Clinical trial NCT04455815
Conditions: COVID-19 Infection
Keywords: COVID-19 Coronavirus Infections Respiratory Tract Infections Pneumonia, Viral Virus Diseases Camostat Protease Inhibitors Enzyme Inhibitors Serine Proteinase Inhibitors
Sponsor: Cancer Research UK
Start date: 2020-09-23; Completion date: 2022-03-03
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a phase II randomised, multicentre, prospective, open label clinical trial. The trial aims to recruit patients who test positive for COVID-19 who have mild symptoms and therefore can treat their symptoms in the community. Patients who test positive for COVID-19 at hospital may also be able to participate.

Detailed description:
Coronavirus-induced disease 2019 (COVID-19) caused by SARS-CoV-2 infection is a highly contagious disease with a high and unpredictable morbidity and mortality, for which there is currently no specific treatment. Progression from a mild fatigue, fever and cough, to severe respiratory failure requiring mechanical ventilation may occur 1 to 2 weeks into the disease. This provides a window of opportunity in which patients in the early phase of the disease could be treated with a disease-modifying agent, to halt disease progression, prevent hospital admissions with respiratory failure and prevent death.

Camostat is a serine protease inhibitor in clinical use in Japan since 1985 to treat patients with chronic pancreatitis (inflammation of the pancreas) and has an acceptable safety profile. Camostat has been shown to inhibit SARS-CoV-2 entry into epithelial cells in vitro. A trial of this repurposed drug for treatment of COVID-19 in humans is urgently required to assess its impact on disease progression to respiratory failure and whether it can reduce mortality.

This trial will recruit up to 100 patients. Patients will be randomised into a treatment arm (camostat tablets) or control arm (best supportive care). Community patients will be called daily at home for 14 days by the clinical trial team to collect symptoms and record the general well-being of the patient. For those patients recruited from hospital, visits will continue in hospital, where feasible, until discharge when home visits will be able to continue. The primary aim of this trial is to further assess the safety and toxicity profile of camostat to support integration into a Phase III trial. Secondary aims are to determine if camostat can reduce the clinical progression of COVID-19 and therefore the need for hospital admission and supplemental oxygen as well as include collection of patient reported health status, severity of symptoms and biological markers of the virus and confirm PK profile for the active metabolite of camostat. As the understanding of COVID-19 develops and improves, the inclusion criteria may be adapted to support the trial outcomes. Patients will be recruited through various settings which may include primary care 'COVID-19 hub' clinics, COVID-19 community-based testing centres, identification through other hospital departments, NHS digital, Test and Trace (or equivalent) or other clinical environments.

Arms: arm 1: Patient to receive treatment with camostat tablets, 200mg four times daily (qds) for 14 days. arm 2: Patient to receive best supportive care.
Interventions: intervention 1: Camostat
Intervention descriptions: intervention 1: Patient to receive treatment with camostat tablets, 200mg four times daily (qds) for 14 days.

Protocol documents:
Prot_000.pdf: 
ClinicalTrials.gov  
Document Cover Page 
NCT No.: NCT04455815 
Protocol No.: CRUKD/20/002 
ClinicalTrials.gov Upload Document Cover Page 
NCT Number 
NCT04455815 
EudraCT Number 
2020-002110-41 
Sponsor Protocol Number 
CRUKD/20/002 
Official Title 
A Randomised Phase II trial in early COVID-19, assessing use of 
camostat by blocking SARS-CoV-2 Spike protein-initiated membrane 
fusion. 
Document, Version & Date 
Protocol Version 6.0 dated 20 September 2021 


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© Cancer Research UK 
SPIKE-1 TRIAL: A Randomised Phase II trial in early COVID-19, 
assessing use of camostat by blocking SARS-CoV-2 Spike protein-
initiated membrane fusion. 
Date and Version No: 
20 September 2021, Version 6.0 
Protocol No.:  
CRUKD/20/002 
EudraCT No.:  
2020-002110-41 
Chief Investigator: 
Professor Kevin Dhaliwal, University of Edinburgh 
Sponsor:




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Section 6.1: Inclusion criteria and reference to COVID-age for 
participant eligibility (associated Appendix 4 for COVID-age 
risk tool) 
Section 6.1: Reference to COVID-19 symptoms will be as per 
guidance issued by the UK health authorities.  
Section 7.2.5: Camostat administration to be taken in a fasted 
state (rationale provided in revised Section 3.0) 
Non-substantial 
x Amendment history table: Liver Function Test exclusion 
criteria added (omitted in error from v2.0 summary of 
changes). 
x Other minor updates/clarifications. 
4.0 dated 25Jan2021 
Substantial 
Section 6.1 Patients are now eligible if they have a 
‘symptomatic COVID-19 infection’, and any patient that in the 
investigator’s opinion would not make the patient a good 
candidate for the clinical trial should be excluded.  
 
Section 6.2 Any patient that, in the investigator’s opinion would 
not make the patient a good candidate for the clinical trial 
should be excluded.  
 
 
Section 8.3 Clarification of Day 28 and post-discharge visits. 
Section 12.5 SAEs relating to COVID will not need reporting 
post the Day 28 visit. 
Section 13.1 Definition of patient evaluability clarified. 
Trial dates expanded. 
Introduction of optional patient application (‘app’). 
Non-substantial 
Clarification of processes (testing, recruitment, home visit, trial 
pack delivery, sampling) and administrative changes.  
5.0 dated 15Apr2021 
Substantial 
Trial changed from Phase II/III to Phase II only. 
Section 3.2 Text re-added relating to proposed dose and 
dosing schedule as per protocol version V3.0 as removed by 
error from V4.0. 


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Section 4 Primary objective of efficacy removed and safety and 
tolerability 
of 
camostat 
added 
as 
primary 
objective. 
Pharmacokinetics added as secondary objective. 
Removal of secondary objective relating to overall mortality 
assessed one year following randomisation. 
Section 5 Trial design modified to eliminate continuation 
phase. 
Section 6 Inclusion Criteria removed requirement for 
moderate to severe COVID-19 age risk calculation 
Section 8 COVID-19 age risk to be collected at baseline  
Section 9 Recruitment expanded to include patients presenting 
to Emergency Departments, Acute Assessment Units and 
hospitalised patients who are admitted (for any reason) who 
subsequently test positive for COVID-19. Patients will also be 
identified through other methods such as NHS digital and Test 
and Trace 
Section 5&8 Text added in relation to the COVID-19 vaccine; 
permitted prior to entry but current NHS guidelines do not allow 
the vaccine to be given within 28 days following a positive text. 
Please refer to current NHS guidelines. 
6.0 dated 20Sep2021 
Changes include those relating to potential collaboration with 
several global study teams conducting camostat trials with 
similar study design to the CRUKD/20/002 trial with the aim of 
pooling all data and analysing the effect of camostat on viral 
load and clinical outcome. Changes include an update to the 
end of trial definition and end of trial date as well as the 
statistical section. 
 
 


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TABLE OF CONTENTS 
1 
ABBREVIATIONS .......................................................................................................... 9 
2 
SYNOPSIS ................................................................................................................... 13 
3 
BACKGROUND AND RATIONALE ................................................................................ 17 
3.1 
Investigational Medicinal Product – Camostat ............................................................... 18 
3.2 
Proposed dose and dosing schedule for CRUKD/20/002 ................................................. 18 
3.3 
Safety considerations ..................................................................................................... 21 
3.3.1 
Adverse events ........................................................................................................................... 21 
3.3.2 
Patient population ...................................................................................................................... 21 
3.3.3 
Risk and benefit assessment ...................................................................................................... 22 
4 
OBJECTIVES AND ENDPOINTS .................................................................................... 23 
5 
TRIAL DESIGN ............................................................................................................ 25 
5.1 
Summary of trial design ................................................................................................. 25 
5.2 
Safety oversight and committees ................................................................................... 26 
5.2.1 
Trial Management Group ........................................................................................................... 26 
5.2.2 
Trial Steering Committee............................................................................................................ 26 
5.2.3 
Safety oversight .......................................................................................................................... 26 
5.3 
Intervention ................................................................................................................... 26 
5.3.1 
Randomisation ........................................................................................................................... 26 
5.3.2 
Dose modification ...................................................................................................................... 27 
5.3.3 
Dose interruptions/ Withdrawal criteria .................................................................................... 27 
5.3.4 
Day 7 visit ................................................................................................................................... 27 
5.3.5 
Patient hospital admission during Days 1-14 ............................................................................. 27 
5.3.6 
Pharmacokinetic sampling ......................................................................................................... 28 
5.3.7 
Concomitant medications .......................................................................................................... 28 
5.3.8 
Trial partners .............................................................................................................................. 28 
5.3.9 
Expenses and benefits ................................................................................................................ 28 
6 
PATIENT SELECTION ................................................................................................... 29 
6.1 
Inclusion Criteria ............................................................................................................ 29 
6.2 
Exclusion Criteria ........................................................................................................... 29 
7 
PHARMACEUTICAL INFORMATION ............................................................................ 30 


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7.1 
Supply of Investigational Medicinal Product .................................................................. 30 
7.2 
Pharmaceutical Data ...................................................................................................... 31 
7.2.1 
Formulation of camostat ............................................................................................................ 31 
7.2.2 
Storage conditions ...................................................................................................................... 31 
7.2.3 
Stability and labelling of camostat ............................................................................................. 31 
7.2.4 
Dispensing of camostat .............................................................................................................. 31 
7.2.5 
Camostat administration ............................................................................................................ 31 
7.2.6 
Camostat accountability ............................................................................................................. 32 
7.2.7 
Camostat supply to primary and secondary care pharmacies ................................................... 32 
8 
TRIAL PROCEDURES ................................................................................................... 32 
8.1 
Baseline assessments ..................................................................................................... 32 
8.2 
Confirmation of eligibility .............................................................................................. 34 
8.3 
On study assessments/procedures ................................................................................. 34 
8.3.1 
Days 1-14: Daily monitoring via video or phone call .................................................................. 34 
8.3.2 
Days 7 and 14: Home visit consultation with clinical professional ............................................. 34 
8.3.3 
Days 21 and 28: Monitoring via video or phone call .................................................................. 35 
8.3.4 
Days 1-28 .................................................................................................................................... 35 
8.4 
Sample collection and transport .................................................................................... 35 
8.5 
Escalation of patient management ................................................................................. 35 
9 
RECRUITMENT ........................................................................................................... 39 
9.1 
Identification of patients ................................................................................................ 39 
9.1.1 
Testing at COVID hubs (GP practices or walk-in centres) ........................................................... 39 
9.1.2 
Emergency Departments (EDs)................................................................................................... 40 
9.1.3 
Acute Assessment Units (AAUs) ................................................................................................. 40 
9.1.4 
Hospitalised patients (admitted for any reason other than COVID-19) who subsequently test 
positive for COVID-19 .............................................................................................................................. 40 
9.2 
Informed Consent .......................................................................................................... 40 
10 
DEFINITION OF END OF TRIAL ................................................................................. 42 
11 
DISCONTINUATION/ WITHDRAWAL OF PATIENTS FROM STUDY TREATMENT ........ 43 
12 
SAFETY REPORTING ................................................................................................ 44 
12.1 
Definitions ..................................................................................................................... 44 


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12.1.1 
Adverse Event (AE) ................................................................................................................. 44 
12.1.2 
Adverse Drug Reaction (ADR) ................................................................................................ 44 
12.1.3 
Serious Adverse Event (SAE) .................................................................................................. 44 
12.1.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ................................................... 45 
12.1.5 
Urgent Safety Measures (USM) ............................................................................................. 45 
12.2 
Causality ........................................................................................................................ 45 
12.3 
Procedures for Recording Adverse Events ...................................................................... 46 
12.4 
Procedures for recording pregnancies ............................................................................ 47 
12.5 
Reporting Procedures for Serious Adverse Events .......................................................... 47 
12.6 
Specific Events of Interest .............................................................................................. 48 
12.7 
Annual Development Safety Update Reports (DSUR) ..................................................... 48 
13 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................................. 49 
13.1 
Description of statistical methods .................................................................................. 49 
13.2 
Sample size determination ............................................................................................. 49 
13.3 
Clinical Study Report ...................................................................................................... 50 
14 
DATA MANAGEMENT ............................................................................................. 51 
14.1 
Source data .................................................................................................................... 51 
14.2 
Access to data ................................................................................................................ 51 
14.3 
Data recording and record keeping ................................................................................ 51 
14.3.1 
Recording of daily calls ........................................................................................................... 52 
15 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ................................. 52 
15.1 
Risk assessment ............................................................................................................. 52 
15.2 
Monitoring..................................................................................................................... 52 
15.3 
Quality assurance .......................................................................................................... 53 
15.4 
Protocol deviations and amendments ............................................................................ 53 
15.5 
Serious Breach of GCP .................................................................................................... 53 
16 
ETHICAL CONSIDERATIONS ..................................................................................... 53 
16.1 
Approvals ...................................................................................................................... 53 


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16.2 
Patient confidentiality ................................................................................................... 54 
16.3 
Indemnity ...................................................................................................................... 54 
17 
REFERENCES ........................................................................................................... 55 
18 
APPENDICES ........................................................................................................... 56 
18.1 
Appendix 1: The Chelsea Critical Care Physical Assessment tool (Cpax) – Copyright of 
Chelsea and Westminster NHS Foundation Trust (01MAR2010) (Corner, 2012) ......................... 56 
 
 
 
 
18.3 
Appendix 3: New York Heart Association (NYHA) scale ................................................... 60 
18.4 
Appendix 4: COVID-age calculation ................................................................................ 61 
 


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1 ABBREVIATIONS  
AAU 
Acute Assessment Unit 
ABPI 
Association of British Pharmaceutical Industry 
ACEI 
Angiotensinogen-converting enzyme inhibitors  
ACE-2 
Angiotensin-converting enzyme 2 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALAMA 
Association of Local Authority Medical Advisors 
ALP 
Alkaline phosphatase  
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
AR  
Adverse reaction 
AST 
Aspartate aminotransferase  
CDD 
Centre for Drug Development 
CDM 
Clinical Data Manager 
CI 
Chief Investigator 
Cmax 
Maximum observed plasma concentration 
CoA 
Certificate of Analysis 
COVID-19 
Coronavirus disease 2019 
 
  
CRA 
Clinical Research Associate 
CRUK 
Cancer Research UK 
CSM 
Clinical Study Manager 
CSR 
Clinical Study Report  
CT  
Computerised tomography  
CTA 
Clinical Trials Authorisation 
CTIMP 
Clinical Trial of an Investigational Medicinal Product  
CTRG 
Clinical Trials & Research Governance, University of Oxford 
CXR 
Chest X-ray 
DMP 
Data Management Plan 
DPA 
Data Protection Act 
DSUR 
Development Safety Update Report  
EC50 
Half maximal effective concentration 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
EoT 
End of Trial 
FBC 
Full blood count 
 
 
GBPA 
4-(4-guanidinobenzoyloxy) phenyl acetic acid 
GGT 
Gamma-glutamyl transferase  
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GMP 
Good Manufacturing Practice 
GP 
General Practitioner 
GTP 
Gamma-glutamyl transpeptidase 
Hb 
Haemoglobin  
HRA 
Health Research Authority 
IB 
Investigator’s Brochure 
IC10 
10% of maximal inhibitory concentration 
IC50 
Half maximal inhibitory concentration 
ICD 
Informed Consent Document 
ICH 
International Conference of Harmonisation 
ID 
Identification  
iDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
IV 
Intravenous  


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IWRS 
Interactive web response system 
LFT 
Liver function tests 
MERS-CoV 
Middle East Respiratory Syndrome coronavirus 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NLR 
Neutrophil:lymphocyte ratio 
NHS 
National Health Service 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
NYHA 
New York Heart Association 
PI 
Principal Investigator 
PK 
Pharmacokinetic  
PSRB 
Protocol and Safety Review Board 
PT 
Prothrombin time 
qds 
quater die sumendum (to be taken four times daily) 
QP 
Qualified Person 
qPCR 
Quantitative (real-time) polymerase chain reaction 
REC 
Research Ethics Committee 
RNA 
Ribonucleic acid 
RRT 
Renal replacement therapy  
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SARS-CoV 
Severe Acute Respiratory Syndrome coronavirus  
SARS-CoV-2 
Severe Acute Respiratory Syndrome coronavirus 2 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
tds 
ter die sumendum (to be taken three times daily) 
T1/2 
Terminal half-life 
Tmax 
Time to maximum concentration 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee  
UK 
United Kingdom 
U&E 
Urea and electrolytes 
USM 
Urgent Safety Measure 
Vd 
Volume of distribution 
WBC 
White Blood Cells 
 
 
 


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PROTOCOL SIGNATURES 
 
Sponsor Signature 
The Sponsor has read and agrees to the protocol, as detailed in this document. I am aware of 
my responsibilities as the Sponsor under the UK Clinical Trials Regulations1, the guidelines of 
Good Clinical Practice (GCP)2, the Declaration of Helsinki3, the applicable regulations of UK 
law and the trial protocol. The Sponsor agrees to conduct the trial according to these 
regulations and guidelines and to appropriately direct and assist sponsor’s staff who will be 
involved in the trial and ensure that all staff members are aware of their clinical trial 
responsibilities. 
 
