HYPERtension Reduction Through WALKing Stairs Versus Brisk Walking in Individuals With Increased Cardiometabolic Risk - The HYPERWALK Randomized Controlled Trial
Phase: NA
Conditions: Metabolic Disease, Cardiovascular Diseases, Hypertension, Obesity and Overweight
Sponsor: Karolinska Institutet

The HYPERWALK randomized controlled trial, Protocol v.1, 3/19/25 modified 13/10/205 
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HYPERtension reduction through WALKing stairs versus 
brisk walking in individuals with increased cardiometabolic 
risk - The HYPERWALK randomized controlled trial 
Emmanuel A. Zavalis¹, David Ebrahimi¹, Ruha Cerrato², Anna Ugarph-Morawski³, 
Sandra af Winklerfelt Hammarberg³, Helena Wallin⁴, Mai-Lis Hellénius⁵, Anna 
Norhammar⁵, Ragad Said⁶, Edvin Ström³, Kay Sundberg³, Ivar Skoger² Camilla 
Krizhanovskii², Jessica Norrbom¹, Evelina Flodkvist⁷, Marie Lind⁷, Ellinor Kenne¹, 
Raffaele Scorza², Henrike Häbel⁷, Giulia Ferrannini², Carl Johan Sundberg¹, Pontus 
Andell¹, 
1. Department of Physiology and Pharmacology, Karolinska Institutet 
2. Department of Clinical Science and Education, Södersjukhuset, Karolinska 
Institutet 
3. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet 
4. Department of Laboratory Medicine, Karolinska Institutet 
5. Department of Medicine, Solna, Karolinska Institutet 
6. Clinical Physiology Huddinge, Karolinska Institutet 
7. Department of Learning, Informatics, Management and Ethics, Karolinska 
Institutet 
CREDiT Statement: 
PA, CJS, EK, RS, AUM, SW, HW, MH, AN, IS, RC, ES, GF, JN, DE, KS and EAZ 
contributed to conceptualization, methodology, and investigation. 
PA, CJS, EK, RS, AUM, SW, HW, MH, AN, RSa, ES, EF, ML, GF, CK, JN, HH, DE 
and EAZ were involved in writing, review, and editing. 
PA and EAZ contributed to original draft writing. 
DE, HH and EAZ contributed to software. 
PA, CJS, RS, SW, HW, MH, EK, CK, RC, GF, and JN handled supervision and 
project administration 
PA, CJS, RS, AUM, EK, DE, SW, MH, AN, ES, GF were responsible for funding 
acquisition. 
EF managed project administration, 
ML handled project communication. 
 
 
 
 

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Contents 
HYPERtension reduction through WALKing stairs versus brisk walking in individuals with 
increased cardiometabolic risk - The HYPERWALK randomized controlled trial .................... 1 
Administrative information ..................................................................................................... 3 
Introduction ........................................................................................................................... 4 
Trial design ............................................................................................................................ 5 
Randomization procedure .................................................................................................. 5 
Blinding .............................................................................................................................. 5 
Study setting ...................................................................................................................... 5 
Primary hypothesis ............................................................................................................ 5 
Secondary hypotheses ...................................................................................................... 6 
Subgroup hypotheses ........................................................................................................ 6 
Substudies ......................................................................................................................... 6 
Study population .................................................................................................................... 7 
Eligibility criteria ................................................................................................................. 7 
Inclusion criteria ............................................................................................................. 7 
Exclusion Criteria ........................................................................................................... 7 
Recruitment ....................................................................................................................... 8 
Retention ........................................................................................................................ 8 
Sample size ....................................................................................................................... 8 
Intervention ..........................................................................................................................10 
Monitoring and promoting adherence ............................................................................10 
Criteria for discontinuation and concomitant care .......................................................... 11 
Insurances ..................................................................................................................... 11 
Measurements......................................................................................................................12 
Data management and auditing ....................................................................................... 12 
Auditing ............................................................................................................................ 12 
Data collection methods ................................................................................................... 12 
Harms .............................................................................................................................. 15 
Dissemination policy .............................................................................................................16 
References ...........................................................................................................................17 
Statistical analysis plan for the HYPERWALK randomized controlled trial. ...........................19 
Statistical Principles ......................................................................................................... 19 
Analysis methods ............................................................................................................. 20 
 

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Administrative information 
Writers of the Protocol, signature and date: 
 
 
___________________ 
Emmanuel Zavalis 
 
 
___________________ 
David Ebrahimi 
 
 
Signature of senior statistician responsible, signature and date: 
 
 
___________________ 
Henrike Häbel 
 
Chief investigators, signature and date: 
 
 
___________________ 
Pontus Andell 
___________________ 
Carl Johan Sundberg 
 
 
Protocol v.1  
Intended for registration on ClinicalTrials.gov  
Funding  
The following grants have been received for the study. 
 
