supplemental 
oxygen 
 
 
 
 
Hospitalised, 
on 
non-invasive 
ventilation or high flow oxygen 
devices 
 
 
 
 
Hospitalised, on invasive mechanical 
ventilation or ECMO (Extracorporeal 
membrane oxygenation) 
 
 
 
 
Death 
 
 
 


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05-04-2021 
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Table 7: Secondary outcomes - Clinical Severity According to Treatment Group. 
 
 
Brensocatib  
N = 
Placebo 
N = 
Effect estimate 
(95% CI) 
Time to clinical improvement (1 category) 
 
 
 
Clinical status at Day 3 on the 7-point 
ordinal scale — no. of patients (%) 
 
 
 
 
Not hospitalised, no limitations on 
activities 
 
 
 
 
Not 
hospitalised, 
limitation 
on 
activities 
 
 
 
 
Hospitalised, 
not 
requiring 
supplemental oxygen 
 
 
 
 
Hospitalised, requiring supplemental 
oxygen 
 
 
 
 
Hospitalised, 
on 
non-invasive 
ventilation or high flow oxygen 
devices 
 
 
 
 
Hospitalised, on invasive mechanical 
ventilation or ECMO (Extracorporeal 
membrane oxygenation) 
 
 
 
 
Death 
 
 
 
Clinical status at Day 5 on the 7-point 
ordinal scale — no. of patients (%) 
 
 
 
 
Not hospitalised, no limitations on 
activities 
 
 
 
 
Not 
hospitalised, 
limitation 
on 
activities 
 
 
 
 
Hospitalised, 
not 
requiring 
supplemental oxygen 
 
 
 
 
Hospitalised, requiring supplemental 
oxygen 
 
 
 
 
Hospitalised, 
on 
non-invasive 
ventilation or high flow oxygen 
devices 
 
 
 
 
Hospitalised, on invasive mechanical 
ventilation or ECMO (Extracorporeal 
membrane oxygenation) 
 
 
 
 
Death 
 
 
 


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05-04-2021 
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Clinical status at Day 8 on the 7-point 
ordinal scale — no. of patients (%) 
 
 
 
 
Not hospitalised, no limitations on 
activities 
 
 
 
 
Not 
hospitalised, 
limitation 
on 
activities 
 
 
 
 
Hospitalised, 
not 
requiring 
supplemental oxygen 
 
 
 
 
Hospitalised, requiring supplemental 
oxygen 
 
 
 
 
Hospitalised, 
on 
non-invasive 
ventilation or high flow oxygen 
devices 
 
 
 
 
Hospitalised, on invasive mechanical 
ventilation or ECMO (Extracorporeal 
membrane oxygenation) 
 
 
 
 
Death 
 
 
 
Clinical status at Day 11 on the 7-point 
ordinal scale — no. of patients (%) 
 
 
 
 
Not hospitalised, no limitations on 
activities 
 
 
 
 
Not 
hospitalised, 
limitation 
on 
activities 
 
 
 
 
Hospitalised, 
not 
requiring 
supplemental oxygen 
 
 
 
 
Hospitalised, requiring supplemental 
oxygen 
 
 
 
 
Hospitalised, 
on 
non-invasive 
ventilation or high flow oxygen 
devices 
 
 
 
 
Hospitalised, on invasive mechanical 
ventilation or ECMO (Extracorporeal 
membrane oxygenation) 
 
 
 
 
Death 
 
 
 
Clinical status at Day 15 on the 7-point 
ordinal scale — no. of patients (%) 
 
 
 
 
Not hospitalised, no limitations on 
activities 
 
 
 


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05-04-2021 
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Not 
hospitalised, 
limitation 
on 
activities 
 
 
 
 
Hospitalised, 
not 
requiring 
supplemental oxygen 
 
 
 
 
Hospitalised, requiring supplemental 
oxygen 
 
 
 
 
Hospitalised, 
on 
non-invasive 
ventilation or high flow oxygen 
devices 
 
 
 
 
Hospitalised, on invasive mechanical 
ventilation or ECMO (Extracorporeal 
membrane oxygenation) 
 
 
 
 
Death 
 
 
 
Clinical status at Day 29 on the 7-point 
ordinal scale — no. of patients (%) 
 
 
 
 
Not hospitalised, no limitations on 
activities 
 
 
 
 
Not 
hospitalised, 
limitation 
on 
activities 
 
 
 
 
Hospitalised, 
not 
requiring 
supplemental oxygen 
 
 
 
 
Hospitalised, requiring supplemental 
oxygen 
 
 
 
 
Hospitalised, 
on 
non-invasive 
ventilation or high flow oxygen 
devices 
 
 
 
 
Hospitalised, on invasive mechanical 
ventilation or ECMO (Extracorporeal 
membrane oxygenation) 
 