 
Name: 
 
 
 
 
 
Title 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Guideline Integrated Addendum to ICH E6: Guideline for Good Clinical Practice E6(R2) Step 4 dated 09 
November 2016  
3 WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects adopted by the 18th WMA 
General Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 


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PROTOCOL SIGNATURES 
 
Chief Investigator Signature 
I have read and agree to the protocol, as detailed in this document. I am aware of my 
responsibilities as a Chief Investigator under the UK Clinical Trials Regulations1, the guidelines 
of Good Clinical Practice (GCP)2, the Declaration of Helsinki3, the applicable regulations of 
the relevant NHS Trust/Boards and the trial protocol. I agree to conduct the trial according to 
these regulations and guidelines and to appropriately direct and assist the staff under my 
control, who will be involved in the trial, and ensure that all staff members are aware of their 
clinical trial responsibilities. 
 
 
 
 
Chief Investigator's 
Name: 
 
 
 
 
 
Name of site: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Guideline Integrated Addendum to ICH E6: Guideline for Good Clinical Practice E6(R2) Step 4 dated 09 
November 2016  
3WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects adopted by the 18th WMA 
General Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 














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On the basis of this PK data, dosing camostat in a fasted state  at 200 mg every 8 hours (the approved 
dosing schedule), and given a T1/2 of 100 min, the plasma concentration of camostat would only be 
expected to remain above the IC50 of 
 for approximately 
after each dose.   
Options to increase exposure levels and the duration of exposure above the target level of 
 in 
the CRUKD/20/002 trial, were considered by the Sponsor and a dose of 
 
was initially considered. 
The effect of increasing the dose to 
 on Cmax can be estimated from dose proportionality. If 
dose proportionality is assumed to be linear, then 
 However, 
in a separate study the plasma concentration reported following a 
 
, resulted in a Cmax of 
. Comparing 
this to a Cmax of 
 reported after an oral dose of 
 (administered in a fasted state), the 
dose proportionality for Cmax is closer to 
, therefore predicting a Cmax of 
 
 dose administered in a fasted state (refer to the current version of the 
‘Camostat Investigator’s Brochure’ for further details). 
Recent unpublished data provided by Ono Pharmaceutical Co. Ltd from an ongoing Phase I trial in 
healthy male adult volunteers (NCT04451083), is also consistent with a dose proportionality in Cmax 
of approximately ×1.5 for doses of camostat administered in a fasted state 
 
 (Ono Pharmaceutical Co., Ltd., 2020). Preliminary PK parameters from this trial following 
administration of a single dose of camostat, 600 mg in a fasted state (Day 1), are: 
 
 This trial additionally 
compared PK parameters from two cohorts (
, Japanese healthy males per cohort) after repeat 
dosing at 
 in both a fed and fasted state. Draft unpublished results have shown 
that there is a notable food effect on dosing, with plasma exposure (Cmax) significantly lower in subjects 
administered a single dose of camostat after food as compared to dosing in a fasted state. This is most 
clearly evidenced by comparing the Cmax and AUC values from subjects dosed in a fasted state 
 with values obtained when the subjects received 
doses after food 
 
For further details of this study refer to the current version of the 
‘Camostat Investigator’s Brochure’. 
The target camostat plasma concentration for inhibition of viral entry based on preclinical data is 
estimated to be 
 Using the expected plasma Cmax for a 300 mg dose administered fasted, the 
plasma concentration over time was simulated to estimate how long a concentration 
 
would be expected to be sustained; the higher dose of 300 mg is predicted to have only a minimal effect 
on the time that a plasma concentration of 
 will be maintained (Figure 2). Further PK 
modelling was performed to consider dosing 
 
(Figure 2). With this dosage and dosing regimen, the camostat plasma concentration is maintained 
above the 
, for a longer period of time (
 
 resulting in greater exposure to the drug. The effect 
of variation in dosing interval on plasma concentration with 
 
, was also modelled (Figure 3) and illustrates that a
 
 
target concentration of 
 As the half-life of camostat is 
, supported by the results 
from the recent Ono Pharmaceutical Co.Ltd Phase I trial (NCT04451083) referenced above (refer to 
the current version of the ‘Camostat Investigator’s Brochure’ for further details).
 
 
 
 




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. It is likely that the safety data for the 
use of camostat in the treatment of chronic pancreatitis (total daily dose 600 mg [200 mg tds]) will have 
been generated from a mixed population in terms of dosing in both a fed and fasted state, but with no 
obvious difference in adverse event (AE) profile noted and a known, acceptable safety profile for the 
agent at the recommended dose and schedule. 
Additional safety data to support the 200 mg qds dosing schedule in a fasted state is provided from the 
ongoing NCT04451083 trial. As noted above, two cohorts of healthy Japanese male adults (n=7 per 
cohort) were administered a single dose of camostat 
 on Day 1 and then 
 
 
 dose proposed in the CRUKD/20/002 trial [200 mg qds]). In 
this trial,
 
 
 
 
(Ono Pharmaceutical Co., Ltd., 2020). Pharmacokinetic 
parameters reported in this trial for doses administered fasted, 
 
 
 
 
 
 
 (refer to the current version of the ‘Camostat Investigator’s Brochure’ for further 
details). 
The camostat dose proposed for the treatment arm in the CRUKD/20/002 trial is therefore a total daily 
dose of 800 mg (200 mg qds) for 14 days. Whilst the proposed 14-day dosing period is double that 
explored in the ongoing NCT04451083 trial, the total daily dose to be administered is three-fold less 
and considered acceptable based on the safety data available and lack of accumulation observed. 
Patients will be required to take their doses one hour before each meal and then before bed, with an 
interval of approximately three hours between eating and the next dose, so approximately four hours 
apart (except for the overnight interval between the last dose on one day and first dose of the next day 
which will be longer) and at the same time each day. 
 
3.3 Safety considerations 
For further information on the safety of camostat and specific safety considerations refer to the current 
version of the ‘Camostat Investigator’s Brochure’. 
3.3.1 
Adverse events 
Camostat has been in clinical use for over 30 years in Japan and Korea and has a known, acceptable 
safety profile. Adverse reactions reported during the safety surveillance of camostat for its licensed 
indications include shock or anaphylactoid symptoms, thrombocytopenia, changes in liver enzymes. 
gastrointestinal disorders, rash and hyperkalaemia, all with low reported incidences (<1% patients). 
3.3.2 
Patient population 
The majority of clinical studies supporting the original registration of FOIPAN® in Japan were conducted 
in a Japanese/Asian population.  
Two Phase I PK studies have been performed in Caucasians, one by Forrest,1989 and one by Midgley, 
1994. Camostat is rapidly metabolised in vivo by a carboxyesterase to its active metabolite GBPA and 
the inactive by product 4-guanidinobenzoic acid (GBA) (Midgley, 1994). The active metabolite GBPA is 
further metabolized by arylesterase, glucuronidated and excreted in the urine (Midgley, 1994). Genetic 
variations due to ethnicity have not been reported for any of these enzymes involved in the metabolism 


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of camostat. From the available data, it is concluded that the PK/PD differences between the Asian and 
Caucasian populations are predicted to be minimal and that the known safety of camostat in Asians 
and Caucasians is expected to be similar (Forrest, 1989) (Midgley, 1994). 
3.3.3 
Risk and benefit assessment 
For the overall risk and benefit assessment for the investigation of camostat in protocol CRUKD/20/002, 
refer to Section 5.8 in the current version of the ‘Camostat Investigator’s Brochure’. 
 
 






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5 TRIAL DESIGN 
5.1 Summary of trial design 
A randomised, multicentre, prospective, open label clinical trial. 
The trial aims to recruit up to 100 patients. 
The Trial Management Group (TMG) described in Section 5.2.1, will perform ongoing review of the 
emerging data to inform adaptive decision making during the trial. Please see Section 5.2.1. for further 
details.  
During the trial, patient enrichment strategies may be implemented e.g. adapting the inclusion criteria 
to include emerging co-morbidities, neutrophil/lymphocyte ratio, other blood biomarkers, age, in order 
to support trial endpoints and feasibility. All clinical data will be reviewed on a regular basis by the 
Sponsor and TMG to inform this adaptive design, collaborating with the Trial Steering Committee (TSC) 
as per Section 5.2.2.  
If review of the data (during any part of the trial) results in proposed substantial amendments, these will 
be submitted to the Medicines and Healthcare products Regulatory Agency (MHRA) and Research 
Ethics Committee (REC) for an opinion.   
Patients may be identified in/through various settings e.g. GP practices, primary care COVID hubs, 
community-based testing centre, drive through testing facilities, advertisement, secondary care or 
equivalent clinical settings. Further detail on how patients will be recruited is provided in Section 9.1.  It 
is likely that testing availability and strategy will change in the UK and the trial will respond by engaging 
with testing sites as applicable, to support recruitment. Before any new sites are opened for this trial, 
risk assessments will be performed to ensure that the protocol and procedures can be performed safely 
for both patients and site staff. 
If a patient consents to the trial and fulfils eligibility criteria, they will be randomised to either the 
treatment arm or the control arm. Patients in the treatment arm will be asked to take camostat for 
14 consecutive days and patients in the control arm will be asked to continue with best supportive care. 
 
A clinical research team member will call the patient daily during this period. On 
Days 7 and 14, patients will be visited at home by the clinical research team, for blood draws and 
COVID-19 swab (or equivalent) testing.  Home visits may be replaced by patient site visits (e.g. to a 
‘red hub’) but only in accordance with government and clinical advice. If the Sponsor and site decide 
that sampling is not required, this will be communicated to the patient.  The video (phone) calls on Days 
7 and 14 will still go ahead as planned regardless of sampling. Patients will also be called weekly (Days 
21 and 28) before the follow up period ends.   
Patients who are in hospital for non COVID-19 related reasons may be recruited if they tested positive 
while in hospital. In this situation daily phone calls may be substituted by face to face visits, if feasible, 
by the hospital team until the patient is discharged. At that point the patient will be managed as 
described above. Further detail on how patients will be recruited and managed in this situation is 
provided in Section 9.   
Adverse events (AEs) or hospital admissions related to camostat or COVID-19 will be followed up as 
per Section 12.0. 
During the trial period (Days 1-28), patients who are hospitalised will also be followed up, up to 28 days 
post discharge.  
 


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5.2 Safety oversight and committees  
5.2.1 
Trial Management Group 
The TMG is responsible for the day to day running of the trial including but not limited to, the Sponsor, 
Chief Investigator (CI), Trial Statistician, Principal Investigators (PIs) and Co-Investigators who will have 
oversight of all clinical and safety data throughout both phases of the trial. A core study team will 
oversee management of the trial and make decisions at the operational level.  
Early assessment of recruitment and trial feasibility will be critical therefore the TMG will provide 
ongoing review of emerging clinical and feasibility data during the trial and propose modification where 
required for regulatory/ethical approval as appropriate. The TSC will be asked for an opinion as 
appropriate when these modifications are proposed by the TMG. 
5.2.2 
Trial Steering Committee 
A TSC will be convened to review safety and pharmacokinetic data from the trial on an ongoing basis.  
The TSC will include the CI, Sponsor representatives including the Medical Advisor, at least two 
independent experts with expertise in COVID infection and/or other relevant specialities, trial statistician 
and one member of the Sponsor’s Protocol and Safety Review Board6 (PSRB). 
The TSC will provide expert advice in the event of any concerns around toxicity and will have the 
authority to suspend or terminate the trial and/or make recommendations to the Sponsor to modify the 
trial design. 
Meetings of the TSC will be convened by the Clinical Study Manager (CSM) for the trial to review data 
generated at time points where key decisions are required. Additional ad hoc meetings may be 
convened should unforeseen events occur, and independent expert advice would be beneficial. 
The responsibility for calling and organising TSC meetings lies with the CSM for the trial in association 
with the Chair of the TSC. Meetings will take place at least every six months if a review has not already 
taken place. The TSC, CI or Sponsor can request additional meetings at any time. 
A TSC Charter will be made available to support the trial. The charter will include reference to the 
Statistical Analysis Plan (SAP) and how results from any analysis will be communicated to the TSC to 
inform decision making. 
5.2.3 
Safety oversight 
Safety evaluations by the TMG will be conducted at regular intervals throughout patient recruitment. 
Data reviewed includes all clinical data, safety data listings and trial feasibility. Any concerns relating to 
safety can be escalated to the TSC for an opinion and recommendation. 
 
5.3 Intervention 
5.3.1 
Randomisation 
Patients will be randomised by the site staff using an interactive web response system (IWRS). 
Confirmation of the patient randomisation will be sent to the Investigator, site clinical trial team and 
Sponsor following enrolment and randomisation of the patient. The patient will be notified of their 
allocated group by the clinical research team. 
Randomisation will be to one of two arms and a randomisation ratio of 1:1 will be applied: 
 
Treatment arm: patient to receive treatment with camostat 200 mg qds for 14 days.  
 
Control arm: patients will receive best supportive care. 
 
6 The PSRB acts as an independent body across the portfolio of studies at the CR UK Centre for Drug Development (CDD). The 
PSRB charter mandates that the members are independent from CR UK, CDD and can act as an independent body.  


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All patients randomised will receive a trial pack to include 
 
 
instructions for use as well as a diary card to record these readings 
and, if randomised to camostat, to document their compliance with dosing. If patients wish to do so, 
they can use the Medidata patient application (‘app’) in addition to the diary card. The trial pack will 
include an app instruction and consent document.  The research team or courier will deliver the 
appropriate trial pack. 
For patients recruited while in hospital, all assessments will be performed and camostat will be given 
by the hospital staff (if the patient is randomised to camostat). Patients will receive a trial pack to include 
 instructions for use 
only on discharge. If patients wish to do so, they can use the Medidata patient application (‘app’) in 
addition to the diary card and app instructions and consent form can be provided.  
Patients randomised to the treatment arm will also be offered best supportive care in managing the 
disease. 
5.3.2 
Dose modification 
The planned dose for all patients who are randomised to the treatment arm is 800 mg per day (200 mg 
qds) for 14 days. Dose modifications may occur such as reducing the daily dose. Dose reductions for 
individual patients may be considered based on emerging clinical data and if agreed with the Sponsor, 
CI and PIs.  These dose reductions could take the form of reduction of times that camostat is 
administered e.g. qds to tds or to a reduction at each of the daily administrations e.g. 200 mg qds, down 
to 100 mg qds.  
The patient will be contacted daily during the treatment period by the clinical research team for 
assessment of any AEs and difficulties the patient may be experiencing with the administration schedule.  
Escalation of patient management is further discussed in Section 8.5. 
5.3.3 
Dose interruptions/ Withdrawal criteria 
x 
If a clinically significant abnormality is identified, camostat will be interrupted and blood samples 
will be taken for analysis.  
x 
If abnormal results are identified, the patient will be referred to the GP for further assessment 
where local protocols will be followed. 
x 
If required, patient hospital attendance with a suspected adverse event will trigger SAE 
reporting and the Investigator and Sponsor will make a causality assessment. 
x 
Possible, Probably and Highly Probable causality assessment to camostat will result in 
treatment withdrawal. 
x 
If the patient recovers symptomatically and biochemical analysis returns to the normal range, 
re-starting camostat can be considered by the Investigator and Sponsor to include an 
assessment whether the patient is likely to be past the initial stage of infection. For patients 
where it is deemed appropriate to re-start the patient, a maximum of 48 hrs treatment 
interruption will be allowable. 
5.3.4 
Day 7 visit 
It is intended that the Day 7 interaction with the patient is made by a clinical professional who can 
assess whether the patient has recovered. Patients may be visited at home on Day 7 (to collect 
research bloods and 
 as well as receiving the daily video (phone) 
call.  If at this visit/during the call, it is assessed that the patient (on the treatment arm) has recovered, 
the patient may be asked to discontinue with camostat administration, and the drug will be disposed of 
as per an approved process. Follow up calls and visits as per protocol will continue.  
5.3.5 
Patient hospital admission during Days 1-14 
If during Days 1-14 the patient is admitted to hospital due to COVID-19, patients on the treatment arm 
will be asked to continue to take their camostat as per protocol following agreement from the treating 


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clinician. A patient identification (ID) card will be provided to all patients with relevant contact details. 
Patients requiring hospital admission will continue to take camostat unless contraindicated by their 
clinical condition or other clinical care. 
For patients who are hospitalised, clinical research teams should still seek to perform the protocol 
mandated assessments as per Section 8.3, so long as they do not interfere with clinical care and 
management of the patient. 
5.3.6 
Pharmacokinetic sampling 
The Sponsor may propose that for patients who are hospitalised, if they have consented, and so long 
as the sampling schedule does not interfere with their hospital care, pharmacokinetic (PK) blood 
samples may be taken at Sponsor defined timepoints for analysis as per laboratory manual.  
The patient will be asked to consent to this when first recruited to the trial and then asked again for 
verbal affirmation of consent (recorded in the patient’s medical record) before these blood samples are 
taken.  If the patient is unable to give consent or incapacitated, these samples will not be taken. 
A maximum of 4 mL of blood will be taken at each timepoint for this analysis. 
During the course of the trial, patients who remain able to recover at home, may also be asked to 
consent to PK sampling.  Patients will be asked to consent to this at the time of recruitment and verbal 
affirmation of consent will be confirmed with the patient (and documented in the patient’s medical record) 
before these samples are taken. 
The process for PK sampling for this trial will be included in the laboratory manual. PK samples will be 
analysed to confirm that the PK profile aligns with the established PK profile for the active metabolite of 
camostat, 4-(4-guanidinobenzoyloxy) phenyl acetic acid (GBPA) and will be assessed by population 
estimates from population PK analysis (popPK). 
5.3.7 
Concomitant medications 
Routinely used medications for the alleviation/treatment of symptoms of COVID-19 are permitted. Only 
approved anti-viral therapies to treat SARS-CoV-2 will be permitted.  
Any other medication (including over the counter or prescription medicines, vitamins, and/or herbal 
supplements) that the patient is receiving at the time of enrolment (including screening) or receives 
during the study must be recorded in the eCRF along with:  
x 
Reason for use.  
x 
Dates of administration including start and end dates.  
x 
Dosage information including dose and frequency.  
The COVID-19 vaccine is currently not recommended for anyone who has had a positive test within 28 
days or 28 days after symptoms started and not before symptoms have resolved. Please also refer to 
the current NHS guidelines for information. 
5.3.8 
Trial partners 
Patients will be asked to nominate a Trial Partner that the clinical research team can contact if the 
patient cannot respond during the trial period e.g. if the patient is sick at home, or because they are in 
hospital or have died. This is not a requirement of trial participation but a proposed way of supporting 
the patient’s participation on the trial. 
5.3.9 
Expenses and benefits 
Reasonable travel expenses for any visits additional to normal care will be reimbursed, although no 
such additional visits are envisaged to be required. 


