Effect of an Exercise Rehabilitation Program on Symptom Burden and Quality of Life in Hemodialysis: A Randomized Controlled Study
Phase: NA
Conditions: End-stage Renal Disease, Renal Failure Chronic Requiring Hemodialysis
Sponsor: University of Manitoba

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EFFECT OF AN EXERCISE REHABILITATION PROGRAM ON
SYMPTOM BURDEN AND QUALITY OF LIFE IN HEMODILAYSIS:
A RANDOMIZED CONTROLLED TRIAL
NCT02259413

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RENAL REHAB PROTOCOL
EFFECT OF AN EXERCISE REHABILITATION PROGRAM ON
SYMPTOM BURDEN IN HEMODIALYSIS: A RANDOMIZED
CONTROLLED STUDY
Study Principal Investigator:
Clara Bohm, MD
Assistant Professor,
Internal Medicine
University of Manitoba
GE445B Health Sciences Center
820 Sherbrook St, Winnipeg, Manitoba
Tel:  204-787-3583
Fax: 204-787-3326
cbohm@hsc.mb.ca
Sponsor: University of Manitoba
Funding: Kidney Foundation of Canada
Version: 10
Date: 11 Jul 2022
The information within this document is confidential and is not to be disclosed without prior permission of the Study Principal
Investigator.

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Table of Contents
Statement of Compliance ................................................................................................................... 5
Protocol Synopsis ................................................................................................................................ 6
Schematic of The Study Design ........................................................................................................ 8
1
Key Roles ....................................................................................................................................... 9
2
Introduction, Background Information and Rationale ...........................................................11
2.3
Potential Risks and Benefits ..........................................................................................................................14
2.3.1
Known Potential Risks ...............................................................................................................14
2.3.2
Known Potential Benefits ..........................................................................................................15
3
Objectives and Purpose ..............................................................................................................16
4     Study Design and Endpoints .....................................................................................................17
4.1
Description of the Study Design ....................................................................................................................17
4.2
Study Outcomes ...........................................................................................................................................18
4.2.1
Primary Outcomes .....................................................................................................................18
4.2.2
Principal Secondary Outcome ...................................................................................................18
4.2.3
Secondary Outcomes .................................................................................................................19
5     Study Enrollment and Withdrawal ...........................................................................................21
5.1
Participant Enrolment Inclusion Criteria ........................................................................................................21
5.2
Participant Enrolment Exclusion Criteria .......................................................................................................21
5.3
Strategies for Recruitment and Retention .....................................................................................................21
5.4
Participant Withdrawal or Termination .........................................................................................................22
5.4.1
Reasons for Withdrawal or Termination ..................................................................................22
5.4.2
Handling of Participant Withdrawals or Termination ............................................................22
5.4.3
Participant Suspension from the Study ....................................................................................23
5.5
Premature Termination or Suspension of the Study ......................................................................................23
5.5.1 Independent Data Safety Monitoring Board (DSMB) ......................................................................23
6     Study Agent .................................................................................................................................25
6.1
Study Agent(s) and Control Description ........................................................................................................25
7     Study Specific Procedures ..........................................................................................................26
7.1
Study Procedures/Evaluations ......................................................................................................................26
7.1.1
Demographic Data Collection ...................................................................................................27
7.1.2
Clinical Data Collection .............................................................................................................27
7.1.3
Laboratory Data Collection .......................................................................................................27
7.2
Study Outcome Evaluations ..........................................................................................................................28
7.3.1
Screening Phase, Consent, Enrolment ......................................................................................29
7.3.2
Randomization and Blinding ....................................................................................................29
7.5
Concomitant Medications, Treatments, And Procedures ...............................................................................33
7.6
Prohibited Medications, Treatments, And Procedures ..................................................................................33
7.7
Exercise Records...........................................................................................................................................33
7.8
Safety Precautions ........................................................................................................................................33
8     Assessment of Safety ..................................................................................................................34
8.1
Specification of Safety Parameters................................................................................................................34
8.1.1
Definition of Adverse Events (AEs) ..........................................................................................34
8.1.2
Definition of Serious Adverse Events (SAEs) ...........................................................................34
8.2
Classification of an Adverse Event .................................................................................................................35

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8.2.1
Severity of Event ........................................................................................................................35
8.2.2
Relationship of an Adverse Event .............................................................................................35
8.2.3
Expectedness ..............................................................................................................................36
8.3
Time Period and Frequency for Event Assessment and Follow-Up .................................................................36
8.4
Reporting Procedures ...................................................................................................................................36
8.4.1
Adverse Event Reporting ..........................................................................................................36
8.4.2
Serious Adverse Event Reporting .............................................................................................36
8.5
Safety Oversight ...........................................................................................................................................37
9     Statistical Considerations ...........................................................................................................38
9.1
Statistical and Analytic Plan ..........................................................................................................................38
9.2
Sample Size and Power .................................................................................................................................38
9.3
Description of Statistical Methods ................................................................................................................38
9.3.1
Primary Outcome .......................................................................................................................38
9.3.2
Planned Sub-group Analyses ....................................................................................................39
9.3.3
Secondary Outcomes and Analyses ..........................................................................................40
9.3.4
Demographic Data .....................................................................................................................40
9.3.5
Study Completion ......................................................................................................................41
9.3.6
Final Study Analysis ..................................................................................................................41
10     Study Administration and Ethical Considerations ...............................................................42
10.1
Source documents and Access to Source Data/Documents ...........................................................................42
10.2
Ethics Approval ............................................................................................................................................42
10.2.1
Protocol Deviation Definitions ..................................................................................................42
10.2.2
Reporting and Managing Protocol Deviations .........................................................................42
10.3
Informed Consent Process ............................................................................................................................43
10.4
Participant and Data Confidentiality .............................................................................................................43
10.5
Data Collection and Management .................................................................................................................44
10.6
Study Records Retention ..............................................................................................................................44
10.7
Publication and Data Sharing ........................................................................................................................44
11     References ..................................................................................................................................46
12 Appendices ....................................................................................................................................52
Appendix 1.  List of Abbreviations ................................................................................................................................52
Appendix 2.  Study Definitions .....................................................................................................................................53
Appendix 3.1  Dialysis Symptom Index .........................................................................................................................55
Appendix 3.2  EuroQol 5D-5L Health-Related Quality of Life Questionnaire ..................................................................58
INSTRUCTIONS ...............................................................................................................................61
CALCULATIONS ..............................................................................................................................61
EXAMPLE ...........................................................................................................................................61
a) STRENUOUS EXERCISE (HEART BEATS RAPIDLY) ..........................................................62
b) MODERATE EXERCISE (NOT EXHAUSTING) .....................................................................62
c) MILD EXERCISE (MINIMAL EFFORT) ..................................................................................62
Times Per Week ..................................................................................................................................62

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STATEMENT OF COMPLIANCE
Protocol: The Effect of an Exercise Rehabilitation Program
on Symptom Burden in Hemodialysis: a Randomized
Controlled Study
Version/Date: Version 10, 11 Jul 2022
Study Principal Investigator: Clara Bohm, MD, MPH
 Site: University of Manitoba
I confirm that I have read the above protocol in the latest version.  I understand it, and I will
work according to the principles of Good Clinical Practice (GCP) as described in Health
Canada’s section C.05.010/Division 5 of the Food and Drug Regulations and the International
Conference on Harmonization (ICH) document E6 Good Clinical Practices: Consolidated
Guidance. As the Site Principal Investigator, I agree to conduct and carry out the study by
the criteria written in the protocol and understand  that no changes can be made to this
protocol without written permission of the Study Principal Investigator and approval from
the Research Ethic’s Board (REB), except where necessary to eliminate an immediate
hazard(s) to the trial participants. All personnel involved in the conduct of this study have
completed Human Subjects Protection training.
           __________________________________
            Principal Investigator (Print)
            __________________________________                         _______________________
             Principal Investigator (Signature)                                                     Date

