The Effect of Altering Myocardial Lipid Content on Cardiac Physiology in Patients With Aortic Stenosis
Phase: NA
Conditions: Aortic Valve Stenosis
Sponsor: University of Oxford

Date and version No:     11.11.2020 version 2.1 
 
Division of Cardiovascular Medicine 
Radcliffe Department of Medicine, 
OCMR, Level 0  
John Radcliffe Hospital,  
Oxford, OX3 9DU. 
http://www.cardiov.ox.ac.uk/ 
 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 1 of 44 
Study Title: The effect of altering myocardial lipid content on cardiac physiology in patients with 
Aortic Stenosis 
 
Short title: Ox- FAST Study (Oxford – Fibrates in Aortic Stenosis Study) 
 
Ethics Ref: 
IRAS ID: 252047 
 
Date and Version No: 11 November 2020 version 2.1 
 
Chief 
Investigator: 
Dr Masliza Mahmod, Division of Cardiovascular Medicine, University of Oxford 
Email: masliza.mahmod@cardiov.ox.ac.uk 
Investigators:  Dr Shveta Monga, Division of Cardiovascular Medicine, University of Oxford 
Prof Saul Myerson, Division of Cardiovascular Medicine, University of Oxford 
Prof Stefan Neubauer, Division of Cardiovascular Medicine, University of Oxford 
Prof Chris Rodgers, Division of Cardiovascular Medicine, University of Oxford 
Prof Houman Ashrafian, Division of Cardiovascular Medicine, University of Oxford 
Dr Jim Newton, Division of Cardiovascular Medicine, University of Oxford 
Sponsor:  
University of Oxford  
Funder: 
British Heart Foundation 
Chief 
Investigator 
Signature:  
 
 
There are no conflicts of interest to declare. 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than 
the Sponsor, the Investigator Team, HRA, host organisation, and members of the Research Ethics 
Committee, unless authorised to do so. 
 

Date and version No:     11.11.2020 version 2.1 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
       
Page 2 of 44 
 
 
 
 
 
 
 
TABLE OF CONTENTS  
 
1. 
SYNOPSIS .......................................................................................................................................... 4 
2. 
ABBREVIATIONS ............................................................................................................................... 6 
3. 
BACKGROUND AND RATIONALE ................................................................................................. 8 
4. 
OBJECTIVES AND OUTCOME MEASURES .............................................................................. 11 
5. 
STUDY DESIGN (Appendix A and B) ........................................................................................... 12 
6. 
PARTICIPANT IDENTIFICATION .................................................................................................. 13 
6.1. 
Study Participants ..................................................................................................................... 13 
6.2. 
Inclusion Criteria ....................................................................................................................... 13 
6.3. 
Exclusion Criteria ...................................................................................................................... 14 
7. 
STUDY PROCEDURES .................................................................................................................. 14 
7.1. 
Recruitment ............................................................................................................................... 14 
7.2. 
Informed Consent ..................................................................................................................... 15 
7.3. 
Study Assessments .................................................................................................................. 16 
7.3.1. 
Visit 1 - Screening and Baseline assessments (0 months) ............................................ 16 
7.3.2. 
Visit 2 - Safety and compliance assessment (3 months ± 7 days) ................................ 18 
7.3.3. 
Visit 3 – End of treatment assessments (6 months) ........................................................ 19 
7.3.4. 
Visit 4 – Study completion (1 month after end of treatment) .......................................... 19 
7.4. 
Sample Handling ...................................................................................................................... 19 
7.5. 
Investigational Medicinal Product (IMP) ................................................................................ 20 
7.5.1. 
IMP description ..................................................................................................................... 20 
Fenofibrate ......................................................................................................................................... 20 
Placebo matching Fenofibrate ........................................................................................................ 20 
7.5.2. 
Selection of dose for the study ........................................................................................... 21 
7.5.3. 
Randomisation, blinding and code-breaking ..................................................................... 21 
7.5.4. 
Supply of IMP ........................................................................................................................ 22 
7.5.5. 
Packaging, labelling and re-supply .................................................................................... 23 
7.5.6. 
Storage Conditions ............................................................................................................... 23 
7.5.7. 
Accountability of trial treatments ......................................................................................... 23 
7.5.8. 
Concomitant medication ...................................................................................................... 24 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 3 of 44 
7.5.9. 
Compliance with study medication ..................................................................................... 25 
7.5.10. 
Post study treatment ........................................................................................................ 25 
7.6. 
Discontinuation/Withdrawal of Participants from Study ...................................................... 25 
7.7. 
Definition of End of Study ........................................................................................................ 26 
8. 
INTERVENTIONS ............................................................................................................................ 26 
9. 
SAFETY REPORTING ..................................................................................................................... 26 
9.1. 
Definition of Serious Adverse Events .................................................................................... 26 
9.2. 
Reporting Procedures for Serious Adverse Events ............................................................. 27 
10. STATISTICS AND ANALYSIS ........................................................................................................ 27 
10.1. 
Description of Statistical Methods ...................................................................................... 27 
10.2. 
The Number of Participants ................................................................................................ 28 
10.3. 
Analysis of Outcome Measures .......................................................................................... 28 
11. DATA MANAGEMENT ..................................................................................................................... 28 
11.1. 
Access to Data ...................................................................................................................... 28 
11.2. 
Data Recording and Record Keeping ................................................................................ 28 
11.3. 
Data  Blinding ........................................................................................................................ 29 
12. QUALITY ASSURANCE PROCEDURES ..................................................................................... 29 
13. ETHICAL AND REGULATORY CONSIDERATIONS ................................................................. 29 
13.1. 
Declaration of Helsinki ......................................................................................................... 29 
13.2. 
Guidelines for Good Clinical Practice ................................................................................ 29 
13.3. 
Approvals ............................................................................................................................... 30 
13.4. 
Reporting ................................................................................................................................ 30 
14. PARTICIPANT CONFIDENTIALITY .............................................................................................. 30 
14.1. 
Expenses and Benefits ........................................................................................................ 30 
14.2. 
Other Ethical Considerations .............................................................................................. 30 
15. EXCEPTIONAL CIRCUMSTANCES .......................................................................................................... 35 
16. FINANCE AND INSURANCE ......................................................................................................... 35 
16.1. 
Funding .................................................................................................................................. 35 
16.2. 
Insurance ............................................................................................................................... 35 
17. PUBLICATION POLICY ................................................................................................................... 36 
18. INTELLECTUAL PROPERTY (IP) ................................................................................................. 36 
19. REFERENCES .................................................................................................................................. 37 
20. APPENDIX A:  STUDY FLOW CHART ......................................................................................... 42 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
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© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
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21. APPENDIX B:  SCHEDULE OF STUDY PROCEDURES .......................................................... 43 
22. APPENDIX C:  AMENDMENT HISTORY ..................................................................................... 44 
 
1. SYNOPSIS 
 
Study Title 
The effect of altering myocardial lipid content on cardiac physiology in 
patients with aortic stenosis 
Internal ref. no. / short 
title 
Ox-FAST Study 
Study Design 
Prospective randomised, double-blind, placebo-controlled 
Study Participants 
Asymptomatic moderate to severe aortic stenosis patients 
Planned Sample Size 
62 
Planned Study Period 
36 months 
 
Objectives 
Outcome Measures 
Primary 
 
To assess change in myocardial 
triglyceride content (MTG) before 
and after 6 months of treatment 
with fenofibrate/placebo  
Change in myocardial lipid 
content (lipid/water) measured 
by Proton magnetic resonance 
spectroscopy (1H-MRS) 
Exploratory 
 
To assess the following changes in 
cardiac physiology before and after 
treatment with fenofibrate/placebo 
– 
LV strain  
– 
LV mass  
– 
 Myocardial energetics 
– 
Peak oxygen consumption 
(VO2 max) 
– 
Pericardial fat 
– 
Change in left ventricular 
strain measured by tagged 
CMR 
– 
Change in left ventricular 
mass measured by CMR 
– 
Change in Phospho-
creatinine/ATP ratio 
(PCr/ATP) measured by 
Phosphorous magnetic 
resonance spectroscopy 
(31P-MRS) 
– 
Change in peak oxygen 
consumption measured by 
CPET 
– 
Change in pericardial fat 
volume measured by CMR 
 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 5 of 44 
 
