High Intensity Interval Training In pATiEnts With Intermittent Claudication (INITIATE): a Proof-of-concept Prospective Cohort Study to Assess Acceptability, Feasibility and Potential Clinical Efficacy
Phase: NA
Conditions: Peripheral Arterial Disease, Intermittent Claudication
Sponsor: Hull University Teaching Hospitals NHS Trust

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Title:  High INtensity Interval Training In pATiEnts with intermittent claudication (INITIATE) 
Short title: INITIATE 
Protocol details: 
Version 1.2 06/04/18 
Version 1.3 28/01/19 
Version 1.4 04/03/19 
Version 1.5 15/08/19 
IRAS ID: 237067 
Trial registry number: NCT04042311 
Draft 
Version number and date of amendments: 
Version 1.6 25/02/21 
This protocol has regard for the HRA guidance and order of content;  
Chief Investigator:  
Professor Ian Chetter 
Academic Vascular Dept.  
1st Floor, Tower block 
Hull University Teaching Hospitals NHS Trust 
Hull Royal Infirmary 
HU3 2JZ 
‘This trial will be conducted in compliance with the protocol, GCP and the applicable 
regulatory requirements’. 
Signature:  
 
 
 
Date: 
Sponsor: 
Hull University Teaching Hospitals NHS Trust, Hull Royal Infirmary, Anlaby Road, Hull, HU3 2JZ. 

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Signature: 
 
 
 
Date: 
 
List of abbreviations: 
PAD = Peripheral Arterial Disease 
PVD = Peripheral Vascular Disease 
CAD = Coronary Artery Disease 
IC = Intermittent Claudication 
SEP = Supervised Exercise Programme 
HEP = Home-based Supported Exercise Programme 
HIIT = High-Intensity Interval Training 
CPET = Cardio-Pulmonary Exercise Testing 
PPO = Peak Power Output 
PFWD = Pain-Free Walking Distance 
MWD – Maximum Walking Distance 
ABPI = Ankle Brachial Pressure Index 
TBPI = Toe Brachial Pressure Index 
BP = Blood Pressure 
SBP = Systolic Blood Pressure 
DBP = Diastolic Blood Pressure 
BMI = Body Mass Index 
HR = Heart Rate 
VO2Peak = Peak Oxygen Consumption 
VO2Max = Maximal Oxygen Consumption 
VAT = Ventilatory Anaerobic Threshold 
RPE = Rating of Perceived Exertion 

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RER = Respiratory Exchange Ratio 
VO2 = Oxygen Uptake 
RCT = Randomised Control Trial 
REC = Research Ethics Committee 
ECG = Electrocardiogram 
VCO2 = Carbon Dioxide Production 
VE = Minute Ventilation 
AE = Adverse Event 
SAE = Serious Adverse Event  

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Background Information: 
What is Peripheral Arterial Disease? How does it manifest as intermittent claudication? 
Peripheral arterial disease (PAD) is caused by occlusive atherosclerotic lesions of the arteries 
that supply blood to the legs (1, 2). The National Institute for Health and Care excellence 
(NICE) clinical guidance 147 notes that the incidence of PAD is approximately 20% in those 
over the age of sixty (3). The incidence is also high in certain populations such as diabetics, 
smokers and those with coronary artery disease (CAD) (3). However, some PAD patients 
may be asymptomatic, meaning that it’s true incidence may be underestimated (2). There is 
an increased 10-year mortality risk associated with PAD, which is 3- and 6-fold for all-cause 
and CV mortality respectively, when compared to those with no evidence of the disease (4). 
One common symptomatic manifestation of PAD is a reproducible lower limb muscle pain 
on ambulation or during exercise known as intermittent claudication (IC). This is caused by 
reduced blood flow due to the narrowing of the arteries, resulting in an oxygen supply-
demand imbalance (5, 6). The risk factors associated with IC are similar to those relating to 
myocardial infarction and angina pectoris such as smoking, hypercholesterolemia and 
diabetes (5). It is therefore unsurprising that within a cohort of 381 patients with lower 
extremity ischaemia, only 10% had normal coronary arteries identified via angiography (7).  
What effect does it have on the patient? 
IC can have a profoundly negative effect on a patient’s life due to a number of factors, 
including a reduction in walking capacity, altered gait and balance and a likely reduction in 
muscle strength. In addition, this symptomatic disease affects functional capacity whilst also 
disrupting daily activities due to its restriction on ambulation (5, 8).  A recent qualitative 
analysis explored patient experiences of IC and found that most patients described their 
symptoms as being detrimental to daily activities (9). Furthermore, research has 
demonstrated that IC can also have a negative effect on a patient’s quality of life (QoL). In 
comparisons to members of the general population, IC sufferers have a worse QoL for all 
health aspects including; general health, vitality, social and physical functioning, physical 
role and bodily pain all of which are further reduced with increasing disease severity (10).   
How is it diagnosed and managed? 
IC is diagnosed based on history, clinical assessment and an abnormal ankle-brachial 
pressure index (ABPI). The classic symptoms of IC are pain in one or both legs on walking, 
which primarily affects the calves and only subsides with rest (1). An index of between 0.91-
1.30 is considered normal, with claudicants usually presenting with an ABPI between 0.41-
0.90. Those with values of 0.40 or less are considered to have critical leg ischaemia (1). It is 
also important to note that values >1.30 may be falsely elevated due to calcified vessels that 
are non-compressible. In these patients, further tests should be carried out, such as toe 
brachial pressure index (TBPI) to determine the presence of PAD (1). 