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PROTOCOL SYNOPSIS
Title & Protocol #
The Effect of an Exercise Rehabilitation Program on Symptom Burden in Hemodialysis: a
Randomized Controlled Study
Sponsor
University of Manitoba
 Investigators and
Sites
Study PI: Clara Bohm, MD, MPH (Winnipeg); co-PI: Jennifer MacRae MD, MSc (Calgary); co-Invest:
Todd Duhamel, PhD (Winnipeg); Mauro Verrelli, MD (Winnipeg); Claudio Rigatto MD, MSc
(Winnipeg); James Zacharias, MD, MSc (Winnipeg); Navdeep Tangri  MD, PhD (Winnipeg)
Objectives
Primary: To characterize the effect of a 12-week exercise rehabilitation program on symptom
burden at 12 weeks in adults on hemodialysis (HD)
Secondary: To characterize the effect of a 12-week exercise rehabilitation program on:
 - Symptom burden at 12, 26 and 52 weeks in adults on HD
 - Generic health related quality of life at 12, 26 and 52 weeks in adults on HD
Tertiary: To determine the effect of a 12-week exercise rehabilitation program on:
 - Self-reported time required for recovery post hemodialysis at 12, 26, and 52 weeks
 - Physical activity behavior at 12, 26, and 52 weeks
 - Exercise capacity at 12, 26 and 52 weeks
 - Frailty status at 12, 26, and 52 weeks
 - Self-efficacy to exercise at 12, 26, and 52 weeks
 - Hospitalization rate over 1 year and hospital length of stay
 - Mortality at 1 year
Duration
4 years
Population
Adults on chronic in-centre hemodialysis for greater than 3 months with at least one hemodialysis-
related symptom will be enrolled (n=150).
Design
Single centre randomized controlled trial with 1-to-1 parallel design, allocation
concealment and assessor blinding.
Inclusion / Exclusion
Criteria
Inclusion Criteria: Participants must be able to understand and provide written informed consent
in English; greater than or equal to 18 years old; greater than 3 months after starting chronic HD;
no expected change in dialysis modality or relocation outside of Winnipeg during intervention
period (12 weeks); assessed to be safe and able to exercise by HD unit nephrologist;
Exclusion Criteria: acute coronary syndrome in past 3 months; unstable arrhythmia; shortness of
breath at rest or with minimal activity (NYHA Class 4); symptomatic hypoglycemia (> 2x/week in
week prior to enrolment); currently participating in the MRP clinical intradialytic cycling program;
score of 0 on DSI when administered at time of consent
Study Arms
Intervention arm: Standard care plus a 12 week structured rehabilitation program including
lifestyle education, home-based resistance exercise and cycling during HD; n=75
Control arm: Standard care including baseline exercise counseling; n=75
Study Endpoints
Primary, Secondary
and Mechanistic
Primary outcome: Change in symptom burden over time (12 weeks) as measured by Dialysis
Symptom Index (DSI) severity score.
Secondary outcomes:  Change in generic health-related quality of life over time (12, 26, 52 weeks)
as measured by EuroQol 5D-5L and EuroQol visual analogue scale
Change in: modified symptom burden (modified DSI severity score); time for recovery post-HD;
frailty status (Fried criteria); physical activity level (accelerometer and Godin-Shephard Leisure
Time Physical Activity Questionnaire); exercise capacity (Incremental Shuttle Walk Test); self-

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efficacy for exercise (Self-Efficacy for Exercise Questionnaire; hospitalization rate (number hospital
days admitted/patient year); all cause 1 year mortality
Brief Summary of
Analysis
Sample size: The following assumptions were made: alpha 0.05; power 0.80; 30% dropout and 25%
absolute difference in proportion of individuals in whom DSI severity score decreases by 7 points or
more (minimal clinically important difference). Therefore, assuming a baseline symptom prevalence
of 50% of individuals in each study group, 150 patients (75 in each arm) will be randomized and we
will be able to detect a 25% reduction in the primary outcome.
Primary analysis: Intention-to-treat, available-case basis, in the intervention versus control arm,
using Chi-square test and logistic regression for categorical outcomes and t-tests/MannWhitney U
for continuous outcomes.
Secondary outcomes: Descriptive statistics, Kaplan Meier analysis, Poisson regression and linear
mixed modeling and will be used as appropriate.

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SCHEMATIC OF THE STUDY DESIGN
Enrolment and consent: Once informed consent is obtained, the Dialysis Symptom Index (DSI)
will be administered to all participants. Those who score 0 on the DSI (no symptoms) will be
deemed ineligible for the study
Randomization: To avoid bias, randomization will be performed following the baseline
assessment.
Intervention phase: Participants in “intervention” group will receive study intervention during
this time.
Study
Enrolment
and Consent
DSI
administered
Study
Assessment
#1
Baseline
Time=0
Randomizatio
n
Study Intervention
From  0-26 wks
Study
Assessment#2
End
Intervention
Time=12 wks
Study
Assessment#3
6 month
Time=26 wks
Study
Assessment
#4
End Study
Time=52
wks

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1 
KEY ROLES
Study Principal Investigator
Clara Bohm, MD, MPH
Assistant Professor, Internal Medicine
University of Manitoba
Health Sciences Centre
GE445B, 820 Sherbrook St.
Winnipeg, Manitoba R3A 1R9
Tel:  204-787-3583
cbohm@hsc.mb.ca
Co-Principal
Jennifer MacRae, MD, MSc
Investigator:
Associate Professor, Cumming School of Medicine
University of Calgary
FMC Room C210, 1403 29th St. NW
Calgary, AB T2N2T9
Tel:  (403) 944-8168
jmmacrae@ucalgary.ca
Study Kinesiologist:
Eric Garcia, BSc, MSc
Research Kinesiologist
University of Manitoba
Sherbrook Dialysis Unit
765 Sherbrook St.
Winnipeg, MB R3A 1R9
Tel: 204-787-1719
egarcia2@hsc.mb.ca
Study Coordinator:
Emilie Ford, Bkin, MPH
Research Coordinator, Internal Medicine
University of Manitoba
GE445B, 820 Sherbrook St.
Winnipeg, Manitoba R3A 1R9
Tel:  204-632-3367
eford2@sogh.mb.ca
Co-investigators:
Todd Duhamel, PhD
Professor, Faculty of Kinesiology and Rec Management
University of Manitoba
208 Active Living Centre
Winnipeg, MB R3T 2N2
Tel: (204) 474-7634
todd.duhamel@umanitoba.ca

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Co-investigators continued:
Mauro Verrelli, MD
Associate Professor, Internal Medicine
University of Manitoba
St. Boniface Hospital
N1031-409 Tache Ave.
Winnipeg, MB R2H 2A6
Tel: (204) 237-2121
mverrelli@sbgh.mb.ca
Claudio Rigatto, MD, MSc
Associate Professor, Internal Medicine
University of Manitoba
Seven Oaks General Hospital
2300 McPhillips Street
Winnipeg, Manitoba R2V 3M3
Tel: (204) 631-3834
crigatto@sbgh.mb.ca
James Zacharias MD, MSc
Assistant Professor, Internal Medicine
University of Manitoba
Health Sciences Centre
GE644, 820 Sherbrook St.
Winnipeg, Manitoba R3A 1R9
Tel: (204) 787-2863
jzacharias@hsc.mb.ca
Navdeep Tangri, MD, PhD
Associate Professor, Internal Medicine
University of Manitoba
Seven Oaks General Hospital
2300 McPhillips Street
Winnipeg, Manitoba R2V 3M3
Tel: (204) 631-3834
ntangri@sogh.mb.ca