 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 6 of 44 
2. ABBREVIATIONS  
 
1H-MRS 
Proton Magnetic Resonance Spectroscopy 
31P-MRS 
Phosphorous Magnetic Resonance Spectroscopy 
ALP 
Alkaline Phosphatase 
ALT 
Alkaline Transaminase 
AS 
Aortic Stenosis 
AVR 
Aortic Valve Replacement 
BNF 
British National Formulary 
CI 
Chief Investigator 
CK 
Creatinine Phosphokinase 
CMR 
Cardiac Magnetic Resonance scan (MRI scan of the heart) 
CPET 
Cardiac Pulmonary Exercise Test 
CRF 
Case Report Form 
DNA 
Deoxy ribonucleic Acid 
ECG 
Electrocardiogram 
FA 
Fatty Acids 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HRA 
Health Research Authority 
ICF 
Informed Consent Form 
ISF 
Investigator Site File 
LV 
Left Ventricular 
MedDRA 
Medical Dictionary for Drug Related Activities 
MRS 
Magnetic Resonance Spectroscopy 
MTC 
Myocardial Triglyceride Content 
MTG 
Myocardial triglyceride content 
NHS 
National Health Service 
NRES 
National Research Ethics Service 
NUH 
Nottingham University hospital 
OCMR 
University of Oxford centre for Clinical Magnetic Resonance Research 
OUH 
Oxford University hospitals 
PCr/ATP 
Phosphocreatinine to ATP ratio 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 7 of 44 
PI 
Principal Investigator 
PIL 
Participant/ Patient Information Leaflet 
PPARα 
Peroxisome Proliferator-Activated Receptor Alpha 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SOP 
Standard Operating Procedure 
TAVI 
Transcatheter Aortic Valve Implantation 
VO2 max 
Peak oxygen consumption 
WOCP 
Women of child bearing potential 
ZDF 
Zucker Diabetic fatty 
 
 
 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 8 of 44 
3. BACKGROUND AND RATIONALE 
Aortic valve disease is common and its prevalence increases with age.1 As the population ages, 
this condition becomes an ever more important public health problem.2 
 
Altered myocardial substrate metabolism and steatosis in aortic stenosis 
Hypertrophied hearts, such as in aortic stenosis (AS) undergo a shift in substrate metabolism with 
a preference towards glucose utilisation, as glucose is a more efficient fuel compared to fatty acids 
(FAs).3-6 This results in imbalance between fatty acid uptake and oxidation, giving rise to 
myocardial lipid/fat accumulation (steatosis). This accumulation provides a source for non-
oxidative metabolism of excess FAs to diacylglycerol and ceramide, potentially resulting in 
lipotoxicity, cell death and cardiac dysfunction.7  
 
Although in humans there is no direct evidence as to whether this constitutes cause or effect, 
preclinical studies, as summarised below, have demonstrated a causal link between steatosis and 
left ventricular (LV) dysfunction. 
 
Chiu et al 8 generated transgenic mice that overexpressed long-chain acyl-CoA synthetase in the 
heart and showed that mismatch between myocardial FA uptake and utilisation leads to cardiac 
lipotoxicity. Haematoxylin & Eosin staining revealed vacuolated myocytes, consistent with 
intracellular accumulation of lipid. There was evidence of DNA fragmentation and increased 
cardiac ceramide content consistent with stimulation of apoptotic pathways. These were observed 
after lipid accumulation and before development of significant LV dysfunction, suggesting that 
lipid-induced programmed cell death contributes to the development of cardiomyopathy.  
 
Similarly, Zhou et al showed a causal relationship between abnormal FA metabolism and reduced 
myocardial contractility in obese Zucker Diabetic Fatty (ZDF) rats. Myocardial triacylglycerol was 
higher in ZDF rats due to under expression of FA oxidative enzymes and PPARα. Ceramide levels 
were increased compared to controls causing cell death and lipotoxic cardiomyopathy. A causal 
relationship was further supported by the fact that antisteatotic agent, Trioglitazone, which reduced 
cardiac triacylglycerol, prevented both cardiac apoptosis and loss of myocardial function.8-10  
 
There is increasing evidence implicating altered myocardial substrate utilisation and consequent 
steatosis in hypertrophy and heart failure.5, 11, 12 Our research group at University of Oxford centre 
for Clinical Magnetic Resonance research (OCMR) has shown that steatosis is present in both 
symptomatic and asymptomatic severe AS and that it independently correlates with impaired 
myocardial deformation (strain), a measure of early LV contractile dysfunction.13 Furthermore, in 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 9 of 44 
symptomatic severe AS, positive oil red O (ORO) staining of lipid deposition (a marker of steatosis) 
in myocardial biopsies was associated with systolic strain abnormalities.13 This is supported by a 
previous study by Marfella et al demonstrating a significant association between myocardial lipid 
staining and LV dysfunction in AS patients with the metabolic syndrome.12  
 
Role of the PPARα agonist, Fenofibrate in steatosis regression 
The capacity to produce energy via the utilisation of fats by the human heart is controlled in part 
at the level of expression of nuclear genes encoding enzymes involved in mitochondrial fatty acid 
β-oxidation (FAO).5, 6 The principal transcriptional regulator of FAO enzyme genes is the 
peroxisome proliferator-activated receptor α (PPARα), a member of the ligand-activated nuclear 
receptor superfamily.14 PPARα is highly expressed in the heart.5 Among the ligand activators of 
PPARα are long-chain fatty acids, therefore, increased uptake of fatty acid substrate into the 
cardiac myocyte induces a transcriptional response leading to increased expression of FAO 
enzymes.5, 14 PPARα-mediated control of cardiac metabolic gene expression is activated during 
postnatal development,14 short-term starvation15 and in response to exercise training.5, 16 In 
contrast, certain pathophysiological states, such as pressure overload-induced hypertrophy, result 
in deactivation of PPARα and subsequent dysregulation of FAO enzyme gene expression, which 
sets the stage for abnormalities in cardiac lipid homeostasis and energy production.5, 6, 14 Thus, 
PPARα not only serves a critical role in normal cardiac metabolic homeostasis, but also alterations 
in PPARα signalling likely contribute to the pathogenesis of a variety of disease states including 
pressure-overload hypertrophy in AS.17-19  
 
Fibrate drugs such as fenofibrate, gemfibrozil, and bezafibrate, which are PPARα activators are 
used for treating dyslipidaemia. Various animal and clinical studies have shown fenofibrate to 
inhibit LVH25 and phenotypic changes in cardiac gene expression26 as well as to reduce excessive 
myocardial lipid accumulation.27 Myocardial lipid accumulation (steatosis) can be directly 
cardiotoxic and cause unfavourable LV remodelling.28  
 
Cardiac Magnetic Resonance imaging and spectroscopy  
Cardiac Magnetic Resonance (CMR) is a scanning technique, which does not use ionising or other 
forms of radiation.  It allows the acquisition of moving images of the heart and heart valves.  CMR 
is an invaluable tool in assessing the progression of patients with AS. It is accurate, reproducible 
and well validated for measuring cardiac volumes and mass.29, 30 Assessment of change in 
myocardial shape and dimensions during cardiac cycle (strain) using CMR tissue tagging can 
provide accurate quantification of global and regional deformation.31  
 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 10 of 44 
Magnetic Resonance Spectroscopy (MRS) provides fundamental insights into in vivo cardiac 
metabolism. Proton (1H) magnetic resonance spectroscopy (MRS) allows non-invasive 
measurement of myocardial lipid (triglyceride) content7 by measuring lipid (based on the specific 
resonance of methylene -CH2) as a percentage of water signal in the same region of myocardium 
and is also able to distinguish between extracellular and intracellular lipids.32  This method has 
previously been validated in several body organs and animal models.32-34 Our research group at 
OCMR has recently validated an ECG gated breath-hold technique with excellent reproducibility.35 
The development of this rapid breath hold acquisition has rendered the measurement of 
myocellular lipid feasible and reliable in a clinical research setting.  
 
31P-MRS allows measurement of high energy phosphate metabolism in the myocardium in 
response to substantial changes in cardiac workload and provides new insights into physiological 
and pathological cardiac metabolism. By using the non-invasive in vivo technique 31P-MRS, we 
and others have demonstrated that AS shows impaired myocardial energetics, indicated by a 
reduced ratio of phosphocreatine to adenosine triphosphate (PCr/ATP), which is a hallmark of 
energetic derangement in cardiac hypertrophy.38-40 While PCr/ATP has been shown to improve 
post AVR,38 the effect of a PPAR alpha agonist on myocardial energetics has never been studied 
before.  
 
Evidence for a link between steatosis and myocardial deformation (strain) in AS 
Our group has previously examined the relationship between myocardial triglyceride content 
(MTC) and myocardial deformation. By using 1H-MRS, we and others have shown that cardiac 
steatosis occurs in AS, metabolic syndrome, obesity, type 2 diabetes mellitus and HIV.13, 36, 37 Our 
group has also successfully validated in vivo MTG determined by 1H-MRS with histological 
analysis of myocardial fat in human biopsies obtained intraoperatively13 in our study of 39 patients 
with severe AS and normal LV ejection fraction.13 25 symptomatic, 14 asymptomatic and 20 age- 
and sex-matched healthy controls underwent cardiac 1H-MRS for the determination of MTC and 
CMR imaging for determination of  circumferential strain (measured by tagging). Strain was 
significantly lower in both symptomatic and asymptomatic AS when compared to controls. 
Myocardial steatosis was detected in both symptomatic and asymptomatic patients with AS, with 
significantly higher myocardial triglyceride content when compared to controls. Importantly, the 
study showed that steatosis was an independent correlate of impaired LV strain. Eight months 
after AVR, steatosis and strain improved significantly, suggesting that myocardial steatosis is 
modifiable.  
 