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NICE (147) notes that the first-line treatment which should be offered to all patients with IC 
is a supervised exercise programme (SEP) (3). A recent Cochrane review demonstrated that 
SEP’s are efficacious for improvements in both pain-free (PFWD) and maximum walking 
distance (MWD) whilst also potentially providing improvement in QoL for those who suffer 
with IC (11). However, the UK guidelines for SEPs are limited and recommend that it should 
entail two hours of supervised exercise per week for three months whilst encouraging 
patients to exercise to the point of maximal pain. This is somewhat arbitrary and previous 
researchers have noted that for IC patients there is a glaring omission of the most 
appropriate exercise intensity and that within the PAD trial literature, SEP interventions are 
not sufficiently described, especially with regard to exercise mode and intensity (12, 13). 
This has implications for the replication of exercise protocols in clinical practice (13), 
meaning that there is no standard rehabilitation programme. 
Furthermore, despite being the recommended first-line treatment for IC, a systematic 
review demonstrated that only one in three patients were eligible and willing to take part in 
a SEP (14). In addition, a survey of all UK vascular centres demonstrated that only 42% had 
exercise programmes for their patients to access (14). Therefore, there is clearly a gap in the 
literature to develop an exercise programme that is more accessible and / or acceptable to 
patients (14).  
Two possible developments are high-intensity interval training (HIIT) and home-based 
supported exercise programmes (HEP). One previous study in the USA using a HIIT 
programme demonstrated that patients in the HIIT group had similar improvements in peak 
oxygen uptake (VO2Peak), PFWD and MWD compared to those who completed low-intensity 
exercise (12). However, high-intensity was prescribed using 80% of the maximum workload 
(i.e. treadmill grade) achieved during the initial baseline maximal effort test (12), which is 
slightly conservative, given that HIIT is usually prescribed between 85-95% of peak workload 
or HR (15, 16). Despite this limitation, this study does suggest that HIIT may be at least as 
effective as current exercise programmes and should be explored as an alternative SEP 
treatment option.  
In comparison to HIIT there has been much more evidence for the use of HEP. One 
randomised controlled trial (RCT) in the USA demonstrated that HEP significantly improved 
PFWD and MWD with results equivalent to the SEP (17). With increasing technologies HEPs 
or “facilitated self-managed exercise programmes” are becoming more prominent. Indeed, 
a study identifying patient preference in the IC literature demonstrated that over half of 
patients would prefer to exercise in the home setting (Harwood et al, JVN 2018). 

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Study Aims: 
This study aims to compare the efficacy and acceptability of two novel exercise 
interventions (HIIT and HEP) versus current practice (SEP) for exercise rehabilitation in IC. As 
a cycle-based HIIT protocol has not been previously investigated in the IC population an 
initial observational cohort study of HIIT will be conducted, followed by semi-structured 
interviews, meaning the research will be split into two work-streams. 
Work-stream 1: Considering the safety, tolerability, acceptability and efficacy of high-
intensity interval training as a novel intervention for the treatment of intermittent 
claudication. 
Study-design: A Two-centre, mixed methods, prospective, “proof of concept” cohort study. 
Objective: To investigate the utility, safety, tolerability, acceptability and efficacy of high-
intensity interval training as a novel intervention for the treatment of intermittent 
claudication. 
Primary outcomes measures: Utility, assessed by screening, eligibility, recruitment and 
adherence rates. Safety, assessed by determining the occurrence of adverse and serious 
adverse events, and tolerability, assessed by patient ability to achieve and maintain exercise 
in the appropriate exercise intensity domain. 
Secondary outcome measures: Acceptability assessed via semi-structured interview and 
changes in MWD and PFWD assessed via graded treadmill test, VO2Peak, ventilatory 
anaerobic threshold (VAT) assessed via CPET, ABPI and QoL. 
Primary endpoint 
The primary endpoint for this study will be assessing the utility, safety and tolerability of a 6-
week HIIT intervention.  
Secondary endpoints 
Additional endpoints will include acceptability and improvements in MWD, PFWD, VO2Peak, 
VAT, ABPI and QoL.  
Study design 
Identification and screening of patients: 
Potential participants will be identified by vascular surgeons / nurses / technologists (as 
appropriate to each site) in vascular outpatient clinics or multidisciplinary team meetings (as 
appropriate to each site) at two tertiary vascular centres, Hull Royal Infirmary (Hull, United 
Kingdom) and University Hospital Coventry and Warwickshire (Coventry, United Kingdom) 

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and referred to research nurses / research fellows or exercise physiologists (appropriate to 
each site) for screening..  
Patient Selection 
Patients will have a confirmed diagnosis of intermittent claudication made by their 
consultant either clinically or by questionnaire. Diagnosis will be made with an ABPI of <0.9, 
a drop-in ankle pressure of ≥20mmHg after exercise, or documented significant 
atherosclerosis on radiological imaging. 
 
Patient consent 
Patients will be sent a letter and patient information sheet. This will provide details of the 
study, the 6-week HIIT programme and the interview. Patients will then be contacted via 
telephone call at least a week later to ask any questions and decide whether they would like 
to partake in the study intervention. Those who do not wish to partake in the research will 
be offered the usual care SEP without research as is usual practice for IC. Those who also 
decline this will be referred back to their consultant for future management. 
Those who decide to participate will be asked to attend a baseline visit prior to beginning 
their exercise programme to determine if they are suitable. The research project will be re-
explained and questions encouraged. Following this, informed consent will be obtained if 
appropriate. A clause outlining the conduction of an interview, voice recording and use of 
anonymous quotes will be included in the consent form, but this will be optional. Patients 
will still be able to participate in the study without completing an interview. 
Baseline and follow-up visits 
Baseline and follow-up visits will be completed for all research participants who complete 
the full intervention timeframe (i.e. 6-8 weeks). Those choosing to discontinue the 
intervention before completing the full intervention timeframe will be withdrawn. Follow-
up visits will be completed immediately following completion of the HIIT programme, and 
then 12-weeks post-intervention. An additional follow-up will also be completed 4-weeks 
post-intervention at the Hull site only.  
Travel expenses for study visits (baseline and follow-ups) will be reimbursed. Patients can be 
reimbursed a maximum of £75 to cover the costs of transport/parking that may be accrued.  
Patients will be asked not to eat a heavy meal or smoke for 3 hours before the visit and 
testing (18). Patients will also be asked to dress appropriately, especially in terms of 
footwear and instructed to avoid unusual physical activity efforts in the preceding 12 hours 
(18). As testing will not be performed for diagnostic purposes, patients will not be asked to 
withdraw or refrain from taking any medications (18). At each study visit, the patient’s 
medical notes will be reviewed before assessment of current and past medical history. 
Patients will be asked questions relating to previous medical history including previous 

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diagnoses, current symptoms, and medications to determine the presence of any 
contraindications to exercise testing (18, 19).  
Resting blood pressure and HR will then be taken followed by height, weight, body mass 
index (BMI), waist circumference, hip circumference and waist to hip ratio.  During the 
baseline and subsequent visits, a number of objective physiological and subjective patient-
level measures will be performed.  