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2 
INTRODUCTION, BACKGROUND INFORMATION AND RATIONALE
2.1
Background information
Individuals with end-stage kidney disease (ESKD) require renal replacement therapy such
as hemodialysis (HD), peritoneal dialysis, or renal transplantation to sustain life. In Canada,
the majority (76%) of the 5500 individuals who enter this stage of kidney disease annually
start in-centre HD.1 Individuals on HD are known to have low self-reported functional status,
and poor health-related quality of life (HRQOL) when compared to general population
controls.2, 3Functional status is an important component of HRQOL and refers to the ability
to perform activities required for daily life.
Symptom burden, the combined impact of the number and severity of symptoms
experienced by an individual, is high in HD and contributes to poor functional status and
HRQOL. Cross-sectional studies show that 30-80% of individuals on HD have at least one
symptom that is related to ESKD or dialysis treatment, with a mean of 6-20 symptoms
endorsed per individual.4-8 In a systematic review of symptom burden in chronic kidney
disease (CKD), fatigue was identified as the most widespread symptom, with a weighted
mean prevalence of 81%.5 Frequent symptoms (>50% prevalence) also included lack of
sleep, pain, muscle cramping, pruritus (itch), decreased appetite, drowsiness and dry skin.5,
9 Other symptoms identified in more than 30% of patients include restless legs syndrome,
difficulty concentrating, anxiety and depression.4, 5, 10
Increased physical activity through exercise programming may play a role in symptom
control. Increased prevalence of symptoms is correlated with low physical activity in
individuals on dialysis.11, 12 Even in low functioning HD patients, exercise programming has
been shown to be safe and to improve outcomes closely associated with symptom burden,
such as functional status and HRQOL.13, 14 As well, several small randomized controlled trials
(RCTs) have demonstrated improvement in specific individual HD-related symptoms such as
restless legs and insomnia.15-25 Using RCT methodology, we aim to characterize the role of
exercise rehabilitation in managing symptom burden in chronic HD to determine if such a
program can ameliorate common symptoms like insomnia, pain and fatigue, resulting in
improved quality of life and reduced disability over the long term.
2.1.1 
HD-related symptoms are a research priority
Multiple studies have shown that symptom burden in individuals on HD is similar to those
living with metastatic cancer.5 HD therapy itself does little to improve symptom burden and
may worsen symptoms. In a study of 698 hemodialysis patients followed for 1 year after
starting HD, symptoms worsened in 23%, did not change in 56% and improved in only 19%
of patients over the first year on HD.26 Furthermore, healthcare providers have limited
awareness of the presence and severity of symptoms in patients on HD.  When responses
to the Dialysis Symptom Index (DSI) were compared between 75 HD patients and 18
providers (nephrologists, nurse practitioners, physician assistants and nurse managers),
providers underreported 97% of symptoms and underestimated symptom severity in 63%.4
Even when recognized, limited effective treatments exist for most symptoms. For those few

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symptoms for which there are effective pharmacological therapies (uremic pruritus, restless
legs syndrome, and depression), patients may be hesitant to take additional medications
due to pre-existing medication burden (median of 19 medications per day) or attribution of
symptoms to acute events.27-29
Most importantly, the identification of effective treatments for HD-related symptoms has
been identified as an important knowledge gap for HD patients and their caregivers. Using
methodology established by the James Lind Alliance, patients, caregivers and healthcare
providers from across Canada identified the improvement of symptom burden and quality
of life as research priorities for individuals at or nearing dialysis.30 Using similar
methodology, international groups have identified fatigue/energy, sleep, anxiety/stress and
decreased appetite as key outcomes to be assessed in any future research studies.31, 32
2.1.2 
Exercise programming may play a role in symptom control
Low physical activity is correlated with increased prevalence of symptoms in individuals
on dialysis.11, 12 In an observational study of 1643 incident dialysis patients, each 10-point
increase in self-reported physical activity level measured using the Human Activity Profile
was associated with a 20% decrease in symptoms of insomnia and restless legs and a 37%
decrease in symptoms of depression.12
Evidence from small RCTs suggests that exercise can improve specific HD-related
symptoms.  In two RCTs with a combined total of 48 patients, cycling during HD for 30
minutes, 3x/week for 16 and 26 weeks led to a significant decrease in International Restless
Leg Scale score as compared to no intradialytic exercise.15, 16 Similarly, a single RCT with 28
male participants showed significant improvement in Pittsburgh Sleep Quality Index score
after 3 weeks of intradialytic cycling (5.85; SD 2.61) as compared with the control group (-
1.00; SD –1.00).18 However, another study with 22 participants showed no significant
difference between exercise and control groups in change in sleep quality measured by
sleep diary after 26 weeks.15 Hadian et al. demonstrated that 83% of participants who
exercised (walking for 20 minutes, thrice weekly for 8 weeks) had decreased cramping as
compared with 31% of participants in the control group (p=0.014).19 Finally, using the Beck
Depression Inventory and various exercise regimens (intradialytic cycling, walking or jogging
outside of dialysis) for between 10 weeks to 1 year duration, several small RCTs have
observed a 35-40% reduction in depressive symptomatology in exercisers as compared with
non- exercise controls.20-24 The effect of exercise on mood has been more variable in studies
that used other self-reported tools to measure symptoms of anxiety and depression.20, 23,
24,25
Although the signal provided by these small heterogeneous studies is promising, the
impact of exercise on several common HD-related symptoms (nausea, extremity pain,
dyspnea) is unknown and no study has examined the effects of exercise on overall symptom
burden in HD. The opportunity to reduce symptom burden, address a knowledge gap
important to patients and potentially improve functional status and HRQOL using an
accessible, non-pharmacologic intervention underscores the importance of further research
into the effects of exercise on symptom burden in ESKD.
2.1.3 
Reduced symptom burden may be a major driver of improved HRQOL in ESKD

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Not surprisingly, increased symptom burden is strongly associated with poor HRQOL and
low functional status in individuals on HD. In 120 individuals within 3 months of
commencing HD, greater symptom burden was associated with lower HRQOL as measured
by the physical and mental components scores of the Short Form 36 (SF-36).9 Using the DSI,
Weisbord et al demonstrated that the burden of mental and physical symptoms in HD
patients were independently associated with poor HRQOL measured using the Illness
Effects Questionnaire (r=0.6 and 0.61, respectively).6 Finally, in a cohort of 301 Chinese HD
patients with heavy symptom burden as measured by DSI, symptom burden was strongly
correlated with reduced HRQOL as measured using the SF-36 (rs = −0.619; p<0.001).33
Several recent systematic reviews of exercise programming in HD have demonstrated
improvement in HRQOL as measured by generic self-reported instruments.14, 34 It is
plausible that improved symptom control is a major driver of the improvement seen in
HRQOL after exercise participation in this population. However, only a single study has
investigated the effect of exercise on dialysis-related symptom burden using a
questionnaire with limited previous validation and showed no benefit.25 Using validated
measurement tools for symptom burden and HRQOL with extensive previous use (DSI and
EuroQol-5D3L respectively), we hope to further characterize the role of symptom burden in
the improvements to HRQOL seen with exercise in the HD population.
2.1.4  Reduced symptom burden through exercise may decrease adverse outcomes
Dialysis confers an elevated risk of morbidity, which is further magnified in
individuals with low physical function and physical activity levels.35 Prospective
observational studies in both incident and prevalent HD patients have found that
individuals who are less active have a 30% higher mortality risk than individuals who are
more active, even when adjusted for multiple confounders including age, sex, race,
albumin, comorbidities, smoking and socioeconomic status.36, 37 This association was
linear at all levels of activity, suggesting that even low functioning individuals on dialysis
would benefit from becoming as active as possible.37 Similarly, multiple observational
studies have also shown that frail status and/or low self-reported physical function are
associated with a 15-50% increase in falls, institutionalization and hospitalization rates
among hemodialysis patients.38-43
Symptom burden also plays a role in the high rates of morbidity and mortality seen
in the HD population.38, 44 In a large international observational study using DOPPS data
that demonstrated a 25% increased risk of hospitalization and mortality with each 10
point decline in HRQOL, symptoms alone (measured by the Kidney Disease Component
Summary), increased the risk of mortality and hospitalization by 8% when adjusted for
albumin, comorbidities and other variables known to be associated with adverse
outcomes.39 In addition, restless legs, worsening insomnia and symptoms of depression
have all been associated with a 30-40% increase in all-cause mortality risk in incident HD
patients when adjusted for age, race, and comorbidities.17, 45, 46 Similarly, depressive
symptoms have also been associated with increased risk of hospitalization in incident HD
patients.