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6 PATIENT SELECTION 
During the trial, there will be ongoing review of the emerging data to inform adaptive decision making if 
required. Patient enrichment strategies may be implemented e.g. revision to inclusion criteria regarding 
co-morbidities, neutrophil/lymphocyte ratios, age. 
 
6.1 Inclusion Criteria 
1. 
Patient willing and able to give informed consent. 
2. 
Adults, 18 years of age and above  
3. 
Symptomatic COVID-19 infection  
4. Evidence of current COVID-19 infection from a validated assay. 
 
6.2 Exclusion Criteria 
The patient may not enter the trial if ANY of the following apply: 
1. Significant electrolyte disturbance (e.g. hyperkalaemia, potassium > site specific upper 
limit of normal). 
2. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and/or alkaline 
phosphatase (ALP) > 2.5 x ULN. 
3. Any condition that, in the Investigator's opinion, would not make the patient a good 
candidate for the clinical trial or would prevent adequate compliance with trial therapy e.g. 
mild cognitive impairment (unable to follow instructions for self-assessment readings as 
assessed by the Investigator). 
4. Patients on long term supplementary oxygen requirement (patients for whom hospital 
admission would not be considered e.g. care plan in the community is in place, are not 
excluded).  
5. Known hypersensitivity to camostat.  
6. Platelet count <100 x 109/L. 
7. Co-enrolment with a Clinical Trial of an Investigational Medicinal Product (CTIMP) will not 
be permitted. Co-enrolment with a clinical investigation of a Medical Device or a non-
interventional clinical study will be considered on a study-by-study basis and in discussion 
with the relevant Chief Investigators and Sponsors and industrial collaborators.  
8. Co-enrolment involving non-interventional research (including questionnaire or tissue only 
studies) will be allowed provided this is not expected to affect the outcomes of both studies 
or place undue burden upon participants and their families.  
9. Female patients who are able to become pregnant7(or are already pregnant or lactating). 
However, those patients who are of child bearing potential and have a negative serum or 
urine pregnancy test before enrolment and agree to use two forms of contraception (one 
effective form plus a barrier method [oral, injected or implanted hormonal contraception 
 
7 A woman is considered of childbearing potential i.e. fertile, following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
Post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 


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and condom; intra-uterine device and condom; diaphragm with spermicidal gel and 
condom]) or agree to sexual abstinence* 8 , effective from the first administration of 
camostat, throughout the trial and for 28 days afterwards are considered eligible. 
(*Abstinence is only considered to be an acceptable method of contraception when this is 
in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.) 
10. Male patients with partners of child-bearing potential7(unless they agree to take measures 
not to father children by using a barrier method of contraception [condom plus spermicide] 
or to sexual abstinence*8 effective from the first administration of camostat, throughout the 
trial and for 28 days afterwards. Men with partners of child-bearing potential must also be 
willing to ensure that their partner uses an effective method of contraception for the same 
duration for example, hormonal contraception, intrauterine device, diaphragm with 
spermicidal gel or sexual abstinence). Men with pregnant or lactating partners must be 
advised to use barrier method contraception (for example, condom plus spermicidal gel) 
to prevent exposure of the foetus or neonate. 
(*Abstinence is only considered to be an acceptable method of contraception when this is 
in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.).   
11. Significant cardiovascular disease (as assessed via the participant’s medical record and 
history) as defined by:  
a. History of congestive heart failure requiring therapy (New York Heart Association 
[NYHA] III or IV – Appendix 3).  
b. History of unstable angina pectoris or myocardial infarction up to 6 months prior 
to trial entry.  
c. Presence of severe valvular heart disease.  
d. Presence of a ventricular arrhythmia requiring treatment.  
Known allergic reactions to components of camostat e.g., lactose intolerance (see Section 7.2.1) 
 
 
7 PHARMACEUTICAL INFORMATION 
Please see IB supplement and SmPC for further information if required. 
 
7.1 Supply of Investigational Medicinal Product 
A complete Certificate of Analysis (CoA) and a Qualified Person (QP) certification must be provided 
with each delivery of camostat. 
For information on camostat and re-ordering of supplies, contact the Clinical Research Associate 
(CRA)/Clinical Study Manager (CSM) responsible for the trial who will arrange further supplies. 
Camostat will be supplied by:  
Fisher Clinical Services U.K. Limited 
 
8 Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 


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The Manufacturing Organisation (Fisher Clinical Services U.K. Limited) must provide confirmation of 
the shipment to the CSM/CRA on despatch of the investigational medicinal product (IMP). 
The primary and secondary packaging for the IMP will be labelled according to Eudralex Volume 4: 
Annex 13 ‘Manufacture of Investigational Medicinal Products’ of the European Union guide to Good 
Manufacturing Practice (GMP). 
Upon arrival at site, patient ID must be added to the applicable variable fields on the primary and 
secondary labels.  
An example of the approved label can be found in the Trial Master File (TMF). 
 
7.2 Pharmaceutical Data 
7.2.1 
Formulation of camostat 
Camostat (camostat mesilate marketed as [FOIPAN®]) will be supplied as 100mg tablets. 
Other ingredients as follows: Hydroxypropylcellulose, Carmellose calcium, Magnesium Stearate, 
Polyoxyethylene (105), polyoxypropylene (5) glycol, Lactose hydrate. 
7.2.2 
Storage conditions 
All supplies must be stored in a secure, limited access storage area in its original packaging. Camostat 
must be stored at room temperature. 
7.2.3 
Stability and labelling of camostat 
The tablets are supplied in boxes containing 5 blister packs. Patients should be instructed to store 
camostat at room temperature and out of sight and reach of children. 
Labelling applied by pharmacy for camostat must include the following information: 
Name of IMP; dose; expiry time/date; patient ID (and any other local requirements e.g. Pharmacy batch 
number). 
NB: Any Pharmacy applied labels must not obscure the Annex 13 labels applied by the Manufacturing 
Organisation. Example labels should be filed in the TMF and approved by the Sponsor. 
7.2.4 
Dispensing of camostat 
Sufficient tablets of camostat must be dispensed on each occasion to cover the prescribed dose for the 
full treatment period i.e. Days 1-14. 
Patients should be supplied with the required quantity of camostat in the original boxes to cover the 
prescribed dose. Blister packs must not be cut to reduce tablet numbers at dispensing. 
The tablets are supplied in blister packs and must not be removed from the primary packaging (provided 
to the patient) and placed in any other container. Tablets should be stored at room temperature and out 
of sight and reach of children. 
7.2.5 
Camostat administration 
For patients randomised to the treatment arms: 
Before dispensing the camostat tablets, the exact dosage must always be double-checked by a second 
suitably qualified person. All checks and double-checks must be documented (signed and dated) and 
the documentation must be available for the CRA/CSM to verify. 


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The camostat tablets must be swallowed whole (with water) and not chewed, crushed, dissolved or 
divided. Patients will be provided with instructions for when they should take their camostat. 
Patients will be asked to take their camostat four times a day, one hour before each meal. After the 
patient has finished eating, they should wait approximately three hours before taking the next dose. 
Again, the patient should wait one hour after dosing before they can eat. The patient should aim to take 
their last dose of camostat before they go to bed. 
Patients should be advised that there should be approximately a four-hour interval between doses, 
except between their last dose of the day and the next dose the following morning; this overnight interval 
will be longer.  
Should a patient miss a scheduled dose in error, for example, forgetting to take the dose, then the 
patient can take that delayed dose within two hours of the scheduled dose (but will need to refrain from 
eating for an hour afterwards). Subsequent doses will be delayed accordingly.  
The patient will be supplied with a diary card and asked to record each dose (time and dose) and timing 
of each meal.   
For dose modification guidance, see Section 5.3.2. 
7.2.6 
Camostat accountability 
Accurate records of all IMP shipments, tablets dispensed, and all IMP returned must be maintained. 
This inventory record must be available for inspection at any time by clinical research associates (CRAs) 
or CSMs of the Sponsor. Investigational Medicinal Product supplies are to be used only in accordance 
with this protocol and under the supervision of the Investigator. 
The Investigator undertakes not to destroy any unused or returned IMP unless authorised to do so by 
the Sponsor. Any unused IMP must be destroyed according to hospital procedures and properly 
accounted for using the IMP Destruction Form and on the IMP Accountability Record. During the course 
of the trial the CRA will check the numbers of camostat tablets shipped to the centre, the number used, 
and the number destroyed or returned. The pharmacy will give an account of any discrepancy. 
7.2.7 
Camostat supply to primary and secondary care pharmacies 
For trial sites affiliated to a hospital Trust/Board, camostat will be supplied to the hospital pharmacy and 
maintained by the clinical trial pharmacists.  
If trial sites are opened where camostat is to be held in secondary pharmacies e.g. GP pharmacies, the 
Sponsor will perform a risk assessment to confirm the process by which camostat is managed and 
dispensed to patients and document this in the risk assessment and site management plan.  
 
 
8 TRIAL PROCEDURES 
8.1 Baseline assessments 
All patients must have received a positive COVID-19 test result via oropharyngeal/nasopharyngeal 
swab (or other validated method) prior to baseline assessments being performed. 
 
Other validated methodology may be used 
during the course of the trial e.g. saliva test, to improve the patient experience and assuming equal to 
or improved test validation and sensitivity. 
When the patient has indicated their interest in the trial as per Section 6, the following information will 
be ascertained by the clinical research team member via an initial conversation (via video or phone call 
for community patients)*:  
 
Demographics – date of birth, gender. 
 
Height and weight. 


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 
Symptoms of COVID-19, ancillary symptoms and length of symptoms – e.g. fever (> 37.8°C), 
persistent dry cough, muscle pain, shortness of breath, diarrhoea, headache, anosmia, other 
symptoms. 
 
COVID-age risk (Appendix 4) 
 
Other potential risk factors including smoking (pack year history), ethnicity, occupation, 
symptomatic household (or other) contact, other relevant medication history. 
 
Previous medical history – particularly chronic disease (specifically hypertension, 
cardiovascular disease, diabetes mellitus, hyperlipidaemia, cancer and existing respiratory 
conditions), history of influenza vaccination and COVID-19 vaccination (past two years). 
*Alternatively, for patients recruited in a hospital setting, all baseline assessments would be performed 
during their attendance in the hospital, including a COVID-19 test if not previously performed. 
If the above assessments are supportive of a home visit to conclude the below eligibility assessments, 
the patient will be asked to provide consent as per Section 9.2. The following will then be performed: 
 Biochemical and haematological investigations to include: 
 
Haematology – haemoglobin (Hb), white blood cells (WBC), neutrophils, lymphocytes, 
and platelets. 
 
Biochemistry – sodium, potassium, magnesium, adjusted calcium, phosphate, urea, 
creatinine, total protein, albumin, bilirubin, alkaline phosphatase (ALP), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), clotting- prothrombin time 
(PT), 
activated 
partial 
thromboplastin 
time 
(APTT), 
gamma-glutamyl 
transferase (GGT), troponin, D-dimer. 
 
 
 
Pregnancy test for women of childbearing potential. 
 
 
 
 
 
  
 
 
 
 
 
 
Ordinal scale status assessment (as per secondary endpoint). 
 
During this process the potential patient will be asked, if possible, to include a phone number 
and email address for a Trial Partner, who may be contacted by the clinical research team if 
the patient is unavailable 
Radiological investigations over normal clinical care are not required as part of this trial, but if performed 
as part of clinical care, chest x-rays and chest CT scans will be assessed and included in analysis by 
accessing the secondary care patient records.  
Additional laboratory investigations or procedures performed as part of clinical care during the trial 
period will be included in the analysis.   
 


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8.2 Confirmation of eligibility 
Patients with a positive COVID-19 result and who are eligible according to the inclusion/exclusion 
criteria (post review of the assessments performed during baseline assessments), will be contacted by 
the clinical research team.  They will be randomised by the clinical research team and informed of their 
allocated group. 
 
8.3 On study assessments/procedures 
All patients will be contacted as follows: 
8.3.1 
Days 1-14: Daily monitoring via video or phone call 
Community patients will be monitored via video or phone call daily. If feasible for hospital patients daily 
monitoring will be performed face to face. 
 
 
 
 
 
  
 
  
Number of patients asked to perform this test and days of testing may be adapted based on 
test availability. 
 
 
 
Ordinal scale status assessment (as per secondary endpoint). 
Those patients who have consented can enter their data 
 
 on the Medidata patient 
application ‘app’. 
The video (phone) calls made to the patient may be recorded for quality assurance purposes. Patients 
will be asked to consent to recording of their calls during the main consenting process and at the 
beginning of each call, the patient will be asked to verbally confirm their consent. These recordings will 
be emailed immediately afterwards to a secure NHS email address where they will be stored securely 
on the NHS server until the end of the trial. See Section 14.3.1. This is not a requirement of trial 
participation but a proposed way of supporting the patient’s participation on the trial. 
8.3.2 
Days 7 and 14: Home visit consultation with clinical professional 
The intention is that for community patients home visits occur on Days 7 and 14 to take research 
bloods 
.  However, this requirement may change if patients are able to provide samples 
by visiting the site but only in accordance with government and clinical advice. For those patients in 
hospital, Day 7 and 14 visits can occur in hospital face to face. If the Sponsor and site decide that 
sampling is not required, this will be communicated to the patient.  The Days 7 and 14 video (phone) 
calls will still go ahead as planned regardless of sampling. 
 
 
 
Biochemical and haematological investigations to include: 
 
Haematology – Hb, WBC, neutrophils, lymphocytes, and platelets. 
 
Biochemistry – sodium, potassium, magnesium, adjusted calcium, phosphate, urea, 
creatinine, total protein, albumin, bilirubin, ALP, ALT, AST, clotting-PT, APTT, GGT, 
troponin, D-dimer. 


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 
Raised parameters will be managed as per usual Trust clinical management. If results indicate 
that the patient should be admitted, the clinical research team will contact the patient and 
arrange for them to come into hospital for further assessment. For dose interruption/withdrawal 
criteria, see Section 5.3.3 
 
 
 
Blood sample for pharmacokinetics (PK) assessment (patient will be asked to consent to PK 
sampling within main study ICD and that this will also be document within the patient’s medical 
notes)  
 
 
8.3.3 
Days 21 and 28: Monitoring via video or phone call 
Community patients will be monitored via video or phone call on Days 21 and 28. If feasible for hospital 
patients this monitoring will be performed face to face. 
 
 
 
Ordinal scale status assessment – As per secondary endpoint. 
 
 
 
 
Those patients who have consented can enter their data 
 
 on the Medidata patient 
application ‘app’. 
The video (phone) calls made to the patient may be recorded for quality assurance purposes. Patients 
will be asked to consent to recording of their calls during the main consenting process and at the 
beginning of each call, the patient will be asked to verbally confirm their consent. These recordings will 
be emailed immediately afterwards to a secure NHS email address where they will be stored securely 
on the NHS server until the end of the trial. See Section 14.3.1. This is not a requirement of trial 
participation but a proposed way of supporting the patient’s participation on the trial. 
8.3.4 
Days 1-28 
Review of hospital and primary care records to evaluate use of any form of supplementary oxygen, 
CXR/ CT reports or images to assess progression or evolution of pneumonia and evidence of pulmonary 
thromboembolic events plus documentation of death (COVID-19 related mortality) during trial period. 
Patients who are hospitalised will be followed up following discharge. The Day 28 visit can be done up 
to 28 days post discharge if the patient was hospitalised at the time of day 28.  
 
8.4 Sample collection and transport 
Local arrangements for collection of samples taken at home may vary depending on the trial centre and 
feasibility but will include home visits by the clinical research team or patients attending site, if permitted 
(e.g. GP ‘red hub’).  
 
