Clinical trial NCT04765644
Conditions: Healthy
Keywords: NSAID Endothelial function COX-2 Celecoxib biomarker
Sponsor: Imperial College London
Start date: 2021-06-10; Completion date: 2022-01-24
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A single centre, placebo controlled, blinded (participant, investigator, outcome assessor) trial to evaluate the effects of COX-2 inhibition with celecoxib on endothelial function in healthy male volunteers.

Detailed description:
Primary Objective: To perform a systemic analysis of how COX-2 inhibition by celecoxib affects vascular function and 'omic biomarkers including those associated with the COX-2/prostacyclin/ADMA axis in healthy male volunteers

Secondary Objective: To investigate how this is altered by L-arginine supplementation

Methods: A single centre, double blind, placebo controlled trial will be carried out in healthy male volunteers between 18 and 40 years of age. In phase 1, participants will be blinded and randomised to receive either Celecoxib 200mgBD for 7 days or placebo. The primary endpoint is endothelial function measured by EndoPAT. In Phase 2, the same participants will receive either Celecoxib 200mgBD for 7 days + 10g L-arginine supplementation or placebo + 10g L-arginine supplementation to see if L-arginine can reverse any endothelial dysfunction caused by Celecoxib. Secondary outcomes will include measurement of 'omic biomarkers.

Arms: arm 1: Phase 1: Twenty volunteers will receive celecoxib 200 mg, 2 times/day (total 400 mg/day) for 7 days. At this point, the study team will perform an interim analysis of the data. If our primary endpoint is not achieved we may revise our endpoints and/or if additional power is required, we may recruit up to an additional n=20 volunteers per group. This analysis may also serve as a stop-go checkpoint for continuation of the second phase of the study. If we do not see any effects of celecoxib on endothelial or cardiovascular function, we will not proceed to phase 2. If we do see a negative effect, we will proceed to phase 2.

In phase 2 participants will be re-invited to the study site following a 4-8 week washout period. Participants will then receive either treatment with placebo + 10g L-arginine supplementation (20 participants) or celecoxib + 10g arginine supplementation (20 participants) for a total of 7 days arm 2: Phase 1: Twenty volunteers will receive a placebo capsule, 2 times/day (total 400 mg/day) for 7 days. At this point, the study team will perform an interim analysis of the data. If our primary endpoint is not achieved we may revise our endpoints and/or if additional power is required, we may recruit up to an additional n=20 volunteers per group. This analysis may also serve as a stop-go checkpoint for continuation of the second phase of the study. If we do not see any effects of celecoxib on endothelial or cardiovascular function, we will not proceed to phase 2. If we do see a negative effect, we will proceed to phase 2.

In phase 2 participants will be re-invited to the study site following a 4-8 week washout period. Participants will then receive either treatment with placebo + 10g L-arginine supplementation (20 participants) or celecoxib + 10g arginine supplementation (20 participants) for a total of 7 days
Interventions: intervention 1: Celecoxib intervention 2: Placebo intervention 3: L-arginine + placebo intervention 4: L-arginine + celecoxib
Intervention descriptions: intervention 1: Two 200 mg capsules per day (400 mg/day) for 7 days intervention 2: 2 capsules/day for 7 days intervention 3: L-arginine = Five capsules of 2 mg per day (10 mg/day) for 7 days Placebo = 2 capsules/day for 7 days intervention 4: L-arginine = Five capsules of 2 mg per day (10 mg/day) Celecoxib = Two 200 mg capsules per day (400 mg/day) for 7 days

Protocol documents:
Prot_SAP_000.pdf: 
Joint Research
Compliance Office
Arginine Supplementation to improve Cardiovascular and
Endothelial function after NSAID Treatment (ASCENT)
Version 5, 17th December 2021
Protocol
MAIN SPONSOR: Imperial College London
FUNDER: British Heart Foundation
STUDY COORDINATION CENTRE: Imperial/NIHR Clinical Research Facility
SPONSOR Project ID: 18IC4757
IRAS number: 280354
NCT04765644
Protocol authorised by:
Name & Role
Date
Signature
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Study Management Group
Chief Investigator: Prof Jane Mitchell
Co-investigators:
 Prof Peter Collins
Dr Nicholas Kirkby
Dr Ricky Vaja
Dr Plinio Ferreira
Study coordinator: Dr Ricky Vaja
Address: NHLI, Alexandra Fleming Building, Exhibition Road, South Kensington Campus,
London SW7 2AZ
Tel: 07872 850 342
Email: j.a.mitchell@imperial.ac.uk
Clinical queries
Clinical queries should be directed to the study coordinator who will direct the query to the
appropriate person.