 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 11 of 44 
Study population  
This study will recruit asymptomatic moderate to severe AS patients with at least two of the 
following: aortic valve area <1.5 cm2, peak pressure gradient >36 mmHg or mean pressure 
gradient >25 mmHg and not yet eligible for aortic valve replacement (AVR) or transcatheter aortic 
valve implantation (TAVI). 
 
If fenofibrate is successful in modulating steatosis and strain, this will not only be a breakthrough 
result with potential to slow the progression of AS in asymptomatic patients, thus delay and in 
some cases even avoid the need for aortic valve surgery altogether, but also offer a potential 
alternative treatment strategy for those symptomatic patients who refuse surgery or are not 
candidates for either AVR or TAVI. 
 
4. OBJECTIVES AND OUTCOME MEASURES 
The main objective is to study the effects of a fibrate drug, fenofibrate (a PPARα agonist, a key 
regulator of lipid metabolism) on myocardial triglyceride content (MTG) and cardiac physiology 
including circumferential strain in patients with asymptomatic moderate-severe AS. We 
understand from various previous human 24 and animal studies 25,27 that the effect of fenofibrate 
on cellular lipid metabolism becomes evident within six to fourteen weeks after treatment. In our 
pilot study13 eight months post AVR, both myocardial steatosis and strain were found to be 
significantly reduced. Based on this evidence, we believe that a study duration of 6 months will 
show expected physiological effect. Thus, we hypothesise that fenofibrate will result in steatosis 
regression and may result in changes in cardiac physiology in these patients over a period of 6 
months. 
 
Primary objective 
Outcome measure 
Timepoint(s) of 
evaluation 
To assess change in myocardial 
triglyceride content (MTG) before and 
after 6 months of treatment with 
fenofibrate/placebo 
 
Change in myocardial lipid content 
(lipid/water) measured by 1H-MRS 
 
At baseline and 
6 months 
 
Exploratory objectives 
Outcome measures 
Timepoint(s) of 
evaluation 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 12 of 44 
To assess the following changes in 
cardiac physiology before and after 
treatment with fenofibrate/placebo 
– 
LV strain  
– 
LV mass  
– 
Myocardial energetics 
– 
Peak oxygen consumption (VO2 
max) 
– 
Pericardial fat 
– 
Change in left ventricular strain 
measured by tagged CMR 
– 
Change in left ventricular mass 
measured by CMR 
– 
Change in PCr/ATP ratio 
measured by 31P-MRS 
– 
Change in peak oxygen 
consumption measured by 
CPET 
– 
Change in pericardial fat 
volume measured by CMR 
At baseline and 
6 months 
 
5. STUDY DESIGN (Appendix A and B) 
This research project is a single-centre, proof-of-concept cardiac magnetic resonance study to 
investigate the effect of altering MTG using fenofibrate on cardiac physiology in patients with 
asymptomatic moderate-severe AS. All patients will participate in a randomised, double-blind, 
parallel design placebo-controlled study for 6 months. The patients will be divided into two groups. 
 
– 
Group 1: This will include forty-nine patients who will receive treatment with fenofibrate for six 
months duration. 
– 
Group 2: This group will act as controls, comprising of thirteen patients who will be randomly 
assigned to receive placebo for six months duration. 
 
The study will be conducted in a single centre specialising in cardiac imaging. Both groups of 
patients will be identified from the large pool of outpatient clinics at John Radcliffe Hospital (Oxford) 
and district general hospitals in the region. Patients with asymptomatic moderate to severe aortic 
stenosis not planned for AVR or transcatheter aortic valve implantation (TAVI) will be reviewed 
against the eligibility criteria and invited to participate in the study. 
 
Based on previous studies it is estimated that approximately 100 patients will need to be reviewed 
in total in order to identify 62 eligible patients. Vetting will continue until eligible patients have been 
randomised into both groups. A log of all participants recruited into the study will be maintained in 
the investigator site file (ISF) at the investigational site irrespective of whether they have been 
treated with investigational drug or not. Re-screening of patients who do not meet the 
inclusion/exclusion criteria will not be permitted, however assessments may be repeated within 
the screening period and the latest assessment prior to randomisation must always be used to 
assess eligibility. 
 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 13 of 44 
Subsequently, all eligible patients will undergo informed consent and baseline tests - bloods will 
be drawn for lipid profile, renal and liver function, glucose and free fatty acids, and urine for 
pregnancy test in women of child bearing potential. 1H-MRS to assess MTG, 31P-MRS to assess 
myocardial energetics (PCr/ATP), standard cardiac magnetic resonance imaging to assess LV 
strain and LV mass, late gadolinium enhancement (fibrosis), physiological exercise assessments 
to measure VO2 max and 6 minute walking distance. Patients will then be randomly assigned in a 
double blind fashion to either receive fenofibrate 200mg once daily or placebo. Randomisation will 
be done by local pharmacy using randomisation code list provided by Nottingham pharmacy. The 
subject and study investigators will be blinded to the randomisation schedule. 
 
At three months, patient will be asked to re-visit for evaluation via history taking and drug review 
to check for any issues and compliance to the study. At the end of six months, patients will attend 
for another study visit at which all baseline investigations will be repeated. Additional blood test 
for creatinine phosphokinase may be undertaken at this visit in patients at risk of/or with symptoms 
of myopathy. 
 
Appendix A (page 40) provides a schematic overview of the study design. 
 
6. PARTICIPANT IDENTIFICATION 
6.1. Study Participants 
Sixty-two asymptomatic moderate to severe aortic stenosis patients. 
 
6.2. Inclusion Criteria 
• 
Participant is willing and able to give informed consent for participation in the study. 
• 
Male or Female, aged 18 years or above 
• 
Asymptomatic with diagnosed moderate to severe AS (at least two of the following:  aortic 
valve 
area 
<1.5 cm2, 
peak 
pressure 
gradient >36 mmHg 
or 
mean 
pressure 
gradient >25 mmHg)  
• 
Not planned for AVR or TAVI 
• 
No other significant valvular pathology 
• 
No contraindication to magnetic resonance imaging  
• 
Able (in the investigator’s opinion) and willing to comply with all study requirements 
• 
Female participants of child bearing potential ensure effective use of contraception by 
themselves or their partner during the study and six months thereafter. 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 14 of 44 
• 
Participant on stable doses of current regular medications for at least 6 weeks prior to entry 
to the study 
 
6.3. Exclusion Criteria 
The participant may not enter the study if ANY of the following apply: 
• 
Known coronary artery disease, history of angina, myocardial infarction or presence of 
regional wall motion abnormalities 
• 
Presence of other underlying cardiomyopathy 
• 
Left ventricular EF<50% 
• 
Presence of uncontrolled hypertension 
• 
Presence of type 1 or type 2 diabetes mellitus 
• 
Presence of liver impairment 
• 
Female participant who is pregnant, lactating or planning pregnancy during the course of 
the study  
• 
BMI >40 kg/m2 
• 
Significantly impaired renal function (eGFR<30ml/min) 
• 
Intolerance to or concurrent use of fibrates or PPARα agonists. 
• 
Contraindications to CMR imaging (implantable devices or other metal implants, internal 
cardioverter-defibrillator, cranial aneurysm clips, metallic ocular foreign bodies, 
hypersensitivity to gadolinium) 
• 
Inability to tolerate MRI scanning (claustrophobia, inability to lie flat) 
• 
Any other significant disease or disorder which, in the opinion of the investigator, may 
either put the participant at risk because of participation in the study, or may influence the 
result of the study, or the participant's ability to participate. 
 
7. STUDY PROCEDURES 
7.1. Recruitment 
Participants will be recruited via the following routes: 
1. Those attending general cardiology/valve clinic at John Radcliffe Hospital, Oxford and 
general cardiology clinics in regional district hospitals identified by their routine clinical 
team. A member of the clinical team will also identify potential participants directly from 
cardiology and echocardiography clinics.  
2. Through advertisement via REC approved study posters and leaflets placed in University 
of Oxford and Oxford University Hospital locations as well as REC approved social media 
adverts/posters. 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
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IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
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© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 15 of 44 
 
The research team will approach a potential participant only after either their clinical team or 
primary care GP has confirmed that he/she is both eligible (as checked against pre-defined 
inclusion/exclusion criteria) and willing to further discuss the study with the research team. 
Clinical care team or GP will hand over the study information to the potential participant for a 
brief overview of the study. Verbal agreement to be approached for the study will be recorded 
in the patient's notes by their clinical/primary care team. For those identified via referral letter, 
a letter of invitation will be sent along with the study leaflet and PIL. The invitation letter will 
indicate the contact details of the research team for the participant to respond. Research team 
will also contact them by telephone in the near future to discuss the study and answer any 
questions they may have. If the potential participant is interested in participating then the 
research team will arrange a convenient time for the first study visit where informed consent 
will be obtained.  
Recruitment of potential participants will be completed in the OCMR as part of the informed 
consent process at the baseline visit. 
 
7.2. Informed Consent 
Interested participants will be presented with written and verbal versions of the Participant PIL 
and Informed Consent form (ICF) detailing no less than the exact nature of the study; what it 
will involve for the participant; the implications and constraints of the protocol; the known side 
effects and any risks involved in taking part. It will be clearly stated that the participant 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. 
 