8.5 Escalation of patient management 
Patients will be informed of 
 indications of progressive 
breathlessness, or other concerning symptoms (safety rule set developed by the TMG) that should 


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trigger immediate self-referral to seek health advice from the appropriate channels as they normally 
would, according to urgency e.g. GP or dialling NHS 111 or 999. Hospital patients will be monitored by 
the hospital clinical team and any of these events will be managed accordingly. 
x 
As well as the safety rules being provided to the patient, these rules will also be provided to the 
clinical research team making the call to the patient.  
x 
Patients will be able to self-refer as per above however in the absence of patient action in 
response to a threshold being met, when the clinical researcher becomes aware during the call, 
this will trigger the clinical researcher to remind the patient of the safety rule set and their self-
referral as needed.  
x 
Data collected from each call will be entered on the same day by the clinical researcher and 
therefore be available to the PIs for review on a daily basis.  
Daily video call (or phone) assessments will support reinforcement and safety netting of these safety 
rules, allowing for self or clinical research team referral for appropriate primary care, 111 or 999 review, 
in accordance with local clinical pathways. These calls to the patient will follow a set script to ensure 
consistent data collection and will take place at a consistent time for patient convenience but also at a 
time which will allow sufficient time for the Principal Investigator and/or Co-Investigator to review the 
data and to therefore contact the patient as needed.  
Any escalation of patient management, triggered by safety signals experienced by a patient, the clinical 
research team will also notify the Sponsor. 
Patients requiring hospital admission will have clinical investigations performed in line with clinical care. 
Patients requiring hospital admission will continue to take camostat unless contraindicated by clinical 
condition or other clinical care. Patients will be provided with a trial ID card. 
For dose interruption/withdrawal criteria, see Section 5.3.3. 




 
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A. 
The intention is that home visits, by a clinical professional, occur on Days 7 and 14 to take research bloods, PK bloods and repeat swab.  However, this requirement may change if patients are 
permitted to provide samples by visiting the site. If the Sponsor and site decide that sampling is not required, this will be communicated to the patient.  The Day 7 and 14 video (phone) calls will 
still go ahead as planned regardless of sampling. 
 
  
C. 
If randomised to the camostat arm, patients will also receive camostat tablets to last for 14 days. 
D. 
Two readings a day. 
E. 
Trial packs and, for those patients randomised to the treatment arm, camostat may be delivered by courier or site staff. 
 
 
G. 
For community patients, home visits can be performed on site if permitted by government guidance. For hospital based patients these assessments may be performed face to face, if 
feasible. 
 


 
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9 RECRUITMENT 
9.1 Identification of patients 
The protocol is deliberately flexible so that it is suitable for several settings from which patients could be 
identified and recruited.  These settings can include but are not limited to: 
x 
GP practices (either as trial sites or patient identification centres texting/phoning potential 
patients) 
x 
social media, traditional media, webpage, poster and leaflet advertisement 
x 
advertisement at testing centres 
x 
COVID hubs 
x 
identification through other hospital departments (e.g. Emergency Department, Accident and 
Emergency, Oncology etc.) 
x 
NHS Digital 
x 
hospitalised patients who are admitted (for any reason) and subsequently test positive for 
COVID-19 
x 
test and trace, or equivalent  
At the time of initial regulatory submission, the approach for community/outpatient testing was, for those 
patients with mild symptoms, to stay at home and self-isolate, and only present to hospital/consult NHS 
111 if symptoms got worse. Testing availability was also changing on a regular basis in the UK.  
However, testing is expected to expand rapidly and guidance for those with mild symptoms is also 
subject to change, especially if patients are in a high-risk group for more severe disease. 
Sites with confirmed patient pathways for testing (and collection of results) and able to identify patients 
for out-patient support, will be selected in the first instance to support trial recruitment. In parallel, the 
Sponsor continues to liaise with primary care and hospital clinicians for regional variations in how 
patients are being tested and therefore will open further sites once there is clarity regarding the 
recruitment process. These sites will be submitted as a substantial amendment for appropriate 
regulatory approval. The Sponsor will document the patient recruitment process for each site in site 
management plans  
Risk assessments will be performed for each site selected to ensure appropriate monitoring, training 
and consenting processes are in place to ensure protection of the patient’s rights, safety and well-being. 
As testing availability evolves across the UK, further sites will be confirmed in the primary care and 
hospital settings. These site management plans will be held in the TMF. 
Prior to any involvement in the trial, patients who suspect they have COVID-19 should arrange COVID 
testing in line with government advice.  
9.1.1 
Testing at COVID hubs (GP practices or walk-in centres) 
If the patient results confirm COVID-19 infection and they are aware of the trial, the patient can contact 
the clinical trial team to register their interest in participating. Alternatively, GP sites can contact patients 
that they know to have newly tested positive for COVID. At this point, the main patient Information 
Consent Document (ICD) can be emailed to the patient and the trial can be discussed with the patient 
with opportunity to ask questions via a video (phone) call. The patient may also undertake basic 
screening questions with the clinical research team. 
If the patient wishes to consent to the trial, the patient will be asked to give verbal consent over the 
video (phone) call, with the researcher signing the consent form at that point with the patient on the call. 
To complete screening assessments, blood samples and assessments are required which require a 
face to face visit. The intention is that community research nurses or other suitably qualified medical 
professionals will attend to the patient in the home. Consent will be reaffirmed before any trial 
procedures take place and a paper version of the ICD will be signed at the earliest opportunity, by the 
patient which they will then keep (to avoid risk from paper copies handled by people with infection). See 
Section 9.2. 


 
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If eligibility is confirmed, the patient will be randomised by the clinical trial team and the patient informed 
of whether they are on the treatment or control arm. All randomised patients will receive a trial pack (to 
include diary card, Medidata patient app instructions and consent
 
 
 and for those patients on the treatment arm, camostat tablets to cover 14 
days of treatment.  These packs will be delivered to the patient. The clinical trial team will speak to the 
patient to ensure the patient is clear with the instructions on how to use the contents of the pack. 
9.1.2 
Emergency Departments (EDs) 
A positive COVID-19 result is required for enrolment in the CRUKD/20/002 trial. 
In the absence of a known positive result, a Point of Care test (e.g. Lateral Flow test) will be performed. 
This is standard care in some departments, but not all. If not standard care, verbal consent for screening 
will be required prior to performing this test. Verbal consent should be recorded in the patient’s medical 
notes.    
In the event of a positive COVID-19 result: 
If routine blood samples have already been analysed during the patient’s attendance in the Emergency 
Department (ED), the results may be used for screening purposes (any trial-specific tests that are not 
performed as standard may be requested following written consent); an additional research blood draw 
will be taken where possible as per the patient information sheet.  
Patients consented in the ED and confirmed eligible will be randomised in the department and provided 
with the trial pack +/- camostat. Home visits and the daily phone calls will be carried out according to 
the protocol. This may be by the local Primary Care Clinical Research Network Nurses or other 
community-based team. 
9.1.3 
Acute Assessment Units (AAUs) 
Patients who present to AAUs are typically referrals from GP practices. In this setting, the process will 
follow that of the Emergency Department setting. 
9.1.4 
Hospitalised patients (admitted for any reason other than COVID-19) who subsequently 
test positive for COVID-19  
Following admission to hospital, should a patient subsequently test positive for COVID-19, hospital 
teams will contact the research team (if different to the hospital team) to notify them of a possible patient. 
The hospital / research team will inform and consent the patient as well as coordinate the screening 
assessments. Patients consented in this setting and confirmed eligible will be randomised in the hospital 
and subsequent visits can either be performed face to face, if feasible, by the research / hospital team 
or via video / phone calls according to the protocol. For patients recruited while in hospital, all 
assessments will be performed and camostat will be given by the hospital staff (if the patient is 
randomised to camostat) and their routine hospital care will not be affected while participating in the trial. 
If patients wish to do so, they can use the Medidata patient application (‘app’) in addition to the diary 
card and app instructions and consent form can be provided.
 
 
 
9.2 Informed Consent 
Written and/or verbal versions of the ICD will be presented to the patients detailing the exact nature of 
the trial; what it will involve for the patient; the implications and constraints of the protocol; and any risks 
involved in taking part. It will be clearly stated that the patient is free to withdraw from the study at any 
time for any reason without prejudice to future care, without affecting their legal rights, and with no 
obligation to give the reason for withdrawal. 


 
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Given the acute nature of COVID-19 and the potential for rapid progression of symptoms, patients will 
be given sufficient time to consider their decision.  
Wherever possible the patient will be provided with a copy of the ICD in a paper format.  If paper is not 
permitted, an electronic version of the ICD will be provided that the clinical research team will go through 
with the patient either in person or over the telephone or video link. 
In whatever way the information is presented, the patient must be given adequate time to think about 
their commitment to the trial and to allow them to ask any questions about the trial.  
The patient may provide verbal consent under the current restrictions and be asked to sign a copy of 
the ICD (at the earliest opportunity) to be made available at a later date to the research team (this could 
take the form of a photograph which is sent to/taken by the clinical trial team).  This consent in whichever 
form must be documented fully by the person taking consent and the person taking consent should sign 
a consent form also.  Reconciling the two consent forms will take place later once restrictions are lifted, 
or if this is not possible, the documentation in the patient’s records will serve to show that consent had 
been obtained and the way in which consent was obtained. The notation in the patient’s record should 
also include a statement of why the ICD signed by the patient was not retained e.g. due to potential 
contamination of the document by infectious material). 
It is acknowledged that usual research practice is for the researcher and the patient to both sign and 
date the same ICD, in person when together. However, given the nature of the COVID-19 outbreak and 
to minimise avoidable risks, the preceding process has been agreed and providing careful and thorough 
documentation, consent can be taken in this way. The patient’s GP will be made aware of their 
participation in the trial via letter. 
Patients who choose to use the Medidata patient app in addition to the diary card will be asked to sign 
a separate consent, covering data protection and instructions, for use of the app. Management of this 
consent will be the same as for the main trial consent.  
 
 


 
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10 DEFINITION OF END OF TRIAL 
It is the responsibility of the Sponsor to inform the MHRA and the REC within 90 days of the End of Trial 
(EoT) that the trial has closed. 
In cases of early termination of the trial (for example, due to toxicity) or a temporary halt by the CDD, 
the CDD will notify the MHRA and the REC within 15 days of the decision and a detailed, written 
explanation for the termination/halt will be given. 
Recruitment will cease when: 
x 
Camostat is considered too toxic to continue before the required number of patients have been 
recruited.   
x 
The stated number of patients to be recruited has been reached. 
x 
The stated objectives of the trial are achieved. 
x 
The stated objectives of the trial are unlikely to be met based on emerging data from camostat 
trials worldwide, and it is confirmed the trial is to stop due to futility (end of trial will be the date 
of this decision). 
x 
The stated objectives of the trial are likely to be met based on emerging data from camostat 
trials worldwide, and it is confirmed the trial is to stop due to efficacy proven elsewhere (end of 
trial will be the date of this decision). 
 
Regardless of the reason for termination, all data available for patients at the time of discontinuation of 
follow-up must be recorded in the electronic/case report form (e/CRF). All reasons for discontinuation 
of treatment must be documented.   
In terminating the trial, Investigators must ensure that provision is made to ensure appropriate ongoing 
care for the patient. 
The End of Recruitment is defined as the date the last patient is recruited. 
The End of Trial is defined as the date when the Day 28 data has been obtained for the last patient or 
the final follow-up visit or, if the trial is closed due to emerging data from camostat trials worldwide, the 
date of the Sponsor’s decision to close the trial (whichever is the latter).  
For analysis and reporting plans, please see Section 13. 
To note: If camostat related SAEs are still ongoing at the EoT point, these will continue to be followed 
up as per protocol. 
 
 


 
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11 DISCONTINUATION/ WITHDRAWAL OF PATIENTS FROM 
STUDY TREATMENT 
Each patient has the right to withdraw from the trial at any time.  In addition, the investigator may 
discontinue a patient from the trial at any time if the investigator considers it necessary for any reason 
including:  
x Ineligibility (identified retrospectively). 
x Significant protocol deviation. 
x Significant non-compliance with treatment regimen or trial requirements. 
x Consent withdrawn*. 
The reason for withdrawal will be recorded in the patient’s records and e/CRF. In the case of a patient 
being withdrawn from the trial, attempts will be made to recruit a replacement.  
*A decision by a patient that they no longer wish to continue receiving trial treatment should not be 
considered to be a withdrawal of consent for follow-up. However, patients are free to withdraw consent 
for some or all aspects of the trial at any time if they wish to do so. In accordance with regulatory 
guidance, de-identified data that have already been collected and incorporated in the trial database will 
continue to be used (and any identifiable data will be destroyed). 
 
 


 
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12 SAFETY REPORTING 
12.1 Definitions 
12.1.1 Adverse Event (AE) 
An AE or adverse experience is: 
An adverse event (AE) is any untoward, undesired or unplanned medical occurrence in a patient 
administered an investigational medicinal product (IMP), a comparator product or an approved drug.  
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of the trial medication, whether or not 
considered related to the trial medication. 
AEs should be reported for all patients regardless of which arm they were randomised to. 
12.1.2 Adverse Drug Reaction (ADR) 
All untoward and unintended responses to a medicinal product related to any dose. 
The phrase "responses to a medicinal products" 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 adverse reactions.   
12.1.3 Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
x Results in death 
x Is life-threatening, NOTE: A "life-threatening" event is defined as an event when the patient was 
at substantial risk of dying at the time of the AE occurring; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
x Requires in-patient hospitalisation where they are admitted for more than 24 hours or prolongs 
existing in-patient hospitalisation (although some hospitalisations are exempt from SAE reporting, 
i.e. hospital admissions planned prior to the patient entering the trial; overnight stays for planned 
procedures). NOTE: if a patient is in hospital when they sign informed consent to participate in 
the trial, any event after consent that would have resulted in hospitalisation, or any event that 
prolongs the existing in-patient hospitalisation should be reported as serious. 
x Results in persistent or significant disability/incapacity, or 
x Is a congenital anomaly/birth defect. 
x Other important medical events. NOTE: A medically important event is defined as any event that 
may jeopardise the patient or may require intervention to prevent one of the outcomes listed 
above. Examples include allergic bronchospasm (a serious problem with breathing) requiring 
treatment in an emergency room, serious blood dyscrasias (blood disorders) or 
seizures/convulsions that do not result in hospitalisation. Development of drug dependency or 
drug abuse including overdose would also be examples of important medical events. Other 
events that may not result in death, are not life threatening, or do not require hospitalisation, may 
be considered a serious adverse event when, based upon appropriate medical judgement, the 
event may jeopardise the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed above. 
To ensure no confusion or misunderstanding of the difference between the terms "serious" and "severe", 
which are not synonymous, the following note of clarification is provided: 


 
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The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This is not the same as "serious," which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to a patient's 
life or functioning as defined in the bullet points above.  Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
12.1.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is a suspected, unexpected serious, adverse reaction that is deemed related to IMP, where 
the nature of the adverse event or severity of the event is not consistent with the applicable product 
information (e.g. reference safety information). All AEs and SAEs will be assessed by CDD for 
seriousness, causality and expectedness. The Pharmacovigilance Department will expedite all SUSARs 
to the relevant Competent Authority/Authorities and the relevant Ethics Committee(s) within the 
timelines specified in legislation (SI 2004/1031 as amended).  
12.1.5 Urgent Safety Measures (USM) 
The Sponsor or Investigator may take appropriate USMs in order to protect the patient of a clinical trial 
against any immediate hazard to their health or safety. This includes procedures taken to protect 
patients from pandemics or infections that pose serious risk to human health.  
USMs may be taken without prior authorisation from the competent authority. However, The Medicines 
and Healthcare products Regulations Agency (MHRA) and the Research Ethics Committee (REC) must 
be notified within three days of such measures being taken. 
Should the site initiate a USM, the Investigator must inform the Sponsor immediately either by: 
 
 
 
 
The notification must include the minimum information:  
• 
the date of the USM;  
• 
who took the decision;  
• 
what action has been taken and  
• 
why the action was taken. 
The Sponsor will then notify the MHRA and the REC within three days of USM initiation. 
 
12.2 Causality  
The relationship of each adverse event to the trial medication must be determined by a medically 
qualified individual according to the following definitions: 
 
Highly probable 
 
Starts within a time related to the IMP administration and 
No obvious alternative medical explanation. 
Probable 
 
Starts within a time related to the IMP administration and 
Cannot be reasonably explained by known characteristics of the patient’s 
clinical state. 
Possible 
Starts within a time related to the IMP administration and 
A causal relationship between the IMP and the AE is at least a reasonable 
possibility. 
Unlikely 
 
The time association or the patient’s clinical state is such that the trial drug is 
not likely to have had an association with the observed effect. 


 
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Not related 
The AE is definitely not associated with the IMP administered. 
Note: Drug-related refers to events assessed as possible, probable or highly probable. 
The Investigator must endeavour to obtain sufficient information to determine the causality of the AE 
(i.e. IMP, other illness etc.) and must provide his/her opinion of the causal relationship between each 
AE and IMP. This may require instituting supplementary investigations of significant AEs based on their 
clinical judgement of the likely causative factors and/or include seeking a further opinion from a specialist 
in the field of the AE. 
The following guidance should be taken into account when assessing the causality of an AE: 
• 
Previous experience with the IMP and whether the AE is known to have occurred with the IMP. 
• 
Alternative explanations for the AE such as concomitant medications, concurrent illness, non-
medicinal therapies, diagnostic tests, procedures or other confounding effects. 
• 
Timing of the events between administration of the IMP and the AE. 
• 
IMP blood levels and evidence, if any, of overdose. 
• 
De-challenge, that is, if the IMP was discontinued or the dosage reduced, what happened to the 
adverse reaction? 
• 
Re-challenge, that is, what happened if the IMP was restarted after the AE had resolved? 
 