Sponsor
Imperial College London is the main research Sponsor for this study. For further information
regarding the sponsorship conditions, please contact the Head of Research Governance and
Integrity at:
Joint Research Compliance Office
Room 215, Level 2, Medical School Building
Norfolk Place
London, W2 1PG
Tel: +44 020 7594 1862
http://www3.imperial.ac.uk/clinicalresearchgovernanceoffice
Funder
British Heart Foundation
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This protocol describes the Arginine Supplementation to improve Cardiovascular and
Endothelial function after NSAID Treatment (ASCENT) study and provides information about
procedures for entering participants. Every care was taken in its drafting, but corrections or
amendments may be necessary. These will be circulated to investigators in the study.
Problems relating to this study should be referred, in the first instance, to the Chief
Investigator.
This study will adhere to the principles outlined in the UK Policy Framework for Health and
Social Care Research. It will be conducted in compliance with the protocol, the Data
Protection Act and other regulatory requirements as appropriate.
Table of Contents
1. INTRODUCTION................................................................................................................7
1.1. 
BACKGROUND..............................................................................................................7
1.2. 
RATIONALE FOR CURRENT STUDY..........................................................................8
2. STUDY OBJECTIVES .......................................................................................................8
3. STUDY DESIGN ................................................................................................................8
4. PARTICIPANT ENTRY......................................................................................................9
5. ADVERSE EVENTS.........................................................................................................10
6. ASSESSMENT AND FOLLOW-UP ................................................................................12
7. STATISTICS AND DATA ANALYSIS.............................................................................12
8. REGULATORY ISSUES..................................................................................................12
9. STUDY MANAGEMENT..................................................................................................13
10.     PUBLICATION POLICY...............................................................................................14
11.     REFERENCES..............................................................................................................14
GLOSSARY OF ABBREVIATIONS
COX-2
Cyclooxygenase-2
NSAIDs nonsteroidal anti-inflammatory drugs
NO
Nitric oxide
NOS
Nitric oxide synthase
eNOS
Endothelial nitric oxide synthase
ADMA
Asymmetric dimethylarginine
BMI
Body mass index
KEYWORDS
COX-2, prostacyclin, ibuprofen, Vioxx, thrombosis, nitric oxide, ADMA, L-arginine
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STUDY SUMMARY
TITLE
COX-2/prostacyclin/ADMA/NO axis in the cardiovascular system
DESIGN
Two arm, single centre mechanistic study. Subjects will be computer
randomised to either arm.
AIMS
·
To perform a systemic analysis of how COX-2 inhibition by celecoxib affects vascular
function and ‘omic biomarkers including those associated with the COX-
2/prostacyclin/ADMA axis in healthy male volunteers
·
To investigate how this is altered by L-arginine supplementation
OUTCOME MEASURES
Primary endpoint: endothelial function measured using EndoPAT
Secondary endpoints: Blood pressure, cardiovascular biomarkers, eicosanoid and
methylarginine/amine levels, plasma proteome and blood transcriptome
POPULATION
Healthy male volunteers
ELIGIBILITY
Inclusion Criteria
·
Male, 18-40 years old
·
No abnormal findings on medical history,
screening, physical examination, haematology,
biochemistry, urinalysis and vital signs (sitting
blood pressure, resting pulse rate, respiratory
rate and body temperature within two weeks of
commencement date
·
Normal fasting lipid profile (Soverson et al, 1994)
·
Non-smoking
·
Clear venous access in upper limbs
·
BMI 18-30
·
No history or signs of drug abuse
·
No other medication 4 weeks before or during
study
·
Informed written consent
Exclusion Criteria
·
Any history of allergy to NSAIDs or arginine
·
Significant medical conditions
·
Pulse rate<50 beats/minute
·
Sitting systolic blood pressure <80 or >160
mmHg
·
Sitting diastolic blood pressure <60 or >100
mmHg
·
Baseline endothelial dysfunction (as defined by
EndoPAT; LnRHI<0.51)
·
Participation in other clinical study 8 weeks
before or during study
·
Donation of blood 8 weeks before or during
study
·
COVID-19 vaccination within 4 weeks
·
Positive COVID-19 test
TREATMENT
Celecoxib: 200 mg b.i.d (400mg total/day)
L-arginine 5g b.i.d. (10g total/day)
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Celecoxib, L-arginine or placebo will be dispensed against an individual prescription by a
registered pharmacist. Drugs will be stored at the Imperial/NIHR Clinical Research Facility.
