An Interactive E-health Intervention to Promote Walking Capacity and Life-style Changes in Peripheral Artery Disease (iPAD)
Phase: NA
Conditions: Intermittent Claudication
Sponsor: Sahlgrenska University Hospital

 
Clinical Study Protocol 
 
ClinicalTrials.gov entry no. 
NCT05029739 
 
Version number 
1.0 
 
Date of ethical approval  
July 13, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
A Mobile Intervention for Patients with Peripheral Artery 
Disease (I-PAD): a Prospective Randomized Open Blinded 
End-point (PROBE) study 
 
 
 
 
 
 
 
 
 
 
 
 
 

I. BACKGROUND AND SIGNIFICANCE 
Peripheral artery disease (PAD) is a highly prevalent atherosclerotic syndrome with 
an estimated global population burden of ~200 million people (1). Patients with 
PAD are at heightened risk for adverse cardiovascular and limb events and impaired 
quality of life (2). Cigarette smoking is the most important modifiable risk factor for 
PAD. Patients with PAD who smoke have higher disease progression rates, greater 
risk of complications, poor post-procedural outcomes, compromised functional 
status, and increased hospitalizations, accounting for a higher patient and societal 
burden (3).  
A significant goal of PAD treatment includes risk factor modification and prevention 
of cardiovascular events. Guideline directed therapy includes cardioprotective 
pharmacotherapies (i.e., antiplatelet therapy; statins; and blood pressure control, 
preferably with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin 
receptor blockers (ARBs)), and lifestyle modification (i.e., changes in diet, physical 
activity, and smoking cessation) (2). Nevertheless, adherence to pharmacologic and 
lifestyle recommendations in PAD is uncertain (4). Effective non-pharmacologic 
therapies for PAD also exist, including smoking cessation, exercise support, and diet 
counseling (5). However, limited data is available on mobile applications offering 
digitally delivered lifestyle change support, including a structured exercise program 
and smoking cessation support (6). This study aims to digitally provide lifestyle 
change support, including a structured and PAD-focused lifestyle program and 
smoking cessation support via a mobile platform (Sidekick Health) with the primary 
aim to increase patients' walking ability and secondary aims to reduce smoking and 
improve medication adherence.  
II. SPECIFIC AIM 
The specific aim is to determine whether a 12-week digitally delivered behavior 
change intervention for patients with peripheral artery disease increases walking 
ability, reduces smoking, improves quality of life and improves medication 
adherence. A follow-up visit after 12 months will be planned, to assess longer term 
effect on outcomes and healthcare cost. 
Hypotheses 
a) At the end of the 12 weeks, the interventional arm will reach a clinically 
meaningful change in walking ability, as compared to controls, measured by 
a change in the 6-MWT at twelve-week, and 12 months; the minimal 
clinically important difference (MCID) is defined as +12m (7). 
 

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d) Healthcare cost will be reduced at 12 month follow-up in the intervention 
arm. 
III. METHODOLOGY 
We will implement a randomized controlled study of a 12-week lifestyle intervention 
for patients with peripheral arterial disease, delivered via the digital platform 
Sidekick Health. Participants will be recruited and randomized in a 1:1 manner to 
the digitally delivered intervention + standard of care or standard of care only. The 
standard of care group will receive an information leaflet on important lifestyle 
factors for PAD and smoking cessation and medical adherence will be encouraged 
by the health care provider.  The interventional arm will receive a digital program 
delivered to their mobile phone alongside standard of care. Replicating a real-life 
scenario a personalized approach will be applied in the interventional arm, 
especially regarding smokers. Therefore, two pathways are possible in the 
interventional arm in this trial, one for smokers who want assistance in smoking 
cessation (PAD-SC) and another for non-smokers or those who smoke and do not 
desire to quit (PAD-Reg). Patients will be followed up at 12 weeks. We aim to do a 
separate follow-up at twelve months. The primary outcome will be a change in 
pain-free and maximal walking ability, measured by the 6-minute walking test. 
Secondary outcomes will include smoking status change (in PAD-SC group as 
compared to the control arm), medication adherence and lifestyle changes 
(increased physical activity, changes in self-assessed stress/energy/sleep quality 
levels ), health-related quality of life, and a reduced need for hospitalization or 
revascularization due to PAD at 12 months of follow up. 
 
Subject selection 
Individuals willing to participate and who provide written informed consent to the 
study will be further assessed and screened based on the inclusion and exclusion 
criteria presented in Table 1. 