The potential participant will be allowed as much time as they require to consider the 
information, and the opportunity to question the Investigator, their GP or other independent 
parties to decide whether they will participate in the study.  
 
Written Informed Consent will then be obtained by the investigators and study team who are 
familiar with the study protocol and procedures and have been delegated the role by the Chief 
investigator. The participant must personally sign and date the informed consent form before 
any study procedures are performed. A copy of the signed Informed Consent will be given to 
the participant. The original signed form will be placed in the participants medical records/ 
notes and a copy retained at the study site. 
 
 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 16 of 44 
7.3. Study Assessments 
 
7.3.1. Visit 1 - Screening and Baseline assessments (0 months) 
This will include the following: 
1. Eligibility check and informed consent 
 
2. History 
 
3. Physical Examination (5 mins) 
Anthropometric measurements including height, weight, BMI and waist to hip ratio will 
be established. Brief clinical examination including blood pressure and heart rate will 
be undertaken. 
 
4. Resting 12 lead ECG 
 
5. Venous Cannulation and blood collection (15-20 minutes) 
Prior to undergoing CMR scanning, each participant will be cannulated to prepare the 
participant for the administration of contrast agent gadolinium, and at the same time 
baseline blood samples (25mls) will be taken as detailed in section 7.4. 
 
Patients will be instructed to fast at least six hours before the scheduled visit as fasting 
blood samples will be required (refer to section 7.4). We will also ask participants to 
refrain from strenuous exercise for 24 hours prior to the study visit to decrease the 
potential for spuriously elevated biomarkers that reflect the influence of vigorous 
physical activity. 
 
The venous cannulation and blood collection will be performed in an appropriate 
University of Oxford clinical research facility environment meeting OUHFT clinical and 
infection control standards, by appropriately trained study investigators.  
 
The study visits will be scheduled with consideration to allow the option of early light 
breakfast or lunch to avoid unnecessarily long fasting periods, especially in the case 
of elderly patients. The study visit timing will be discussed with the patients on an 
individual basis depending on their convenience as well as the availability of the 
scanner. 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
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          Page 17 of 44 
 
6. Cardiac Magnetic Resonance (60-75 mins with short breaks) (please see appendix C) 
All participants will undergo CMR scanning on a 3Tesla MR scanner.  
 
All participants will undergo CMR scan and participants will be asked for their consent 
to have their de-identified images stored at the time of initial consent. Participants will 
lie in a supine position and a dedicated CE marked cardiac coil placed around their 
chest. Images are obtained using breath hold and ECG gating.  
 
Cine images will be acquired for cardiac volume analysis using a 3T MR System using 
steady state free precession cine imaging as previously described.43 Analysis of 
cardiac volumes, function and mass will be performed using cvi42 post-processing 
software (Circle Cardiovascular Imaging Inc., Calgary, Canada). Aortic valve area will 
be measured with direct planimetry of aortic valve cine.44 Late gadolinium 
enhancement (LGE) will be performed and analysed as previously described.45, 46 
Tagged MR images will be acquired and analysed as previously described.13 
 
Magnetic Resonance Spectroscopy (MRS) at 3T 
1H-MRS  
Myocardial 1H-MR spectra will be obtained from the mid-interventricular septum. 
Spectroscopic acquisitions will be performed using ECG trigger at end-expiration to 
minimize motion artefacts 47. 
31P MRS 
31P-MR spectroscopy will be performed to obtain the PCr/ATP ratio from a voxel placed 
in the midventricular septum, with the subjects lying prone with their heart over the 
centre of the phosphorus coil in the iso-centre of the magnet48.  
Magnetic Resonance Spectroscopy at 7 Tesla Magnetic Field strength (optional):  The 
7 Tesla (7T) MRI scanner, operating at a higher magnetic field strength than typical 
clinical MRI systems will be used for additional 31P MR spectroscopy assessment. This 
will take approximately 90 minutes. There will not be any need for a cannula insertion, 
or blood assessments. Participants will not be given any contrast agent for this test. 
Participants will be asked to lie in the scanner for the duration and resting images will 
be acquired. This study can be carried out either on a separate day or the same day 
as the baseline MR assessments visit, depending on the participants’ preference. Up 
to 15 patients will be invited to undergo scanning at 7T MR scanner as part of the 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 18 of 44 
study. It will be made clear to the participants that this additional part of study 
assessment is optional.  
 
7. 6 minute walk test 
Participants will perform a 6 minute walk test (6MWT) by walking at their own pace 
backwards and forwards along a 30 metre length for 6 minutes. The standard validated 
protocol will be followed which is established for use in clinical and research practice. 
Total distance covered will be recorded along with Borg scores for dyspnoea and 
fatigue. 
 
8. Cardiopulmonary Exercise Testing 
Cardiopulmonary exercise testing (CPET) will be undertaken using an upright bicycle 
ergometer protocol with simultaneous respiratory gas analysis as previously 
described.50 An incremental ramp protocol will be utilised whereby workload will be 
gradually increased with continual heart rate, blood pressure and ECG recording. 
Subjects will be exercised to volitional fatigue with a corresponding adequate 
respiratory exchange ratio (RER) achieved as a requirement for satisfactory effort 
defined as respiratory exchange ratio (RER) of >1.1. Peak oxygen consumption (peak 
VO2) will be determined by averaging VO2 measures over 30 seconds of peak 
exercise. The exercise protocol is a validated incremental protocol with established 
use in clinical and research practice. During the exercise testing we will measure the 
oxygen uptake of the exercising thigh muscles. This is recorded using near-infrared 
spectroscopy which measures the refraction of light from circulating haemoglobin to 
measure the oxygen concentration. The device measures the change in oxygen 
concentration to provide a measure of the muscle oxygen uptake via two sticky 
sensors attached to one of the thigh muscles of the participant.  
 
After the baseline assessments, patients will be randomised to either receive fenofibrate 
or placebo. At this visit, study medication sufficing for the first three-month treatment period 
will be dispensed to participants in a double-blinded manner as described in section 5 
(Study design) 
 
 
7.3.2. Visit 2 - Safety and compliance assessment (3 months ± 7 days) 
 
This will include the following: 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
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          Page 19 of 44 
1. Evaluate the participant’s safety by history taking 
2. Check medication packaging and compliance (refer to section 7.3.9) 
3. Dispense study medication for the remaining three-month study period 
 
7.3.3. Visit 3 – End of treatment assessments (6 months) 
 
Same assessments as baseline visit 1 will be undertaken: 
1. History and physical examination 
2. Resting ECG 
3. Venous cannulation and blood collection 
4. CMR and MRS at 3.0T and 7.0T MRS (optional) 
5. 6 minute walk test 
6. Cardiopulmonary exercise testing (CPET) 
 
Any excess medication will be returned during this visit. 
 
7.3.4. Visit 4 – Study completion (1 month after end of treatment) 
Visit 4 will mark the completion of the study for the individual participant. It is expected 
that this follow up will be executed via telephone call although a clinic visit may be 
scheduled where the patient reports any symptoms or if there are any study related 
concerns.  
7.4. Sample Handling 
Blood samples will be sent to the John Radcliffe Oxford University Hospitals (OUH) 
laboratory for analysis. Plasma and serum samples will be pseudo-anonymised and 
stored in the Division of Cardiovascular Medicine under the custodianship of the CI for 
the duration of the study and will be accessible to the study team for this project. De-
identified samples may be used in collaboration with other organisations which may 
be outside the EU. No identifying information would be shared or leave the research 
site. De-identified samples may also be used in future ethically approved research with 
the consent of the participant. 
 
Laboratory tests: 
Using a cannula venous blood samples (approximately 25mls) will be collected at the 
time points indicated in Appendix B. Laboratory parameters to be tested are as shown 
below: 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
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          Page 20 of 44 
 
Haematology (blood sample) 
• 
Full blood count 
Clinical Chemistry (fasting blood samples) 
• 
Liver function tests (Albumin, ALP, ALT, bilirubin) 
• 
Renal function profile (Sodium, potassium, urea, creatinine) 
• 
Creatinine Phosphokinase (CK) – only where clinically indicated 
Lipid Profile (fasting blood samples) 
• 
Total cholesterol 
• 
HDL cholesterol 
• 
Calculated LDL cholesterol 
• 
Triglycerides 
• 
Free fatty acids 
Pregnancy test in women of child bearing potential (WOCP) 
• 
Urine sample for pregnancy test 
 
 
7.5. Investigational Medicinal Product (IMP) 
7.5.1. IMP description 
Fenofibrate 
Substance 
Micronised Fenofibrate 
Pharmaceutical formulation 
Gelatine capsules 
Source 
Nottingham University hospital pharmacy 
Unit strength 
200mg and 67mg  
Posology 
1 tablet, once daily 
Route of administration: 
Oral 
 
Placebo matching Fenofibrate 
Substance 
Placebo matching Fenofibrate 
Pharmaceutical formulation 
Gelatine capsules containing lactose powder 
Source 
Nottingham University hospital pharmacy 
Unit strength 
Not applicable 
Posology 
1 tablet, once daily 
Route of administration: 
Oral 
 