Drugs or placebo will be administered orally.
DURATION 7 days of active treatment in each study arm (see flowchart below)
STUDY FLOWCHART AND TIMELINE
n=20 
Placebo
n=20 
Celecoxib
7 days
Washout/
interim analysis
>4 weeks
Placebo +
Arginine (10g/
day)
Celecoxib +
Arginine (10g/
day
7 days
Screening
Visit
Baseline
Samples
7 day
Samples
Baseline
Samples
7 day
Samples
Daily home
blood pressure
measurements
Daily home
blood pressure
measurements
Exam
Informed consent
Medical history
Physical
exam/questionnaire
Blood pressure
Heart rate
Breathing rate
Temperature
Height
Weight
Urine sample
Blood sample 50ml
EndoPat
Study
medication(s)
dispensed
Visit number
0
(Screening)
x
x
x
x
x
x
x
x
x
x
x
x
1
2
3
4
x              x               x               x
x              x               x               x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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ANALYSIS/STORAGE OF SAMPLES
Samples will be stored in freezers or refrigerators or other appropriate place within secure,
swipe access only facilities at Imperial College London. Results obtained during the study
which will be stored on University Computers (including University Laptops) in a
pseudonymised format; as part of our study we will measure gene expression and a large
number of different proteins and other mediators in the volunteer’s blood. Under GDPR
(Recital 34) the gene expression data that we measure is classified as ‘identifiable personal
data’. However, the type of analysis that we are performing involves RNA and not genomic
DNA which means that it would not be possible for a ‘motivated individual with no special skill in
genetics and no access to non-public datasets’ to be able to identify individuals.
Furthermore, we have performed a data-protection risk assessment on this study.
We will also send samples for analysis to collaborators within and outside of the EEA. All
samples and data will be coded before leaving the study team. For some measurements the
samples will be sent to service providers under contracts and for others to academic
collaborators. All samples would be pseudonymised before leaving the study team and
analysis conducted either done under contract for payment and/or as part of an academic
collaboration. Where required a transfer agreement will be in place. Samples will be stored
for future use subject to any requirement for future ethical approval.
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1. INTRODUCTION
1.1.BACKGROUND
Cyclooxygenase-2 (COX-2) is an inducible enzyme expressed in inflammation and
cancer. However, COX-2 in discreet regions including areas of the vasculature and in
the kidney1, 2 is a powerful cardiovascular protective pathway that works via
formation of prostacyclin. In blood vessels, prostacyclin acts on smooth muscle and
platelets to produce vasodilation and platelet inhibition, and in the kidney, regulates
renal function and vasoactive hormone pathways to indirectly affect the systemic
vasculature. These cardiovascular protective roles of COX-2 and prostacyclin are
illustrated by the fact that nonsteroidal anti-inflammatory drugs (NSAIDs), which work
by blocking COX-2 and include some of the world’s most commonly taken drugs,
cause the high profile cardiovascular side effects that have led to black box warnings
on all drugs in this class2, 3.
It was initially thought that cardiovascular side effects were limited to drugs that
selectively target COX-23-5, such as Vioxx® (rofecoxib) and Celebrex® (celecoxib),
introduced in the early 2000’s6, 7. However, as a result of subsequent epidemiology
analyses8, 9 and, most recently, the publication of two large clinical cardiovascular
outcome studies, SCOT10 and PRECISION11, it is clear that traditional NSAIDs,
including ibuprofen and naproxen, carry at least as great a cardiovascular risk as the
COX-2 selective drug celecoxib with ibuprofen, which is remarkably still an over the
counter medication, emerging as significantly more toxic to the kidney11.