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Observational data suggest a link between low physical activity, low physical
function, HD-related symptoms, poor HRQOL and increased hospitalization and mortality
risks. No interventional trial has investigated the role of exercise programming on long-term
outcomes. Our knowledge translation plan (Appendix 4) includes leveraging the
methodology already in place for our study to gather the information required to design
and implement a multicenter trial looking at the effect of exercise rehabilitation on long-
term clinical outcomes, including frailty, hospitalization and mortality in HD.
2.2 Significance and rationale
Individuals on HD have high symptom burden, low functional status and poor HRQOL, for
which effective treatments known to impact clinical outcomes are extremely limited.  The
identification of effective treatments for dialysis-related symptoms has been identified as a
research priority by HD patients, their caregivers and healthcare providers in Canada.30
In other chronic disease programs, exercise rehabilitation programs, incorporating
resistance and aerobic exercise and lifestyle education, have demonstrated benefits to
outcomes closely associated with symptom burden such as physical function, and HRQOL.47,
48 Although the immediate post-program benefits of such organized programs have been
demonstrated for physical function and HRQOL outcomes in the ESKD population,21, 49, 50
the effect of exercise rehabilitation on symptom burden in HD patients is unknown.
We hypothesize that an exercise rehabilitation intervention will decrease symptom
burden resulting in improved HRQOL and clinical outcomes such as functional status and
frailty. Such results would have significant implications for individual Canadians with kidney
disease, their caregivers and the healthcare system overall.
2.3
Potential Risks and Benefits
2.3.1 
Known Potential Risks
The risks associated with study participation will be fully disclosed to participants.
Occurrence of events will be monitored at every study visit, and will constitute grounds for
termination of study intervention in study patients – these participants will remain in the
study on a strictly observational basis.
Risk of Disclosure of Personal Health Information: There is a potential risk of disclosure of
personal health information with any clinical study and database.  All study personnel have
undergone ethics, GCP CITI training, and taken a Pledge of Confidentiality (PHIA).
A secure study database will be maintained for the trial purposes. The study database will
utilize appropriate security measures to protect patient privacy and data.  All study
participant information will be entered using a unique study identifier.  All data and samples
will be analyzed using the study identifier with no personal health information linked to it.
Each Site Principal Investigator will hold the key to the de-identified information in a locked
and secure office. The Subject Identification Code List that links the identity of the
participant with subject ID for de-identified data will be maintained with the trial’s master
file, according to ICH-GCP, Section 8.3.

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Risk of Exercise: Participation in this trial of monitored exercise is low risk.  Multiple previous
studies of intradialytic exercise in individuals with ESKD have demonstrated no significant
adverse events with such interventions.  However, it should be noted that none of these
studies were powered for safety outcomes. Participants will be carefully pre-screened for
safety to exercise by the attending HD unit nephrologists and study staff and the program
of exercise will be modified for each individual’s personal health status and gradually
incremental in intensity and duration. However, there is a certain degree of risk involved in
the initiation of any exercise program.  Patients will be monitored for the following risks:

Muscle or joint soreness following initiation of an exercise program

Low blood pressure on hemodialysis after exercising

Develop chest pain (angina) during or after exercise

Develop an irregular/fast heart rhythm (arrhythmia) during or after exercise

Develop an acute coronary syndrome during or after exercise

Develop hypoglycemia during or after exercise in setting of diabetes on medications

Develop tendon rupture during or following exercise

There is a very small risk of death related to the above side effects if they occur
2.3.2 
Known Potential Benefits
The identification of effective treatments for dialysis-related symptoms has been
identified as a research priority by HD patients, their caregivers and healthcare providers in
Canada. In other chronic disease programs, exercise rehabilitation programs, incorporating
resistance and aerobic exercise and lifestyle education, have demonstrated benefits to
outcomes closely associated with symptom burden such as physical function, and HRQOL.47,
48  Although the immediate post-program benefits of such organized programs have been
demonstrated for physical function and HRQOL outcomes in the ESKD population,21, 49, 50
the effect of exercise rehabilitation on symptom burden in HD patients is unknown.
Decreased symptom burden through exercise programming and the resulting
improvements in HRQOL and clinical outcomes such as functional status and frailty would
have significant implications for individual Canadians with kidney disease, their caregivers
and the healthcare system overall.

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3 
OBJECTIVES AND PURPOSE
The primary objective of this study is to determine the effect of a 12-week exercise
rehabilitation program consisting of structure lifestyle education, resistance exercise and
intradialytic cycling on symptom burden at 12, 26 and 52 weeks in adult individuals on
chronic hemodialysis.
Our primary hypothesis is that a participation in 12-week exercise rehabilitation program
will decrease symptom burden immediately after the program at 12, 26 and 52 weeks in
individuals on chronic hemodialysis.
Our secondary objectives include:
1. To determine the effect of a 12-week exercise rehabilitation program on health-related
quality of life at 12, 26, and 52 weeks.
2. To determine the effect of a 12-week exercise program on:
a. Time required for recovery post hemodialysis
b. Physical activity behavior at 12, 26, and 52 weeks
c. Exercise endurance/capacity at 12, 26 and 52 weeks
d. Frailty status at 12, 26, and 52 weeks
e. Self-efficacy to exercise at 12, 26, and 52 weeks
f. Hospitalization rate over 1 year and hospital length of stay
g. Mortality at 1 year

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4
STUDY DESIGN AND ENDPOINTS
4.1
Description of the Study Design
This is a Phase 4 single-center prospective randomized controlled trial of prevalent adult
chronic HD patients.  Patients will be screened for eligibility and one hundred and fifty
patients with dialysis-related symptoms as confirmed by baseline DSI symptom burden
score > 0 will undergo 1:1 randomization to the two-step intervention (intensive and
maintenance phase) and control arms for 1 year.  The total study duration is approximately
4 years.
Please see the Schematic of the Study Design, p. 8.
4.1.1 Study Timeline
Year 1
Year 2
Year 3
Year 4
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4
Patient Recruitment
Ongoing Follow-up
Statistical Analyses
Knowledge Translation

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4.2
Study Outcomes
4.2.1 
Primary Outcomes
Change in symptom burden from baseline to 12weeks as measured by the Dialysis
Symptom Index (DSI) Severity Score (Appendix B-1). This will be measured as the proportion
of individuals who have a decline of 7 points or more in symptom burden as defined by DSI
symptom severity score from baseline to 12weeks. The DSI is a 30-item self-administered
questionnaire with low administrative burden developed to measure the presence (yes/no)
and severity (“how much did it bother you” by 5 point Likert-scale ranging from “not at all”
to “very much”) of common emotional and physical symptoms over the previous week in
individuals receiving maintenance HD.51 Symptom severity scores can range from 0 to 150.
A 7-point change in severity score is likely to be clinically significant because this magnitude
of change is: a) consistent with the resolution/addition of 1 “very bothersome” symptom
plus a 1 point change in severity of 2 symptoms and likely to be significant to patients; and
b) is approximately 1 standard error of the mean based on our pilot data (SD 30, n=18) and
consistent with distribution-based methods. The DSI has been shown to be reliable in
predicting HRQOL in multiple studies in North American and European HD populations.6, 51-
53
Change in symptom burden from baseline to 12weeks as measured by modified DSI
Severity Score. Based on our experience and evidence from small clinical trials, we
anticipate that the maximum benefit from exercise will occur in a subset of symptoms on
the DSI.  These include: a) muscle cramps; b) restless legs; c) feeling tired or lack of energy;
d) difficulty concentrating; e) worrying; f) feeling nervous; g) trouble falling asleep; h) feeling
irritable; i) feeling sad; j) feeling anxious.  Thus, we will perform a subgroup analysis of DSI
severity scores for the 11 symptoms listed above. This pragmatic approach will lead to less
participant burn out than if individual measures were used for each symptom.
4.2.2 
Principal Secondary Outcome
Change in generic HRQOL from baseline to 12, 26 and 52 weeks as assessed using the
EuroQol (EQ) 5D-5LTM and EQ Visual Analogue Score (VAS) (Appendix B-2). This short self-
administered generic tool consists of a descriptive system with 5 questions in 5-point Likert-
type format, which assess how significantly the domains of mobility, self-care, usual
activities, pain/discomfort and anxiety/depression are affected in daily life. The EQ-5D-5L
Index, based on health state valuations elicited from the general public 54, 55, is anchored at
0.0 (dead) and 1.0 (full health). A minimum increment of 0.03 in the EQ-5D-DL index score
can be considered clinically important as it corresponds to the smallest coefficient for a
change from ‘No problem’ to ‘Some problems’ within a dimension of the EQ-5D-DL. The EQ
VAS asks individuals to rate their current state of health from “worst imaginable” to “best
imaginable” on a 100-point scale.56 EQ-5D-5LTM is brief and has been extensively validated
in various populations and disease states.  Normative data for Canadians and ESKD exist.11,
57