 
 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
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          Page 21 of 44 
7.5.2. Selection of dose for the study 
Fenofibrate 200 mg once daily is effective in reducing levels of triglycerides, total 
cholesterol, and LDL-C and increasing levels of HDL-C in patients with dyslipidemias. Its 
efficacy and tolerability in the treatment of hypertriglyceridemia and combined 
hyperlipidemia have been demonstrated in numerous clinical trials.22,23. As a PPARα 
agonist, it has been shown to regulate cellular lipid metabolism and have protective 
cardiovascular effects.24-27 These modes of action support the scientific rationale of using 
fenofibrate in this study and 200mg once daily is the recommended initial adult dose. In 
elderly patients without renal impairment, the normal adult dose is recommended. In renal 
dysfunction, the dose of fenofibrate may need to be reduced. Our recruitment criteria will 
exclude patients with eGFR<30ml/min. In patients with eGFR 30-59ml/min, the BNF 
recommended dose of 67mg daily will be administered. Nottingham University hospital 
(NUH) pharmacy will supply both 200mg and 67mg dose preparations to the local 
pharmacy. Patients will be randomised in a double blind fashion to receive either placebo 
or active drug (fenofibrate dose based on eGFR) by the local pharmacy as explained in 
section 7.5.3.  Patients renal functions will be assessed at the beginning and end of the 
study as mentioned in section 7.4. 
 
7.5.3. Randomisation, blinding and code-breaking 
• Randomisation and Blinding: Nottingham University hospital (NUH) pharmacy will supply 
both the active drug and placebo bottles, with annex 13 (EU guidelines to Good 
Manufacturing Practice) compliant labels containing a sequential pack number according 
to randomisation list, to the site pharmacy. The small tear off section on the bottle stating 
whether the product is active or placebo will be removed at the point of dispensing by the 
site pharmacy and attached to an accountability log as proof of which product the patient 
has been administered. The local pharmacy will also be made aware of patient’s eGFR 
thus enabling them to dispense the correct dose of the active drug. Hence, with the 
exception of the site pharmacy, all patients, investigators and everyone else involved in 
study conduct/analysis or with any other interest in this double-blind study will remain 
blinded with regard to the randomised treatment cohort until all patients have completed 
the study and database lock has taken place. The randomisation code will be kept secret 
by the site pharmacy until the database lock.   
 
• Generation of the allocation sequence:  This will be generated by the Nottingham university 
pharmacy using website randomization.com and they will supply a list to the site pharmacy, 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 22 of 44 
who will be unblinded. Participants will be enrolled and assigned to the intervention/study 
arm by site pharmacy based on this randomisation list. 
 
• Code-breaking: Code break envelopes will be provided by Nottingham University 
Pharmacy for each participant number according to the randomisation list to the site 
pharmacy. Emergency unblinding will be available to study investigators or clinical teams 
via site pharmacy 24 hours a day, 7 days a week, but will only be used in an emergency 
situation when the identity of the study drug must be known to the investigator/participant’s 
clinical team in order to provide appropriate medical treatment or otherwise assure safety 
of study participants. Whenever possible and if time allows, the need for unblinding will be 
discussed with the CI before the unblinding of study medication takes place. The reason 
for unblinding will be documented in the source documents along with the date and the 
initials of the person who broke the code. If unblinded, the participant may continue in the 
study as planned, unless in the opinion of the investigator there is a reason why the 
participant must discontinue.  
 
7.5.4. Supply of IMP 
Study medication will be assigned via flagged labels at randomisation and dispensed in a 
double-blind manner. At Visit 1 the patient will be dispensed sufficient medication for three-
month treatment period. Further dispensing for rest of the treatment period will occur on 
visit 2. In the event that the patient requires replacement medication, extra dispensing will 
be arranged. 
 
From the start of the treatment period patients will be instructed to take the study 
medication once daily with a glass of water. Fenofibrate should be taken with food. To 
ensure a dose interval of about 24 hours, the medication should be taken in the morning 
at approximately the same time every day. If a dose is missed by more than 12 hours, that 
dose should be skipped and the next dose should be taken as scheduled. No double doses 
should be taken. On the day of Visit 2 and Visit 3 the dose should be taken at the usual 
scheduled time, regardless of the timing of assessments. Daily dosing should continue until 
the day of Visit 3, when the last dose is taken.  
To allow for any delay in scheduling Visit 3 whilst avoiding bias (since half-life of fenofibrate 
ranges from 10 to 35 hours) patients will be provided with sufficient extra medication. 
 
In extenuating circumstances, IMP may be provided to participants by courier or other 
secure delivery method for example via a nominated person. Participants will be asked to 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 23 of 44 
provide verbal consent to providing contact details for shipping purposes and for a 
nominated person to deliver. Participants may also return IMP to the research team this 
way, for example if they are withdrawn from the study. 
 
 
7.5.5. Packaging, labelling and re-supply 
Active 200mg Fenofibrate capsules will be removed from their original blister pack and 
placed into an empty hard shell gelatine capsule. The capsule will then be back filled with 
lactose powder to prevent the capsule moving inside the capsule shell. These capsules 
will then be packed into bottles, each containing 30 capsules. 
 
 Matching placebo capsules will be manufactured using the matching capsule shells and 
 packed into bottles in the same quantities described above. 294 bottles containing 30 X 
 200mg fenofibrate capsules over-encapsulated into suitably sized capsules and back 
 filled as required for the 49 treatment group patients, and 78 bottles containing 30 X 
 matching colour placebo capsules adequate for the 13 patients in the placebo group will 
 be supplied. This is sufficient for the duration of the study. 
 
The investigational products will be provided by Nottingham University pharmacy. They will 
be manufactured, packaged and labelled in accordance with the principles of Good 
Manufacturing Practice (GMP). Re-supply to the site will be managed by the study team in 
collaboration with site pharmacy, which will also monitor expiry dates of supplies available 
at the site.  
  
7.5.6. Storage Conditions 
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with site pharmacy SOPs and the recommended storage conditions on 
the medication label. A temperature log will be maintained for documentation. If the storage 
conditions are found to be outside the specified range, the process outlined in site 
pharmacy SOPs will be followed. 
 
7.5.7. Accountability of trial treatments 
The pharmacist and/or investigational drug storage manager at site pharmacy will receive 
the investigational drugs delivered by the sponsor or delegate when the following 
requirements are fulfilled: 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 24 of 44 
• 
Approval of the clinical study protocol by the ethics committee; 
• 
Availability of a signed and dated study contract between the sponsor and the 
investigational site, 
• 
Approval/notification of the regulatory authority, e.g. competent authority, 
• 
Availability of the curriculum vitae of the Principal Investigator, 
• 
Availability of a signed and dated study protocol, 
• 
Availability of the proof of a medical license for the Principal Investigator 
Investigational drugs are not allowed to be used outside the context of this protocol. 
Patients should be instructed to return unused investigational drug. 
 
The investigator and/or pharmacist and/or investigational drug storage manager will 
maintain records of the product’s delivery to the study site, the inventory at the site, the 
use by each patient, and the disposal of unused products. If applicable, the sponsor or 
drug distribution centre will maintain records of the disposal. These records will include 
dates, quantities, batch/serial numbers, expiry (‘use-by’) dates, band the unique code 
numbers assigned to the investigational product and study patients. The investigator/ 
pharmacist/investigational drug storage manager will maintain records that document 
adequately that the patients were provided the doses specified by the study protocol and 
reconcile all investigational products received from the sponsor. At the time of returning 
investigational product to the site pharmacy pharmacist/investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by 
the study patients and that no supplies will remain in the investigator’s possession. 
 
7.5.8. Concomitant medication 
Fenofibrate is approved for treatment of hypercholesterolemia and is relatively safe with 
most of the medications. Common known drug interactions include those with warfarin and 
statins. Patients already on warfarin may need their dose adjusted based on their INR. 
Such patients and their GP’s will be given all relevant information and advice. Concomitant 
use of statins and fenofibrate can increase risk of myopathy in certain patients. Patients 
will be monitored throughout the study for any such symptoms and blood levels for CK will 
be checked where indicated. Accordingly, necessary dose adjustment/action will be taken. 
Other drug interactions, if any, with participant’s concomitant medications will be checked 
to ensure safety. To eliminate confounding bias, only those participants who have been 
stable on their current regular medications for at least six weeks prior to the entry to the 
study will be recruited. 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 25 of 44 
 
Participants will be provided with study specific telephone number to contact if they have 
any issues or concerns. 
 
 
 
 
7.5.9. Compliance with study medication 
Patients will be requested to bring all remaining study medication including empty package 
material with them when attending visits. Based on tablet counts, treatment compliance 
will be calculated as shown in the formula below. 
 
Treatment compliance (%) = 100 x
Number of tablets actually taken
Number of tablets which should have been taken 
 
Compliance should be between 80% and 120%. If the number of doses taken is not 
between 80-120%, site staff will explain to the patient the importance of treatment 
compliance. If the assessment of compliance at Visit 3 indicates a compliance of less than 
80%, the investigator may decide to perform limited Visit 3 assessments as the patient will 
not be used for the primary analysis. 
 