The scale of use of NSAIDs (estimated to be regularly taken by 20-30% of the
population) and the degree of associated risk (increased by 30%12) means that these
drugs are a significant risk factor for heart attacks and strokes in their own right,
potentially accounting for up to 50,000 of the 458,000 heart attacks and strokes in the
UK each year (Jan 2016). Moreover, we now know that this risk emerges with just 1-2
weeks of use13. Concern over adverse cardiovascular events caused by NSAIDs has
led to cautious prescribing of COX-2 selective NSAIDs in favour of older NSAIDs, which
are more toxic to the gut, or opioids, which carry problems of tolerance, addiction
and additional health burdens, and to the withdrawal in Europe of celecoxib for the
prevention of colon cancer.
Mediators of protection: the power of arginine as a therapy
Endothelial nitric oxide synthase (eNOS) is expressed throughout the vasculature
where it protects the entire cardiovascular system against atherosclerosis, thrombosis
and hypertension. The power of eNOS and COX-2 together in protecting the
cardiovascular system is biologically enhanced since NO and prostacyclin work
additively to maintain vascular function and in a synergistic manner against
thrombosis14. Thus, this pathway, which links COX-2 with prostacyclin and eNOS,
provides a plausible mechanism that explains how NSAIDs precipitate cardiovascular
side effects. This is supported by our15 and others’16 previously published findings
showing that loss of COX-2 in mice is sufficient to impair systemic eNOS function in
blood vessels ex vivo15, 16 and that this was rescued by supplying the eNOS substrate L-
arginine in vitro15.
Whilst this provides essential proof of concept data we now need to complete
and expand this work. In addition to basic science research, we need to translate
these findings into man. We will do this by conducting a clinical study in healthy male
volunteers using a study design model based on our previous work15 that will
determine the effects of COX-2 inhibition on cardiovascular endpoints and their
sensitivity to reversal by L-arginine.
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These data will provide essential information on (i) how COX-2 inhibition and the
COX-2/prostacyclin/ADMA axis effect vascular function and (ii) the potential of L-
arginine as a rescue therapy for NSAID cardiovascular toxicity.
1.2.RATIONALE FOR CURRENT STUDY
Hypothesis: COX-2 inhibition compromises endothelial function, which can be
prevented by L-arginine.
2. STUDY OBJECTIVES
Investigate arginine as a means of preventing or alleviating the detrimental effects of
celecoxib on measured functional endpoints and biomarkers.
3. STUDY DESIGN
Two arm, single centre mechanistic study.
Forty healthy male volunteers, twenty in each arm.
Primary endpoint: Endothelial function measured using EndoPAT
Secondary endpoints:
Sitting blood pressure, cardiovascular
eicosanoid 
and 
methylarginine/amine 
levels, 
plasma 
proteome
transcriptome.
biomarkers,
and blood
Functional Endpoints
·
EndoPAT- endothelial function
·
Blood pressure
Biomarkers
·
Methylarginines- ADMA, SDMA and L-NMMA
·
Amino acids- full range including L-arginine, L-ornithine, L-
citrulline.
·
Eicosanoids- full range including prostacyclin and PGI-M
·
Cardiovascular Biomarkers- thromboxane, endothelin-1,
nitric oxide, renin, angiotensin, apolipoproteins, D-dimer,
Sicam-1 and CRP
·
Renal biomarkers- creatinine, urea, cystatin C, KIM-1 and
albumin
Healthy male volunteers will be randomized to 7 days’ treatment with celecoxib
(200mg b.i.d.; the standard maximum anti-inflammatory dose) or placebo in a double
blinded format. Samples and measurements will be made at baseline and after the
final dose. Following a washout of at least 4 weeks, L-arginine (Lamberts Healthcare
Limited) may be administered in a dose of 5g b.i.d. (10g total/day) as per the study
flowchart (page 5). A rational approach was taken in selecting the arginine dose since
10g/day increases plasma arginine by ≈40%17. At each visit, the primary endpoint will
be endothelial function, measured using EndoPAT, which measures changes in flow-
mediated endothelial function in the microvasculature. Importantly, EndoPAT is
clinically validated with scores that correlate with cardiovascular risk18. Additionally, at
each study visit, blood pressure, cardiovascular biomarkers (by ELISA) and
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eicosanoid and methylarginine/amine levels (by GC/LCMS/MS) will be measured.