Swedish Society of Medicine (SLS): GF C331207023 
 
Region Stockholm / SLSO: ES FoUI-1003505 
 
Karolinska Institutet (KI) Research Funds: PA C331208023 
 
ALF Clinical Research Position: PA FoUI-989887 
 
Swedish Heart-Lung Foundation (HLF): CJS C331201303 + C331201313 
 
NSV Project Funding 2025: CJS  
 
The study funders had no role or authority regarding the study. 
 
Ethics approval number: 2014-05912-01 
This protocol and the analytical methods have been devised in accordance to the SPIRIT(1) 
and the SAP checklist(2). 
[13092025] Protocol amendment prior to start of enrollment: stratification by site and age 
instead of by sex and age to adjust for potential differences in population and to provide 
better support for substudies. 
 

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Introduction 
Physical inactivity is a significant contributor to a wide range of chronic health conditions, 
including type 2 diabetes, cardiovascular diseases, cancer, and cognitive dysfunction, 
ultimately leading to a reduced lifespan (3–6). Hypertension, a leading risk factor for 
cardiovascular morbidity and mortality, is particularly influenced by sedentary behavior, even 
in a recent randomized trial (7, 8). Despite the well-established benefits of physical activity, 
including its comparable effects to antihypertensive medications (9) sedentary lifestyles 
remain widespread, affecting approximately 37% of individuals in Western countries (10–13). 
 
Even modest increases in physical activity can positively impact health outcomes. For 
example, incorporating short bursts of activity during sedentary periods has been shown to 
provide health benefits (14–17), with high-intensity exercises providing the greatest benefits 
(18, 19). Stair walking, a simple and accessible form of high-intensity exercise, offers a cost-
effective and time-efficient strategy for increasing physical activity levels. However, prior 
randomized controlled trials (RCTs) on stair walking have been limited by small sample sizes 
(20, 21) and the need for supervised training programs which may be impractical for 
widespread implementation (22). 
 
Physical activity interventions remain underutilized in hypertension management, despite 
consensus regarding their inclusion in clinical guidelines (23). Furthermore, the World Health 
Organization’s 2024 recommendation of 2.5 hours of moderate-intensity physical activity per 
week, provide general guidance but lacks specific, actionable strategies proven by 
randomized trials (24). This limits their practical implementation by both clinicians and 
patients. 
 
To address these gaps, the HYPERWALK trial investigates the impact of doubling physical 
activity levels through remote monitoring, personalized feedback, and goal-oriented 
motivation on systolic blood pressure (SBP), with and without the inclusion of stair walking. 
The trial will compare two active interventions with each other and with a control group that 
receives no reminders, feedback, or tailored goals. 
 

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Trial design 
The trial is designed as a randomized, controlled, investigator- and analyst-blinded 
multicenter trial with three parallel groups and a primary endpoint of SBP at six months. It will 
test for superiority of combined stair walking and brisk walking to solely brisk walking, and 
the superiority of both active arms to a passive control group. Randomization will be 
conducted with equal allocation in/among the groups.  
 
The three randomization arms are: 
A. Combined stair walking and brisk walking 
B. Brisk walking only 
C. Control 
 
Arms A and B are the active, experimental arms. 
 
Randomization procedure 
Random numbers generated by a computer will be used to randomize participants, stratified 
by sex site grouped according to anticipated population similarities into four groups as 
follows:  
- 
Liljeholmen + Boo 
- 
SÖS + Ersta 
- 
Huddinge separate 
- 
Södertälje separate 
[13092025]  
and age (cutoff 65 years) through a randomization list with random permuted blocks created 
and uploaded by the external trial statistician. Allocation will be done by a researcher in the 
trial team that will not meet the participants. If a participant discontinues their involvement, 
their trial-specific code will not be reused, and they will not be allowed to re-enter the trial. 
Allocation will be performed by informing the patient after the completion of baseline data 
collection, with randomization conducted directly using the eCRF. Participants will be notified 
remotely.  
 
Blinding 
Blinding participants is not possible due to the nature of the intervention. To decrease the risk 
of bias, allocation will be revealed after baseline data collection by personnel not involved in 
outcome assessments. To preserve blinding of assessors, participants will be instructed to 
not disclose their group during follow-up. Additionally, study personnel will report whether 
blinding was upheld after data collection is completed during the follow-up.  
 