Table 1. Participant Criteria 
Inclusion 
Exclusion 
Adults with confirmed PAD 
referred to a vascular surgery 
unit for evaluation and 
treatment, currently on best 
medical treatment and 
own/have access to a mobile 
smartphone 
Critical limb ischemia, prior 
amputation, or other diseases/ 
impairment that limit the walking 
ability and the 6-minute walk test's 
proper conduct 
Stable PAD disease and limb 
symptoms during the last 3 
months. 
Cognitive impairment 
PAD is the activity-limiting 
disease 
Prior revascularization less than one 
year ago 
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>7?(#$(&(?6@(A#*+/)3)$0,*)(BCD(
$)2E0+,#"7( 
A planned revascularization procedure 
during the upcoming 12 months 
(known at baseline) 
Subject enrollment 
Patients will be recruited by a clinic nurse or a medical doctor at participating 
centers (via telephone or during a scheduled in-person visit). Once agreed to 
participate and after signing informed consent, then the inclusion and exclusion 
criteria will be explored. Patients failing the screening process (do not meet the 
inclusion/exclusion criteria) may not participate in this study. Reasons for screen 
failure will be documented, but no other data will be collected. Participants who 
meet the criteria will be randomized to intervention or usual care in a 1:1 manner.  
Based on a G*power analysis, the total number of patients in the two groups 
(intervention and control) will be 134, 67 in the intervention group and 67 in the 
control group, with an anticipated effect size of f = 0.15, alpha = 0.05, power = 
0.80 and correlations between time points (baseline and final timepoint) estimated 
at r=0.25. Foreseeing an attrition rate of 15%, we aim to recruit 155 patients to 
the trial.  
Study procedures 
All participants:  

After recruitment, measurements and data collections will occur at each clinic by a 
experienced clinic or research nurse, as shown in table 2 and further detailed under 
section VIII. Furthermore, a 6-minute walking test will be administered by a trained 
clinic nurse at baseline, after 12 weeks and for a separate follow-up at 12 months. 
The American Thoracic Society protocol for the 6-minute walking test, modified for 
patients with intermittent claudication (IC), will be used. The 6MWT has excellent 
test-retest reliability for patients with IC. (8, 9). A central computerized procedure 
will randomly assign participants to treatment arms, stratified for study site and 
smoking status. 
Intervention: 
Participants will be instructed to download the SKH mobile app, and they will 
receive an access code to activate the PAD lifestyle change program. After the first 
week of the program, participants who smoke will be offered to incorporate 
smoking cessation support into their PAD program. These changes are minor and 
not intended to divide the intervention group in two but instead personalize the 
experience. Personalization of the program is essential for engagement and to 
deliver the most meaningful impact on clinical outcomes. The program aims to 
empower positive lifestyle change by gamification, altruistic rewards, and engaging 
content with relevant tasks or missions to be completed. Beyond this, all patients in 
the interventional arm will also receive standard of care as defined below for the 
control arm. 
Participants in the intervention group will also be asked to do a separate and 
virtually delivered 6-minute walking test to validate the digital in-app 6MWT. 
Control: 
All patients in the control arm will receive best medical treatment including start or 
optimization of secondary preventive pharmacotherapy, smoking cessation advise 
and advise on modifiable risk factors. The control arm will also receive an 
information leaflet about relevant lifestyle modifications for PAD. After baseline 
measurements and data collection, there will be no scheduled visits by a health 
care provider until week 12.  
 
 
 
 
 

Table 2. Timing of Proposed Data Collection and Instruments Used 
 
 
Data collection/Instruments 
Baseline 
Post-
Intervention 
(after week 12) 
12-month 
follow-up 
All participants (intervention and control) 
 
 
 
Demographic and Clinical/Medical Baseline 
Information (e.g., tobacco use, other risk factors, 
and comorbidities) 
Yes 
 Yes 
Yes 
 6-Minute Walking Test 
Yes 
Yes 
Yes 
Vascular Quality of Life Questionnaire (VascuQoL-
6)  
Yes 
Yes 
Yes 
 Morisky Medication Adherence Scale (MMAS-8) 
Yes 
Yes 
Yes 
Quality of life questionnaire – assessed by 
EQ5D5L 
Yes 
Yes 
Yes 
Assessment of health literacy (HLS-EU-Q16 
Swedish version) 
Yes 
- 
- 
Carbon Monoxide breath monitor (smokers only) 
Yes 
Yes 
Yes 
 Smoking Readiness to Quit Ladder (smokers 
only) 
Yes 
 Yes 
Yes 
 Daily frequency of cigarettes smoked (smokers 
only) 
Yes 
 Yes 
Yes 
Intervention arm only  
 