Samples will also be collected for measurement of ‘omic’ biomarkers including
transcriptomics, proteomics, lipidomics and metabolomics. Additionally volunteers will
monitor and record their blood pressure readings daily using a home monitoring device
and protocols validated and suggested (respectively) by the British and Irish
Hypertension Society. In vivo aspects of this study will be performed using validated
protocols15 and using facilities and staff at the NIHR/Wellcome Trust Imperial College
Clinical Research Facility.
4. PARTICIPANT ENTRY
Pre-registration evaluations and study evaluations
We will advertise for volunteers within Imperial College London by email
advertisements, noticeboards and social media and using the established healthy
volunteer database at the NIHR/Wellcome Trust Imperial College Clinical Research
Facility. A research nurse or other suitably qualified person will explain the study to
interested volunteers and go through the participant information sheet with them,
giving the volunteer an opportunity to ask any questions regarding the study. If the
volunteer consents to the study they will sign the study consent form and will be given a
copy of the participant information sheet to keep.
The volunteer will then undergo a screening assessment to check eligibility (fulfilment
of inclusion/exclusion criteria). This will include:
·
Medical history questionnaire, including questions of history of drug abuse
·
Sitting blood pressure, heart rate, respiratory rate and temperature
·
Height and weight to calculate BMI
·
Blood sample to measure routine haematology and biochemistry (including lipid
profile)
·
Urine sample to measure glucose and specific gravity
·
EndoPAT measurement to confirm normal endothelial function
·
Participants will be asked not to change their lifestyle while they are taking part
in the study. However, they will be asked not to take any other medications
including paracetamol and ibuprofen for the duration of the study.
·
Once enrolled to the study subjects will undergo blood pressure, heart rate and
EndoPAT tests. Urine and blood will be collected for study analysis.
Eligible participants who have had a COVID-19 vaccination will need to wait at least 4 weeks
before entering into any phase of the study.
Participants will be provided with home COVID-19 rapid lateral flow kits. Participants will be
asked to perform a test prior to each study visit. Participants with a positive test will be advised
to follow government advice, perform PCR test and self-isolate. They will be excluded from
the study.
Inclusion/exclusion criteria
Inclusion Criteria
·
Male, 18-40 years old
Exclusion Criteria
·
Any history of allergy to NSAIDs or arginine
·
Significant medical conditions
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·
No abnormal findings on medical history,
screening, physical examination, haematology,
biochemistry, urinalysis and vital signs (sitting
blood pressure, resting pulse rate, respiratory
rate and body temperature within two weeks of
commencement date
·
Normal fasting lipid profile (Soverson et al, 1994)
·
Non-smoking
·
Clear venous access in upper limbs
·
BMI 18-30
·
No history or signs of drug abuse
·
No other medication 4 weeks before or during
study
·
Informed written consent
Joint Research
Compliance Office
·
Pulse rate<50 beats/minute
·
Sitting systolic blood pressure <80 or >160
mmHg
·
Sitting diastolic blood pressure <60 or >100
mmHg
·
Baseline endothelial dysfunction (as defined by
EndoPAT; LnRHI<0.51)
·
Participation in other clinical study 8 weeks
before or during study
·
Donation of blood 8 weeks before or during
study
·
COVID-19 vaccination within 4 weeks
·
Positive COVID-19 test
Withdrawal criteria
Participants will be free to withdraw from taking part at any time, and they will be asked
to provide a reason for withdrawal which will be recorded but their right to withdraw
without providing a reason will be respected. Information collected from participants
who have withdrawn may be used, but the investigators will attempt to replace the
withdrawn participants with someone who completes the full protocol.
If a subject consents but then fails to fulfil the inclusion/exclusion they will be
considered a ‘screen failure’ and their results will not be used. If screening, or during
study visits, results need further follow-up then a medically qualified investigator (Prof
Collins or Dr Ricky Vaja) will contact the general practitioner of the volunteer to request
further follow-up.
As the study evaluates, (i) a well-known and relatively safe drug (celecoxib) used in
many clinical trial settings, is available on prescription world-wide, and has a similar
mechanism of action to ibuprofen and (ii) a drug/supplement (L-arginine) freely
available without prescription from high street health food outlets and as a well-
tolerated prescription medication for treatment of urea cycle disorders, we do not
anticipate that study participants will withdraw due to the study medication.