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Trial Procedures
Patient seen by consultant, 
diagnosis of IC confirmed and 
referred for exercise 
programme. 
Patient is sent patient 
information sheet detailing 
the 6-week HIIT exercise 
intervention and will be 
called at least a week later 
Patient declines to partake in 
the research. Is offered usual 
12-week SEP without 
research. If this is declined 
they will be referred to the 
consultant.  
Patient chooses to partake in 
research and baseline 
assessment arranged. 
Baseline assessment – 
eligibility confirmed, 
informed consent obtained 
and outcome measures 
assessed. 
Intervention takes place – 6 
weeks (18 sessions) of HIIT. 
Immediate post-intervention 
follow-up – outcome 
measures reassessed and 
semi-structured interview 
conducted  
4-week follow-up – outcome 
measures reassessed (Hull 
only). 
12-week follow-up – outcome 
measures reassessed and 
patient exits trial and are 
referred back to their 
consultant for management. 

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Measurement of primary and secondary endpoints 
Primary endpoint – safety, utility and tolerability 
Safety will be determined by the occurrence of any adverse events (AE) or serious adverse 
events (SAE). In accordance with the GCP decision tree for adverse event reporting all 
events will be reported to the sponsor and recorded to determine the safety of the 
intervention.  
Utility will include eligibility (n = eligible/screened), recruitment (recruited/eligible), and 
adherence (number of patients completing the HIIT programme). The number of patients 
screened, recruited and commencing the HIIT programmes will be monitored at each 
hospital site. A register (if required, i.e. more than one patient attending), will be taken at 
each exercise class to record patient adherence and the completeness of each session will 
be recorded (i.e. how many minutes the patient completed). It is estimated that all patients 
should complete 18 sessions in total within 6 weeks. However, where any sessions are 
missed, the intervention period can be extended to 8 weeks to allow these sessions to be 
added on. Those not completing 18 sessions over the extended 8-week period will be 
deemed to have satisfactorily completed the intervention as long as they have completed 
>80% of the intervention (i.e. ≥15 out of 18 sessions). All patients completing the allotted 6-
8 weeks for the intervention (regardless of whether they have completed ≥ or <15 sessions) 
will still be followed up. Those choosing to discontinue the intervention before completing 
the full intervention timeframe will be withdrawn. 
Tolerability will be assessed by identifying if patients are able to reach and maintain the 
prescribed training range required to perform HIIT, for each full interval. Heart rate (HR) 
data will be collected throughout each HIIT session and saved on an encrypted USB stick this 
will then be compared to the 85-100%HRMax training range that has been prescribed – to 
determine if patients are able to achieve it. This range will be in line with an ongoing HIIT 
trial in CAD at 85-90% peak power output (PPO), aiming to achieve >85%HRMax, derived 
from CPET (15). If patients are not able to achieve 85-100%, this will determine the 
suitability of this HIIT protocol in this population. Reasons for stopping the HIIT exercise 
sessions (e.g. leg pain), will be recorded.    
Secondary endpoints  
Acceptability 
Acceptability will be assessed by patient feedback using semi-structured interviews.  
conducted using a sample of patients in three groups: 
Group 1: Patients who are eligible for the study but decide not to participate (non-
consenters). The interviews will explore reasons why patients chose not to participate in the 

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study and whether study material could be amended to be more appealing.  Patients in this 
group will be signposted to the relevant interview section of the patient information sheet 
that they have already received. Those who agree to participate in an interview will sign an 
interview specific consent form. 
Group 2: Those who agree to participate in, and complete, the exercise programme. 
The interviews will explore patient’s experiences of the HIIT programme, how easy/hard 
they found it, whether they enjoyed it and whether they would be willing to undertake it 
again. They will also be asked to provide any additional information related to potential 
problems/barriers to the programme and any changes they may feel are required.  
Group 3: Those who agree to participate but discontinue after at least one session. 
Patients will be asked the same initial questions as group 1, but they will be asked why they 
dropped out of the programme and what could have been changed to prevent them doing 
so.  
An interview guide with a pre-determined set of open questions will be used but the 
interviews will be flexible to allow the interviewer to ask further probing questions based on 
patient responses. All interviews will be conducted face-to-face in a private room, recorded 
using a Dictaphone, transcribed verbatim and anonymised. Patients will be informed that 
they do not have to answer any questions that they feel uncomfortable with and all 
responses are confidential.  
Clinical outcome measures: 
Pain-free and maximal walking distance: 
The test that will be used starts at 2mph and 0% grade, with grade increasing by 2% every 
two minutes whilst speed remains constant (20). This test will be used to determine PFWD 
and MWD at each study visit. A stopwatch will be started when the patient walks, they will 
indicate to the researcher when they begin to feel IC pain, which will be recorded as PFWD. 
The patient will continue to walk until the pain is too severe and they need to stop, this will 
be recorded as MWD.  
Quality of life:  
Two questionnaires will be used;  
Generic: The SF-36 is a generic health measure which does not target specific populations 
but is recommended as the most appropriate generic QoL tool for those with lower limb 
ischaemia (21-23). It fulfils strict reliability and validity criteria and is practical, acceptable, 
brief and easy to use, which is important for researchers who can use it to add a general 
health measurement tool to a disease specific questionnaire (21). The SF-36 contains 36 
questions, yielding an eight-scale scoring profile including; physical function (PF), role-