12.3 Procedures for Recording Adverse Events 
All AEs will be recorded in the eCRF.   
The following information will be recorded: patient ID including the patient trial number, age and gender; 
verbatim term for the AE description, date of onset and end date as well as outcome, severity of the 
event, assessment of relatedness to trial medication, other suspect drug or device and action taken.  
Follow-up information should be provided as necessary. AEs should be recorded on the CRF from the 
date of written/verbal informed consent (whichever is the earlier) being given until they have completed 
the 28 days from Day 1 follow up period.  
AEs considered related to the trial medication or COVID-19, as judged by a medically qualified 
investigator or the sponsor will be followed until resolution or the event is considered stable.  All related 
AEs that result in a patient’s withdrawal from the trial or are present at the end of the trial, should be 
followed up until a satisfactory resolution occurs. 
It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient severity to require 
the patient’s removal from treatment.  Although the Sponsor will hold the final decision if there is a 
disagreement in the management of the patient’s treatment.  A patient may also voluntarily withdraw 
from treatment due to what he or she perceives as an intolerable AE.  If either of these occurs, the 
patient must undergo an end of study assessment and be given appropriate care under medical 
supervision until symptoms of the AEs cease or the condition becomes stable. 
The severity of events will be assessed on the following scale:  1 = mild, 2 = moderate, 3 = severe and 
as judged by a medically qualified investigator. 
For hospitalised patients who are admitted (for any reason other than COVID-19) and subsequently test 
positive for COVID-19, medical occurrences or symptoms of deterioration that are expected as a 
consequence of the participant’s admission hospital should be recorded in the patient’s medical notes 
and only be reported as AEs in the eCRF if medically judged to have unexpectedly worsened during the 
study.  AEs considered related to the trial medication or COVID-19, as judged by a medically qualified 
investigator or the sponsor will be reported in the eCRF.   


 
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12.4 Procedures for recording pregnancies 
Any pregnancy occurring during the clinical trial (within 28 days after the last dose of camostat) and the 
outcome of the pregnancy (including the partner of a male patient), should be recorded using a 
pregnancy notification form and followed up until 6 months post a known outcome. If the outcome of the 
pregnancy results in an SAE such as congenital abnormality or birth defect, an SAE should be reported 
in accordance with Section 12.5. 
The Investigator should document within the patient notes, the patient confirming consent for the 
Sponsor to collect pregnancy follow-up information. In the case that the partner of a patient becomes 
pregnant, a consent form should be provided to the patient’s partner in order to obtain consent for 
collecting privacy data, in accordance with data protection regulation. 
If a pregnancy is confirmed (for a female trial patient) whilst on the trial, the patient must be withdrawn 
from trial treatment. 
 
12.5 Reporting Procedures for Serious Adverse Events 
For eligible patients, SAE collection and monitoring (as per risk assessed monitoring plan) will 
commence at the time the patient gives their written/verbal consent (whichever is the earlier) to 
participate in the trial and will continue for 28 days from Day 1.  
In addition to the SAE reporting criteria in Section 12.1.3, 
During the trial period (Days 1-28): 
x 
All hospitalisations as per the definition stated in Section 12.1.3 (regardless of causality) will be 
followed up until resolution, discharge or death. 
x 
Patients who are hospitalised will also be followed up, up to 28 days after they are discharged.  
Following the trial period, up to the Day 28 , only SAEs related to camostat are reportable. These will 
be followed up until resolution, discharge or death.  
Should an Investigator become aware of any IMP-related SAEs after this period, these must also be 
reported to the CDD within the expedited timelines.  
All SAEs regardless of causality must be reported to the Pharmacovigilance Department within 24 hours 
of becoming aware of the event. SAEs should be documented on an SAE report form, using the 
completion guidelines provided. SAE report forms should be emailed to the Pharmacovigilance 
Department mailbox: 
 The following information must be provided as a minimum: 
• 
Patient identifiers including patient trial number and initials, age or date of birth and gender,   
• 
SAE term, onset date and causality assessment 
• 
A description of the SAEs 
• 
Dose and duration of the treatment with the medicine  
• 
The batch number of the medicine  
• 
Any other medications being taken at the same time including non-prescriptive medicines, herbal 
remedies and contraceptives 
• 
Any other health conditions the patient has or may have 
Follow-up of SAEs by the Pharmacovigilance Department will continue until the events resolve or 
stabilise. The Pharmacovigilance Department will make requests for further information on SAEs to the 
Investigators at regular intervals. Requested follow-up information should be reported to the 


 
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Pharmacovigilance Department in a timely manner and as soon as possible after receipt of the follow-
up request or within 24 hours of becoming aware of new/updated information.  
 
12.6 Specific Events of Interest 
The following events will be closely monitored as trial specific events of interest: 
x 
Shock or anaphylactoid symptoms such as decreased blood pressure, dyspnoea and pruritis  
x 
Rash, pruritis  
x 
Gastrointestinal events (nausea, abdominal discomfort, abdominal distension) 
x 
Changes in liver enzymes (AST, ALT, GGT) or jaundice 
x 
Thrombocytopenia  
x 
Hyperkalaemia  
 
12.7 Annual Development Safety Update Reports (DSUR) 
In addition to the expedited reporting above, CRUK will submit a DSUR in accordance with ICH E2F to 
the Competent Authority (MHRA in the UK) and the REC. 
 


 
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13 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
13.1 Description of statistical methods 
All statistical aspects of the study will be fully documented in a comprehensive Statistical Analysis Plan 
authored by the study statistician and agreed by the independent Trial Steering Committee.  
The primary outcome will be an exploration of camostat safety and toxicity, in terms of the number and 
severity of AEs and SAEs.   
Descriptive statistics will be used to describe the demographics for each randomised group and overall. 
For categorical data, frequencies will be reported, and for continuous variables means and standard 
deviations, or for skewed data, medians and interquartile ranges will be reported.  
Secondary outcomes will be reported in a similar way to the demographic data, with an estimate of the 
difference and standard error between the treatment groups for continuous or ordinal scale data. 
Medians and IQRs will be used where data are non-normally distributed. Absolute percentage difference 
and standard error will be reported for binary variables. Kaplan-Meier plots and life tables will be used 
to estimate median survival times 
Subgroups will be explored where there are sufficient patients in each group. Data will be split by age 
(фϲϱǇĞĂƌƐǀƐшϲϱ years), fall in lymphocyte (<20% fall ǀƐшϮϬйĨĂůů), and neutrophil:lymphocyte ratio 
(<2.18 ǀƐшϮ͘ϭϴ) for key explanatory variables. 
No significance testing will be performed. Differences between treatment groups will be reported solely 
to inform future trials. 
All enrolled patients who receive at least one dose of camostat in the treatment arm and complete Day 1 
in the control arm will be evaluable for safety. 
In order to be evaluable for efficacy, treatment arm patients must receive camostat for a minimum of 
five days, and control arm patients must either complete up to Day 14 or come off trial at an earlier 
timepoint due to an endpoint (e.g. hospitalisation).  
Safety data will be collected from the date of written, or verbal, consent. Safety variables will be 
summarised by descriptive statistics.  
Adverse events will be reported as tables of frequency of AEs by MedDRA system organ class and by 
worst severity grade observed. Tables should indicate related and unrelated events 
Adverse events will be reported for each arm and presented as tables of frequency of AEs by MedDRA  
system organ class and by worst severity grade observed. Tables should indicate related and unrelated 
events.  
The clinical landscape of COVID-19 treatment continues to evolve, with a number of clinical trials of 
camostat ongoing globally. During the trial and prior to the final analysis, a data analysis and/or statistical 
review, may be performed. This review  may include available information from other Camostat trials 
globally, to provide a recommendation to either continue or stop accrual for efficacy or for futility based 
on available clinical data. Prior to conducting such a review, criteria for decision making will be defined 
and agreed with the TSC. 
 
13.2 Sample size determination 
No formal hypothesis tests are required. However, in order to inform a future trial, the recruitment rate,  
that is, the proportion of patients who are randomised relative to those who are eligible and approached, 
will be calculated. One hundred recruited patients will allow us to estimate a recruitment rate of 50%, 
with a 95% CI of 43% to 57%, a standard error of 3.5%. 
 


 
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13.3  Clinical Study Report 
At appropriate intervals, interim data listings will be prepared to give the Investigators the possibility to 
review the data and check the completeness of information collected. All clinical data will be presented 
at the end of the trial on final data listings. The Sponsor will prepare a Clinical Study Report (CSR) 
based on the final data listings. The report will be submitted to the Investigator(s) for review and 
confirmation it accurately represents the data collected during the course of the trial. Summary results 
of the trial will be provided by the Sponsor to the Regulatory Authority (MHRA) and to the Research 
Ethics Committee. 
 
 
 


 
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14 DATA MANAGEMENT 
The plan for the data management of the trial are outlined below. Further details of the data 
management aspects of the study will be fully documented in a comprehensive Data Management Plan 
(DMP) authored by the trial Clinical Data Manager (CDM). 
 
14.1 Source data 
Source documents are where data are first recorded, and from which patients’ eCRF data are obtained. 
These include but are not limited to: primary or secondary care records (from which medical history and 
previous and concurrent medication may be summarised into the CRF), clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. For some 
data, the data will be recorded directly into the eCRF and therefore acts as both source and CRF. All 
documents will be stored safely in confidential conditions. On all trial-specific documents, other than the 
signed consent, the patient will be referred to by the trial patient number/code, initials, not by name. 
Patients will be given the option of using the Medidata patient app in addition to a paper diary card, to 
record their vital signs and responses to the questionnaire. Separate consent, covering data protection, 
will be collected for all patients who choose to use the app. Data entered in the app will be considered 
source and uploaded directly into the database.  
The DMP will clearly state which data is entered directly into the eCRF and which data is derived from 
other source documents for entering. 
 
14.2 Access to data 
Direct access will be granted to authorised representatives from the Sponsor, host institutions and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. 
 
14.3 Data recording and record keeping 
The eCRF for this trial will be a RAVE clinical database. As per Section 14.1, source data may be 
separate documentation/diaries/records, however the eCRF itself may also act as a source for certain 
data items. As per the DMP, source documents will be clearly stated and the Sponsor may ask that 
certified copies are scanned/posted as appropriate for source data verification in a timely fashion, as it 
is anticipated that on-site monitoring visits may not be possible due to restrictions at sites.  
The Investigator and/or Sponsor must retain copies of the essential documents for a minimum of 25 
years following the end of the trial. 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate 
records to enable both the conduct of a clinical trial and the quality of the data produced to be evaluated 
and verified. These essential documents (as detailed in Chapter V of Volume 10 (Clinical Trials) of The 
Rules Governing Medicinal Products in the European Union based upon Section 8 of the ICH GCP 
Guidelines), including source documents such as worksheets, scans, hospital records, diary cards, trial 
related documents and copies of the e/CRFs, associated audit trail and serious adverse event (SAE) 
report forms, shall show whether the Investigator has complied with the principles and guidelines of 
Good Clinical Practice (GCP). 
All essential documents required to be held by the Investigator must be stored in such a way that 
ensures that they are readily available, upon request, to the Regulatory Agency or Sponsor, for the 
minimum period required by national legislation or for longer if needed by Sponsor. Records must not 
be destroyed without prior written approval from Sponsor. 


 
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The medical files of trial subjects shall be retained in accordance with national legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private practice. 
14.3.1 Recording of daily calls 
During the trial, patients will be asked for permission and consent to record their daily video (phone) 
calls with the clinical trial team. Patients will be asked to consent during main trial consent and to also 
confirm consent verbally before each video/phone call begins. After each call is completed, the 
recording will immediately be emailed to a secure NHS email for storage on a secure NHS server. The 
recording will be deleted thereafter from the original recording device. Each NHS Trust/Board will be 
responsible for the security and confidentiality of these recordings. These recordings will not be shared 
with the Sponsor to protect the patient’s confidentiality. The NHS Trust/Board will be solely responsible 
for the recording, transfer, storage and deletion of the recording. All recordings will be deleted from the 
NHS secure server at the end of the trial. 
 
This is not a requirement of trial participation but a proposed way of supporting the patient’s participation 
on the trial. 
 
15 QUALITY CONTROL AND QUALITY ASSURANCE 
PROCEDURES  
15.1 Risk assessment 
A risk assessment and monitoring guidelines will be prepared before the trial opens and will be reviewed 
periodically throughout the trial to reflect significant changes to the protocol or monitoring activities. 
 
15.2 Monitoring  
In order to ensure that quality data is collected and that sites are adhering to the protocol, ICH GCP and 
other guidelines and local regulations, data will be monitored at regular intervals by the Sponsor. 
The level of monitoring will be informed by the trial specific risk assessment and captured in the trial 
monitoring plan. 
The Investigator and clinical trial teams will be responsible for entering trial data into the eCRF and 
providing certified copies of source data where applicable to facilitate source data verification. It is the 
Investigator’s responsibility to ensure the accuracy of the data entered into any source document 
provided to the Sponsor, and to ensure that any patient data provided to the Sponsor is suitably 
anonymised. 
Once source documents have been completed by site staff they will be scanned and emailed to the 
Sponsor. Any missing data or any data that requires querying with the site staff will be raised by the 
Sponsor. 
Movement of people may be restricted, therefore, monitoring of patient medical records will be 
completed remotely where possible in accordance with the trial-specific monitoring plan. 
Monitoring of the data will occur as the data is being entered into the database. 
In order to verify that the trial is conducted in accordance with ICH GCP, regulatory requirements, and 
the trial protocol, and that the data is authentic, accurate and complete, source data will be verified. 
Upon trial completion, a Closedown Visit will be conducted. 
 


 
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15.3 Quality assurance 
The Sponsor will assess each trial site to verify the qualifications of each Investigator and the site staff 
and to ensure that the site has all of the required equipment. A Study Initiation meeting will occur where 
among other things the Investigator will be informed of their responsibilities and procedures for ensuring 
adequate and correct trial documentation. During this meeting, training will be provided to the 
investigator and the local study team, in accordance with the study-specific monitoring plan. 
The Investigator is required to prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the trial for each patient. Trial data for each enrolled 
patient will be entered into the Source Worksheets by study site personnel. 
 
15.4  Protocol deviations and amendments 
The protocol should be adhered to throughout the conduct of the trial, if a situation arises where the 
conduct of the trial may not be in line with the protocol, then site should contact the Sponsor to discuss 
this. 
Amendments to the protocol may only be made with the approval of the Sponsor. A protocol amendment 
may be subject to review by the assigned REC, Health Research Authority (HRA) and the MHRA. 
Written documentation of the Ethics Committee and HRA (and if appropriate the MHRA) ‘favourable 
opinion’ (i.e. approval) must be received before the amendment can be implemented and incorporated 
into the protocol if necessary. 
 
15.5  Serious Breach of GCP 
A serious breach is a breach which is likely to effect to a significant degree: the safety or physical or 
mental integrity of the subjects of the trial, or the scientific value of the trial. 
In order that the Sponsor can fulfil their obligations in terms of reporting serious breaches of GCP to the 
MHRA within seven calendar days of identification, site staff must inform the Sponsor of any unplanned 
deviations to the trial protocol (or GCP principles) as soon as possible after the deviation occurs to allow 
prompt evaluation by the Sponsor. 
 
16 ETHICAL CONSIDERATIONS 
Before starting the trial, the protocol and ICD must receive the favourable opinion of the REC. 
It is the Chief/Principal Investigator’s responsibility to update patients (or their authorised 
representatives, if applicable) whenever new information (in nature or severity) becomes available that 
might affect the patient’s willingness to continue in the trial. The CI/PI must ensure this is documented 
in the patient’s medical notes and the patient is re-consented. 
The Sponsor and CI/PI must ensure that the trial is carried out in accordance with the GCP principles 
and requirements of the UK Clinical Trials regulations (SI 2004/1031 and SI 2006/1928 as amended), 
the ICH GCP guidelines and the WMA Declaration of Helsinki - Ethical Principles for Medical Research 
Involving Human Subjects adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and all subsequent amendments including Oct 2013. 
 
16.1 Approvals 
The protocol, ICD and any proposed advertising material will be submitted as appropriate to the REC, 
regulatory authorities (MHRA in the UK), and host institution(s) for written approval.   


 
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The Sponsor will submit and, where necessary, obtain approval from the above parties for all substantial 
amendments to the original approved documents.    
 
16.2 Patient confidentiality 
The trial staff will ensure that the patients’ anonymity is maintained.  The patients will be identified only 
by initials and patient ID number on worksheets and any electronic database. Patient names and 
telephone numbers will be stored securely at each NHS Trust/Board by the clinical trial team and will 
only be accessible by the clinical trial team at site.  All documents will be stored securely and only 
accessible by trial staff and authorised personnel.  
The collection and processing of personal data from the patients enrolled in this clinical trial will be 
limited to those data that are necessary to investigate the efficacy, safety, quality and usefulness of the 
drug used in this trial. The data must be collected and processed with adequate precautions to ensure 
patient confidentiality and compliance with applicable data privacy protection according to the applicable 
data protection regulations. The data collected will comply with the EU General Data Protection 
Regulation (GDPR) 2016/679 on the protection of individuals with regard to the processing of personal 
data and the Data Protection Act (DPA), 2018. 
Patients who agree to use the Medidata app will not be required to enter any personal data into the app 
other than their vital signs and responses to the questionnaire. 
For long term follow up, patients will be asked to explicitly consent to this on the ICD. 
 