7.5.10. Post study treatment  
 
There is no indication or requirement for any post study treatment in this study 
 
7.6. Discontinuation/Withdrawal of Participants from Study 
Each participant has the right to withdraw from the study at any time.  In addition, the 
Investigator may discontinue a participant from the study at any time if the Investigator 
considers it necessary for any reason including: 
• 
Pregnancy 
• 
Ineligibility (either arising during the study or retrospectively having been overlooked at 
screening) 
• 
Significant protocol deviation 
• 
Significant non-compliance with treatment regimen or study requirements 
• 
Withdrawal of Consent 
• 
Loss to follow up 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 26 of 44 
Withdrawal from the study will not necessarily result in exclusion of the data for that participant 
from analysis. Withdrawn participants will be replaced. The reason for withdrawal will be 
recorded in the CRF. 
 
Patients will receive follow-up phone call one month post completion of study to check for any 
side-effects from the study medication or any other issues. 
 
 
7.7. Definition of End of Study 
The end of study is the date of the last analysis of the last sample. 
 
 
8. INTERVENTIONS  
The study will investigate the effect of fenofibrate on myocardial lipid content in patients with 
asymptomatic moderate to severe aortic stenosis. All subjects will be randomised such that 49 
patients receive fenofibrate 200mg once daily and 13 patients receive matching placebo tablets 
for 6 months +/- 1 month in a double-blind randomized parallel design. Outcome measures will be 
assessed at baseline and at the end of 6 months. For detailed information on IMP, refer to section 
7.5. 
 
9. SAFETY REPORTING  
Vital signs, physical examinations, or other safety-relevant data observed at screening, baseline, 
during the course of the study and at the end-of-study evaluation will be assessed with regard to 
possible changes compared to findings before start of treatment. 
 
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will be done 
via comparison of laboratory data to their reference ranges. Values outside the reference range 
as well as values defined as clinically relevant will be summarised.   
 
9.1. Definition of Serious Adverse Events 
A serious adverse event is any untoward medical occurrence that: 
• 
results in death 
• 
is life-threatening 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
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          Page 27 of 44 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation, 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect. 
• 
Other 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 participant and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
 
9.2. Reporting Procedures for Serious Adverse Events 
A serious adverse event (SAE) occurring to a participant should be reported to the REC that 
gave a favourable opinion of the study where in the opinion of the Chief Investigator the event 
was ‘related’ - resulting from administration of any of the research procedures and 
‘unexpected’ in relation to those procedures. Reports of related and unexpected SAEs should 
be submitted within 15 working days of the Chief Investigator becoming aware of the event, 
using the HRA report of serious adverse event form. 
 
All related AEs that result in a patient’s withdrawal from the study or are present at the end of 
the study, 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. 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 would 
undergo an end of study assessment and be given appropriate care under medical 
supervision until symptoms cease or the condition becomes stable. 
 
10. STATISTICS AND ANALYSIS 
10.1. Description of Statistical Methods 
Power and sample size calculations are based on our previous data13 on asymptomatic AS 
with MTG of 0.75 ± 0.36% vs 0.45 ± 0.17% in normal controls. In this current study, we 
acknowledge that pressure overload will not be reduced as patients will not undergo surgical 
intervention along with the uncertainty of change in MTG in moderate-severe AS patients. 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
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          Page 28 of 44 
Accordingly, we have chosen a sample size of 62 (n=49 in treatment group, n=13 in placebo 
group) to detect a mean difference in MTG of 0.15% (compared to normals) instead of 0.3%, 
with SD 0.36 and 80% power. 
 
In our proposed study, the primary focus is to detect physiological effect i.e. change in MTG 
before and after fenofibrate in the treatment group. Thus, our power calculations aim to detect 
expected changes from baseline in the treatment group alone, and the comparison between 
treatment group and placebo is not included in the calculation. The purpose of including the 
placebo group is to blind the study team during the data analysis process. Hence, we have 
higher number of patients in the treatment group compared to placebo. 
 
10.2. The Number of Participants 
To detect a mean difference in MTG of 0.15% in the treatment group (i.e half the difference 
to normals when compared to our previous study) with a SD of 0.36, power of 80% and a p 
<0.05, a minimum sample size of 38 will be required. We have allowed for 23% dropouts 
based on data from a previous randomised controlled trial on similar patient cohort 42. Taking 
into account the 23% dropouts, the number of subjects required in the treatment group will be 
49, and 13 in the placebo group, thus, taking the total number of recruited patients to 62 (n=49 
for treatment group and n=13 for placebo).  
 
10.3. Analysis of Outcome Measures 
 Based on literature data, the primary endpoint of change from baseline in MTG is regarded 
as normally distributed. The change from baseline of MTG after 6 months of treatment will 
therefore be analysed by paired student’s t-test. The primary objective will be addressed by a 
one-sided test at level alpha=0.05. For continuous exploratory endpoints, the same model as 
the primary one will be used. 
 
11. DATA MANAGEMENT 
11.1. Access to Data 
Direct access will be granted to authorised representatives from University of Oxford and 
Oxford University Hospital Trust for monitoring and/or audit of the study to ensure compliance 
with regulations. 
 
11.2. Data Recording and Record Keeping 
The study staff will ensure that the participants’ anonymity is maintained.  The participants will 
be identified only by a participant ID number on all study documents and any electronic 

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Ox-FAST Study (Oxford – Fibrates in Aortic 
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database, with the exception of the CRF, where participant initials may be added.  The code-
break document which links participant ID with participant name and identifying information 
will be held on the medical sciences high security server, which is specifically designed for 
the storage of sensitive information. All documents will be stored securely and only accessible 
by study staff and authorised personnel.  
 
All study data will be entered onto an Excel spreadsheet using the de-identified subject ID 
number in accordance with SOPs for data entry and validation. The name and any other 
identifying detail will not be included. Data will be analysed on Medcalc 9.5.2.0, SPSS or 
similar by delegated study investigators. As explained above, the participants will be identified 
only by a participant ID number on the CRF and any electronic database.  All documents will 
be stored securely and only accessible by research staff and authorised personnel. 
  
The Consent forms will be retained with the study master file and archived for up to 10 years 
after which they will be destroyed along with the study master file.  
 
11.3. Data  Blinding 
We have delegated responsibilities within the study team such that the investigator analysing 
images will be blinded to blood test results and vice-versa so that any risk of unblinding 
through corelation of findings by a study team member is eliminated. 
 
12. QUALITY ASSURANCE PROCEDURES 
Data collected for the study may be reviewed for auditing and monitoring by authorised persons 
from the Sponsor (University of Oxford), regulatory authorities or the local host institution to make 
sure that the study is being carried out correctly. All investigators have a duty of confidentiality to 
research participants and nothing that could reveal their identity would be disclosed outside the 
research study team or site. 
 
13. ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of 
the Declaration of Helsinki. 
 
13.2. Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant 
regulations and with Good Clinical Practice. 

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13.3. Approvals 
The protocol, informed consent form, participant information leaflet and any proposed 
advertising material will be submitted to an appropriate Research Ethics Committee (REC), 
and HRA for written approval. 
 
The Investigator will submit and, where necessary, obtain approval from the above parties for 
all substantial amendments to the original approved documents. 
 
13.4. Reporting 
The CI shall submit once a year throughout the study, or on request, an Annual Progress 
report to the REC Committee, HRA (where required) host organisation and Sponsor. In 
addition, an End of Study notification and final report will be submitted to the same parties. 
 
14. PARTICIPANT CONFIDENTIALITY 
The study staff will ensure that the participants’ anonymity is maintained.  The participants will 
be identified only by a participant ID number on all study documents and any electronic 
database, with the exception of the CRF, where participant initials may be added.  All 
documents will be stored securely and only accessible by study staff and authorised 
personnel. The study will comply with the General Data Protection Regulation (GDPR) and 
the Data Protection legislation 2018, which requires data to be de-identified as soon as it is 
practical to do so. 
 
14.1. Expenses and Benefits 
Reasonable travel expenses for any visits additional to normal care will be reimbursed on 
production of receipts, or a mileage allowance provided as appropriate. On those visits where 
patients are asked to fast participants will be offered light refreshments or reimbursed the cost 
of light refreshments. 
 
14.2. Other Ethical Considerations 
Venous Cannulation 
Risk to Participants: Common risks associated with phlebotomy are pain during the procedure 
and bruising (with associated pain afterwards). These risks will be minimised by ensuring that 
all staff are fully trained in phlebotomy. All participants will be fully informed about these risks 
in the Participant Information Leaflet. The worry associated with taking blood may cause some 
participants to feel unwell or faint before, during or after the procedure. The risk associated 

Date and version No:    11.11.2020 version 2.1 
 
 
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IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
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CONFIDENTIAL 
 
 
 
 
 
 
 
 
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with this will be reduced by having an adequately equipped facility for performing the 
procedure (see above) and having a staff member trained in basic life support. Although 
phlebotomy is a very safe procedure, it does create a puncture wound on the skin which may 
very rarely lead to infection around the puncture site. The risk of this will be minimised by 
ensuring strict hygiene during the procedure and by not recruiting participants who are at 
increased risk of infection. In the event that a participant reports symptoms of an infection 
(local redness, swelling, pain or discharge of pus) they should be referred to their GP or to 
A+E urgently.  
 