Study setting 
The trial will recruit participants from six study sites in Stockholm, Sweden, including three 
hospitals—Karolinska University Hospital in Huddinge, Södersjukhuset, and Södertälje 
Hospital—and three primary care or outpatient cardiology clinics: Liljeholmen Primary Care 
Center, Boo Primary Care Center, and Ersta Cardiology Outpatient Clinic. Participants will be 
primarily referred from primary care, with some referrals from specialized care. Additional 
partner sites from Region Örebro, Västra Götalands Region, and Region Sörmland may join 
the trial to facilitate multi-regional and timely participant inclusion. In addition, we may recruit 
through online self-signup via social media advertisement. 
 
Primary hypothesis 
Doubling physical activity through goal-directed physical activity regimens is expected to 
reduce SBP at a 6-month follow-up compared to routine care. This study will specifically have 
two primary hypotheses to assess the efficacy of this intervention with two different activity 

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regimens i) incorporating stair-walking or ii) only brisk walking. The hypotheses to be tested 
are:  
- 
Any goal-directed instruction (i.e. both active arms) is superior to no instruction, 
where participants carry the activity tracker without feedback (passive control). Hence 
the analysis will be arms A & B vs arm C 
- 
Combined stair-walking and brisk walking is superior to brisk walking alone. Hence 
the analysis will be arm A vs arm B 
 
 
Secondary hypotheses 
Physical activity acts as a polypill, influencing multiple pathways in individuals with increased 
cardiometabolic risk (25). Therefore, the same group comparisons as in the primary 
hypothesis will be made for diastolic blood pressure, glucose metabolism (homeostatic 
model assessment - HOMA index and glycated hemoglobin A1c - HbA1c), and lipid levels 
(low-density lipoprotein - LDL cholesterol and triglycerides). Additionally, physical activity 
levels during the intervention period will be assessed to determine which intervention is most 
effective at increasing physical activity. 
 
Subgroup hypotheses 
A subgroup analysis incorporating age (35-65 vs. >65), sex, body mass index (BMI) (27-30 
vs. >30), and baseline physical activity levels (0-75 vs. ≥75 active minutes) into the statistical 
model will be performed to assess potential interactions as exploratory analyses. 
 
Substudies 
Within the HYPERWALK trial, we aim to perform a variety of hypothesis-generating 
substudies to explore the broader effects of the interventions based on multiple 
measurements including on: 
- 
Cardiometabolic parameters, including additional lipid and glucose metabolism 
analyses, including oral glucose tolerance testing or mixed meal tolerance testing. 
- 
Arrhythmias, e.g. ventricular extra systoles, and atrial fibrillation burden as well as 
electrocardiogram (ECG) phenotype. 
- 
Parameters of importance to the strata ≥65 of age such as orthostatism, falls, and 
frailty.  
- 
Functional capacity, fitness, and muscular strength in further detail. 
- 
Self-assessed health-related outcomes and adherence deep dive: Assess the effect 
of a diverse range of predictors of adherence to better tailor future interventions. 
- 
Health economic analysis  
- 
Long-term follow-up of clinical outcomes from national registries 
- 
Mechanistic and translational pathways through assessment of adipose tissue and 
muscle tissue biology and possibly echocardiogram parameters. 
 
 
 

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Study population 
Eligibility criteria 
The HYPERWALK study aims to assess the effect of different exercise strategies for 
increasing physical activity in sedentary individuals with hypertension and increased BMI. 
 
BMI has shown a strong correlation to cardiovascular risk (26), which is more pronounced at 
or above the threshold of 30 kg/m2 (27); therefore, we aim to primarily include obese 
participants. However, an upper limit of 40 kg/m2 will be set to decrease the risk of exercise-
related injuries. To ensure comparability with the evidence on glucagone-like peptide-1 
receptor (GLP-1R) agonists like semaglutide (28, 29) overweight people (BMI ≥27) will also 
be included. 
 
Assessing sedentary lifestyle is challenging, as objective measuring of physical activity 
(through digital activity trackers) is costly and time-consuming and may influence prospective 
participants’ behavior. Self-reported physical activity levels, meanwhile, tend to be inflated 
(30). To address this, an inclusive approach will be employed through widely used and 
validated questionnaires: the Stanford Brief Activity Survey (31) and the Swedish indicator 
questions, similar to the Exercise Vital Sign of Kaiser Permanente (32), which is validated 
and recommended in the Swedish clinical setting (33). Participants classified as sedentary by 
either questionnaire will be eligible to improve sensitivity in detecting participants with low 
levels of physical activity. As previously outlined in the Introduction, sedentariness is 
associated with increased metabolic and cardiovascular risk. 
 
Inclusion criteria 
Men and women, 35 years of age or older with increased cardiometabolic risk defined by all 
the following three criteria:  
1. Clinically confirmed diagnosis of hypertension (any diagnosis of hypertension in 
the Electronic Health Record - EHR), with or without medical treatment. 
2. Overweight or obese. BMI ranging between 27 - 40 
3. An inactive lifestyle is defined by either of two approaches:  
a. Light intensity or inactive lifestyle according to the Stanford Brief Activity 
Survey (SBAS) 
b. Light intensity or inactive lifestyle according to the physical activity section 
of the Swedish National Board of Health and Welfare Lifestyle 
questionnaire.  
 