 
 
In-app 6-minute walking test 
Yes 
Yes 
Yes 
Free-living physical activity (measured as total 
step count per day) 
Yes (week 1) 
 Yes 
- 
In-app metrics (e.g. stress/sleep/energy level 
self-assessment) 
Yes (week 1) 
Yes 
- 
 
Measures – copies of questionnaires will be included in this protocol when finalized 
in section VIII below (Study Questionnaires) 

 
IV. BIOSTATISTICAL ANALYSIS 
Variables to be collected 
Participants' demographic and background information, including age, gender, 
height, weight (and BMI), tobacco use, co-morbid medical or psychiatric conditions, 
and information on any current medical therapy they may or may not be receiving 
will be collected. All participants should be on the best medical PAD treatment 
available for them, and the control arm will receive an information leaflet about 
relevant lifestyle modifications for PAD. A 6MWT, questionnaires, and validated 
survey instruments (10) will be administered both pre-and post-intervention and 12 
months from the start of the intervention.  
 
Primary Outcomes (Intervention KPIs) 
 
As far as possible, evaluation of endpoints will be done by evaluators blinded to the 
treatment assignment (PROBE design). 
 
● Walking Ability: Change in patients objectively measured walking ability 
(measured by the 6-Minute Walk Distance Test) from pre- to post-
intervention and 12 months. 
 
Secondary Outcomes  
 
● Smoking status: Change in patients' daily smoking patterns from pre to post-
intervention and at twelve months. This will be based on information from 
the patient, supported by read-outs from the carbon monoxide breath 
monitor at baseline, 12 weeks and one year. 
● Medication adherence improvement. 
● Lifestyle behavioral changes (measured in-app):  
○ Changes in free living physical activity, measured as total step count 
per day (from baseline to week 12) 
○ Changes in self assessed stress levels, measured on an ordinal scale 
from 0-10 (from baseline to week 12)  
○ Changes in self assessed energy levels, measured on an ordinal scale 
from 0-10 (from baseline to week 12)  
○ Changes in self assessed sleep quality, measured on an ordinal scale 
from 0-10 (from baseline to week 12)  

● Disease-specific health-related quality of life. 
● Increased readiness to quit smoking. 
● Comparing outcomes to health literacy.  
● Comparing healthcare costs between groups. Following completion of the 
long-term follow-up at 12 months for all patients, a separate cost-
effectiveness analysis will be undertaken, based on the prospectively 
collected EQ5D-5L data and accumulated costs per patient as registered in 
the participating hospital’s cost-per-patient databases. Quality Adjusted Life 
Years (QALYs) and Incremental Cost-Effectiveness Ratio (ICER) will be the 
main analyzed endpoints. 
 
Retention and Engagement 
 
●  Program uptake (number of app downloads, how many 
participants/potential quitters registered (including gender and age) 
●  Length of program participation  
●  Program usage patterns (how often do people visit, how many tasks are 
performed, which tasks (videos, daily tasks, other) are used/accessed, 
etc.) 
●  Pre/post assessment of medication therapy (as registered medication 
taken) 
 
 
End of study 
The formal trial completion is when the recruited patients have completed the 12-
week intervention, but an extended follow-up at twelve months from study start will 
also be arranged. 

 
 
Statistical Methods 
Analyses will be performed according to the intention-to-treat principle and per-
protocol analyses. Baseline characteristics and raw score questionnaire outcomes 
will be summarized as mean and SD for continuous measures and absolute 
numbers and percentages in each group. Changes in each outcome between 
baseline, post-intervention, and later a 12-month follow-up will be compared 
between and within the groups using t-tests or non-parametric statistical tests as 
appropriate. For the between-group differences, 95% Confidence Intervals will be 
reported. Correlations will be run to explore relationships between variables. For 
the primary outcome analyses, Ancovas or Mixed Anovas (repeated measures 
anovas) will be used, correcting for covariates that are significantly different 
between groups. The size of the change in HRQoL will be related to minimal 
important change values for the VascuQoL-6. It will be further assessed through 
effect size calculations (effect size=the difference in mean values between baseline 
and follow-up, divided by the SD at baseline). Cohen's criteria for interpreting effect 
sizes will be applied (small, 0.2–0.5; moderate, 0.5–0.8 and large, over 0.8). The a 
priori level for statistical significance will be set at a 2-sided P<.05.  
 