Risk to Researchers/Other Staff: Taking blood carries a risk of needle stick injury to the 
phlebotomist, which in turn carries a risk of exposure to blood borne infections. This risk will 
be minimised by a) ensuring staff are adequately trained, b) ensuring staff have been 
vaccinated against, and show immunity to Hepatitis B and c) having a local policy for needle 
stick injury which describes the process of being assessed for and receiving post exposure 
prophylaxis.  
  
Investigational Medicinal Product 
Fenofibrate has been in use since 1975 and is one of the most commonly prescribed 
fibrates.20 It is usually safe and well tolerated and is recommended for the treatment of 
hypertriglyceridemia and hypercholesterolemia.21, 
22.The fenofibrate dose has been 
comprehensively validated 23,24in various large studies. Patients can experience a few 
common side effects with fenofibrate like itchy skin rash or photosensitivity reaction, nasal 
congestion or runny nose, sneezing, headache, backache, nausea, constipation and 
abdominal pain which usually do not need medical attention and are likely to go away during 
treatment as their body adjusts to the medication.  Serious side-effects that occur less 
commonly and require medical attention include increase in liver enzymes, muscle weakness, 
severe allergic reaction and peripheral neuropathy. Participants will be well informed of these 
potential side-effects and their frequency in the PIL. Participants with low eGFR will be given 
reduced dose of fenofibrate as recommended by BNF. Blood tests will be taken at the time 
points as detailed in section 7.3. They will be provided with a study specific telephone number 
to contact during working hours and would be advised to contact GP or emergency services 
as appropriate if they feel unwell outside of the normal working hours. Participants will also 
be provided with a number for their clinical team to contact should they need to be unblinded 
in a medical emergency. 
 

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Ox-FAST Study (Oxford – Fibrates in Aortic 
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Both fenofibrate and placebo will be packaged into similar looking gelatine capsules and back 
filled with lactose powder. This may be of concern to patients who are vegetarian/ have certain 
religious beliefs or those who are lactose intolerant. Patients will be accurately informed of 
the bovine/porcine origin of the gelatine and presence of lactose powder in the capsules 
before enrolment into the study so that they are able to make an informed decision. 
 
CMR 
CMR is a safe and non-invasive technique with no known risk when appropriately supervised. 
It does not involve ionising radiation (X-rays). Potential participants with ferromagnetic objects 
in their bodies or with implanted devices which can be damaged by the magnet will be 
excluded by carefully screening all subjects for ferromagnetic objects, metal implants and 
other metal (e.g. shrapnel injury) every time prior to entering the scanner environment.  
 
The MRI facilities are fully equipped for resuscitation (including defibrillation) in the unlikely 
event of a medical emergency during scanning and doctors performing and/or supervising the 
scans are trained in Advanced Life Support.  
 
While most people do not experience discomfort in a MRI environment, the enclosed space 
of the scanner can potentially feel uncomfortable, especially for more elderly participants. 
Discomfort from lying still for a long period of time will be minimised with comfortable padding, 
short break during coil change and positioning. People with a history of claustrophobia would 
be excluded from participation in the study. Participants will be given a chance to see the 
scanner before the study starts.  Whilst in the scanner, participants are able to use the alarm 
button or can squeeze a bulb placed in their hands if they wish to communicate with the 
operator or to interrupt the scanning at any stage of the scanning process. As the MRI scanner 
is noisy, participants would be given ear-plugs and/or acoustically shielded headphones (3T 
and 7T) to minimize the noise and aid communication between participants and investigators.  
 
Participants will be asked to wear a gown for the CMR scans that preserves their modesty 
while remaining loose in the scanner to avoid potential burns from synthetic clothing. To help 
maintain participant dignity they will be asked to leave their underwear on, so long as it has 
no metal parts (e.g. zips, bras clasps or studs). Participants will be asked to change in a 
changing room near to the scanner and will be given a locker to securely store their 
belongings. If they are unable to change into the gown by themselves a member of staff will 
be on hand to offer assistance.  
 

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IRAS ID 
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The 7 Tesla (7T) MRI scanner operates at a higher magnetic field strength than typical clinical 
MRI systems. The Health Protection Agency (HPA) and European (ICNIRP) advice has stated 
that field strengths up to 8 Tesla can be safely used as long as the participant is aware of the 
possibility of experiencing various effects including dizziness, nausea, phosphenes (flashes 
of light) and a metallic taste in the mouth. These effects are transitory and no long-term 
exposure effects were detected. All participants will be informed of the possible effects by the 
operator in the information sheet at the consent stage and again before they go in the scanner. 
To further minimise the possibility of experiencing dizziness, the speed by which the 
participant moves into the scanner will be minimised. If they do experience dizziness, they 
may choose to temporarily halt the table movement or to stop all procedures.  
 
In the unlikely event of seeing any structural abnormalities on an MRI scan, a designated 
clinical specialist will discuss the implications with the participant and arrange for further 
investigations as necessary. However, it is important to note that scans are not carried out for 
diagnostic purposes, and therefore the scans are not a substitute for a clinical appointment. 
Rather, the scans are intended for research purposes only. 
 
Contrast Agent 
Gadolinium contrast is widely used for clinical indications in CMR and is safe to use. 
Occasionally (< 1 in 1000), it may cause a mild headache, rash and very rarely a more severe 
allergic reaction. These severe reactions generally respond very well to standard emergency 
drug treatment, similar to that given for other severe allergic reactions.  However, in people 
with reduced kidney function, it can lead to a rare condition called nephrogenic systemic 
fibrosis (NSF); hence, as per departmental SOPs based on Royal College of Radiologists 
guidelines, (2007) only research participants with estimated glomerular filtration rate (eGFR) 
>30ml/min can be given gadolinium.  For this study, all potential participants with eGFR 
<30ml/min will not be recruited. Participants' consent will be sought to obtain a pre−scan point-
of-care blood test to check kidney function if there is no laboratory blood result for creatinine 
within the last 6 months prior to consent, or if investigators make a clinical judgement that a 
new creatinine result is needed and in accordance with the MRI facilities SOPs. As explained 
to the participant in the PIL, no gadolinium will be given before this result is available.  
 
To-date, there have been no specific recommendations for the use of Gadolinium based 
contrast agents (GBCAs) in research MRI scans, either from the FDA, the Society for 
Cardiovascular Magnetic Resonance Research (SCMR), or the International Society for 
Magnetic Resonance in Medicine (ISMRM). The ISMRM presented its views on the clinical 

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IRAS ID 
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Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
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and research use of GBCAs in their publication in Lancet Neurology in July 2017. Recently 
published reports in 2017 in the peer-reviewed literature showed that subjects who had 
repeated use of GBCA showed small amounts of GBCA deposited in the brain that can be 
seen in later non-contrast studies (Lancet Neurology in July 2017). There are two types of 
GBCAs based on their chemical structures: linear and macrocyclic. It appears that certain 
GBCAs (with a linear structure) have a higher risk of this than other GBCAs with a macrocyclic 
structure, although deposition of gadolinium has also been observed with both types of 
contrast, and the extent of gadolinium deposition varies between agents. Currently, there is 
no known adverse clinical effect due to the gadolinium deposition in the brain but further 
investigations are being conducted. It should be emphasized that deposits have primarily 
been observed only after repeated or very high doses of GBCAs. This study uses lowest 
required dose of GBCA for the MR scan protocol to minimise risks. To date, the only known 
adverse health effect related to gadolinium retention is a rare condition called nephrogenic 
systemic fibrosis (NSF) that occurs in a small subgroup of patients with pre-existing kidney 
failure. 
 
The Participant Information Leaflets (PILs) includes relevant information on the risks of 
GBCAs, including allergic reactions, screening and checking for severe impairment of kidney 
function, and that it is known that small amounts of gadolinium may remain in the body, 
including the skin, bone and brain. The PIL also explains that in the event that new information 
becomes available describing adverse biological or clinical effects associated with gadolinium 
deposition, participants would be informed and it would be appropriate to include that 
information as part of the consent process. 
 
Cardiopulmonary exercise testing 
Cardiopulmonary exercise testing is very safe and is even used in people with heart failure. 
However, as with all forms of hard exercise, very occasionally some people have significant 
changes in their heart rate and rhythm that requires medical attention. Although the risk of 
this happening is small, the test is carried out in a room equipped with emergency monitoring, 
emergency medications and resuscitation equipment. Medical personnel will be available 
throughout the testing. Participants' heart rate and electrocardiography (ECG) are monitored 
throughout the exercise testing and the exercise test will be stopped if there are any concerns. 
 