16.3 Indemnity 
This trial is sponsored by CR UK and therefore injury to a patient caused by the compounds under trial 
will not carry with it the right to seek compensation from the pharmaceutical industry. CR UK will provide 
patients with compensation for adverse side effects, in accordance with the principles set out in the 
Association of the British Pharmaceutical Industry (ABPI) guidelines on compensation for medicine-
induced injury. 
 
 


 
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17 REFERENCES 
. 
Arabi, Y. M. (2020). COVID-19: A Novel Coronavirus and a Novel Challenge for Critical Care. 
Intensive Care Medicine, March. https://doi.org/10.1007/s00134-020-05955-1. 
Corner, E. W. (2012). The Chelsea Critical Care Physical Assessment Tool (CPAx): validation 
of an innovative new tool to measure physical morbidity in the general adult critical care 
population; an observational proof-of-concept pilot study. Physiotherapy Journal, 
https://www.physiotherapyjournal.com/article/S0031-9406(12)00028-4/fulltext. 
Forrest. (1989). Tolerance and Pharmacokinetics of Camostat Mesylate (FOY-305) in Normal 
Human Subjects after Single Rising i.v. Infusion Doses. European Journal of Clinical 
Pharmacology, PP14.68 no. 36 (Suppl.). 
Hoffmann. (2020). SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and is Blocked 
by a Clinically Proven Protease Inhibitor. Cell , 181, 1-10. 
Hoffmann. (APR 2020). Nafamostat mesylate blocks 1 activation of SARS-CoV-2: New 
treatment 
option 
for 
COVID-19. 
Anitmicrob. 
Agents 
Chemother., 
doi:10.1128/AAC.00754-20. 
Iwata-Yoshikawa. (2019). TMPRSS2 Contributes to Virus Spread and Immunopathology in the 
Airways of Murine Models after Coronavirus Infection. Journal of Virology, 93: 6. 
Kawase. (2012). Simultaneous Treatment of Human Bronchial Epithelial Cells with Serine and 
Cysteine Protease Inhibitors Prevents Severe Acute Respiratory Syndrome 
Coronavirus Entry. Journal of Virology, 86: 12. 
Liu, C. Q. (2020). Research and Development on Therapeutic Agents and Vaccines for 
COVID-19 and Related Human Coronavirus Diseases. ACS Central Science, 6 (3): 
315–31. 
Matsuyama. (2010). Efficient Activation of the Severe Acute Respiratory Syndrome 
Coronavirus Spike Protein by the Transmembrane Protease TMPRSS2. Journal of 
Virology, 12658–12664. 
Midgley. (1994). Metabolic Fate of 14C-Camostat Mesylate in Man, Rat and Dog after 
Intravenous Administration. Xenobiotica; the Fate of Foreign Compounds in Biological 
Systems , 24 (1): 79–92. 
Ono Pharmaceutical Co., Ltd. (2020). FOY-305-02 Pharmacokinetic Analysis Results (Draft 
report dated 21 August 2020).  
Osborne, R. H. (2011). Development and Validation of the Influenza Intensity and Impact 
Questionnaire (FluiiQTM). Value in Health: . The Journal of the International Society 
for Pharmacoeconomics and Outcomes Research, 14 (5): 687-99. 
Rabi. (2020). SARS-CoV-2 and Coronavirus Disease 2019: What We Know So Far. 
Pathogens, 9, 231. 
Ruan, S. (2019). Likelihood of Survival of Coronavirus Disease 2019. . The Lancet. Infectious 
Diseases, , March. https://doi.org/10.1016/S1473-3099(20)30257-7. 
Sato. (1992). A Dose-Finding Study of FOY-305 in Postoperative Reflux Esophagitis – A 
Double-Blind Comparative Study. J Clin Ther Med.  
Shirato, K. M. (2013). Middle East Respiratory Syndrome Coronavirus Infection Mediated by 
the Transmembrane Serine Protease TMPRSS2. Journal of Virology, 87 (23): 12552–
61. https://doi.org/10.1128/JVI.01890-13. 
Shulla. (2011). A Transmembrane Serine Protease Is Linked to the Severe Acute Respiratory 
Syndrome Coronavirus Receptor and Activates Virus Entry. Journal of Virology, , 873-
882. 
Yamamoto. (2016). Identification of Nafamostat as a Potent Inhibitor of Middle East 
Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the 
Split-Protein-Based Cell-Cell Fusion Assay. Antimicrobial Agents and Chmotherapy, 
6532-6539. 
Yan. (2020). Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. 
Science 367, 1444-1448. 
Zhou, Y. (2015). Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res., 
http://dx.doi.org/10.1016/j.antiviral.2015.01.011. 










 
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18.3 Appendix 3: New York Heart Association (NYHA) scale  
 
Class I –  
Patients with cardiac disease but without resulting limitation of physical activity; 
ordinary physical activity does not cause undue dyspnoea (or fatigue, palpitation or 
anginal pain).  
Class II –  
Patients with cardiac disease resulting in slight limitation of physical activity; they are 
comfortable at rest; ordinary physical activity results in dyspnoea (or fatigue, 
palpitation or anginal pain).  
Class III –  
Patients with cardiac disease resulting in marked limitations of physical activity; they 
are comfortable at rest; less than ordinary physical activity causes dyspnoea (or 
fatigue, palpitation or anginal pain).  
Class IV –  
Patients with cardiac disease resulting in inability to carry out physical activity without 
discomfort; symptoms of dyspnoea (or of angina) may be present even at rest; if any 
physical activity is undertaken, discomfort is increased.  
 
 
 


 
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18.4 Appendix 4: COVID-age calculation 
 
https://alama.org.uk/covid-19-medical-risk-assessment/ (last accessed April 2021). 
 
The COVID-age calculation tool authored by the Association of Local Authority Medical Advisors (ALAMA), 
will be collected for the SPIKE1 trial during on trial assessments.   
The tool was originally created to help assess an individual’s vulnerability to COVID-19 as part of an 
occupational health assessment of fitness for work. It is not intended for use in clinical treatment pathways. 
As new scientific evidence becomes available, its estimates of vulnerability may change.  
 
COVID-age helps assess an individual’s vulnerability to COVID-19. It is based on published evidence for 
the main identified risk factors.  
COVID-age summarises vulnerability for combinations of risk factors including age, sex and ethnicity and 
various health problems. It works by “translating” the risk associated with each factor into years which are 
added to (or subtracted from) an individual’s actual age.  This then gives a single overall measure of 
vulnerability. It can be used in people with no underlying medical conditions or multiple medical conditions. 
One measure combines all of an individual’s risk factors with their actual age. 
 
COVID-age is translated into a risk level of low, moderate, high and very high. This score of moderate, high 
or very high, will be collected from participants in the SPIKE1 trial. 
 
There are times when the internet is not available or the ALAMA website goes down for maintenance. The 
risk tables can be downloaded as an Excel spreadsheet calculator in the link above.  
 
 

SAP_001.pdf: 
ClinicalTrials.gov  
Document Cover Page 
NCT No.: NCT04455815 
Protocol No.: CRUKD/20/002 
ClinicalTrials.gov Upload Document Cover Page 
NCT Number 
NCT04455815 
EudraCT Number 
2020-002110-41 
Sponsor Protocol Number 
CRUKD/20/002 
Official Title 
A Randomised Phase II trial in early COVID-19, assessing use of 
camostat by blocking SARS-CoV-2 Spike protein-initiated membrane 
fusion. 
Document, Version & Date 
Reporting Analysis Plan Version 2.0 dated 03 March 2022 


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1 
 
CANCER RESEARCH UK 
Reporting Analysis Plan 
Protocol Number: CRUKD/20/002 
Protocol Name:  A Randomised Phase II trial in early COVID-19, 
assessing use of camostat by blocking SARS-CoV-2 Spike protein-
initiated membrane fusion. 
EudraCT Number: 2020-002110-41 
 
 
 
 
RAP Final Version: 
Final V2.0 
Date: 
03Mar2022 
 
Replaces Version: 
1.0  
Date: 
27Sep2021 
 
Name: 
 
Date: 
Title: Clinical Study Manager (Sponsor) 
 
Signature: 
 
Name: 
 
Date: 
Title: Medical Advisor (Sponsor) 
 
Signature: 
 
 
Name: 
 
Date: 
Title: Chief Investigator 
 
Signature: 


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Name: 
 
Date: 
Title: Statistician  
 
Signature: 
 
 
 
Name: 
 
 
 
Date: 
Title: Statistician  
 
Signature: 
 
 
SUMMARY OF CHANGES TO PREVIOUS REPORTING ANALYSIS PLAN VERSION 
This summary of changes is intended to highlight the important revisions that were made during 
the most recent update to the reporting analysis plan (RAP) to generate the current version. 
This document has been written based on information contained in the study protocol and data 
management plan detailed in the table below. 
 
Protocol 
version 
DMP 
version 
RAP 
version 
Revised 
section of 
RAP 
Summary of changes 
Date 
updated 
5.0 
3.0 
1.0 
N/A 
N/A – First Version 
 
 
 
 
 
 
 
Final review prior to database lock 
Protocol 
version 
DMP 
version 
RAP 
version 
Revised 
section of 
RAP 
Summary of changes 
Date 
updated 
5.0 
3.0 
2.0 
6, 7 and 
SAP 
 
 
 
 
 
 
 
 
x 
Ethnicity added to baseline 
characteristics table 
x 
Treatment compliance table 
added 
x 
Table replaced graphs for 
neutrophil V lymphocytes 
ratio 
x 
Population 
confirmation 
throughout 
x 
Updates to ct.gov section in 
line with current guidelines 
03Mar2022 


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x 
SAP 
clarification 
on 
secondary endpoints and 
outputs 
 
 
 
 
 
 
Protocol amendments may be applicable during the study.  The RAP will be reviewed against the 
amendments and updated where necessary. 
The summary of changes table above should record all changes to the RAP in light of protocol 
amendments however if no changes were required, this should be recorded also.    
 
 
 
CONTRIBUTORS 
Clinical Study Manager: 
 
 
Medical Writer: 
 
 
 
Clinical Data Manager: 
 
 
Clinical Database Programmer: 
 
Medical Advisor: 
 
 
 
Translational Scientist:  
 
  
Statistician:  
 
 
  
Statistician:  
 
 
 
 
 
 
 
 




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1. TABLE OF CONTENTS 
Summary of changes to previous Reporting Analysis Plan version ....................................................................... 2 
LIST of abbreviations and definition of terms ........................................................................................................ 4 
1. 
Table of Contents ............................................................................................................................................ 5 
2. 
Introduction .................................................................................................................................................... 8 
3. 
Trial Objectives .............................................................................................................................................. 9 
4. 
Trial Design .................................................................................................................................................. 10 
5. 
Patient Population and endpoints .................................................................................................................. 12 
5.1 
Patient Populations .............................................................................................................................. 12 
6. 
Data Conventions and General Analysis ...................................................................................................... 13 
6.1 
Patient disposition ............................................................................................................................... 13 
6.2 
Baseline characteristics ....................................................................................................................... 13 
6.3 
Patient withdrawal / Completion ......................................................................................................... 14 
6.4 
Protocol deviations .............................................................................................................................. 15 
6.5 
Treatment compliance ......................................................................................................................... 15 
6.6 
Safety .................................................................................................................................................. 16 
6.7 
Adverse Events ................................................................................................................................... 16 
6.8 
Laboratory results................................................................................................................................ 17 
6.9 
Efficacy ............................................................................................................................................... 18 
6.10 
General data conventions .................................................................................................................... 19 
6.11 
Decimal places .................................................................................................................................... 20 
6.12 
Statistical software .............................................................................................................................. 20 
6.13 
Supplementary analysis (data collected outside of the clinical database) ........................................... 20 
6.13.1 
Pharmacokinetics ........................................................................................................................ 20 
6.13.2 
Tertiary/research endpoint/s ....................................................................................................... 20 
6.14 
Other statistical analysis ...................................................................................................................... 21 
7. 
Clinicaltrials.gov ........................................................................................................................................... 22 
7.1 
Arms and Interventions ....................................................................................................................... 22 
7.2 
Participant Flow .................................................................................................................................. 22 
7.3 
Reported Adverse Events (clinicaltrials.gov template sections) ......................................................... 24 
7.4 
Endpoints/outcome measures to be reported ....................................................................................... 25 
8. 
Tables listings and figures ............................................................................................................................ 30 
8.1 
LISTINGS: .......................................................................................................................................... 30 
Completed or Discontinued patients ............................................................................................................. 30 
Treatment compliance End of monitoring period (Control arm) ........................................................... 30 
End of study ................................................................................................................................................ 30 
Protocol deviations ......................................................................................................................................... 30 
Patients excluded from efficacy analysis....................................................................................................... 30 
Screening failures ....................................................................................................................................... 30 
EnrolmentDemographic and Baseline Data ................................................................................................. 30 
Demographics .............................................................................................................................................. 30 
Randomisation ............................................................................................................................................ 30 


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Medical history ........................................................................................................................................... 30 
Risk factors .................................................................................................................................................. 30 
COVID-19 symptoms ................................................................................................................................. 30 
Influenza or COVID-19 Vaccination ........................................................................................................ 30 
Concomitant medications ........................................................................................................................... 30 
Medical procedures .................................................................................................................................... 30 
Compliance and/or Drug Concentration Data ............................................................................................. 30 
Treatment compliance Efficacy Response Data ........................................................................................... 30 
 
 
9-point ordinal scale for clinical improvement ......................................................................................... 30 
 
COVID-19/Camostat related hospitalisation details ............................................................................... 30 
Oxygen therapy and ventilation ................................................................................................................ 30 
Hospitalisation follow up ............................................................................................................................ 30 
Safety Data ...................................................................................................................................................... 30 
Adverse Events (by subject) ....................................................................................................................... 30 
Adverse Events by SOCPregnancy  test ................................................................................................... 30 
Laboratory results ...................................................................................................................................... 30 
Imaging ........................................................................................................................................................ 30 
8.2 
TABLES ............................................................................................................................................. 31 
Demographic Data .......................................................................................................................................... 31 
Baseline characteristics by treatment arm ............................................................................................... 31 
Reasons for patient withdrawal / completion ........................................................................................... 31 
Compliance ...................................................................................................................................................... 31 
Treatment modifications and/or non-compliance (treatment arm only) ............................................... 31 
Efficacy Data ................................................................................................................................................... 31 
Ordinal Scale ............................................................................................................................................... 31 
Summary  of Secondary Endpoint Data ................................................................................................... 31 
Safety Data ...................................................................................................................................................... 31 
Overview of  Treatment Emergent Adverse Events (Inclusive and post Day 1) ................................... 31 
Frequency of All Adverse Events .............................................................................................................. 31 
Frequancy of pre-treatment AEs ............................................................................................................... 31 
Frequency of TEAEs .................................................................................................................................. 31 
Frequency of All Camostat related treatment emergant AEs ................................................................. 31 
Frequancyof all COVID-19 related treatment emergent AEs ................................................................ 31 
Frequency of all treatment emergent SAEs .............................................................................................. 31 
Breakdown of TEAEs leading to Patient withdrawal .................................................................................. 31 
Neutrophils:Lymphocytes ratio per patient (treatment and control arm respectively) ....................... 31 
9. 
References .................................................................................................................................................... 31 
Appendix – Statistical Analysis plan .................................................................................................................... 32 
List of Abbreviations ............................................................................................................................................ 34 


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1. 
Introduction .................................................................................................................................................. 35 
2. 
Statistical Methods section from the protocol............................................................................................... 35 
3. 
Overall Statistical Principles ......................................................................................................................... 36 
3.1 
Populations .......................................................................................................................................... 36 
3.2 
Missing data ........................................................................................................................................ 36 
3.3 
Adjusting for centre ............................................................................................................................. 36 
3.4 
Subgroup analyses ............................................................................................................................... 37 
4. 
List of Analyses ............................................................................................................................................ 37 
4.1 
Interim evaluation ............................................................................................................................... 37 
4.2 
Main study findings ............................................................................................................................. 37 
4.3 
Transformations .................................................................................................................................. 38 
4.4 
Outputs ................................................................................................................................................ 38 
5. 
Validation and QC ........................................................................................................................................ 38 
 
 
 
 


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2. INTRODUCTION 
This document explains in detail the reporting analyses that will be carried out for SPIKE-1.  
The analyses described in this RAP are based upon and supplement those described in the current 
study protocol.   
To support reproducibility of the research, a clear and comprehensive account of pre-planned 
reporting (or statistical) analyses must be available. This RAP will establish the essential items to be 
considered for interim and/or final reporting requirements within the CSR and for the results upload 
to clinicaltrials.gov. 
 
 
 
 






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There are two arms: 
Treatment arm: Patient to receive treatment with camostat 
tablets, 200mg four times daily (qds) for 14 days  
Control arm (non-treatment): Patient to receive best supportive 
care. 
B 
Patient group 
Patients with COVID-19 infection who are symptomatic 
C 
Sample size 
Up to 100 patients will be entered into this trial. Up to 50 patients 
in each arm. Patients will be randomised 1:1 into each arm. 
D 
Study intervention 
Patients in the treatment arm will be asked to take camostat for 
14 consecutive days and patients in the control arm will be asked 
to continue with best supportive care.  
 