Exclusion Criteria 
- 
Any medical condition that is an absolute contraindication to physical activity 
per FYSS (Physical Activity in the Prevention and Treatment of Disease) 2021 p. 
182(34) or Pacemaker/implantable-cardioverter defibrillator (ICD): 
o Severe symptomatic aortic stenosis. 
o Acute pulmonary embolism, myocarditis, pericarditis, or systemic infection 
(including fever, muscle pain, lymphadenopathy). 
o Suspected or known aortic dissection. 
o Severe hypertension (grade 3 – SBP > 180 mmHg or diastolic blood pressure 
- DBP > 110 mmHg) (regardless of symptoms, as a precaution). 
o Unstable coronary artery disease (unstable angina/sub-optimally treated 
stable angina/recent acute myocardial infarction <8 weeks). 
o Symptomatic uncontrolled arrhythmia. 
o Symptomatic uncontrolled heart failure. 
o Pacemaker or ICD. 
o Pregnancy. 
- 
Other exclusion criteria 

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o Smartphone with operating system incompatible with Fitrockr (iOS < 
16/Android OS <10) 
o Inability to understand Swedish or English. 
o Any other condition that may interfere with the participant’s ability to comply 
with the study protocol, e.g. severe mental illness or cognitive disorder. 
o Inability to walk stairs. 
 
Recruitment 
For a clinically representative population, we aim to recruit continuously from routine annual 
hypertension visits at academic primary care centers. This approach minimizes the potential 
confounding of medication changes through/during the intervention period. Screening visits 
will be scheduled >1 month after the primary care visit. Online sign-ups will also be allowed. 
Consent will be collected digitally through electronic consent, allowing for remote pre-
screening. 
 
Retention 
Personnel will attempt to verify withdrawal or motivate continuation in all patients that are lost 
to follow-up. The reason for withdrawal will be tabulated. Efforts will be made to verify and 
ascertain reasons for loss to follow-up. Time point for withdrawal or loss to follow-up will be 
tabulated as well. The number, along with the reasons of losses to follow-up (dropouts and 
withdrawals) over the course of the trial will be summarized by the treatment arm. 
 
To promote retention, participants will receive a text chat message via FitRockr, 
approximately once per month, allowing the opportunity to discuss their study experience 
and any issues, including feedback regarding study participation. Additionally, staff will 
contact participants to ensure that participants charge their accelerometer. 
 
Enrolment information 
We will provide the following recruitment metrics: number of days recruiting, number of 
patients screened, and the number of patients recruited (per day and total). Furthermore, 
screened but non-recruited individuals will be documented, including the reason for non-
recruitment.  
 
CONSORT diagram 
A CONSORT flow diagram (Appendix A) will summarize the participant information as seen 
by the attached diagram. Reasons for ineligibility, non-randomization and exclusion will be 
provided.   
 
Baseline characteristics 
Participants will be described based on age, gender, time since hypertension diagnosis, 
standardized daily hypertension treatment dose (as defined in (35)), BMI, diabetes, and BMI 
both overall and separately for each treatment arm. 
 
Categorical data will be summarized as numbers and percentages. Continuous data will be 
summarized as mean and standard deviation (SD) if data are normally distributed or media 
and interquartile range (IQR) for skewed data. Minimum and maximum values will also be 
presented for continuous data. Tests for differences between the groups and possible 
statistical significance will not be undertaken for baseline characteristics, rather the clinical 
importance of any imbalance will be noted. 
 
Sample size 
As the main outcome analysis is an analysis of covariance (ANCOVA), for the primary 
outcome of SBP, sample size calculations were based on ANCOVAs of simulated data. For 
the simulations, we assume a standard deviation of 132 mmHg for all groups and timepoints. 

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Empiric autocorrelations values from a previous individual patient data (IPD) meta-analysis 
(36), which range from 0.137 and 0.5134, were used. Using this information, statistical power 
was assessed through simulations with varying difference between the intervention arms and 
different sample sizes (1000 simulations). With an autocorrelation of 0.137 (most 
conservative) and 50 participants per arm the trial is powered to detect a difference between 
each arm of 2 mmHg (>80% simulated power) for the two primary tests. We consider a 4-
mmHg difference clinically meaningful for comparison of the active arms to the control group 
and 2 mmHg meaningful for the comparison between the active arms. 
 