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physical (RP), bodily pain (BP), generic health (GH), vitality (VT), social functioning (SF), role-
emotional (RE) and mental health (MH) (22). Each scale is scored from 0-100, based on the 
responses given, with 0 indicating worst possible health and 100 best possible health. Scales 
can also be combined to give a summary measure of mental and physical health. PF, RP, BP 
and GH all contribute to the physical component summary (PCS) and VT, SF, RE and MH 
contribute to the mental component summary (MCS) (22). 
Specific: The VascuQol is a disease-specific questionnaire developed for use in studies 
involving patients with lower-limb ischaemia (24). It has demonstrated good reliability and is 
responsive to within patient change (24). It consists of 25 items, which are subdivided into 
five domains; pain (4 items), symptoms (4 items), activities (8 items), social (2 items) and 
emotional (7 items) (24). Each item is rated on a seven-point scale, with 1 representing the 
worst score and 7 the best. A sum score is then calculated by dividing the total score by 25 
(the number of items), with a domain sum score also calculated by dividing the total score 
per domain by the total number of items in that domain (25). 
Cardiorespiratory measures 
CPET/spirometry: 
This study will utilise a cycle CPET with a ramp protocol at each study visit as a non-invasive 
assessment of cardiovascular function, utilising a safety protocol on the basis of the ACSM 
guidelines (19). Prior to the start of the test the patient will observe a 3-minute rest period 
whilst sitting on the cycle ergometer so that resting measurements can be obtained. After 
this, the patient will begin a 3-minute reference or warm-up period of unloaded cycling 
followed by progressive graded exercise with adequately increasing workload to induce 
volitional exhaustion within 8-12 minutes, concluding with a post-maximal effort recovery 
period (26). During the CPET, patients will be continuously monitored via a 12-lead 
electrocardiogram (ECG; applied after adequate skin preparation), with measurements of 
HR, blood pressure and rating of perceived exertion (RPE) taken at regular intervals (19). 
Patients will also be observed for any signs or symptoms and asked to confirm that they are 
asymptomatic periodically throughout (19). Upon completion of the CPET, this monitoring 
will continue for at least 6 minutes or until ECG changes return to baseline and significant 
signs and symptoms subside (19, 27). HR and blood pressure will also be monitored until 
they return to near resting values (19).  Gas analysis will also be conducted on a breath-by-
breath basis to allow determination of important secondary outcome measures such as 
VO2Peak and VAT. VO2Peak will be determined as the average oxygen uptake value during the 
last 30-seconds of the test whilst VAT will be estimated using the widely adopted V-slope 
method and verified using the ventilatory equivalents (28).  
Spirometry, which will be performed prior to CPET, is an effective screening tool of general 
respiratory health that can be used to establish whether exercise intolerance is primarily 

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caused by or contributed to by ventilatory limitation (29, 30). Therefore, unforced (vital 
capacity; VC and inspiratory capacity; IC) and forced (forced expiratory volume in 1 second; 
FEV1 and forced vital capacity, FVC) spirometry manoeuvres will be conducted, in line with 
American thoracic society guidelines, to substantiate the extent of any respiratory limitation 
during CPET (29, 30). 
For the unforced manoeuvres, patients will be relaxed in a seated position and asked to 
breathe regularly until the end-expiratory lung volume is stable. They will then take a deep 
breath to total lung capacity (to record IC), then exhale to residual volume (to record 
expiratory VC) and inhale maximally again. For the forced manoeuvres, the patient will be 
asked to assume the correct posture and inhale completely and rapidly, with a pause of <1s 
at total lung capacity before starting exhalation with an initial blast. Exhalation is continued 
until no more air can be expelled, and an upright posture should be maintained at all times 
(30).  
There is however, only limited information available from resting lung function tests, which 
cannot sufficiently predict the extent to which respiratory disease limits exercise capacity 
(29). Other measures such as maximum voluntary ventilation (MVV) and breathing reserve 
derived from CPET can be used in adjunction to determine normal respiratory function (29). 
MVV, the maximum volume of air ventilated in 60 seconds, can be directly determined by 
breathing deeply and rapidly for 12 or 15 seconds (31). However, MVV is a difficult 
manoeuvre that is reliant upon subject co-operation, effort and technique, meaning that it 
is often estimated from FEV1, with FEV1 x 40 providing the optimal estimate in normal 
subjects and those with obstructive lung disease (31). The breathing reserve is calculated by 
subtracting the maximal exercise ventilation, recorded during CPET, from the MVV. A 
normal breathing reserve value is considered to be >20%MVV, as in healthy subjects 
respiratory capacity usually exceeds the demand of peak exercise (27, 29). Those limited by 
respiratory disease however, will have a breathing reserve close to zero, as cardiovascular 
efficiency exceeds respiratory efficiency (29). 
ABPI 
ABPI will be determined both at rest and after the MWD treadmill test by measuring the 
systolic blood pressure in the brachial, dorsalis pedis and posterial tibial arteries using an 
appropriately sized sphygmomanometer, placed on the arms and above the ankles (1). A 
hand-held Doppler probe will be used to determine systolic pressure by initially locating an 
optimal flow signal before the cuff is inflated. The cuff will then be inflated until the signal is 
no longer audible and the highest pressure at which the flow signal returns during gradual 
deflation will be recorded as systolic pressure. The ABPI is then calculated for each leg by 
dividing the higher ankle pressure of each leg by the highest arm pressure, with a value of 
<0.9 or a post-exercise drop of ³20mmHg indicating presence of PAD (1).  

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An ABPI >1.3 is suggestive of non-compressible, calcified arteries due to other co-
morbidities such as diabetes (32). In this case, TBPI will be measured by placing a small 
occlusive cuff on the first or second toe and the return of toe pulsatility (indicative of 
systolic pressure) is measured via a plethysmographic detection device (32). This index is 
then calculated by dividing the toe pressure by the brachial pressure with values of <0.7 
indicating presence of PAD (32).  