Re-enrolment
Once participants are enrolled and randomised in the study, the study visits (visits 1 & 2
in phase 1 and visits 3 & 4 in phase 2) need to occur exactly 7 days apart. If
participant attends visit 1 but is unable to attend visit 2 for a reason that is unrelated
to the study medication e.g. develops an unrelated illness or cannot attend for personal
reasons, the participant will have the option to re-enrol as a new participant if there is at
least a 4-week washout period if they wish to do so. These participants will need to re-
attend screening and re-consent and will be treated as a new participant with a new
study number. To avoid double counting, any data obtained from the initial enrolment
will not be used and will be superseded by the data generated by re-enrolment.
5. ADVERSE EVENTS
Definitions
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Adverse Event (AE): any untoward medical occurrence in a clinical study subject.
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or
effect that:
·
Results in death
·
Is life-threatening – refers to an event in which the subject was at risk of death
at the time of the event; it does not refer to an event which hypothetically might
have caused death if it were more severe
·
Requires hospitalisation
·
Results in persistent or significant disability or incapacity
·
Is a congenital anomaly or birth defect
Medical judgement will be exercised in deciding whether an AE is serious in other
situations. Important AEs that are not immediately life-threatening or do not result in
death or hospitalisation but may jeopardise the subject or may require intervention to
prevent one of the other outcomes listed in the definition above, will also be considered
serious.
Reporting procedures
All adverse events will be reported. Depending on the nature of the event the reporting
procedures below will be followed. Any questions concerning adverse event reporting
will be directed to the Chief Investigator (Professor Jane Mitchell) and the medically
qualified Investigators (Professor Peter Collins and Dr Ricky Vaja) in the first instance.
Non serious AEs
All such events, whether expected or not, will be recorded.
Serious AEs
A SAE form will be completed and sent to the medically qualified Investigator,
Professor Peter Collins, within 24 hours. However, relapse and death and
hospitalisations for elective treatment of a pre-existing condition do not need reporting
as SAEs.
All SAEs will be reported to the Imperial College Research Ethics Committee where in
the opinion of the Chief Investigator, the event was:
·
‘related’, i.e. resulted from the administration of any of the research procedures;
and
·
‘unexpected’, i.e. an event that is not listed in the protocol as an expected
occurrence
Reports of related and unexpected SAEs will be submitted within 15 days of the chief
investigator/medically qualified investigator becoming aware of the event, using the
NRES SAE form for non-IMP studies. The Chief Investigator will also notify the
Sponsor of all SAEs.
Contact details for reporting SAEs
jrco@imperial.ac.uk
CI email: j.a.mitchell@imperial.ac.uk
Please send SAE forms to: Prof Peter Collins
Fax: 0330 128 8771
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Tel: 0330 128 8112 (Mon to Fri 09.00 – 17.00)
6. ASSESSMENT AND FOLLOW-UP
There will be no follow-up after the study has completed. The end of study definition
is last subject last visit.
7. STATISTICS AND DATA ANALYSIS
Sample size: This is a novel mechanistic study where the primary endpoint is the
effect of celecoxib on endothelial function measured using the EndoPAT device. We
anticipate that we will require n=20-40 in each study arm to detect a difference based
on previous work using similar drugs and alternative measurement approaches. For
example Carlsson and Wennmalm (1983)19 showed a reduction in endothelial function
with ibuprofen (effect size: 0.80 standard deviations) and diclofenac (effect size: 1.06
standard deviations). This equates to a power of 72-92% at n=20 and 95-100% at
n=40 to detect a difference between groups at a nominal significance threshold of
p<0.05. As we are using a different drug and an alternative measurement platform,
power can only be estimated broadly. As such, we will perform an interim analysis of
data after studying n=20 volunteers per group during the ‘wash out’ period. At this
point, actual effect size and variance will be determined and experimental power re-
calculated. If our primary endpoint is not achieved, we may revise our endpoints and/or
if additional power is required, we will reserve the option to recruit up to an additional
n=20 volunteers per group. Dependent upon the results the interim analysis may also
serve as a stop-go checkpoint for continuation of the L-arginine arm of the study.
Data analysis: Data will be analysed according to approaches applicable to the
measurement. This includes standard parametric and non-parametric tools (including
Fisher's exact tests, Student's t-tests, 1-way and 2-way ANOVAs, Mann Whitney U-
tests and Kruskill-Wallis tests) as well as specialised tests for large omic data sets
(including modified t-test with false discovery correction where appropriate). Across all
tests differences will be considered significant where p<0.05.