 

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Intervention 
Insufficient time and knowledge among general practitioners are among the many barriers to 
counseling patients on physical activity (37). The interventions in this trial are designed to 
simplify and personalize current recommendations.  
 
In brief, eligible participants’ baseline physical activity levels will be assessed remotely for a 
week, during which they will be instructed to maintain their usual activity level. Subsequently, 
participants will be randomized to double their activity levels with or without the incorporation 
of stair-walking. The calculated target time (CTT) is expressed in moderate intensity activity 
minutes, with one minute of stair-walking corresponding to two minutes of moderate intensity 
activity. The CTT will be distributed as follows for the two active arms: 
 
Stair-Walking Group 
- 
25% of CTT will come from stair walking. 
o 37.5 minutes of stair walking corresponds to 1750 steps (or 250 steps per 
day) or 46.6 steps per minute. The daily step goal is calculated as: 
 
𝐷𝑎𝑖𝑙𝑦 𝑠𝑡𝑒𝑝𝑠=
భ
ర∗஼்்∗ସ଺.଺ഥ
଻
   or 𝐷𝑎𝑖𝑙𝑦 𝑠𝑡𝑒𝑝𝑠= 𝐶𝑇𝑇∗1. 6ത 
- 
50% (or 2/4) of the calculated target time will come from brisk walking. 
 
For highly sedentary participants (<75 moderate intensity activity minutes per week) the 
minimum protocol will be applied 250 daily stair steps (37.5 min a week) and 75 minutes of 
brisk walking. 
 
Walking Group 
The goal is to double the baseline moderate-intensity activity level exclusively through brisk 
walking. For highly sedentary participants (<75 moderate intensity activity minutes per week) 
the minimum protocol will be applied, corresponding to 150 minutes of brisk walking. 
 
The Passive control group will be recommended to adhere to the guideline-recommended 
level of physical activity. 
 
All groups will receive the Swedish Heart Lung Foundation´s short text on lifestyle habits. 
An incremental titration of activity levels will be performed with increases of 25% increments 
towards intended levels per week. Both active groups will receive instructions on how to 
maintain their prescribed physical activity levels, and wearable activity monitors will track 
their progress. Individual feedback will be provided regularly, to monitor adherence and 
progress throughout the 6-month intervention period. Passive controls will not receive the 
same encouragement. 
 
Monitoring and promoting adherence 
Activity levels will be monitored using a wearable activity tracker (Garmin© Vivosmart 4) in all 
groups throughout the study. Participants will receive individual feedback through the mobile 
app (Fitrockr©), designed to track progress and maintain motivation throughout the study 
period. The design of the adherence monitoring and feedback is based on prior literature and 
will therefore use push notifications, positive reinforcement, and follow-up through phone calls 
monthly (38–40).  
 
During the titration phase, participants will receive more frequent feedback than later in the 
study. After the titration phase they will receive feedback twice every week. For the stair-
walking group, feedback will include number of stair steps walked (and the percentage of 
recommended dose), moderate intensity physical activity minutes (and the percentage of 
recommended dose), and daily steps. The brisk walking group will receive feedback with 
moderate intensity physical activity minutes (and the percentage of recommended dose), and 

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daily steps. All groups will receive standardized reminders to wear and charge their digital 
activity tracker and synchronize their data. 
 
Details regarding the setup of the digital activity tracker (Garmin© Vivosmart 4) and of the 
mobile app (Fitrockr©) for data collection and individualized guidance will be provided before 
the study start and outlined in the final Appendix. 
 
Adherence will be presented in the primary publication as moderate intensity activity minutes 
for the three study arms. 
 
Criteria for discontinuation and concomitant care 
Participants have the right to cease their involvement in the trial at any point at their own 
discretion. Investigators can terminate a subject’s participation due to unacceptable harm. 
The reason for discontinued participation will be tabulated for all participants that exit the 
trial. Participants are allowed any concomitant care as needed. 
 
Insurances 
All participants in the trial are covered by the Swedish Patient Insurance 
(Patientskadeförsäkring). Additionally, a 'särskilt personskadeskydd' insurance is obtained by 
the responsible researcher via Legal, Financial and Administrative Services Agency 
(Kammarkollegiet). Moreover, the responsible researcher holds a professional insurance via 
Folksam and the Swedish Medical Association (Sveriges Läkarförbund). These insurance 
policies ensure comprehensive coverage for trial subjects throughout the study duration. 

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Measurements 
Data management and auditing 
All data will be registered and stored using an electronic Case Report Form (eCRF) based on 
the web application BASS, which is compliant to local information safety requirements (bank-
level security, with pseudonymization). Monitoring will adhere to Good Clinical Practice 
(GCP) guidelines. Data will be managed by a statistician independent of this study (defined 
in the role assignments section). The database will be maintained until further notice (at least 
20 years after inclusion of the last patient) and be reported in accordance with the Personal 
Data Act (PUL, 1998:204). The authority responsible for the database is Karolinska Institutet, 
and the cleaned data will be made available to all principal investigators of the study. 
 