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Intervention: 
High intensity interval training (HIIT) programme 
This study will use a pragmatic and flexible HIIT protocol with a higher intensity than that 
previously used in the IC population (12). The protocol will consist of 3 sessions per week for 
6 weeks, with a work to rest ratio of 1:1 (one-minute interval of HIIT interspaced by one-
minute interval of low-intensity exercise), completing 10 sets of HIIT with an overall exercise 
session time of 20 minutes. The intensity will be set at 85-90% PPO (from CPET) during high-
intensity, (aiming to achieve 85-100% HRMax), and at 20-25%PPO during low-intensity 
bouts. The variation from high to low intensity will be achieved by altering the cycle cadence 
(rpm). This work to rest ratio has been selected as although HIIT is often prescribed in 
similar clinical populations using 4-minute intervals at 85-95%HRMax (33), a large RCT 
recently concluded that HIIT at this intensity is hardly feasible, at least not for a full 4-
minutes (15). Our personal experience with cardiac patients has demonstrated that patients 
may exceed their peak heart rate (from CPET) during HIIT sessions. This is also likely to be 
the case for those with IC, especially those who are unable to achieve a maximal effort 
CPET. We will adopt a pragmatic approach to this by allowing it to occur but monitoring on a 
case-by-case basis and will reduce intensity when deemed appropriate. We will also record 
these occurrences to allow appropriate reporting. 
The HIIT sessions will be preceded and followed by a 10-minute warm up and cool down as 
is standard practice in exercise rehabilitation for older adults with chronic disease. In 
addition, patients will be monitored for up to 10 minutes following the cool-down to ensure 
heart rate is returning to near resting values and/or any symptoms have subsided. 
The HIIT intervention will be performed by using a cycle ergometer with exercise 
prescription based on the workload achieved during a cycle CPET. The use of a treadmill 
may preclude patients from reaching their prescribed HIIT training zones due to the onset of 
claudication whilst a cycle may reduce the risk of falls in very deconditioned patients (34). It 
has been demonstrated that the limiting symptoms during treadmill walking were often 
experienced in the leg, mainly the calf, whereas the limiting symptoms during cycling were 
much more varied (34). Furthermore, one study, albeit small, noted that cycle testing was 
better tolerated than treadmill testing, which is important considering that the HIIT training 
zone requires the patient to exercise to near-maximal levels, similar to during a CPET (35).

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Warm-up 
10 Minutes 
<80%HR Max 
High-Intensity Bout 
1 Minute 
85-90%PPO (from CPET) 
Low-Intensity Bout 
1 Minute 
20-25%PPO 
High-Intensity Bout 
1 Minute 
85-90%PPO (from CPET) 
High-Intensity Bout 
1 Minute 
85-90%PPO (from CPET) 
High-Intensity Bout 
1 Minute 
85-90%PPO (from CPET) 
High-Intensity Bout 
1 Minute 
85-90%PPO (from CPET) 
High-Intensity Bout 
1 Minute 
85-90%PPO (from CPET) 
High-Intensity Bout 
1 Minute 
85-90%PPO (from CPET) 
High-Intensity Bout 
1 Minute 
85-90%PPO (from CPET) 
High-Intensity Bout 
1 Minute 
85-90%PPO (from CPET) 
High-Intensity Bout 
1 Minute 
85-90%PPO (from CPET) 
Low-Intensity Bout 
1 Minute 
20-25%PPO 
Low-Intensity Bout 
1 Minute 
20-25%PPO 
Low-Intensity Bout 
1 Minute 
20-25%PPO 
Low-Intensity Bout 
1 Minute 
20-25%PPO 
Low-Intensity Bout 
1 Minute 
20-25%PPO 
Low-Intensity Bout 
1 Minute 
20-25%PPO 
Low-Intensity Bout 
1 Minute 
20-25%PPO 
Low-Intensity Bout 
1 Minute 
20-25%PPO 
Low-Intensity Bout 
1 Minute 
20-25%PPO 
Cool-Down 
10 Minutes 
<40%HR Max 

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Inclusion criteria: 
• Community dwelling adults aged 18 or over. 
• ABPI <0.9 at rest or a drop of more than 20mmHg after exercise testing 
• Ability to walk unaided 
• English speaking and able to comply with exercise instructions 
Exclusion criteria: 
• Patients who are unable to provide informed consent 
• Critical limb ischaemia/rest pain 
• Active cancer treatment 
• Significant comorbidities precluding participation in exercise testing and/or training 
as per the American College of Sports Medicine Guidelines (19). 
• Resting/uncontrolled tachycardia (>100bpm) and/or Resting/uncontrolled 
hypertension (SBP >180mmHg or DBP >100mmHg) 
• Symptomatic hypotension 
Additional exclusion criteria 
Further to analysis of CPET results, patients will be prevented from continuing their 
involvement in the study if there is indication of: 
• Exercise-induced ischaemia or significant haemodynamic compromise. 
 
N.B. – Patients who are able to perform a maximal effort CPET according to previously 
published guidelines (19) will undergo the intervention which will be prescribed on the basis 
of their initial CPET. This will be referred to as maximal HIIT. 
Patients unable to perform a maximal effort CPET, will still undergo the intervention which 
will be prescribed on the basis of their initial CPET values, but will be referred to as 
submaximal HIIT. 
 
 
 
 