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4.2.3 
Secondary Outcomes
Participation in an exercise rehabilitation program may have additional benefits for
patients that are not captured by the above outcomes.  Therefore, the following secondary
outcomes will be evaluated:
1. Change in time required for recovery following hemodialysis (in minutes) from baseline
to 12, 26, and 52 weeks. At each study assessment, participants will be asked to answer the
question “Approximately how much time does it take to recover from a dialysis session”.
Answers will be recorded in minutes. Prolonged post-HD recovery time, defined as the
answer to the question “How long does it take to recover from a dialysis session” has
recently been identified as a troubling symptom complex and important outcome unique
to individuals receiving HD.58, 59
2. Change in symptom burden from baseline to 26 and 52 weeks as measured by the
Dialysis Symptom Index (DSI) Severity Score (Appendix B-1). This will be measured as the
proportion of individuals who have a decline of 7 points or more in symptom burden as
defined by DSI symptom severity score from baseline to 26 and 52 weeks. The DSI is a 30-
item self-administered questionnaire with low administrative burden developed to
measure the presence (yes/no) and severity (“how much did it bother you” by 5 point Likert-
scale ranging from “not at all” to “very much”) of common emotional and physical
symptoms over the previous week in individuals receiving maintenance HD.51 Symptom
severity scores can range from 0 to 150. A 7-point change in severity score is likely to be
clinically significant because this magnitude of change is: a) consistent with the
resolution/addition of 1 “very bothersome” symptom plus a 1 point change in severity of 2
symptoms and likely to be significant to patients; and b) is approximately 1 standard error
of the mean based on our pilot data (SD 30, n=18) and consistent with distribution-based
methods. The DSI has been shown to be reliable in predicting HRQOL in multiple studies in
North American and European HD populations.6, 51-53
3. Change in physical activity behaviour patterns from baseline to 12, 26 and 52 weeks
assessed:
a. Using total active minutes per day as measured by multi-directional accelerometry. One
week before each study assessment visit, participants will wear Actical Physical Activity
MonitorsTM(Philips Respironics, Bend, OR) on their dominant hip during waking hours for a
period of 7 days with 15 second epochs. This technique is considered the gold standard for
physical activity assessment.60 During any cycling exercise, participants will wear the device
on their dominant ankle. Valid files for analysis will require at least 3 days with a minimum
of 8 h of wear time per day. Total active minutes will be calculated by summing the minutes
per day spent in light intensity and moderate-to-vigorous physical activity (MVPA) based on
pre-specified activity count cut points.61, 62 Accelerometry is included to adjust for physical
activity in the control group and address potential contamination.
b. Using the Godin-Shephard Leisure-Time Exercise Questionnaire, which uses frequency
and intensity of leisure time activity to calculate a total leisure time activity score.(REF)

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The total leisure time activity score has been validated against measures of physical fitness
and objective measures of physical level activity collected by accelerometry in individuals
with chronic disease.63, 64
4. Change in Exercise Capacity from baseline to 12, 26 and 52 weeks as measured by
Incremental Shuttle Walk Test (ISWT) (Appendix B-3). Total distance is recorded as
individuals walk 10-meter lengths to self-reported exhaustion at pre-programmed
progressively increasing speeds as indicated by recorded beeps. ISWT has been used
repeatedly in elderly and CKD populations, minimal clinically important differences have
been established in chronic disease populations and results are correlated with other
measures of exercise capacity.65,66-68 ISWT was chosen to objectively measure physical
function because standardized walking speeds at each stage make it less subject to
measurement error due to variable participant effort than other similar tests.
5. Change in frailty status from baseline to 12, 26 and 52 weeks assessed using the
Modified Fried Criteria.69, 70 Defined as the presence of ≥ 3 criteria of the following criteria:
weight loss; exhaustion; slowness; low physical activity; and weakness. As a predictor of
adverse outcomes and associated with symptom burden, it is important to determine if
frailty status can be modified through exercise
6. Change in self-efficacy for exercise from baseline to 12, 26 and 52 weeks assessed using
the Self-Efficacy for Exercise Survey (Appendix B-4). This self-reported tool consists of 9
brief questions in 10-point Likert scale format.71 The summary score indicates an individual’s
perception of their ability to successfully incorporate physical activity into daily routine and
is the strongest determinant of continued exercise participation following formal exercise
or rehabilitation programs.72 This measure has reliably predicted physical activity behavior
in elderly individuals from various cultural backgrounds.71, 73, 74
7. Hospitalization rate defined as the number of hospitalization days admitted per patient
year. In addition, cause and length of any hospital stay for greater than 24 hours will be
collected.  At each study assessment time point, this will be determined by self-report and
hemodialysis chart review.
8. All-cause mortality defined as the proportion of patients who die over 1-year and cause
of death obtained from dialysis unit records. Depending on number of events, analysis may
be adjusted for time on dialysis, age and comorbidities.

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5
STUDY ENROLLMENT AND WITHDRAWAL
5.1
Participant Enrolment Inclusion Criteria
This pragmatic clinical trial is designed to evaluate a “real-world” setting, requiring a broad
study population. In order to be eligible, study participants must meet the following criteria:
1. Adults (> 18 years old) who are > 3 months after starting chronic HD;
2. No expected change in dialysis modality or relocation outside of Winnipeg during
the intervention period (12 weeks);
3. Assessed to be safe and able to exercise by the HD unit nephrologist1;
4. Able to understand and provide written informed consent
5.2
Participant Enrolment Exclusion Criteria
Individuals meeting any of the following criteria will be excluded from participation:
1. Acute coronary syndrome in the past 3 months;
2. Unstable arrhythmia;
3. Shortness of breath at rest or with minimal activity (NYHA Class 4);
4. Symptomatic hypoglycemia (>2x/week in week prior to enrolment);
5. Currently participating in the Manitoba Renal Program’s clinical intradialytic cycling
program;
6. Score of ‘0’ on Dialysis Symptom Index when administered at time of consent;
5.3
Strategies for Recruitment and Retention
A total of 150 chronic adult hemodialysis patients will be randomized at the 4 Winnipeg
HD units over 2 years or until the target enrolment has been achieved. Approximately 325
individuals commence chronic HD in Winnipeg per year. At any time, there are
approximately 700 prevalent patients receiving in-centre HD in Winnipeg. Assuming
eligibility rate of 40% and a conservative 25% enrolment rate (based on previous studies
and pilot data), the targeted sample size is achievable over the proposed 2-year study
period and would amount to a maximum of 5 patients cycling per shift at each of the 4 HD
units involved in the study at any one time. Based on our clinical cycling program experience
(where we have up to 10 individuals cycling per shift), this rate of enrolment is easily
achievable.
1 Nephrologists will be provided with verbal instructions and written guidelines to loosely follow when assessing for
safety to exercise

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Recruitment feasibility:  We anticipate meeting the target enrolment within the study
period given: a) the size of the target in-centre hemodialysis population outlined above and;
b) we have selected a minimal number of clinically relevant inclusion criteria based on input
from clinicians and clinical trialists (Canadian Nephrology Trials Network, CNTN)75 to
maximize study eligibility and participant generalizability.
Recruitment organization:  Posters and study information brochures may be used to
facilitate recruitment.  All recruitment materials will have been reviewed and approved by
the REB prior to use.
Recruitment management: Enrollment progress will be evaluated monthly, and in the event
that enrollment targets are not met per the recruitment schedule, the recruitment of an
additional study site (Calgary: co-PI J. MacRae) will be considered.
Recruitment retention: Participants will be reimbursed for travel to study appointments at
a rate of $20 per round trip for each study appointment attended.
5.4
Participant Withdrawal or Termination
   5.4.1 Reasons for Withdrawal or Termination
Participants will complete the study after their 12-month study visit is complete.
Participants are free to withdraw from participation in the study at any time, for any reason,
specified or unspecified without penalty.  Participants may also be withdrawn from the
study if, in the opinion of the Investigator, it is in their best interests to do so. Participants
may also be withdrawn from the study for any of the following reasons:
1. The participant is “lost to follow-up” (i.e. no further follow-up is possible because
attempts to re-establish contact with the subject have failed);
2. The participant meets an exclusion criteria, either newly developed or not previously
recognized, that precludes further study participation;
3. Any clinical adverse event (AE), laboratory abnormality, or other medical condition
or situation occurs such that continued participation in the study would not be in
the best interest of the participant;
4. Death.
   5.4.2 Handling of Participant Withdrawals or Termination
Participants who withdraw will not be replaced in the event that the target accrual rate
for randomization is obtained.  If the overall target accrual rate is lower than expected, or
the drop-out rate is higher than expected, than recruitment will continue to reach the target
study number.
If there is a reason for medical withdrawal, the participant will remain under the care of
their primary dialysis nephrologist.  The primary investigator will be available for