 
 
 
V. RISKS AND DISCOMFORTS 
We expect minimal to no risks and discomforts to be associated with this study. The 
lifestyle/behavioral change program is guideline-compliant for PAD patients and has 

been reviewed by several medical doctors, behavioral scientists, and specialists in 
vascular surgery. Psychosocial risks will be minimal as well. 
VI. POTENTIAL BENEFITS 
Potential Benefits to Participating Individuals 
The hope is that the intervention will increase participants' walking ability, reducing 
IC symptoms and prevent revascularization, empower participants to change their 
lifestyle and smoking patterns for the better, or that they will quit smoking 
altogether. Further, this intervention may also improve other patient-reported 
outcomes (e.g., reduce stress, improve sleep) without causing significant harm. 
Although the expected benefits are limited for patients that are allocated to usual 
care in the study, the enhanced follow-up at 12 weeks and 12 months may allow 
for a more careful evaluation and subsequent treatment of their condition following 
the end of study. 
Potential Benefits to Society 
The hope is that this program will contribute to a healthier population. If the 
Sidekick PAD program proves efficient because it is highly scalable, it may alter the 
disease progression and improve millions' lives. The program may also positively 
impact the environment if participants quit smoking as cigarettes are a considerable 
environmental pollutant.  
VII. MONITORING AND QUALITY ASSURANCE 
SKH will regularly monitor study data accuracy and will guarantee safe study data 
storage. Furthermore, SKH will monitor and amend potential technical issues that 
hinder participants' accurate access to and using the smartphone application and its 
full functionality. As soon as the opportunity arises, the obtained data will be 
anonymized and removed from personal health information. All participants will be 
de-identified and assigned research subject IDs (e.g., participant 1). Only the study 
staff will have access to information that can link the subject IDs with the personal 
health information, saved on a secure, shared drive. Further, clinic staff/providers 
will report any adverse events using standard procedures. 
 
 

VIII. VARIABLES TO BE COLLECTED 
Demographic/clinical/anthropometric variables: 
 
1.  Age 
2.  Gender 
3.  Smoking status 
4.  Height 
5.  Weight 
6.  BMI 
7.  Waist circumference 
8.  Ankle-brachial index (ABI) 
9.  Comorbidities (obesity, diabetes type 1 or 2, other CVD) 
10. Relevant medications. Information on medical therapies will focus on 
medicines important for secondary prevention of PAD, will not collect specific 
dosing, and will be dichotomously (yes/no) categorized as follows: 
a. Antihypertensive agent(s) 
b. Antidiabetic agents (both peroral and injectables will be categorized 
into one single category) 
c. Lipid lowering therapy (statins, ezetimibe and PCSK-9 inhibitors will be 
categorized into one single category) 
d.  Antiplatelet therapy 
i. Single antiplatelet therapy 
ii. Dual antiplatelet therapy 
e. Anticoagulation therapy 
i. Low dose rivaroxaban 
ii. Therapeutic anticoagulation 
 
11. Health literacy status 
12. Educational level (primary school, high school, higher education) 
13. Work status (working, unemployed, retired) 
 
 
 
In-app activity collected: 
 
 
Self-reported 
measurements 
Age, gender, height, weight, sleep quality, 
stress level, energy level. 
Logged items 
 
 
Fruits, vegetables, nuts, and seeds 
consumed. Physical activity tasks. Stress 
reduction tasks. Food photos, diet 
improvement tasks.  

Missions/tasks 
 
Some involve in-app logging (see above), 
others not logged.  
6 MWT in-app 
A 6-minute walking test feature available in 
the SK app uses GPS outdoors, roughly 
assessing cardiorespiratory fitness. 
 
 
Measurements and Questionnaires: 
 
1. Protocol for a 6-minute walking test (see appendix A) 
 
2. Vascular Quality of Life Questionnaire (VascuQoL-6) 
 
3. A standard measurement of health status (EQ-5D-5L) 
 
4. The European health literacy survey (HLS-EU-Q16 Swedish version) 
 
5. Morisky Medication Adherence Scale (MMAS-8) 
 
6. Readiness to quit smoking (The Contemplation Ladder) 
 
  
 