 
 
 
Death 
 
 
 
Change in 7-point ordinal scale 
 
 
 
 
Day 3 
 
 
 
 
Day 5 
 
 
 
 
Day 8 
 
 
 
 
Day 11 
 
 
 
 
Day 15 
 
 
 
 
Day 29 
 
 
 


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05-04-2021 
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Table 8:  Secondary outcome: National Early Warning Score (NEWS) 
 
Brensocatib 
N = 
Placebo 
N = 
Effect estimate (95% 
CI) 
Time to discharge or to a NEWS of <= 2 
 
 
 
Change in NEWS from baseline 
 
 
 
 
Day 8 
 
 
 
 
Day 15 
 
 
 
 
Day 29 
 
 
 
 
Table 9: Secondary outcome: Oxygenation, mechanical ventilation, hospitalisation, 
and mortality 
 
 
Brensocatib 
N = 
Placebo 
N = 
Effect estimate (95% CI) 
Oxygenation 
 
 
 
 
No of days free from oxygen 
 
 
 
 
Duration of new oxygen use 
 
 
 
Mechanical ventilation 
 
 
 
 
Number of patients receiving 
new mechanical ventilation 
No of days free from 
ventilation 
 
 
 
 
Duration of new ventilation 
used 
 
 
 
Duration of hospital stay - days 
 
 
 
28-day mortality 
 
 
 
 


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05-04-2021 
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Table 10:  Safety analyses  
 
 
 
Brensocatib 
N = 
Placebo 
N = 
Effect estimate (95% CI) 
% of patients with at least 1 AE 
Incidence of SAEs 
 
 
 
Discontinuation or temporary 
suspension of treatment 
 
 
 
Changes in white cell count 
 
 
 
Changes in haemoglobin 
 
 
 
Changes in platelets 
 
 
 
Changes in creatinine 
 
 
 
Changes in total bilirubin 
 
 
 
Changes in ALT 
 
 
 
Changes in AST 
 
 
 
Adverse events, n (%): 
 
 
 
     Hyperkeratosis (Skin) 
 
 
 
     Infections 
 
 
 
     Dental complications 
 
 
 


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05-04-2021 
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Table 11: Adverse Events 
Adverse Event – n (%) 
Brensocatib 
N = 
Placebo 
N = 
Death 
 
 
Life-threatening 
 
 
Required hospitalisation 
 
 
Resulted in persistent or significant disability 
 
 
Medically significant 
 
 
Total 
 
 
 
Table 12: Summary of all adverse events – System Organ Class Level 
 
Brensocatib 
N = 
Placebo 
N = 
Total 
N= 
Number of participants 
 
 
 
Number of participants with adverse 
events 
 
 
 
Number of participants without adverse 
events 
 
 
 
Number of adverse events 
 
 
 
 
Cardiac disorders 
 
 
 
 
Eye disorders 
 
 
 
 
Gastrointestinal disorders 
 
 
 
 
General disorders and 
administration site conditions 
 
 
 
 
Infections and infestations 
 
 
 
 
Injury, poisoning and procedural 
complications 
 
 
 
 
Investigations 
 
 
 


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05-04-2021 
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Metabolism and nutrition disorders 
 
 
 
 
Musculoskeletal and connective 
tissue disorders 
 
 
 
 
Nervous system disorders 
 
 
 
 
No Code 
 
 
 
 
Psychiatric disorders 
 
 
 
 
Renal and urinary disorders 
 
 
 
 
Respiratory, thoracic and 
mediastinal disorders 
 
 
 
 
Skin and subcutaneous tissue 
disorders 
 
 
 
 
Vascular disorders 
 
 
 
 
Table 13: Summary of all adverse events – Preferred Term Level 
 
 
Brensocatib 
N = 
Placebo 
N = 
Total 
N= 
Number of participants 
 
 
 
Number of participants with adverse 
events 
 
 
 
Number of participants without adverse 
events 
 
 
 
Number of adverse events 
 
 
 
 
Abdominal discomfort          
 
 
 
 
Abdominal pain          
 
 
 
 
Acute kidney injury          
 
 
 
 
Arthralgia          
 
 
 
 
Back pain          
 
 
 
 
Blood glucose increased          
 
 
 
 
Bradycardia          
 
 
 
 
Cerebrovascular accident          
 
 
 


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05-04-2021 
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Chest discomfort          
 
 
 
 
Chest pain          
 
 
 
 
Clostridium difficile infection          
 
 
 
 
Constipation          
 
 
 
 
Cough          
 
 
 
 
Delirium          
 
 
 
 
Diarrhoea          
 
 
 
 
Dizziness          
 
 
 
 
Drug eruption          
 
 
 
 
Dry mouth          
 
 
 
 
Dry skin          
 
 
 