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Subject recruitment 
Patients who are deemed appropriate for referral to SEP as is usual practice will be informed 
of the research study evaluating HIIT as a novel exercise intervention for IC. Patients will 
then be sent a patient information sheet, detailing the aims and details of the study and 
what the intervention entails. Patients will then be contacted via telephone at least a week 
later to discuss their interest to undertake the intervention. Those who choose to 
participate in the study will be asked to attend for baseline assessment. Those who do not 
choose to partake in the research will be offered the usual SEP, without research. Those also 
declining the usual SEP will be referred back to their consultant. 
Withdrawal of subjects 
Participants are free to withdraw at any time and do not have to give a reason for doing so. 
If a participant exhibits any of the exclusion criteria or loses capacity to consent after 
enrolment on the study, they will be withdrawn. Full details of any withdrawal will be 
recorded in the case report form and withdrawal can occur at any time, including during the 
intervention or follow-up. 
Trial exit 
Patients will exit the trial if: 
• They have completed their intervention and all follow-up assessments. 
• They request or are unable to continue intervention or follow-up 
• They suffer an adverse or serious adverse event meaning they are no longer able to 
continue 
• They lose the capacity to consent 
• They die. 
General information 
Potential patient benefits 
SEPs have proven to be effective for improving walking distance in patients with IC but are 
not always feasible or available (11, 14, 36). Other exercise interventions may provide a 
similar benefit and allow access for a greater number of patients. HIIT has demonstrated 
beneficial effects in the cardiac population (33, 37), which may be transferrable to the IC 
population, due to the similar disease aetiology. Therefore, patients may benefit from 
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to choose their preferred option, thus increasing availability and potentially uptake and 
adherence.  
Potential risks/barriers to the patient 
The study requirements and participant expectations will be clearly explained in the patient 
information sheet. This will be sent to the patient and they will be given adequate time to 
read it at their own leisure without any pressure to partake in the study from the 
researcher. Informed consent will only be obtained once patients have understood all study 
requirements, asked any questions they may have and have agreed to participate.  
Patients will be required to attend their exercise sessions 3 times per week for 6 weeks. This 
may be problematic for patients and may cause them to decline this intervention or 
withdraw once recruited. However, this may also provide a patient benefit, as this means 
the patient only has to attend half the number of sessions than is usually required for SEP. 
Furthermore, travel and parking costs may prove to be a barrier. Travel expenses for study 
visits (baseline and follow-ups) will be reimbursed. Patients can be reimbursed a maximum 
of £75 to cover the costs of transport/parking that may be accrued.  
Patients will be required to attend three or four 2-3-hour study visits s. This time, on top of 
the time required to undertake the intervention may preclude some patients from taking 
part in the study. 
Some study elements (such as CPET or HIIT) may propose a risk to the participants. HIIT is a 
novel intervention in the IC population, meaning its safety is unknown. However, a large 
multi-centre RCT in the cardiac population (similar disease aetiology to IC) demonstrated 
that HIIT was a safe intervention (15). Furthermore, standards for exercise testing from the 
American heart association, note that the occurrence of death as a result of testing is rare 
with a frequency estimated at 1 per 10000 tests, maybe less (26). Therefore, although the 
testing and intervention procedures carry some risk, it is minimal and is outweighed by the 
potential patient benefits. 
Sample size 
Due to the pilot nature of this proof of concept study it is not possible to calculate the 
sample size. The main aim is to assess the conceptual benefit of the proposed interventions. 
We aim to recruit 20 patients from the additional Coventry site, which in addition to the 
target of 50 patients at the Hull site, totals 70 patients. 
 
Descriptive statistics and statistical analysis 
Data obtained from all participants will be included in the data analysis and no data will be 
excluded on the basis of intervention and follow-up adherence.  Therefore, all collected data 
at each time point will be analysed. 
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distributed data and using median and range for non-normally distributed data. Categorical 
variables will be presented as frequency and percentages. 
Rates of uptake, completion, dropout, adverse or serious adverse events and missing 
outcome data will be summarised and participation in the intervention will be described as 
the mean number of sessions attended and the mean time to completion (in weeks) to 
allow for comparison between actual and theoretical total intervention time.  
In addition, tolerability will be assessed by comparing the mean heart rate achieved during 
each HIIT session to the 85-100% maximum heart rate range calculated from CPET. 
Secondary endpoints such as changes in MWD, PFWD, VO2Peak, VAT, ABPI and QoL at each 
time-point will be assessed using a repeated-measures general linear model.  
All quantitative analyses will be conducted using the SPSS statistics software at the 
conventional two-sided 5% significance level with results presented as mean difference with 
95% confidence intervals, associated p values and effect sizes where appropriate. Sub-group 
analysis will also be conducted comparing those who are able to give maximal effort during 
baseline CPET (and therefore able to perform maximal HIIT) and those who are not 
(therefore performing submaximal HIIT). Maximal effort will be based on previously 
published criteria (19, 38). Further sub-group analysis will also be performed comparing 
those who satisfactorily completed the intervention (i.e. completed ≥15/18 sessions) and 
those who did not, presuming they do not withdraw from the intervention. 
The qualitative data will also be analysed using an inductive thematic analysis. Thematic 
analysis involves identifying, analysing and reporting themes that become apparent within 
the data (39). Themes collate important or patterned responses from within the data that 
are related to the research question (39). This means that as the researcher reads and re-
reads the transcriptions, a pattern of responses will emerge that are related to the research 
question and can be grouped together under a theme heading. The approach will be 
inductive, which means that the themes are data-driven, thus emerging from the data, do 
not fit into a pre-existing coding frame and are not driven by the researcher’s theoretical 
interest in the area (39).  
In an attempt to minimise missing data from losses to follow-up patients will be contacted 
well in advance of their follow-up appointment and the researcher will attempt to rearrange 
any missed follow-ups. However, any missing data due to loss to follow-up will be recorded 
and reported adequately. Any missing data that should have been collected during a study 
visit will be investigated via source data and patient notes to exhaust all options. If data is 
still missing, it will be coded adequately during analysis and reported in results. Missing data 
will not be imputed by the researcher to avoid bias. 
Safety reporting 
Collecting and reporting data on adverse and serious adverse events will be in accordance 
with GCP and the Research Governance Framework v. 3.3, 2017. 