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consultation as needed. The date and reason for withdrawal will be documented in the
participant’s record.  If a participant is prematurely terminated from the study for any
reason, they will be asked to complete a final study exit visit and/or final outcome
assessments.  Every effort will be made to obtain final data collection on treatments and
outcomes, to reduce potential sources of bias.  Follow-up for unresolved adverse events
reported at the time of withdrawal will be the same as outlined in the adverse event section
of the protocol.
   5.4.3 Participant Suspension from the Study
The site principal investigator may temporarily suspend the study protocol if they judge
that the participant’s health would be temporarily at risk in continuing the study protocol,
such as with the occurrence of an acute illness requiring hospitalization;
Participants should not re-commence the study protocol, until BOTH the attending
dialysis nephrologist and the site principal investigator feel that the medical condition has
resolved and the participant is safe to resume the protocol.
5.5
Premature Termination or Suspension of the Study
The study may be temporarily suspended or prematurely terminated if there is sufficient
reasonable cause. The study PI and the Data Safety Monitoring Board (DMSB) will review
safety data on an ongoing basis.  Notification of, including written documentation of the
reason for study suspension or termination will be provided by the suspending or
terminating party to the PI, REB, and regulatory authorities as applicable.  Circumstances
that may warrant termination of the study or suspension include:
1. Determination of unexpected, significant, or unacceptable risk to participants, such
as:

Severe adverse events related to the exercise intervention, rates above expected
(>20% of participants develop new angina, new arrhythmia, myocardial
infarction, serious hemodialysis access complications or tendon rupture);
2. Across both Intervention and Control Arms, incidence of:

Death rates above expected, and attributable to the study protocol.
3. Insufficient compliance to protocol requirements.
4. Data that is not sufficiently complete and/or evaluable.
   5.5.1 Independent Data Safety Monitoring Board (DSMB)
The DSMB will be composed of 2 third party researchers and a statistician/analyst (Drs.
Quinn and Ravani – University of Calgary, AB; R. Brar, University of Manitoba). Safety data
will be reviewed at least yearly at planned DSMB Data Review Meetings. Serious adverse
events (see below) will be reported and reviewed immediately by the DSMB Chair. The
DSMB will provide recommendations for continuation or early termination of the trial

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based on assessment of safety. The DSMB may also make recommendations related to the
selection, recruitment or retention of participants, their management and adherence to
protocol-specific regimens, and the procedures for data management and quality control.
   5.5.2 Ascertainment and Documentation of Adverse Events for DSMB:
1. At each study assessment visit, study participants will be asked by the independent
outcome assessor at clinic if they have experienced any of the adverse (AE) or serious
adverse events (SAE) on the list below.
2. In addition, the research coordinator will identify any AEs or SAEs through review of
participants’ hemodialysis charts at each assessment time point.
3. Study kinesiologist and research coordinator will also track events if noted during their
interaction with patients.
4. Study staff will communicate with dialysis staff to inform them regarding the types of
issues that constitute AEs and SAEs. Dialysis staff will be asked to report any such
occurrences to study staff as soon as possible.
5.5.3 List of Adverse Events to Be Collected for DSMB
Adverse Events:
1. Fistula blow
2. Muscle aches or pains
3. Symptomatic Intradialytic hypotension (BP < 90 mmHg or 20 mmHg drop from baseline
associated with symptoms such as headache, cramping, dizziness, nausea)
4. Intradialytic cramping
5. Increasing fatigue
6. Symptomatic hypoglycemia (sugar < 4 associated with typical symptoms of
hypoglycemia)
7. Fall
8. Foot ulcer
Serious Adverse Events:
1. Chest pain while exercising (either intradialytic or outside of dialysis)
2. Arrhythmia while exercising (either intradialytic or outside of dialysis)
3. Unstable hemodialysis necessitating transfer to emergency post hemodialysis
4. Tendon rupture
5. Fall with fracture
6. Admission to hospital for any cause
7. Acute coronary syndrome
8. Death from any cause

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6
STUDY AGENT
6.1
Study Agent(s) and Control Description
This study does not involve an investigational drug and is therefore, CTA exempt.

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7
STUDY SPECIFIC PROCEDURES
7.1
Study Procedures/Evaluations
The study-specific procedures and time-points to be done over the course of the study
are summarized below and in Section 7.3 of the protocol:
Enrolled Study Population (both study groups)

Informed Consent (enrolment, visit 0)

Final study eligibility assessment including administration of DSI (enrolment, visit 0)

Randomization (baseline)

Collect Baseline Demographics – age; gender; ethnicity/race (baseline, visit 1)

Collect Past Medical History – cause of end stage renal disease; diabetes;
hypertension; 
smoking; 
cardiac 
disease/arrythmia; 
cerebrovascular
disease/stroke/transient ischemic attack; lung disease; peripheral vascular
disease/lower extremity amputation; arthritis; date of dialysis start; other relevant
medical history (baseline, visit 1)

Collect Concomitant Medications (each study visit)

Collect vital signs/clinical data - height, weight, BMI, systolic and diastolic blood
pressure; dialysis adequacy (Kt/V); weekly intradialytic fluid gains; duration of HD
and heart rate (each study visit; height will only be done on the 1st baseline visit)

Collect Clinical Laboratory results (each study visit):
o
Blood: hemoglobin, calcium, albumin, phosphate

Patient compliance with the study protocol will be monitored in accordance to the
Monitoring Plan (each study visit)

Dialysis Symptom Index (enrolment visit and each study visit)

EQ-5D-5L (each study visit)

Time required for recovery following hemodialysis (each study visit)

Download 7 day accelerometry history (each study visit)

Godin-Shephard Leisure-Time Exercise Questionnaire (each study visit)

Incremental Shuttle Walk Test (each study visit)

Frailty status using the Modified Fried Criteria (each study visit)

Self-Efficacy for Exercise Survey (each study visit)

Cause and length of any hospitalization since last study visit (study visit 2, 3 and 4)

Death (study visit 2, 3 and 4)

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
Physical activity/exercise logs (collected weekly for first 12 weeks then every 2
weeks for next 40 weeks)
Intervention Group – Additional Evaluation

Maximal incremental cycle test to volitional exhaustion78 (After randomized to
intervention and before intervention started)
7.1.1 
Demographic Data Collection
The research assistant will collect demographic data at the baseline assessment visit via
patient interview and hemodialysis chart review. Data collected will include age, gender,
race, cause of renal failure, dialysis vintage (time on hemodialysis), comorbidities
(cardiovascular disease, congestive heart failure, diabetes mellitus, arthritis, peripheral
vascular disease, cerebrovascular disease, malignancy, lung disease), use of walking aid
(type), smoking history.
7.1.2 
Clinical Data Collection
The research assistant will collect clinical data at baseline, 12, 26, and 52-week assessment
visits via hemodialysis chart review.  Data collected will include the following:
1. Medications: (eprex weekly dose, blood pressure medications and dosage, cardiac
medications). The research assistant will photocopy the most recent de-identified Renal
Medication Flow sheet in the hemodialysis chart to include in the research chart.
2. Dialysis Clearance: mean Kt/V for the 3 HD sessions immediately preceding the study
assessment
3. Blood pressure: Systolic and diastolic blood pressure pre and post hemodialysis at the
hemodialysis session immediately preceding the study assessment
4. Heart Rate: Heart rate (sitting) pre and post hemodialysis at the hemodialysis session
immediately preceding the study assessment
5. Duration and frequency of hemodialysis sessions
6. Dialysis prescription: Dialysis time, frequency of HD sessions, Dialysate potassium,
sodium and calcium, dry weight
7. Mean fluid gains: the total volume (L) of fluid gained between interdialytic sessions
during the week (3 HD sessions) prior to the study assessment
7.1.3 
Laboratory Data Collection
The research assistant will collect laboratory data 12, 26, and 52-week assessment visits
via hemodialysis chart review.  The monthly blood work results taken at the closest time
point to the study visit will be transcribed to CRF forms from HD chart at each study
assessment time point.  Monthly blood work samples are taken pre-dialysis on a mid week
dialysis day routinely as standard of care in in-centre hemodialysis. Hardcopy print out of
results is placed in the hemodialysis chart as routine standard of care. Lab results collected