Auditing  
For the first 2 months of enrollment at each center, weekly monitoring will be conducted by 
the trialists. This includes reviewing inputs to the eCRF, eligible patients, randomized 
participants’ initial assessments, and the documentation and instructions for the trial  
 
Data collection methods 
 
After collection of all data points at follow-up visits, the assessor will be questioned whether 
blinding was upheld. All measured variables will be performed 1-2 weeks prior to 
randomization and at the 26-week (6 months) follow-up. Remote monitoring is outlined in the 
chart below. 
 
 
 
 
 
 
Time 
Virtual 
Screening visit (-1-2w) 
Follow-up (26 w) 
(Selection criteria & past medical history)   
30 min  
X 
 
 
Anthropometrics  
BMI, waist circum.
5 min  
 
X 
X 
 
 
 
 
 
Physical examination and physiological 
assessment  
Blood pressure 
Orthostatic test (>65) 
12 lead ECG
30 min  
 
X 
X 
Blood samples  
20 min  
 
X 
X 
Breakfast 
15 min  
 
X 
X 
Fitness assessment  
10s. one-legged stance (>65) 
Sit to stand test 
Hand grip 
6MWT
10 min  
 
X 
X 
Remote monitoring
Monitor install and instruct 
24h BP cuff and instruct 
72h 3-lead aECG (Cortrium C3+)
30 min  
 
X 
X 
(Questionnaires) 
30-40 min 
X 
 
 
(Clinical and risk factor anamnesis) 
15 min  
X 
 
 
Total estimated time 
 
 
~2h 
~2h 

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Selection criteria, and past medical history: - 30 min 
Demographics will be collected during pre-screening. This includes contact information, 
personal identification number, highest level of education and category of monthly income. 
Eligibility criteria pertaining to the selection criteria will be collected (as outlined in the 
Exclusion criteria). 
Past medical history will be collected using information from the electronic healthcare record 
regarding cardiovascular, pulmonary, musculoskeletal, metabolic, psychiatric, and 
oncological disease. The purpose is both to collect baseline information but also to calculate 
cardiovascular risk scores such as NORRISK, Framingham and others for substudies. 
Biological samples: - 10 min 
Certified personnel will collect blood from each participant while they are in a fasting state. 
The blood will be analyzed at certified laboratories with no knowledge of allocation, for 
cholesterol (total/high lipoprotein - HDL/calculated LDL), triglycerides, glucose, HbA1c, and 
insulin, as well as blood phosphatidylethanol (B-Peth) for certain sites. Blood samples will be 
frozen and stored in Karolinska Institutet Biobank, in compliance with local laws.  
Questionnaires: 
Participants above 65 years of age will complete the Tilburg frailty indicator and KASAM-13 
questionnaire (sense of coherence). All participants will complete the Generalized Anxiety 
Disorder 7 (GAD7) questionnaire for anxiety screening and the EQ-5D-5L questionnaire for 
health-related quality of life (HRQOL). They will also be allowed to select among the 
collected data which one they are most interested in addressing with this intervention. 
Anthropometrics 
Participants’ weight, and body composition will be measured using a bioimpedance scale 
provided by the trialists (Omron BF511), and their height will be measured to a precision of 
0.1 cm. Waist circumference will be measured with the participant standing, using a metal 
tape (midaxillary line). 
placed horizontally along the mid-axillary line just below the umbilicus. All measurements will 
be input into the eCRF. BMI will be calculated directly within the eCRF. 
Physical examination and physiological assessment 
Office blood pressure will be measured using a trialist-provided monitor (Omron 9210T) with 
measurements five times, separated by one minute, on the dominant arm and transmitting 
the data with timestamps electronically to the eCRF. The average of the last three 
measurements, computed automatically in the eCRF, will be used for analysis of outcomes.  
An orthostatic blood pressure measurement will be performed following this using standard 
protocols at 1, 3, 5 and 10 minutes after rising from seated position.  
A 12-lead ECG will be performed according to standard protocols in specific sites. 
Patients with grade 2 hypertension (≥160-179/100-109 mmHg) will be referred to primary 
care to ensure immediate initiation or uptitration of medical treatment, adhering to the 2023 
European Society of Hypertension Guidelines. Additionally, participants with a prior diagnosis 
of hypertension who are already under medical treatment but still present with grade 2 
hypertension, will be referred to the primary care to consider an adjustment or increase in 
their treatment regimen.  
Fitness assessments: 
- 
6-minute walk test (meters walked in 6 minutes): used to estimate aerobic capacity. 
Participants will walk back and forth on a flat hard surface as fast as possible for 6 
minutes. The distance walked is measured(41). 