Both groups will be asked to take
 
 A clinical 
research team member will call the patient daily during this 
period. On Days 7 and 14, patients will be visited at home by the 
clinical research team, for blood draws 
 
  Patients will also be called weekly (Days 21 
and 28) before the follow up period ends.   
 
Patients who are in hospital for non COVID-19 related reasons, 
who test positive for COVID-19, may also be recruited. Phone calls 
/ home visits will be conducted where possible within hospital 
face to face. 
E 
Study analysis 
Statistical Analysis Plan (Version 1.0, dated 27Sep2021) 
For full details of the trial design, background and rationale for the study, please refer to the current 
study protocol. 
 
 


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5. PATIENT POPULATION AND ENDPOINTS 
Patients must fulfil all the inclusion/exclusion criteria to be eligible for entry to the trial. Refer to the 
study protocol for the complete list of inclusion and exclusion criteria. 
All enrolled patients who receive at least one dose of camostat will be evaluable for safety. 
In order to be evaluable for efficacy, treatment arm patients must receive camostat for a minimum of 
five days, and control arm patients must either complete up to Day 14 or come off trial at an earlier 
timepoint due to an endpoint (e.g. hospitalisation) 
5.1 Patient Populations 
The analysis sets are defined as follows: 
Full Analysis Population (FAP):  
All enrolled patients. 
Patients who are enrolled in error onto the trial (due to 
ineligibility/administrative error), prior to receiving study 
treatment, will be excluded from the FAP. 
Safety Population:  
All enrolled patients who received at least one dose of 
camostat (or complete Day 1 of the control arm). Safety data 
will be collected from the date of written consent.  
Efficacy Population:  
Treatment arm patients must receive camostat for a 
minimum of five days, and control arm patients must either 
complete up to Day 14 or come off trial at an earlier 
timepoint due to an endpoint (e.g. hospitalisation). 
Pharmacokinetic Population:  
All enrolled patients who received one dose of camostat (or 
complete Day 1 of the control arm) – PK sample required 
(optional).  
 
All other populations will be the same definition as Efficacy Population as defined above. 
 
 
 


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6. DATA CONVENTIONS AND GENERAL ANALYSIS 
6.1 Patient disposition 
Patients excluded from any population (defined in Section 4.1) will be detailed.  
The accrual and trial discontinuation details will be presented descriptively. This should include details 
of: 
x Screening failure patients (screening failure information is available via the e-screening logs).  
x Information on ineligible patients who were enrolled and/or received camosat (and control).  
x Reasons for treatment discontinuation by number of doses received will be described by 
counts and percentages. Reasons for treatment discontinuation other than disease 
progression will be detailed and summarised separately (Section 5.1.2). 
 
6.2  Baseline characteristics 
Demographics and baseline characteristics will be summarised for all enrolled patients. Patients will 
be included to the randomised arm regardless of whether they received treatment or not. 
Table 1: Baseline characteristics by treatment arm 
Full Analysis Population. 
 
All 
Treatment arm 
Control arm 
Patients 
 
 
 
Male Total 
 
 
 
Male ш 65 year old 
 
 
 
Male < 65 years old 
 
 
 
Female Total 
 
 
 
Female ш 65 year old 
 
 
 
Female< 65 years old 
 
 
 
 
 
 
 
Age (Years) 
 
 
 
Mean (SD) 
 
 
 
Median (IQR) 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
 
 
 
BMI 
 
 
 
Mean (SD) 
 
 
 
Median (IQR) 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
 
 
 
Ethnicity 
 
 
 
 
 
 
 
COVID-19 Vulnerability Level 
 
 
 
Low 
 
 
 
Moderate 
 
 
 
High 
 
 
 


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Very High 
 
 
 
 
 
 
 
COVID-19 age 
 
 
 
Mean (SD) 
 
 
 
Median (IQR) 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
 
 
 
Ethnicity 
 
 
 
Asian / Asian British - Indian 
 
 
 
Asian / Asian British - Pakistani 
 
 
 
White-English / Welsh / Scottish 
/ Northern Irish / British 
 
 
 
Any other white background 
 
 
 
In case of pre-treatment characteristics with multiple measurements per patient before the start of 
treatment (laboratory assessments, vital signs), the baseline measurement will be considered the last 
value prior to or on the first day of treatment. 
Other baseline assessments, including medical history, will be covered within the listings per patient.. 
 
6.3  Patient withdrawal / Completion 
Reasons for patient withdrawal will be provided as the data is available and presented for each 
randomised treatment arm.  
Table 2: Reasons for patient withdrawal / completion 
Reason off study 
No. of 
Patients 
(N=XX) 
Patient 
Number 
(patients who 
withdrew 
only) 
No. of 
patients in 
Treatment 
arm 
No. of 
patients in 
Control arm 
Completion of treatment / 
monitoring period 
XX (%) 
 
XX (%) 
XX (%) 
Recovered 
 
 
 
 
Adverse event/Serious 
adverse event 
 
 
 
 
Pregnancy 
 
 
 
 
Death 
 
 
 
 
Investigator withdrawal of 
subject 
 
 
 
 
Subject withdrawal of 
consent 
 
 
 
 
Subject withdrawal from 
treatment (treatment arm) / 
subject withdrawal (allows 
FU) (control arm) 
 
 
 
 
Protocol deviations  
 
 
 
 


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Full Analysis Population 
 
 
6.4 Protocol deviations 
A protocol deviation is defined as any departure from what is described in the protocol of a clinical 
trial approved by an Independent Ethics Committee and Competent Authorities. Therefore, it applies 
to deviations related to patient inclusion and clinical procedures (e.g. assessments to be conducted or 
parameters to be determined), and also to other procedures described in the protocol that concern 
the Good Clinical Practice (GCP) guidelines or ethical issues (e.g. issues related to obtaining the 
patients’ Informed Consent, data reporting, the responsibilities of the Investigator, etc.). 
Protocol deviations are captured throughout the trial open phase on the Sponsor’s central tracker and 
can be filtered by study and by deviation category or on the study specific PK/PD deviations tracker. 
Standard deviation categories have been defined by the Sponsor and are further defined by those 
which are deemed reportable (important deviations) in the Clinical Study Report (CSR). Those 
deviations which have been coded as CSR reportable will be summarised for all patients, according to 
the categories allocated at identification. Deviations are reviewed manually as per Sponsor SOPs. 
A summary table with the number of patients with deviations will be presented per criterion. 
Deviations with no effects on the risk/benefit ratio of the clinical trial (such as minimal delays in 
assessments or visits) will be distinguished from those that might have an effect on this risk/benefit 
ratio. 
The following are pre-defined protocol deviations with a direct bearing on the primary outcome and 
therefore will be reported in the CSR.  A summary including but not necessarily restricted to the 
following categories will be presented: 
 
x 
Ineligible patients as per protocol. 
x 
Patient not withdrawn as per protocol. 
x 
Excluded concomitant medication. 
x 
Incorrect IMP dose or schedule 
 
6.5 Treatment compliance 
 
A list of all treatment compliance by patient will be produced for those patients on the treatment 
arm only. 
Table 3: Treatment modifications and/or non-compliance (treatment arm only) 
Sponsor’s decision to 
terminate the trial 
 
 
 
 
Other 
 
 
 
 
Lost to follow up 
 
 
 
 
Patient 
number 
Date of first 
dose 
Date of 
treatment 
modification 
Description of treatment 
modification/non-compliance 
Comment 
 
 
 
 
 


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Full Analysis Population (Treatment arm only) 
6.6 Safety 
Descriptive statistics will be used for evaluation of safety. The incidence  of AEs will be summarised 
and displayed in frequency tables using counts and percentages. Additional parameters including but 
not limited to 
 , and laboratory results will also be considered when 
evaluating safety. 
Deaths, serious adverse events (SAEs) and events resulting in trial discontinuation will be tabulated.  
Additional safety analyses may be determined at any time, in order to most clearly enumerate rates 
of toxicities and to further define the safety profile of camostat.  
 
x 
The safety population is composed by all patients that receive at least one dose of 
camostat / complete Day 1 of control arm. The safety patient population will be used for 
the general safety presentations.  
 
6.7   Adverse Events 
For patients on the treatment arm Pre-treatment AE’s will be defined as those where “Did this AE start 
prior to first dose of IMP?” is ticked. Treatment Emergent AE’s will be defined as those where “Did 
this AE start prior to first dose of IMP?” is not ticked.  For patients on the control arm pre-treatment 
AE’s will be defined as those where the AE started prior to Day 1. Treatment emergent AE’s will be 
defined as those where the AE started after and inclusive of Day 1. 
 
Treatment related AE’s are those where causality to IMP is considered to be Possible, Probable or 
Highly Probable. 
 
COVID-19 related AE’s will be defined as those where “Is this AE related to COVID-19” is ticked yes. 
 
The frequency of AEs will be summarised overall and by treatment arm. A patient can be counted 
multiple times per row for the No. of Episodes but will only be counted once per row for the No. of 
Patients. 
 
Table 5: Frequency of All Adverse Events 
Safety population 
MedDRA System Organ Class 
(SOC) 
MedDRA Preferred Term 
No. of 
Episodes 
Reported 
No. of Patients   
N=XX 
No. of 
Patients in 
Treatment 
Arm   
N=XX 
No. of 
Patients  in 
Control Arm 
N=XX 
All AE’s 
N 
N (%) 
N (%) 
N (%) 
BLOOD AND LYMPHATIC… 
 
 
 
 
Anemia 
 
 
 
 
CARDIAC DISORDERS 
 
 
 
 
Sinus tachycardia 
 
 
 
 
Etc 
 
 
 
 
 


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There will be additional versions of the above table based on pre-treatment AE’s, treatment emergent 
AE’s, treatment emergent SAE’s (any AE that is considered Serious), related treatment emergent AE’s. 
COVID-19 related AE’s. 
 
Overview of treatment emergent adverse events (by treatment arm). An AE is considered to have led 
to withdrawal if an adverse event with “Did the AE cause the subject to be discontinued from the 
study?” is recorded as yes.  
 
Table 6: Overview of Treatment Emergent Adverse Events (Inclusive and post Day 1) 
Safety population 
 
Patients with TEAEs 
Overall 
No. of Patients   
N=XX 
No. of Patients in 
Treatment arm 
N=XX 
No. of Patients in 
Control arm 
N=XX 
Patients with >=1 TEAE 
N (%) 
N (%) 
N (%) 
Patients with >= 1 TE SAE 
 
 
 
Patients with >= 1 COVID-19 related 
 
 
 
Patients with >= 1 Treatment related 
 
 
 
Patients with >= 1 AE leading to 
withdrawal 
 
 
 
Patients who died 
 
 
 
 
Treatment emergent adverse events leading to withdrawal of treatment will be listed by patient. 
Patients will be included if an adverse event has “Action taken” recorded as “Drug Withdrawn” or “Did 
the AE cause the subject to be discontinued from the study?” is recorded as yes.  
 
Table 7:  Breakdown of TEAEs leading to Patient withdrawal.  
Safety population 
Patient 
number 
MedDRA 
System Organ 
Class (SOC) 
AE Term 
Serious 
Led to IMP 
withdrawal 
Led to 
withdrawal 
from study 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.8 Laboratory results 
 
Full set of Laboratory results will be presented in the listings per patient. Additional tables to 
represent Neutrophils:Lymphocytes ratio per patient will be presented as follows: 
 
Table 8: Neutrophils:Lymphocytes ratio per patient (Treatment arm) 
*Baseline to be included 
 
 
Neutrophils:Lymphocytes ratio (10ज़9/L) 
Patient Number 
Screening 
Day 7 
Day 14 
 
 
 
 
 
 
 
 


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Table 9: Neutrophils:Lymphocytes ratio per patient (Control arm) 
*Baseline to be included 
 
 
Neutrophils:Lymphocytes ratio (10ज़9/L) 
Patient Number 
Screening 
Day 7 
Day 14 
 
 
 
 
 
 
 
 
 
6.9 Efficacy 
To evaluate efficacy of camostat by effect on COVID-19 related clinical improvement.  
 
Time Frame: Days 1-28 
 
 
Time to worst point on the scale or deterioration of two points or more (from randomisation) on a 9-
point category ordinal scale. 
 
9-point category ordinal scale: 
 
0. 
Uninfected, no clinical or virological evidence of infection 
1. 
Ambulatory, no limitation of activities 
2. 
Ambulatory, limitation of activities 
3. 
Hospitalised – mild disease, no oxygen therapy 
4. 
Hospitalised – mild disease, oxygen by mask or nasal prongs 
5. 
Hospitalised – severe disease, non-invasive ventilation or high-flow oxygen 
6. 
Hospitalised – severe disease, intubation and mechanical ventilation 
7. 
Hospitalised – severe disease, ventilation and additional organ support e.g. 
vasopressors, renal replacement therapy (RRT), extracorporeal membrane 
oxygenation (ECMO) 
8. 
Death 
Table 10  Ordinal Scale.  
Efficacy population 
Patient 
Number 
Randomised 
Arm 
(Treatment or 
Control Arm) 
Day 1 Scale 
Worst 
Point 
on Scale 
Deteriorated 
by more than 
2 
points 
(yes/no) 
Time to worst 
point (Days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11:  Summary Table for Secondary Endpoint Data.  
Efficacy population 
 
All 
Treatment arm 
Control arm 


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Number of 
community patients 
admitted to hospital 
due to COVID-19 
 
 
 
Total number of 
patients 
 
 
 
Proportion of 
patients per arm 
 
 
 
 
 
 
 
Supplementary 
oxygen-free days at 
28 days 
 
 
 
Number of patients 
 
 
 
Proportion of 
patients per arm 
 
 
 
 
 
 
 
Ventilator-free days 
at 28 days 
 
 
 
Number of patients 
 
 
 
Proportion of 
patients per arm 
 
 
 
 
6.10 
General data conventions 
Data will be grouped according to the assigned treatment arm, as specified in the study protocol. 
Patients who deviate from the assigned treatment arm will be clearly described in the CSR with regards 
to their treatment modification and if applicable in the list of protocol deviations (Section 5.2). 
Continuous variables will be summarised and presented with summary statistics.  
Categorical variables will be summarised in frequency tables. Percentages in the summary tables will 
be rounded and may therefore not always add up to exactly 100%. 
 
The convention in Rave is that an unknown day resolves to 1st of the month and an unknown month 
resolves to January. Dates may be ordered by this, however CRUK do not perform calculations on 
unknown dates. 
 
Durations of AEs: the start date of an AE is considered as Day 1 of the event and should be included 
in all duration calculations (i.e. if an AE starts and stops on same day, the duration should be reported 
as one day). 
- 
For unrelated AEs, those with missing or partially completed end dates will not be excluded 
from analysis and the duration of the AE will remain as unknown.  
- 
For related AEs, prior to final data lock, an end date will be either i) confirmed AE end date 
or ii) stabilisation of AE.  If lost to follow-up then the AE would stay as not recovered/not 
resolved. In both these cases duration would not be calculated. 
Time to onset of AEs from IMP administration: the time to onset should be calculated from the date 
of the first administration of IMP in the trial (e.g. Day 1 ).  Onset time will be calculated as 0 if the AE 
occurs on the same day as the dose.  
 




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negative swabs by qPCR. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
6.14 
Other statistical analysis 
Please see Appendix 1 for full Statistical Analysis Plan, Version 1.0 dated 27Sep2021 
 


 
 
 
CRUKD/20/002 SPIKE-1 RAP Final V2.0_03Mar2023 
7 CLINICALTRIALS.GOV 
The following tables illustrated for the Clinicaltrials.gov will not be part of the Clinical Study Report (CSR) and will be used for the upload of data to Clinicaltrials.gov only. 
7.1 Arms and Interventions 
The trial will be presented as a randomised trial. 
Intervention Details: Patients will be randomised 1:1 into two arms. 
Treatment arm: Patient to receive treatment with camostat tablets, 200mg four times daily (qds) for 14 days  
Control arm (non-treatment): Patient to receive best supportive care. 
Drug: Camostat 
 
7.2 Participant Flow 
The participant flow section of the results upload will include the following details. Tables will be programmed for Randomised Phase and Treatment Phase for all patients. 
Lines with text in blue are required rows from clinicaltrials.gov 
Period Title 
Overall Study 
 
Programming notes 
Arm/Group Title 
Treatment arm 
Control arm 
 
Arm/Group Description 
Patient to receive treatment 
with camostat tablets, 
200mg four times daily (qds) 
for 14 days  
Patient to receive best 
supportive care 
 
 
Number of Participants 
Number of Participants 
 
Started 
 
 
Day 1 
<to add trial milestone> 
 
 
 
<to add trial milestone> 
 
 
 
<to add trial milestone> 
 
 
 
Completed 
 
 
Complete 
up 
to 
and 
including Day 14 


 
 
 
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Not completed 
 
 
 
 
 
 
Patients started Day 1 and 
did not complete up to and 
including  Day 14 
Adverse Event / Serious 
Adverse event 
 
 
 
Death 
 
 
 
Lack of Efficacy 
 
 
 
Lost to Follow-up 
 
 
 
Physician Decision 
 
 
Investigator withdrawal of 
consent 
/ 
Investigator 
withdrawal of subject 
Pregnancy 
 
 
 
Protocol Deviation 
 
 
 
Withdrawal by Subject 
 
 
Subject withdrawal from 
treatment (treatment arm) 
/ 
subject 
withdrawal 
(allows FU) (control arm) as 
well as subject withdrawal 
of consent (all patients) 
Recovered 
 
 
 
Other 
 
 
 
Number of patients started is defined as: Day 1 
Number of patients Completed is defined as: Day 14 
 


 
 
 
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7.3 Reported Adverse Events (clinicaltrials.gov template sections) 
AE Reporting Timeframe:  Safety data will be collected from the time of informed consent until 28 days from Day 1. Patients who re hospitalised will be followed for up to 28 
days after they are discharged. 
All-Cause Mortality will be presented as per the clinicaltrials.gov template as follows: 
 
Treatment arm 
Control arm 
 
Affect/At Risk (%) 
# Events 
Affect/At Risk (%) 
# Events 
Total 
All 
Cause 
Mortality 
 
 
 
 
Serious Adverse events will be presented as per the clinicaltrials.gov template as follows: 
 
Treatment arm 
Control arm 
 
Affect/At Risk (%) 
# Events 
Affect/At Risk (%) 
# Events 
Total  
 
 
 
 
<AE term> 
 
 
 
 
<AE term> 
 
 
 
 
<AE term> 
 
 
 
 
 
Other (non-Serious) Adverse events will be presented as per the clinicaltrials.gov template as follows: 
Frequency Threshold Above Which Other Adverse Events are Reported: 0%<TBC> 
 
Treatment arm 
Control arm 
 
Affect/At Risk (%) 
# Events 
Affect/At Risk (%) 
# Events 
Total  
 
 
 
 
<AE term> 
 
 
 
 
<AE term> 
 
 
 
 
<AE term> 
 
 
 
 




 
 
 
CRUKD/20/002 SPIKE-1 RAP Final V2.0_03Mar2023 
Information to be presented: Mean and standard 
deviation for each arm at each time point for each 
arm (to be provided in final PK report). 
 