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will include: Hemoglobin, albumin, potassium, calcium, phosphate, parathyroid hormone.
No additional blood samples will be required for this study.
7.2
Study Outcome Evaluations
Outcome assessments (as detailed in Section 4.2) will occur at baseline, 12, 26 and
52 weeks (within +/-10 days of this time point) and be performed pre-dialysis on a
midweek dialysis day to minimize the effects of fluid overload and dialysis fatigue, but
maximize convenience and adherence to the assessment schedule. In our pilot study,
assessment visits took 30 minutes.
7.3 
Study Schedule
A detailed description of each study procedure is available in Section 7.1:
Scheduled Study
Procedure
Screening/
Enrolment
(Visit 0)
Baseline
(Visit 1)
End Intervention
12 weeks
(Visit 2)
Wash-Out Visit
26 weeks
(Visit 3)
Final Visit
52 weeks
(Visit 4)
Informed Consent
X
Final Study Eligibility
X
X
Demographics
X
Medical History
X
Physical/Clinical Assessment
X
X
X
X
Concomitant Medications
X
X
X
X
Safety Monitoring
Adverse Events
X
X
X
X
Protocol Compliance
X
X
X
X
Dialysis Symptom Index
X
X
X
X
X
EQ5D-5L/EQVAS
X
X
X
X
Time to recover from HD
X
X
X
X
Accelerometry
X
X
X
X
Godin-Shephard Leisure
Time Exercise Questionnaire
X
X
X
X
Incremental Shuttle Walk
Test
X
X
X
X
Frailty Status
X
X
X
X
Self-Efficacy for Exercise
Study
X
X
X
X
Hospitalization history
X
X
X
Death
X
X
X
Collection of exercise logs
WEEKLY
EVERY 2 WEEKS
Incremental Cycle Test
(X)*
*In intervention group only between enrolment visit and start of intervention

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7.3.1 Screening Phase, Consent, Enrolment
All prevalent adult renal transplant patients who can provide informed
consent will be considered for enrolment and this will be done at the HD units
(Sherbrook Centre Dialysis; Health Sciences Centre Central Dialysis Unit., St.
Boniface General Hospital Dialysis Unit and Seven Oaks General Hospital
Dialysis Unit).
 A patient’s verbal assent to meet with the research nurse/coordinator will be obtained
by the clinical team.  The patient will be contacted by the research nurse/coordinator, the
study will be briefly described and the applicable inclusion/exclusion criteria will be
reviewed with the patient by the research nurse/coordinator to cursorily assess their study
eligibility. Patients who meet the exclusion criteria after this cursory review will be thanked
for their time and will not proceed further.  If a patient appears to meet the applicable
inclusion/exclusion criteria after this cursory eligibility review and is interested in
proceeding, the study consent form will be provided and reviewed in lay terms with this
patient.  A unique participant identifier will be assigned to each patient consented and
enrolled for the study.  A screening log will be maintained at each site to record all
individuals screened for participation in the study. All participants will provide their written
informed consent form before undergoing any study procedures.
Once informed consent is obtained, the DSI will be administered to all participants. If
patients score ‘0’ on the DSI (no symptoms), they will be deemed ineligible for the study
and will not proceed further. Pilot data suggests 40% of in-centre HD patients will be
eligible; the majority of ineligibility in our pilot study was due to modality or hospital change.
Once final eligibility is confirmed, baseline assessment at the individual’s HD unit will be
arranged, at which all participants will receive standardized counseling regarding the
benefits of physical activity (usual care)76 and undergo baseline testing for study outcomes.
This appointment will also serve as a “run-in phase”. Those that fail to attend will not be
enrolled.
7.3.2 
Randomization and Blinding
Participants will be randomly assigned to the Intervention Arm or Control Arm.
Randomization will be performed by a third party using block randomization with randomly
permuted block sizes with an overall 1:1 allocation. To ensure allocation concealment and
to minimize bias, the randomization code will not be released until baseline testing is
completed.  After randomization has occurred, the site’s research staff will be responsible
for ensuring the assigned randomization number is applied to all study documents for each
participant.  Due to the nature of the intervention in this trial, randomization to the
Intervention Arm cannot be blinded to the site PI’s or participants.  However outcome
assessors and study statistician will be blinded to study group during analysis (Prospective
Randomized Open Blinded-Endpoint study).

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7.4 Study Groups
7.4.1 Control Arm, Standard-of-care
As recommended in clinical practice guidelines for individuals with CKD, participants will
receive standardized exercise counseling at baseline.76, 77 Although not prohibited from
participating in exercise outside of the study protocol, participants in the control group will
not undergo a formal structured exercise intervention and will be asked to refrain from
intradialytic cycling during the 12-week intervention period. Exercise activity will be tracked
via weekly self-reported log sheets.  The study kinesiologist (to control for personal trainer
effect) will collect log sheets weekly during the study period. Outcome measurements will
occur according to the Schedule of Events (Section 7.5).
7.4.2 Intervention Arm, Exercise Rehabilitation Program
Participants will receive exercise counseling as per controls. To standardize intervention
exercise intensity, a maximal incremental cycle test (to volitional exhaustion)78 will be
performed prior to hemodialysis on a mid-week dialysis day on an ergometer in the
hemodialysis unit or at the Wellness Institute depending on availability of testing equipment
and patient preference. Participants will then participate in a 12-week exercise
rehabilitation program as follows (See Section 7.4.5 Study Intervention Schematic):
1. Standardized one-on-one lifestyle education sessions at HD provided by the study
kinesiologist: Self-management exercise education using Wellness Institute Cardiac
Rehabilitation program modules for 1 hr/wk during the first 4 weeks of the intervention. An
additional 4 standardized sessions focused on maintenance of lifelong physical activity will
be provided over the remaining intervention period.
2. Resistance training, using tubing and body weight, based on established guidelines:79, 80
Weekly resistance training education will be provided by the study kinesiologist in one-on-
one format at HD during the first 4 weeks of intervention. Resistance training bands,
instructions and logbooks provided for home exercise (goal 2 sessions/week) during the 26-
week intervention period (See Section 7.4.6 Summary Exercise Rehabilitation Program).
3. Intradialytic cycling during HD (intensive and maintenance phase): Participants will cycle
on TherapyCycleTM (Greely, CO) ergometers modified for dialysis beds or chairs81 with an
initial target exercise intensity of 50-60% of individual maximal workload as determined by
the incremental cycling test.49, 82 Target exercise duration will be 60 minutes in the first half
of each HD session, 3 times per week for 12 weeks. Rest periods will be provided as needed
if participants are unable to complete 60 minutes of continuous exercise.82, 83 Duration of
total exercise time, average workload (Watts) and self-reported exercise intensity as
measured by Borg Rating of Perceived Exertion (RPE) will be recorded by participants for
each exercise session. Target Borg RPE will be 13, which is considered to be moderate
intensity.84 Ergometer resistance will be adjusted over time by the study kinesiologist as
triggered by a 1-point change in Borg RPE.