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- 
Hand Grip Strength: assessed to measure muscle strength. The Jamar hydraulic 
dynamometer will be used, and the participants will measure their grip strength in 
both hands (42). 
- 
10-second one-legged stance test: to assess balance in participants over the age of 
65, participants will stand with elbows extended, place the dorsal part of the non-
support foot on the back of the opposite leg, and fix their gaze on an eye-level point 
at a 2 m-distance. Ability to complete 10-s balance test (yes or no) on right and left 
foot will be tabulated(43).  
- 
VO2 Max: Measured using the Ekblom Bak protocol (44), step-up box (45) and sit to 
stand test (46) will be performed only in specific sites. 
Clinical and risk factor anamnesis 
Tobacco, alcohol, and dietary anamnesis will be collected using the Swedish National Board 
of Welfare’s screening questions for lifestyle factors (found in the appendix). Participants will 
be asked about their medication history and their adherence to medication listed in their EHR 
at the time of the appointment, and input into the eCRF. This allows future assessments of 
adjustments in blood pressure medications during the trial in a standardized way as in Min et 
al. (35). Falls in the elderly strata as well as harms as outlined in the harms section will be 
collected as well. 
Remote monitoring: 
Digital activity tracker (Vivosmart 4 by Garmin) 
Physical activity levels for all participants will be monitored with a digital activity tracker. The 
band should be worn loosely enough that it can move back and forth on the wrist of a 
participant; however, during activity it may benefit from a snugger fit.  
The accelerometer will continuously record each participant’s pulse rate through pulse 
oximetry, movement through accelerometer and barometric-derived altitude measurements. 
Moreover, an array of different data points including sleep, daily steps among many others. 
To be registered in the Fitrockr app, an activity must be ongoing for more than ten minutes, 
however in the research database all movement is recorded and saved. 
Continuous Holter ECG Continuous 2-lead registration for 5-7 days through an adhesive 
patch electrode on the chest to collect information about the heart rhythm in specific sites 
(Cortrium C3+). 
 

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Registry data collected up to 10 years after study completion: 
 
Health economic parameters – Healthcare consumption and health-related 
productivity loss associated with investigated interventions will be assessed by 
extracting resource use from the relevant registries, including data from the Swedish 
Social Insurance Agency. 
 
Incidence of type 2 diabetes mellitus, chronic kidney disease, non-alcoholic 
fatty liver disease, myocardial infarction, heart failure, as well as cardiovascular 
disease, and medication history and vital status – this will be extracted by linking 
with national quality-of-care registries including the Swedish National Patient Registry, 
Regional Primary Care Registries, National Prescribed Drug registry and the Swedish 
Population Registry. 
 
Harms 
Harm here is defined as an untoward event irrespective of causal relationship. Only harms 
that lead to hospitalization or study withdrawal will be tabulated. These may include severe 
injury to the musculoskeletal system, cardiovascular events, and falls among the elderly. 
 
 

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Dissemination policy 
Publication Policy 
The Publications group will review all publications following the guidelines given below and 
report its recommendations to the Steering Committee. 
A. Data analysis and release of results 
Analysis of clinical outcomes will be performed by a blinded statistician. The Steering 
Committee will provide recommendations on the timing and meetings for presenting endpoint 
data. 
B. Review process 
Each paper or abstract, as described below, must be submitted to the appropriate 
Publications group for review of its suitability and scientific merit prior to submission. The 
group may recommend changes to the authors and will submit its recommendations to the 
Steering Committee for approval. 
C. Primary outcome papers 
Primary outcome papers will present primary and secondary outcome data as described in 
this protocol.  
D. Other study papers, abstracts, and presentations 
All studies other than those designated as “Primary Outcome” fall within this category, 
including the publication of the present protocol. All papers and abstracts must be approved 
by the Publications group before they are submitted. If a topic is suggested by a member or 
external individual, they can be considered the lead authors of the study. Disputes regarding 
authorship will be settled by the Study Chair in consultation with the Chair of the Publication 
group. 
XIII. Close-out Procedures 
Regardless of the timing and circumstances of the end of the study, close-out will proceed in 
two stages 1) interim period for analysis and documentation of study results 2) Debriefing of 
participants and dissemination of study results. 
A. Interim 
Efforts will be made to reduce the time between the completion of data collection and release 
of study results. We expect it to take about 3 to 4 months to compile the final results paper 
for an appropriate journal. 
B. Reporting of study results 
The study results will be shared with participating physicians, referring physicians, patients, 
and the general medical community. Results will be openly reported on the site of trial 
registration. No later than 3 years after trial completion, a completely de-identified dataset will 
be delivered to an appropriate data archive for sharing (Individual Participant Data a.k.a. 
IPD). 
 