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Adverse events (AE) 
An adverse event is any untoward occurrence that happens to a subject during the conduct 
of the study. The event may be as a result of the study conduct or intervention or there 
could be no relationship between the study and the AE at all. 
Serious adverse events (SAE) 
An AE is deemed serious if it: 
• Results in death 
• Is life-threatening (patient is at risk of death at the time of the event) 
• Requires hospitalisation or prolongation of existing hospitalisation 
• Results in persistent or significant disability or incapacity 
• Consists of a congenital anomaly or birth defect 
Hospitalisation that was planned before partaking in the study (i.e. elective surgery) should 
not be considered a SAE unless it has to be prolonged.  
Reporting period: 
The AE reporting period for each patient begins as soon as they have given informed 
consent for the trial and ends 30 days after their final study visit.  
The researcher will record any AE’s upon knowledge of the event. Most evets will occur 
outside of study activity and the site team will be informed at a later point. A discussion 
about the patient’s general health will take place at each study visit to identify any AE’s as 
patients may not inform the researcher about an event that they do not believe is related to 
the study, such as having a cold. Once knowledge of the event has been received, the 
researcher will gather as much information as possible and if necessary report to the 
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Reporting serious adverse events 
If a trial subject experiences a serious adverse event which in the opinion of the chief 
investigator is both 
• Related - that is, it resulted from administration of any of the research treatments or 
procedures; and  
• Unexpected - that is, the type of event is not listed in the protocol as an expected 
occurrence. 
Then it will be reported to the Research Ethics Committee (REC) that gave a favourable 
opinion of the study and the Sponsor (Hull University Teaching Hospitals NHS TrustNHS 
Trust R&D department) within 15 days of the Chief Investigator becoming aware of the 
event using the non-CTIMP safety report form, available from: 
https://www.hra.nhs.uk/approvals-amendments/managing-your-approval/safety-reporting/  
Urgent safety measures 
The chief investigator (or sponsor) may take appropriate safety measures to protect 
subjects from immediate hazard to their health or safety, without prior authorisation from a 
regulatory body.  However, the chief/principal investigator must alert the sponsor (HEY 
R&D) as soon as possible of the urgent measures by contacting the R&D Office telephone 
number 461883 or 461903 (Mon - Fri 8am -  6pm) or the Trust Switchboard 875875 (out-of-
office hours) and asking for either the R&D Director or the R&D Manager.  
The main REC will be notified immediately, at least within three days, by completing a 
substantial form and giving information about the measures taken and why. 
Annual progress report: 
An annual progress report will be submitted to the REC that gave the favourable opinion 12 
months from the date of the favourable opinion. The relevant form, available from: 
https://www.hra.nhs.uk/approvals-amendments/managing-your-approval/progress-
reports/ will be used. It will be completed and signed by the chief investigator and emailed 
to the REC within 30 days of the anniversary date of the favourable opinion and annually 
until the trial is completed.  
Data collection, handling, management and record keeping 
Data will be collected by the local principal investigator at all time points during the study. 
Collection of data will be via standardised questionnaires (VascuQoL and SF-36) and physical 
assessment. To ensure completeness of data, questionnaires will be issued and completed 
during the study visits to allow patients to ask questions or clarify information about the 
questionnaire. Data will be collected and retained in accordance with the Data Protection 

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Act 1998. All patients will be given a study code along with the abbreviate hospital title to 
ensure anonymity, for example the first patient recruited at Hull and Coventry would be 01H 
and 01C respectively. Data will be stored on computers in the research office at the vascular 
laboratory in Hull Royal Infirmary and Coventry and Warwickshire University Hospital 
respectively with the same identification code. These computers are password protected 
and have both antivirus and firewall software. Only named investigators will have access to 
the patient data. Transfer of electronic data will be anonymous and only be carried out 
through encrypted password protected USB devices or via the secure www.nhs.net email 
account. Data will be stored for five years following trial completion.  
IT services department has a backup procedure approved by auditors for disaster recovery. 
Servers are backed up to disk media each night which run on a 4-week cycle, meaning 
anything deleted more than 4 weeks previously is lost. Files remain on the server unless 
deleted either accidently or deliberately. Additional ‘archive’ backups are taken for archived 
data, so data should not be lost from this system e.g. FileVision. Disks are stored in a 
fireproof safe. 
Study documents (paper and electronic) will be retained in a secure location during and 
after the trial has finished. All essential documents including source data will be retained for 
a minimum period of 5 years after study completion. A sticker stating the date that 
documents need to be retained until will be placed on the inside front cover of participant 
case report forms.  
Direct access will also be granted to authorised representatives from the sponsor, host 
institution and the regulatory authorities to permit trial-related monitoring, audits and 
inspections – in line with participant consent. 
Project Management Group;  
The overall management of this study will be the responsibility of the Programme 
Management Group. This will be chaired by the R&D Director, HEYHT, who is independent 
of the research team. Membership of the Project Management Group will comprise all 
coapplicants, patient representatives and Susan Walker (Finance Manager). The Trust will 
discharge its sponsorship responsibilities through this Group including research governance 
and financial oversight and will ensure that the research conducted is congruent with that 
specified in the proposal and of value to the NHS. Additionally this group will o provide 
specialist advice in areas of data collection, analysis and interpretation, consider the 
implications of the findings, develop a dissemination strategy, and consider any issues 
brought to their attention by the research staff. The Project Management Group will meet 
on a quarterly basis and receive reports from, and oversee, the work of the Project Delivery 
Group. 
 
Combined Trial Steering / Data Monitoring Committee; will be formed to monitor the 
progress of the study, provide independent advice, and monitor the data arising from the 
study to recommend whether there are any ethical or safety reasons why the study should 
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researchers with appropriate expertise, a patient representative and will also be attended 
by the trial statistician. This committee will meet every 6 months to provide oversight to the 
study. 
Source data 
It is important that information from a patient study visit is recorded clearly into the 
casenotes so that other clinicians and healthcare professionals can be aware of any relevant 
results or information which may affect ongoing care.  
The minimum information recorded in patient notes following each study visit or phone call 
will be: 
• Clearly written date of visit, study short title and visit number. 
• The date that the patient information sheet was given 
• The date informed consent was obtained 
• Medical history (including reasons for referral), concomitant diseases, and 
medications and any changes between visits. Any changes or newly developed 
symptoms or are they asymptomatic.  
• Anything relevant to the ongoing care of the subject 
• Relevant investigations and results of these – i.e. ABPI, CPET (any ECG changes)  
• Brief description of any AE’s with start and end dates if appropriate, any significant 
tests/results or a medical summary of events. 
• Any other relevant information.  
 
Protocol deviations/serious breaches 
Protocol deviations and serious breaches will be acted upon in line with the HRA standard 
operating procedure version 7.2 available from https://www.hra.nhs.uk/about-
us/committees-and-services/res-and-recs/research-ethics-committee-standard-operating-
procedures/.  
Protocol deviations involves not complying with the protocol as a result of fraud or 
misconduct. Accidental protocol deviations must be adequately documented and reported 
to the CI and sponsor immediately. However, the sponsor does not need to notify the REC 
unless the deviation constitutes a serious breach. Any deviations will also be documented in 
the patients notes and with a file note in the site, detailing as much information as possible. 