 
IX. REFERENCES: 
  
1. 
Fowkes FGR, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, et al. 
Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 
2000 and 2010: a systematic review and analysis. Lancet. 2013;382(9901):1329-40. 
2. 
Aboyans V, Ricco JB, Bartelink MLEL, Bjorck M, Brodmann M, Cohnert T, et al. 2017 
ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in 
collaboration with the European Society for Vascular Surgery (ESVS). Eur Heart J. 
2018;39(9):763-+. 
3. 
Authors/Task Force M, Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, et al. 2016 
European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint 
Task Force of the European Society of Cardiology and Other Societies on Cardiovascular 
Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by 
invited experts) Developed with the special contribution of the European Association for 
Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 2016;252:207-74. 
4. 
Berger JS, Ladapo JA. Underuse of Prevention and Lifestyle Counseling in Patients With 
Peripheral Artery Disease. J Am Coll Cardiol. 2017;69(18):2293-300. 

5. 
Mahe G, Boge G, Bura-Riviere A, Chakfe N, Constans J, Goueffic Y, et al. Disparities 
Between International Guidelines (AHA/ESC/ESVS/ESVM/SVS) Concerning Lower Extremity 
Arterial Disease: Consensus of the French Society of Vascular Medicine (SFMV) and the 
French Society for Vascular and Endovascular Surgery (SCVE). Ann Vasc Surg. 2020. 
6. 
McDermott MM, Spring B, Berger JS, Treat-Jacobson D, Conte MS, Creager MA, et al. 
Effect of a Home-Based Exercise Intervention of Wearable Technology and Telephone 
Coaching on Walking Performance in Peripheral Artery Disease: The HONOR Randomized 
Clinical Trial. JAMA. 2018;319(16):1665-76. 
7. 
Gardner AW, Montgomery PS, Wang M. Minimal clinically important differences in 
treadmill, 6-minute walk, and patient-based outcomes following supervised and home-based 
exercise in peripheral artery disease. Vasc Med. 2018;23(4):349-57. 
8. 
ATS statement: guidelines for the six-minute walk test. American journal of respiratory 
and critical care medicine. 2002;166(1):111-7. 
9. 
Sandberg A, Cider A, Jivegard L, Nordanstig J, Wittboldt S, Back M. Test-retest 
reliability, agreement, and minimal detectable change in the 6-minute walk test in patients with 
intermittent claudication. J Vasc Surg. 2020;71(1):197-203. 
10. 
Nordanstig J, Pettersson M, Morgan M, Falkenberg M, Kumlien C. Assessment of 
Minimum Important Difference and Substantial Clinical Benefit with the Vascular Quality of Life 
Questionnaire-6 when Evaluating Revascularisation Procedures in Peripheral Arterial Disease. 
Eur J Vasc Endovasc Surg. 2017 Sep;54(3):340-347.  
 
 
 
 
 
 
 
 
 
 
 

QUESTIONNAIRES:  
 
 

EQ-5D-5L 
 

 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
EUHL16 
  
On a scale from very easy to very difficult, how easy would you say it is to: … 
 
1. Very difficult 
2.Difficult 
3.Easy 
4 .very easy 
5.don't know 
 
a.  find information on treatments of illnesses that concern you? 
 
b.  find out where to get professional help (such as doctor, pharmacist or psychologist) when 
you are ill?  
 
c.  understand what your doctor says to you? 
 
d.  understand your doctor’s or pharmacist’s instruction on how to take a prescribed medicine? 
 
e.  judge when you may need to get a second opinion from another doctor? 
 
f.  use information the doctor gives you to make decisions about your illness? 
 
g.  follow instructions from your doctor or pharmacist? 
 
h.  find information on how to manage mental health problems like stress or depression? 
 
i. 
 understand health warnings about behavior (such as smoking, low physical activity and 
drinking too much)? 
 
j. 
 understand why you need health screenings (such as breast exam, blood sugar test or blood 
pressure)? 
 
k. judge if the information on health risks in media (such as TV, internet or other media) is 
reliable? 
 
l. 
decide how you can protect yourself from illness based on information in media (such as 
newspapers, leaflets, internet or other media)? 
 
m. find out about activities (such as meditation, exercise, walking and pilates) that are good for 
your mental well-being? 
 
n.  understand advice on health from family members or friends? 
 
o.  understand information in the media (such as internet, newspapers and magazines) on how 
to get healthier? 
 
p.  judge which everyday behavior (such as drinking and eating habits, exercise etc.) is related 
to your health? 

Morisky Medication Adherence Scale (MMAS-8) 
 
 
 
 
 
 
 
 
 
 

Readiness to quit ladder (The contemplation ladder)