 
Dysarthria          
 
 
 
 
Dyspepsia          
 
 
 
 
Dyspnoea          
 
 
 
 
Dysuria          
 
 
 
 
Electrocardiogram abnormal          
 
 
 
 
Epistaxis          
 
 
 
 
Extravasation          
 
 
 
 
Eye pruritus          
 
 
 
 
Fall          
 
 
 
 
Flatulence          
 
 
 
 
Gastritis erosive          
 
 
 
 
Gastrooesophageal reflux disease       
 
 
 
Gingival bleeding          
 
 
 
 
Gingival pain          
 
 
 
 
Glossodynia          
 
 
 
 
Hallucination, visual          
 
 
 
 
Headache          
 
 
 
 
Hiccups          
 
 
 
 
Hyperglycaemia 
 
 
 
 
Hyperhidrosis  
 
 
 
 
Hypoaesthesia oral 
 
 
 
 
Hypokalaemia  
 
 
 
 
Insomnia  
 
 
 
 
Lip pain  
 
 
 


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05-04-2021 
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Liver function test abnormal  
 
 
 
 
Lower respiratory tract infection  
 
 
 
 
Malaise          
 
 
 
 
Memory impairment          
 
 
 
 
Mouth ulceration          
 
 
 
 
Musculoskeletal pain          
 
 
 
 
Nausea          
 
 
 
 
Night sweats          
 
 
 
 
Nightmare          
 
 
 
 
No Code          
 
 
 
 
Oral candidiasis          
 
 
 
 
Oral mucosal blistering          
 
 
 
 
Oral mucosal eruption          
 
 
 
 
Pain          
 
 
 
 
Pain in extremity          
 
 
 
 
Palpitations          
 
 
 
 
Paraesthesia oral          
 
 
 
 
Peripheral swelling          
 
 
 
 
Pharyngitis          
 
 
 
 
Pneumonia          
 
 
 
 
Pneumothorax          
 
 
 
 
Pollakiuria          
 
 
 
 
Pruritus          
 
 
 
 
Pulmonary embolism          
 
 
 
 
Pulmonary hypertension          
 
 
 
 
Pyrexia          
 
 
 
 
Rash          
 
 
 
 
Rash macular          
 
 
 
 
Rash papular          
 
 
 
 
Rash pruritic          
 
 
 
 
Rash pustular          
 
 
 
 
Sinus bradycardia          
 
 
 
 
Steroid diabetes          
 
 
 
 
Subcutaneous emphysema          
 
 
 
 
Suicidal ideation          
 
 
 


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05-04-2021 
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Swelling face          
 
 
 
 
Syncope          
 
 
 
 
Thrombosis      
 
 
 
 
Tongue discolouration          
 
 
 
 
Toothache          
 
 
 
 
Transaminases increased          
 
 
 
 
Urinary tract infection          
 
 
 
 
Urosepsis          
 
 
 
 
Vision blurred          
 
 
 
 
Vomiting  
 
 
 
 
Table 14: Summary of all adverse events – descriptors 
 
 
Brensocatib 
N = 
Placebo 
N = 
Total 
N= 
Severity 
 
 
 
 
No Information 
 
 
 
 
Mild 
 
 
 
 
Moderate 
 
 
 
 
Severe  
 
 
 
 
Total 
 
 
 
Relationship to Trial Drug 
 
 
 
 
No Information 
 
 
 
 
None 
 
 
 
 
Possible 
 
 
 
 
Probable 
 
 
 
 
Total 
 
 
 
Action taken 
 
 
 


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05-04-2021 
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No Information 
 
 
 
 
None 
 
 
 
 
Hospitalisation 
 
 
 
 
IMP temporarily stopped 
 
 
 
 
IMP permanently stopped 
 
 
 
 
Con meds commenced 
 
 
 
 
Other (specify) 
 
 
 
 
Hospitalisation, Con meds 
commenced 
 
 
 
 
IMP temporarily stopped; 
IMP permanently stopped 
 
 
 
 
IMP permanently stopped; 
Con meds to commenced 
 
 
 
 
Total 
 
 
 
Outcome 
 
 
 
 
No information 
 
 
 
 
Recovered 
 
 
 
 
Recovering 
 
 
 
 
Not recovered 
 
 
 
 
Unknown 
 
 
 
 
Fatal 
 
 
 
 
Total 
 
 
 
 


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05-04-2021 
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Table 15. Additional treatments  
Additional treatments  
Brensocatib 
N = 
Placebo 
N = 
Co-enrolment in RECOVERY 
Co-enrolment in REMAP-CAP 
Co-medications: 
Antibiotics 
Azithromycin 
Corticosteroids 
Convalescent plasma 
Hydroxychloroquine 
Lopinavir-Ritonavir 
Remdesivir 
Tocilizumab