 
 

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Statistical analysis plan for the HYPERWALK randomized 
controlled trial. 
Following SAP guidelines in Gamble et al. JAMA 2017 Guidelines: Information from sections 
1-3 from is found in the protocol 
Statistical Principles 
Confidence intervals (CI) and p-values 
The applicable tests will be 2-sided and will for the primary outcomes be performed using a 
0.05 significance level. For secondary hypotheses alpha of 0.005 will be considered 
significant, while 0.05 will be considered suggestive following previous recommendations 
(48). The same testing approach as in the primary analysis will be used for the secondary 
outcomes. 
 
Adherence and Protocol Deviations 
Adherence Criteria 
Adherence is defined as participating in more than 80% of the follow-up time monitored 
remotely using the digital activity tracker (Garmin Vivosmart 4). The prescribed level will be 
based on a 1-week baseline measurement, converted into moderate-intensity physical 
activity minutes. The target for the active groups (calculated target time, CTT) will be double 
the baseline moderate-intensity activity minutes, as described in the intervention section of 
the HYPERWALK protocol.  
 
Adherence will be presented as the number and percentage of participants meeting the 
adherence criteria measured by the digital activity tracker. Descriptive statistics will be 
presented by randomization group presenting % and 95% CIs. 
 
Definition of Analysis populations 
The intention-to-treat population will include all randomized patients, according to the 
treatment they were randomized to receive. Per-protocol will be assessed for those 
considered adherent as defined previously as a sensitivity analysis. 
 
 
 

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Analysis methods  
Outcome definitions:  
Primary outcome 
6 months change in systolic blood pressure from baseline (mmHg). 
 
Secondary outcomes 
6 months change in diastolic blood pressure from baseline (mmHg) 
6 months change in fasting LDL directly measured (mmol/L) 
6 months change in fasting Triglycerides directly measured (mmol/L) 
6 months change in fasting HbA1c from baseline (mmol/mol) 
6 months change in HOMA-index (HOMA-IR) from baseline (with glycaemia in mmol/L and 
insulin in mU/L) 
 
Statistical methods 
The average change in SBP at 6 months follow-up will be presented, and the results will be 
analyzed using ANCOVA: a linear regression model including the treatment variable and 
adjusting for baseline SBP and the factors used in the randomization: sex and age 
(categorised as <65 or ≥65). One model will be fitted including the two active arms only (arm 
A vs arm B) and one including a treatment variable coded as (arm A & arm B) vs arm C. 
Evidence for an intervention effect will be assessed using the p-value of the (binary) 
treatment variable No other pre-planned covariates will be included in the models; baseline 
characteristics which show a clinically meaningful imbalance, will be included at the 
discretion of the trial statistician. The same approach as for the primary analyses will be used 
for the secondary outcomes. 
 
Sensitivity analysis 
A sensitivity analysis of the primary outcome will be performed as on treatment for those 
defined as adherent, following the definition of adherence in the section describing the 
intervention.  
 
Subgroup analyses 
A subgroup analysis will assess interaction of the intervention with either age, sex, BMI, or 
baseline physical activity levels for the two fitted models. 
 
Missing data 
Missing data will only be imputed for the longitudinal digital activity tracker data as missing at 
random and use the last observation carried forward approach. 
 
Statistical Software 
R and Python with scripts will be provided in results publication 
 

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Appendix A. CONSORT diagram 
Trial template for the CONSORT diagram showing the flow of participants through each 
stage of this randomized trial. 
 
 
 
Assessed for
eligibility
(n= ...)
Randomized (n= ...)
   Excluded (n= ...)
   Not meeting inclusion criteria (n= ...)
   Refused to participate (n= ...)
   Other reasons (n= ...)
Allocated to stair-   
walking (n= ...)
Received allocated
interevention (n= ...)
Allocated
to walking (n= ...)
Received allocated
intervention (n= ...)
Allocated to control
(n= ...)
Received allocated
intervention (n= ...)
Lost to follow-up 
(n= ...) (give reasons)
Discontinued
intervention (n= ...)
(give reasons)
Lost to follow-up 
(n= ...) (give reasons)
Discontinued
intervention (n= ...)
(give reasons)
Lost to follow-up 
(n= ...) (give reasons)
Discontinued
intervention (n= ...)
(give reasons)
Analysed (n= ...)
Excluded from
analysis (n= ...) (give
reasons)
Analysed (n= ...)
Excluded from
analysis (n= ...) (give
reasons)
Analysed (n= ...)
Excluded from
analysis (n= ...) (give
reasons)
Allocation
Follow-up
Analysis
Enrollment