Unexpected health related findings 
It is possible that the study investigations could uncover unexpected disease findings on the 
MRI scan, blood tests or other research procedures. OCMR has an established SOP to be 

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Ox-FAST Study (Oxford – Fibrates in Aortic 
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followed in the instance of an incidental finding as part of a research scan. If any evidence of 
an unexpected abnormality is detected on the MRI scans the investigators will not attempt to 
interpret them. They will contact the site MR technologist, consultant or radiologist for 
confirmation of an abnormality prior to disclosing any problem to the participant. For any 
abnormalities confirmed, a designated clinical specialist will discuss the implications with the 
participant and may arrange for further investigations as necessary. Participants will be aware 
from the PIL that research scans and procedures are not for diagnostic purposes, and 
therefore are not a substitute for a clinical appointment. Investigators will gain permission from 
the participant to contact their general practitioner (GP) directly so that the GP can then 
arrange appropriate management.  
 
15.  
EXCEPTIONAL CIRCUMSTANCES 
 
In exceptional circumstances, including during the COVID-19 pandemic, amendments as 
detailed below will be made to the study visits in order to minimise participant risk and prevent 
the risk of loss to follow-up. 
 
The participants will only attend for study visits twice in the 6 month study period. They 
will attend for visit 1 in the beginning, and then at the end of the study for visit 3. The 3 
month follow-up visit (visit 2) will be completed remotely, for example, via telephone.  
 
Going forwards all study medication for the duration of the study will be dispensed on the 
first visit. This will ensure that visit 2 can be carried out remotely. 
 
The research team will be contactable throughout the study period in case there are any 
concerns.  
 
16. FINANCE AND INSURANCE 
16.1. Funding 
The study is fully funded by The British Heart Foundation. Indemnity is provided by the 
Research Sponsor, the University of Oxford. 
 
16.2. Insurance 
Negligent Harm 

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Ox-FAST Study (Oxford – Fibrates in Aortic 
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The University has a specialist insurance policy in place which would operate in the event of 
any participant suffering harm as a result of their involvement in the research (Newline 
Underwriting Management Ltd, at Lloyd’s of London).  
 
17. PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases 
and any other publications arising from the study.  Authors will acknowledge that the study was 
funded by the British heart foundation. Authorship will be determined in accordance with the 
ICMJE guidelines and other contributors will be acknowledged. 
 
18. INTELLECTUAL PROPERTY (IP) 
Ownership of IP generated by employees of the University vests in the University.  The protection 
and exploitation of any new IP is managed by the University’s technology transfer office, Oxford 
University Innovations.  
 
 
 

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Ox-FAST Study (Oxford – Fibrates in Aortic 
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IRAS ID 
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Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
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Ox-FAST Study (Oxford – Fibrates in Aortic 
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Grothues F, Smith GC, Moon JCC, Bellenger NG, Collins P, Klein HU and Pennell DJ. 
Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-
dimensional echocardiography in normal subjects and in patients with heart failure or left 
ventricular hypertrophy. American Journal of Cardiology. 90:29-34. 
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Myerson SG, Bellenger NG and Pennell DJ. Assessment of left ventricular mass by 
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Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 40 of 44 
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and Stein DT. Measurement of intracellular triglyceride stores by H spectroscopy: validation in 
vivo. American Journal of Physiology - Endocrinology And Metabolism. 1999;276:E977-E989. 
35. 
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Lipid Content in Humans Using Single Breath-Hold (1)H MRS at 3 Tesla. Magnetic Resonance 
in Medicine. 2011;66:619-624. 
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Levelt E, Mahmod M, Piechnik SK, Ariga R, Francis JM, Rodgers CT, Clarke WT, 
Sabharwal N, Schneider JE, Karamitsos TD, Clarke K, Rider OJ and Neubauer S. Relationship 
Between Left Ventricular Structural and Metabolic Remodeling in Type 2 Diabetes. Diabetes. 
2016;65:44-52. 
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Holloway CJ, Ntusi N, Suttie J, Mahmod M, Wainwright E, Clutton G, Hancock G, Beak 
P, Tajar A, Piechnik SK, Schneider JE, Angus B, Clarke K, Dorrell L and Neubauer S. 
Comprehensive cardiac magnetic resonance imaging and spectroscopy reveal a high burden of 
myocardial disease in HIV patients. Circulation. 2013;128:814-22. 
38. 
Mahmod M, Francis JM, Pal N, Lewis A, Dass S, De Silva R, Petrou M, Sayeed R, 
Westaby S, Robson MD, Ashrafian H, Neubauer S and Karamitsos TD. Myocardial perfusion 
and oxygenation are impaired during stress in severe aortic stenosis and correlate with impaired 
energetics and subclinical left ventricular dysfunction. Journal of cardiovascular magnetic 
resonance : official journal of the Society for Cardiovascular Magnetic Resonance. 2014;16:29. 
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D and Kochsiek K. Cardiac high-energy phosphate metabolism in patients with aortic valve 
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resonance spectroscopy. Lancet. 1991;338:973-6. 
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the British Society of Echocardiography. Echo research and practice. 2015;2:G9-g24. 
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Banning AP, Neubauer S and Myerson SG. A prospective, double-blind, randomized controlled 
trial of the angiotensin-converting enzyme inhibitor Ramipril In Aortic Stenosis (RIAS trial). 
European heart journal cardiovascular Imaging. 2015;16:834-41. 
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and right ventricular and left atrial dimensions using steady state free precession magnetic 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 41 of 44 
resonance imaging. Journal of cardiovascular magnetic resonance : official journal of the Society 
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Magnetic Resonance Imaging. 2007;26:1436-1443. 
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lipid content in humans using single breath-hold 1H MRS at 3 Tesla. Magnetic resonance in 
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Magnetic Resonance in Medicine. 2011;66:619-24. 
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in biomedicine. 2009;22:405-13. 
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RS, Dass S, Sabharwal N, Robson MD, Holloway CJ, Rider OJ, Clarke K, Karamitsos TD and 
Neubauer S. Cardiac energetics, oxygenation, and perfusion during increased workload in 
patients with type 2 diabetes mellitus. European heart journal. 2016;37:3461-3469. 
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Lang CC, Khoo JP, Sprigings D, Steeds RP, Jerosch-Herold M, Neubauer S, Prendergast B, 
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the failing heart: beneficial or detrimental? Cardiovascular research. 2009;81:420-8. 
 
 
 
 
 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 42 of 44 
20. APPENDIX A:  STUDY FLOW CHART 
 
Visit 1 (Baseline Visit) 
•
Clinical information and ECG 
•
Venous cannulation and blood collection 
•
Cardiopulmonary exercise & 6 minute walk test 
•
Cardiac MRI, 1H-MRS and 31P-MRS  
62 moderate-severe AS 
Randomisation 
Data analysis 
Fenofibrate 200mg 
daily for 6 months 
49 patients 
13 patients 
Visit 2 (3 months) 
•
Brief safety evaluation/history 
•
Check medication compliance 
Placebo daily for 6 
months 
Visit 3 (6 months) 
•
Clinical information and ECG 
•
Venous cannulation and blood collection 
•
Cardiopulmonary exercise & 6 minute walk test 
•
Cardiac MRI, 1H-MRS and 31P-MRS  

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 43 of 44 
21. APPENDIX B:  SCHEDULE OF STUDY PROCEDURES 
 
 
Visit 1 
Baseline 
(month 0) 
Visit 2  
(3 months 
± 7 days) 
Visit 3 
(6 months 
± 7 days) 
Visit 4 
(7months ± 
7 days 
Informed Consent 
X 
 
 
 
Inclusion and exclusion review 
X 
 
 
 
History 
X 
X 
X 
 
Physical Examination 
X 
 
X 
 
Blood tests 
X 
 
X 
 
ECG 
X 
 
X 
 
Randomisation   
X 
 
 
 
CMR & MR spectroscopy (75mins) 
X 
 
X 
 
CMR Consumables 
X 
 
X 
 
Drug prescribed (Pharmacy) 
X 
X 
 
 
Drug review 
 
X 
X 
 
Cardiopulmonary Exercise Test 
(CPET) 
X 
 
X 
 
Six minute walk test (6MWT) 
X 
 
X 
 
Follow up phone call 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Date and version No:    11.11.2020 version 2.1 
 
 
Principal Investigator: 
Dr Masliza Mahmod 
IRAS ID 
252047 
Short Title: 
Ox-FAST Study (Oxford – Fibrates in Aortic 
Stenosis) 
Ethics Ref: 
 
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
          Page 44 of 44 
22. APPENDIX C:  AMENDMENT HISTORY 
Amendment 
No. 
Protocol 
Version 
No. 
Date 
issued 
Author(s) 
of 
changes 
Details of Changes made 
01 (minor) 
V2.0 
19/03/2020 
P Kemp 
Addition 
of 
option 
for 
the 
Investigational Medicinal Product 
(IMP) to be delivered to and sent 
from participants. 
02 
minor 
(COVID-19) 
V2.1 
11/11/2020 
Shveta Monga 
During exceptional circumstances 
visit 2 will be carried out remotely, 
and medication for the whole study 
period will be dispensed at visit 1.