Measure Title:  PK parameter  area under the curve 
(AUC) of GBPA 
Measure Description:   Area under the curve (AUC) 
of GBPA, as assessed by population estimates from 
population PK analysis 
Time frame: Days 7 and 14 
Information to be presented: Mean and standard 
deviation for each arm at each time point for each 
arm (to be provided in final PK report). 
 
Measure Title:  PK parameter time to maximum 
concentration (Tmax) of GBPA,  as assessed by 
population estimates from population PK analysis 
 
Measure Description: Time to maximum 
concentration (Tmax) of GBPA, as assessed by 
population estimates from population PK analysis 
Time frame: Days 7 and 14 
Information to be presented: Median and range for 
each arm at each time point for each arm (to be 
provided in final PK report). 
 
Measure Title:  PK parameter to confirm half-life 
(T1/2) of GBPA 
Measure Description: Half-life (T1/2) of GBPA as 
assessed by population estimates from population 
PK analysis 


 
 
 
CRUKD/20/002 SPIKE-1 RAP Final V2.0_03Mar2023 
Time frame: Days 7 and 14 
Information to be presented: Mean and standard 
deviation for each arm at each time point for each 
arm (to be provided in final PK report). 
 
 
To assess the ability of camostat to 
reduce the requirement for 
COVID-19 related hospital 
admission in community patients 
with SARS-CoV-2 infection. 
Rate of COVID-19 related hospital admission 
in community patients with SARS-CoV-2 
infection. 
Measure Title: Number of community patients 
admitted to hospital due to COVID-19 
Measure Description: Number of community 
patients admitted to hospital due to COVID-19 
Time frame: Days 1-28 
Population description: Patients who received 
camostat for a minimum of five days (treatment 
arm) or who either completed up to Day 14 or came 
off trial at an earlier timepoint due to an endpoint 
defined reason (e.g. hospitalisation). 
 
Information to be presented: Number of community 
patients admitted to hospital due to COVID-19 in 
each arm from programmed table. 
To evaluate the requirement for 
supplementary oxygen (non-
invasive or mechanical invasive) in 
patients who have received 
camostat as treatment for SARS-
CoV-2 infection. 
Supplementary oxygen-free days at 28 days 
(from randomisation). 
 
Measure Title: Number of oxygen free days 
Measure Description: Number of oxygen free days 
Time frame: Days 1-28 
Population description: Patients who received 
camostat for a minimum of five days (treatment 
arm) or who either completed up to Day 14 or came 
off trial at an earlier timepoint due to an endpoint 
defined reason (e.g. hospitalisation). 
 
 


 
 
 
CRUKD/20/002 SPIKE-1 RAP Final V2.0_03Mar2023 
Information to be presented:  Median and range of 
oxygen free days by treatment arm (provided in 
Stats report). 
To evaluate the requirement for 
ventilation in patients who have 
received camostat as treatment 
for SARS-CoV-2 infection. 
Ventilator-free days at 28 days (from 
randomisation). 
Measure Title: Number of ventilator - free days 
Measure Description: Number of ventilator - free 
days 
Time frame: Days 1-28 
Population description: Patients who received 
camostat for a minimum of five days (treatment 
arm) or who either completed up to Day 14 or came 
off trial at an earlier timepoint due to an endpoint 
defined reason (e.g. hospitalisation). 
 
Information to be presented:  Median and range of 
ventilator free days by treatment arm  (provided in 
Stats report). 
To evaluate efficacy of camostat 
by effect on COVID-19 related 
clinical improvement. 
Time Frame: Days 1-28 
Time to worst point on the scale or 
deterioration of two points or more (from 
randomisation) on a 9-point category ordinal 
scale. 
9-point category ordinal scale: 
0. Uninfected, no clinical or virological 
evidence of infection 
1. Ambulatory, no limitation of activities 
2. Ambulatory, limitation of activities 
3. Hospitalised – mild disease, no 
oxygen therapy 
4. Hospitalised – mild disease, oxygen 
by mask or nasal prongs 
Measure Title: Time to worst point on the scale or 
deterioration of two points or more (from 
randomisation) on 9 point category ordinal scale. 
Measure Description: Median time and range to 
worst point on the scale or deterioration of two 
points or more (from randomisation) on 9 point 
category ordinal scale 
 
Time frame: Days 1-28 
Population description: Patients who received 
camostat for a minimum of five days (treatment 
arm) or who either completed up to Day 14 or came 
off trial at an earlier timepoint due to an endpoint 
defined reason (e.g. hospitalisation). 
 


 
 
 
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5. Hospitalised – severe disease, non-
invasive ventilation or high-flow 
oxygen 
6. Hospitalised – severe disease, 
intubation and mechanical ventilation 
7. Hospitalised – severe disease, 
ventilation and additional organ 
support – vasopressors, renal 
replacement therapy (RRT), 
extracorporeal membrane 
oxygenation (ECMO) 
8. Death 
Information to be presented:  Median and range of 
times to worst point on the ordinal scale (provided 
in Stats report). 
 
 
 


 
 
 
CRUKD/20/002 SPIKE-1 RAP Final V2.0_03Mar2023 
8 TABLES LISTINGS AND FIGURES 
8.1 LISTINGS: 
Completed or Discontinued patients 
 Treatment compliance End of monitoring period (Control arm) 
End of study 
Protocol deviations 
Patients excluded from efficacy analysis 
Screening failures 
 EnrolmentDemographic and Baseline Data 
Demographics 
Randomisation 
Medical history 
Risk factors 
COVID-19 symptoms 
Influenza or COVID-19 Vaccination 
Concomitant medications 
Medical procedures 
Compliance and/or Drug Concentration Data 
 Treatment compliance Efficacy Response Data 
 
 
9-point ordinal scale for clinical improvement 
 
COVID-19/Camostat related hospitalisation details 
Oxygen therapy and ventilation 
Hospitalisation follow up  
Safety Data 
 Adverse Events (by subject) 
 Adverse Events by SOCPregnancy  test 
 Laboratory results 
Imaging 


 
 
 
CRUKD/20/002 SPIKE-1 RAP Final V2.0_03Mar2023 
8.2 TABLES 
Demographic Data 
 Baseline characteristics by treatment arm 
Reasons for patient withdrawal / completion 
Compliance 
 Treatment modifications and/or non-compliance (treatment arm only) 
Efficacy Data 
Ordinal Scale 
Summary  of Secondary Endpoint Data  
  Safety Data 
Overview of  Treatment Emergent Adverse Events (Inclusive and post Day 1) 
Frequency of All Adverse Events 
Frequancy of pre-treatment AEs 
Frequency of TEAEs 
Frequency of All Camostat related treatment emergant AEs 
Frequancyof all COVID-19 related treatment emergent AEs 
Frequency of all treatment emergent SAEs  
 Breakdown of TEAEs leading to Patient withdrawal 
Neutrophils:Lymphocytes ratio per patient (treatment and control arm respectively) 
 
 
 
9 REFERENCES 
x 
Guidelines for the Content of Statistical Analysis Alans in Clinical Trials, JAMA December 2017, 
Volume 318, Number 23. Gamble et al.  
 




 
 
 
CRUKD/20/002 SPIKE-1 RAP Final V2.0_03Mar2023 
Contents 
List of Abbreviations ...................................................................................................................................... 34 
1. Introduction ................................................................................................................................................. 35 
2. Statistical Methods section from the protocol .......................................................................................... 35 
3. Overall Statistical Principles ...................................................................................................................... 36 
3.1 Populations ................................................................................................................................................ 36 
3.2 Missing data ............................................................................................................................................... 36 
3.3 Adjusting for centre .................................................................................................................................. 36 
3.4 Subgroup analyses ..................................................................................................................................... 37 
4. List of Analyses ............................................................................................................................................ 37 
4.1 Interim evaluation ..................................................................................................................................... 37 
4.2 Main study findings .................................................................................................................................. 37 
4.1 Transformations ........................................................................................................................................ 38 
4.2 Tables ......................................................................................................... Error! Bookmark not defined. 
5. 
Validation and QC ................................................................................................................................. 38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
CRUKD/20/002 SPIKE-1 RAP Final V2.0_03Mar2023 
 
INTRODUCTION 
This Statistical Analysis Plan is based on protocol version 6.0, dated 20 Sep 2021. 
 
This is a Phase II randomised, multicentre, prospective, open label,  clinical trial of camostat 
(200mg four times per day) vs best supportive care for adult patients (18 years) with validated 
COVID-19. Patients will be recruited from testing centres which may include primary care 
‘COVID-19 hub’ clinics, COVID-19 community-based testing centres or equivalent clinical 
environments. Patients may be recruited in hospital if hospitalised for reasons other than 
COVID-19 and who have tested positive while in hospital. Patients will be randomised 1:1 into 
each arm. Patients will be stratified into four groups: Males 65 years or older; males below 65 
years, females 65 years or older; females below 65 years. Up to 100 patients will be recruited, in 
a 1:1 ratio between treatment and control. 
 
See section 13.2 of the protocol for the sample size calculation. 
 
10 STATISTICAL METHODS SECTION FROM THE PROTOCOL 
The primary outcome will be an exploration of camostat safety and toxicity, in terms of the 
number and severity of AEs and SAEs. Recruitment rate will be reported as numerator and 
denominator, with the percentage and exact binomial 95% confidence interval. The other 
feasibility measures will be reported in the same way.  
 
Descriptive statistics will be used to describe the demographics for each randomised group and 
overall. For categorical data, frequencies will be reported, and for continuous variables means 
and standard deviations, or for skewed data, medians and interquartile ranges will be reported.  
 
Secondary outcomes will be reported in a similar way to the demographic data, with an 
estimate of the difference and standard error between the treatment groups for continuous or 
ordinal scale data. Medians and IQRs will be used where data are non-normally distributed. 
Absolute percentage difference and standard error will be reported for binary variables. Kaplan-
Meier plots and life tables will be used to estimate median survival times.  
 
Subgroups will be explored where there are sufficient patients in each group. Data will be split 
by age (фϲϱǇĞĂƌƐǀƐшϲϱ years), fall in lymphocyte (<20% fall ǀƐшϮϬйĨĂůů), and 
neutrophil:lymphocyte ratio (<2.18 ǀƐшϮ͘ϭϴ) for key explanatory variables.  
 
No significance testing will be performed. Differences between treatment groups will be 
reported solely to inform future trials.  
 
All enrolled patients who receive at least one dose of camostat in the treatment arm and complete 
Day 1 in the control arm will be evaluable for safety.  
In order to be evaluable for efficacy, treatment arm patients must receive camostat for a 
minimum of five days, and control arm patients must either complete up to Day 14 or come off 
trial at an earlier timepoint due to an endpoint (e.g. hospitalisation).  
 
Safety data will be collected from the date of written or verbal consent. Safety variables will be 
summarised by descriptive statistics.  
 


 
 
 
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Adverse events will be reported as tables of frequency of AEs by MedDRA system organ class 
and by worst severity grade observed. Tables should indicate related and unrelated events 
 
Adverse events will be reported for each arm and presented as tables of frequency of AEs by 
MedDRA  system organ class and by worst severity grade observed. Tables will indicate related 
and unrelated events 
 
11 OVERALL STATISTICAL PRINCIPLES  
Analysis of the data will primarily be performed using the SAS statistical package (SAS software. 
Copyright © 2002-2012 SAS Institute Inc. SAS and all other SAS Institute Inc. product or service 
names are registered trademarks or trademarks of SAS Institute Inc., Cary, NC, USA.). The 
statistical significance level will be p=0.05, although as a feasibility study, few hypothesis tests 
will be conducted. 
 
11.1 
Populations 
The efficacy population will only include patients from the camostat arm where they have 
completed 5 days of treatment and in the control arm where they have completed 14 days of 
treatment or reached an endpoint (eg hospitalisation). All primary and secondary analyses will 
be conducted with this population. An intention-to-treat analysis of the main secondary 
outcomes (COVID-19 related hospital admissions, supplementary oxygen-free days, ventilator-
free days, time to worst point on the 9-point ordinal scale) will also be conducted, should the 
data allow. 
 
Patients who agree to the taking of blood samples will be included in the analysis of the PK 
data. The mean and SD will reported at each time point (Days 7 and 14), as will the mean 
changes. The data may be log (or other) transformed if not normally distributed. 
 
 Change will be 
change from previous blood test. 
 
 
The safety population will include all patients with at least one dose of treatment (camostat or 
control). Safety data will be collected from the date of written consent. Safety variables will be 
summarised by descriptive statistics. 
 
11.2 
Missing data 
Missing data is thought to be low (around 5%) but nonetheless the robustness of the findings to 
any patterns of missing data will be investigated using appropriate sensitivity type analyses, 
including multiple imputation under an assumption of missing at random. 
 
11.3 
Adjusting for centre 
 Due to the small sample size, adjustment by site is likely to be uninformative. 


 
 
 
CRUKD/20/002 SPIKE-1 RAP Final V2.0_03Mar2023 
11.4 
Subgroup analyses 
Results will be reported by the strata created by the randomisation process (Males 65 years and 
older; males below 65 years; females 65 years and older; females below 65 years). Additional 
subgroup analysis by fall in lymphocyte (<20% fall ǀƐшϮϬйĨĂůů), and neutrophil:lymphocyte 
ratio (<2.18 ǀƐшϮ͘ϭϴ) for key explanatory will be described should there be sufficient data. No 
formal comparisons of strata will be conducted. 
 
12  LIST OF ANALYSES  
 
Although the sample size has been calculated on recruitment rate, the primary outcome will be 
the comparison of adverse events and their severity between treatment arms. These will be 
listed overall and by strata. 
 
12.1 
Interim evaluation 
At appropriate intervals, tables of results will be produced to give the Investigators the 
possibility to review the data and check the completeness of information collected. 
 
This review will include: 
x Feasibility of the trial to achieve the target recruitment. This will be informed by 
o Recruitment – what proportion of eligible patients consent to the trial 
o Retention – what proportion of the randomised trial patients complete the trial 
per protocol 
o Proportion of patients for whom the primary outcome is missing 
o Overall number of adverse events 
o Protocol deviations 
 
 
No unblinded data will be made available to the investigators until the end of the trial or the 
DMEC decides to halt the trial. 
 
 
12.2 
Main study findings 
The primary outcomes for this trial are safety and adverse events. These will be tabulated by 
treatment group and by strata/subgroups. Pregnancy, compliance, protocol deviations will also 
be tabulated in this way. 
 
The majority of secondary outcomes will be reported in the main RAP. The secondary outcomes 
of number of oxygen-free days, ventilator-free days, and number of days to worst point on the 
9-point ordinal scale (see secondary objectives in RAP for definitions) will be reported as 
median and range for the 28 days of follow up post-randomisation. 
 


 
 
 
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12.3 
Transformations 
 
 
 
 
12.4 
Outputs 
Tabular outputs have been described in the main RAP. The following analyses will be in addition 
to these tables. 
 
Population: Efficacy population (at least 5 days of camostat/14 days of control) 
Medians and range for the following variables will be produced by treatment group: 
x Number of oxygen-free days,  
x Number of ventilator-free days,  
x Number of days to worst point on the 9-point ordinal scale 
 
Kaplan-Meier plots of the following variables will be produced by treatment group: 
x Time to worst point on ordinal scale 
 
 
 
 
 
 
 
Plots of daily data will also be produced where this will aid interpretation. 
 
13 VALIDATION AND QC 
 
The statistical report will be read and sense-checked.