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Importantly, frequent and/or recurrent deviations are not acceptable and will require 
immediate action and could lead to a serious breach. 
A serious breach is defined as a breach of the protocol, conditions or principles of GCP 
which is likely to affect to a significant degree the safety or physical or mental integrity of 
the trial subjects or the scientific value of the research. Serious breaches will be reported to 
the sponsor immediately upon knowledge of the breach. The PI will take a leading role in 
resolving any serious breach whilst completing any addition activities required by the 
sponsor to investigate or address the breach.  
The sponsor should also notify the REC of a serious breach within 7 days of being informed. 
A report of the serious breach which should outline when and where it occurred, who was 
involved, the outcome and any information given to the participant should be provided by 
the CI or other representative of the sponsor, and copied to the sponsor. The REC should 
receive an explanation and informed of any further action that the sponsor plans to take.  
End of trial 
The trial will be complete once the last patient has attended their final follow-up visit, for 
this study, the last study visit will be 12-weeks post-intervention.  
The REC which gave the favourable opinion with be notified of the study conclusion by the 
CI within 90 days or within 15 days if the trial is terminated early (with reasons). This 
notification will be in writing (sent via email) using the appropriate form available from: 
https://www.hra.nhs.uk/approvals-amendments/managing-your-approval/ending-your-
project/  
A final research report summary will be emailed by the CI to the REC within 12 months of 
the end of the trial. The summary will include information about whether the research 
achieved its objectives, the main findings and arrangements for publication, including any 
patient feedback. 
Quality control and assurance: 
Peer review 
This study has been peer reviewed by: 
Dr Amy Harwood, Postdoctoral research fellow, academic vascular surgical unit, Hull Royal 
Infirmary. 
Mr. George Smith, consultant vascular surgeon, Hull Royal Infirmary. 
Professor Ian Chetter, consultant vascular surgeon, Hull Royal Infirmary. 
Dr Catriona McDaid, Reader in Trials and member of the Senior Management at the York 
Trial Unit. Dr McDaid is also the lead for the North and East Yorkshire spoke of the Research 
Design Service Yorkshire and Humber (RDS-YH). This application has been developed in 

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collaboration with our PPI members of the “Humberside Peripheral Arterial Research 
Involvement Group  
Monitoring  
Research will be monitored in accordance with GCP. The sponsor has the responsibility to 
ensure that the rights and safety of participants are protected, study data is complete and 
accurate and that conduct of the study complies with the protocol and GCP. Monitoring will 
be risk based as required by the sponsor.   
Ethical considerations 
REC review and reports: 
Before trial commencement, approval will be sought from the REC for the trial protocol, 
informed consent forms and other relevant documents such as GP letters and patient 
information sheets. 
Substantial amendments requiring review from the REC will not be implemented until the 
REC grants a favourable opinion. All correspondence with the REC will be retained in the 
trial master file. 
Indemnity 
This is an NHS-sponsored research study.  If there is negligent harm during the clinical trial 
when the NHS body owes a duty of care to the person harmed, NHS indemnity covers NHS 
staff and medical academic staff with honorary contracts only when the trial has been 
approved by the Trust R&D department. NHS indemnity does not offer no-fault 
compensation and is unable to agree in advance to pay compensation for non-negligent 
harm. Where the Chief/Principal investigator is employed by the University of Hull, the 
University has an insurance policy that includes cover for no-fault compensation in respect 
of accidental injury to a research subject.   
Amendments 
Amendments involve changes to a project after initial approval has been granted. It is the 
responsibility of the sponsor to decide whether an amendment is substantial or non-
substantial. If the sponsor deems an amendment to be non-substantial the template 
available from https://www.hra.nhs.uk/approvals-amendments/amending-approval/ will be 
emailed to hra.amendments@nhs.net. The amendment will receive two possible outcomes; 
‘HRA approval for the amendment confirmed’ or ‘HRA approval for the amendment 
pending’. 
The applicant will communicate this outcome, along with the amendment application, with 
the site team, R&D office and local CRN. For category A and B amendments, the site team 
have 35 days to raise any objections, after which if no objections are raised, the amendment 

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can be implemented. Category C amendments can be immediately implemented. Where 
HRA approval is required, the amendment will be reviewed and approval issued. The 
applicant should then notify the site team and provide the approved documentation.  
A similar process is followed for substantial amendments. The notice of substantial 
amendment form in IRAS will be used to generate a PDF form for the amendment that will 
be emailed to the REC that gave the favourable opinion of the original study. The REC staff 
will validate the amendment and if necessary, categorise it. The applicant will then receive a 
validation letter which will also outline the categorisation – which should be passed onto 
site staff. The REC will then review the amendment, with three possible outcomes; an 
unfavourable opinion, which will require restarting the process and resubmitting, or a 
favourable opinion either with or without further review from the HRA. If either of the 
favourable opinion outcomes is given, the same outcome communication and 
implementation process as described above for a non-substantial amendment will be 
followed.  
An amendment history table will also be used to identify the most recent protocol version 
(appendix 1).  
 
Reporting and dissemination 
The final trial dataset will be developed by the principal investigators but will be owned by 
the Academic Vascular Surgical Unit and as such can be accessed by site investigators. Upon 
completion of the trial, data will be analysed and tabulated with a final trial report prepared 
and submitted to the REC. The study will also be reported in peer-reviewed scientific 
journals, an internal report and conference presentation. Patients will be offered individual 
information regarding post-intervention improvements and access to publications should 
they request it. 
  
Finance and conflicts of interest 
Patients will not be paid for participating in the trial, but will be offered a discounted 
parking permit of £20 per month if required for the intervention period. 
There are no ownership or commercial ties related to any of the interventions. The principal 
investigator in Hull is funded by a University of Hull scholarship.  
 
Study equipment 
Height measure – Leicester height scale, Seca LTD. UK 

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Weight scales – Marsden, Charder M-420, UK 
Resting Blood Pressure monitor – Welch Allyn, Sure Temp. technology, UK 
Ambulatory blood pressure monitor –  
12-lead ECG – Mortara Instruments, T2, USA 
ECG electrodes – 3M Red dot, Canada 
Cycle ergometer – Lode Corival, Neterlands 
CPET system and metabolic cart – MedGraphics Ultima series with BreezeSuite software 
Doppler – Ultrasonic Doppler flow detector, LifeDop, Summit Doppler, Wallach, USA. 
Wattbike – Wattbike Ltd. Nottingham, UK. 
Heart rate monitor – Polar F2, Polar Electro, OY. Kempele, Finland.

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uptake and adherence rates to supervised exercise programs in patients with intermittent 
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Appendix 1: Amendment history 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made