8. REGULATORY ISSUES
Ethics Approval
The Study Coordination Centre has obtained approval from the xxx Research Ethics
Committee (REC) and Health Research Authority (HRA). The study must also receive
confirmation of capacity and capability from each participating NHS Trust before
accepting participants into the study or any research activity is carried out. The study
will be conducted in accordance with the recommendations for physicians involved in
research on human subjects adopted by the 18th World Medical Assembly, Helsinki
1964 and later revisions.
Consent
Consent to enter the study must be sought from each participant only after a full
explanation has been given, an information leaflet offered and time allowed for
consideration. Signed participant consent should be obtained. The right of the
participant to refuse to participate without giving reasons must be respected. After the
participant has entered the study the clinician remains free to give alternative
treatment to that specified in the protocol at any stage if he/she feels it is in the
participant’s best interest, but the reasons for doing so should be recorded. In these
cases the participants remain within the study for the purposes of follow-up and data
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analysis. All participants are free to withdraw at any time from the protocol treatment
without giving reasons and without prejudicing further treatment.
Confidentiality
The Chief Investigator will preserve the confidentiality of participants taking part in the
study.
All participant information collected during the study will be kept strictly confidential,
and any information about participants which leaves the facility will have their name
and address removed. Only authorised persons such as researchers, the sponsor
and research and development audit will have access to the data.
Study data will be collected using REDCap which is a mature and secure web
application for clinical trial data capture. Data is stored on the secure encrypted
imperial college server. All data held in REDCap is anonymised. Only members of the
research team will have access to data.
Written study records will be kept in a locked cabinet. Any written study records will be
pseudonymised such that data, samples and records of participants will be known by a
study number with the key known only to the study team and kept separately from the
psuedonymised study data. Participant Identifiable data (e.g consent forms) will also
be kept in a locked cabinet with restricted access. After the study data have been
analysed and published, all written and electronic study records will be kept for 10
years by Imperial College London.
Psuedonymised electronic records of the data will be kept on a computer at Imperial
College London which is protected by a firewall. If the electronic data are used in
further research then further REC approval will be sought.
Indemnity
Imperial College London holds negligent harm and non-negligent harm insurance
policies which apply to this study.
Sponsor
Imperial College London will act as the main Sponsor for this study.
Funding
The British Heart Foundation is funding this study.
Audits
The study may be subject to inspection and audit by Imperial College London under
their remit as sponsor and other regulatory bodies to ensure adherence to GCP.
9. STUDY MANAGEMENT
The study will be lead by the Chief Investigator, Professor Jane A. Mitchell, who has
overall responsibility for the work. Professor Mitchell, Dr Nicholas Kirkby and Professor
Peter Collins will work together to manage and supervise the study. The day-to-day
management of the study will be co-ordinated through the NIHR Imperial Clinical
research facility and executed by the research team which includes Ms Hime Gashaw,
Dr Plinio Ferreira and Dr Ricky Vaja. Ms Hime Gashaw will manage the day-to-day
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organisation of laboratory and other supplies. Dr Ricky Vaja and Dr Plinio Ferreira will
be responsible for recruitment, screening and all of the procedures and measurements
made. The Principal Investigator for the Imperial College Helathcare NHS trust site
where the Imperial CRF is situated is Professor Peter Collins. Dr Ricky Vaja, together
with Professor Collins, will also be responsible for ensuring that, where screening
results need further follow-up, the general practitioner of the volunteer is contacted
and further follow-up requested. Professor Mitchell, Dr Vaja and Professor Collins will
be responsible for addressing questions concerning adverse event reporting.
The volunteer study will be performed at:
NIHR Imperial Clinical research facility
Imperial Centre for Translational and Experimental Medicine
Imperial College Healthcare NHS Trust
Hammersmith Hospital
Du Cane Road
London W12 0HS
Tel: 020 3313 8070
Email: Imperial.CRF@imperial.nhs.uk
10.PUBLICATION POLICY
Identifiable personal data will not be used when reporting the study results.
Results may be presented at national and international conferences, and published in
the highest possible impact peer reviewed journal, press releases/public engagement
forums.
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