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During the initial 3 intradialytic exercise sessions, the study kinesiologist will supervise
participants closely. Following 3 sessions (or more if required), HD unit staff will assist with
set up of the cycle ergometers and monitoring during exercise sessions.
During the intensive phase of the intervention, the study kinesiologist will check in on a
weekly basis (at a minimum) with participants and staff to address problems and questions
as needed. Subsequently, during the maintenance phase of the intervention, the
kinesiologist will check in every two weeks to help with intensity adjustment,
encouragement, motivation and troubleshooting. All exercise activity performed outside of
HD, including resistance training will be tracked weekly by self-report using home log sheets
during the intervention phase and then bimonthly until study end (see Section 7.4.5 Study
Intervention Design Schematic).
7.4.3 Exercise following the intervention period
If offered as a clinical program in their HD unit, participants will be able to participate in
intradialytic cycling after the intervention phase, regardless of study group.
7.4.4 Adherence to the exercise intervention
Adherence to will be assessed in the intervention group by:
(a) Proportion of resistance and intradialytic cycling exercise sessions logged compared to
total number of possible exercise sessions
(b) Proportion of total minutes of intradialytic cycling achieved based on logbook records
compared to goal intradialytic cycling minutes.

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7.4.5 Study Intervention Design Schematic
7.4.6 Summary of Exercise Rehabilitation Program
Type of
Intervention
Frequen
cy
Time
Duration
Intensity
Location
One-on-One
Exercise Education
1x/wk
1 hour
8 weeks
Not applicable
HD Unit
Resistance Exercise 
2x/wk 
8 muscle groups^
Goal: 12-15
reps/muscle
12 weeks
8 repetition max
Goal RPE*= 12-13
Home
Cycling during HD
3x/wk 
Goal: 60 minutes
12 weeks 
50-60% max workload
(Cycling test)
Goal RPE=13
HD Unit
^ biceps, triceps, chest muscles, hamstrings, quadriceps, hip extensors and hip abductors
Resistance Exercise (home-based)
Resistance Band
8 Muscle Groups; 2-3 mes/week
Lifestyle Educa on
8 sessions ~ once per week
Study kinesiologist
Intradialy c Cycling
3 mes/week
Graded kinesiologist supervision
Goal 60 minutes/session
Individualized Intensity
Voluntary con nued
resistance exercise
Voluntary con nued cycling if
available in HD unit
Interven on Group (n=75)
No Exercise Interven on/Educa on
Asked to Refrain from Cycling in HD
Can par cipate in clinical
cycling program if available in
HD unit
Baseline
Assessment
Standardized
Exercise
Counseling
Randomiza on
Control Group (n=75)
Intensive Phase
Maintenance Phase
Time (weeks)
0*
12*
26*
52*
End Interven on
End Study
Start Interven on
*study assessment
Figure 1: Study Design Schema c

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7.5 
Concomitant Medications, Treatments, And Procedures
All medication prescription and changes, dialysis treatment prescription and changes and
other medical care will be the responsibility of the attending dialysis unit nephrologist and
other usual physicians. Changes in the above parameters will be recorded by research staff
during scheduled study visits.
7.6 
Prohibited Medications, Treatments, And Procedures
Participants in the control arm will be asked to refrain from intradialytic cycling during the
26-week “intervention” period. No medications, treatments or procedures will be otherwise
prohibited as part of the study.
7.7 
Exercise Records
All exercise performed by participants in the control and intervention group will be
recorded by participants on a weekly basis in self-reported log sheets.
7.8 
Safety Precautions
Staff will wear appropriate PPE as per hospital regulations. Any interaction with
patients/participants will follow proper guidelines to limit transmission of COVID-19.  Time
within the unit will be limited and sanitization of bikes/charts will be completed by hospital-
grade sanitizing wipes.

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8
ASSESSMENT OF SAFETY
8.1
Specification of Safety Parameters
 All adverse events (AEs) and serious adverse events (SAEs) will be classified by body
system and preferred term according to the Medical Dictionary for Regulatory Activities
(MedDRA). AEs and SAEs will be summarized as the frequency of each event in the
treatment group.
 Frequency tables by treatment group and category of event (e.g., serious, related to study
therapy, causing the discontinuation of study intervention) and by National Cancer Institute
– Common Terminology Criteria for Adverse Events (NCI-CTCAE) severity grade will be
presented. Selected laboratory values will also be summarized in the treatment group using
the mean and standard deviation of the change from baseline at scheduled visits.
8.1.1 
Definition of Adverse Events (AEs)
An adverse event is any occurrence or worsening of an undesirable or unintended sign,
symptom (including an abnormal laboratory finding), or disease that occurs during
participation in the trial.
8.1.2 
Definition of Serious Adverse Events (SAEs)
An SAE or reaction is any untoward medical occurrence that at any dose leads to any of
the following events:
1.
Death.  A death that occurs during the study or that comes to the attention of the
investigator during the protocol-defined follow-up must be reported whether it is
considered to be treatment related or not.
2.
A life-threatening event.  A life-threatening event is any adverse therapy experience
that, in the view of the investigator, places the patient or subject at immediate risk
of death from the reaction as it occurred.
3.
Inpatient hospitalization or prolongation of existing hospitalization.
4.
Persistent or significant disability.
5.
An event that requires intervention to prevent permanent impairment or damage.
An important medical event that may not result in death, be life threatening, or
require hospitalization may be considered an SAE when, based on appropriate
medical judgment, it may jeopardize the subject and may require medical or surgical
intervention to prevent one of the outcomes listed above.
6.
Congenital anomaly or birth defect.

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8.2
Classification of an Adverse Event
8.2.1 
Severity of Event
The study site will grade the severity of adverse events experienced by study subjects
according to the NCI-CTCAE Version 4.0 (published May 28, 2009).  This document provides
a common language to describe levels of severity, to analyze and interpret data, and to
articulate the clinical significance of all AEs. Adverse event general grade definitions are
summarized as follows:
Adverse events, not included in the NCI-CTCAE, will be recorded and graded 1 to 5 according
to the General Grade Definition provided above.
8.2.2 
Relationship of an Adverse Event
The relationship, or attribution, of an adverse event in the study will initially be
determined by the principal investigator.  The PI will also record the determination of
attribution on the appropriate CRF and/or SAE report form.  The relationship of an adverse
event will be defined by using the descriptors provided in the table below.
Grade 1
Mild
Transient or mild discomforts (< 48 hours), no or minimal medical
intervention/therapy required, hospitalization not necessary
(non-prescription or single-use prescription therapy may be
employed to relieve symptoms, e.g., aspirin for simple headache,
acetaminophen for post-surgical pain).
Grade 2
Moderate
Mild to moderate limitation in activity some assistance may be
needed; 
no 
or 
minimal 
intervention/therapy 
required,
hospitalization possible.
Grade 3
Severe
Marked limitation in activity, some assistance usually required;
medical intervention/therapy required hospitalization possible.
Grade 4
Life-
threatening
Extreme limitation in activity, significant assistance required;
significant medical/therapy intervention required hospitalization or
hospice care probable.
Grade 5
Death
Death.
Code
Descriptor
Definition
UNRELATED CATEGORY
1
Unrelated
The adverse event is definitely not related to the study therapy
regimen.

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8.2.3 
Expectedness
All AEs (grade 2 or higher) that occur after enrollment will be reported.
8.3
Time Period and Frequency for Event Assessment and Follow-Up
Adverse events will be collected from the time the participant completes the first protocol
mandated procedure until the subject has completed the study.  Adverse events may be
discovered through any of these methods:

Observing the subject.

Questioning the subject, this should be done in an objective manner.

Receiving an unsolicited complaint from the subject.

An abnormal value or result from a clinical or laboratory evaluation.

Report from HD unit nephrologists or nurses
In association with the attending dialysis unit nephrologist, the PI will provide appropriate
medical care to participants experiencing AEs until their symptoms resolve, their status
stabilizes, or until 30 days after a participant terminates from the study, whichever comes
first.
8.4
Reporting Procedures
8.4.1 
Adverse Event Reporting
The PI is responsible for the detection and documentation of events meeting the criteria
and definition of an adverse event (AE). All AEs will be recorded in the source documents
and on the appropriate CRF(s).  All data will be reviewed twice yearly by the DSMB, which
may provide recommendations to the study PI about withdrawing any participant and/or
terminating the study because of safety concerns.
8.4.2 
Serious Adverse Event Reporting
The PI is responsible for the detection and documentation of events meeting the criteria
and definition of a serious adverse event (SAE). Serious adverse events will be collected
from the time of the randomization until the study completion, or until 30 days after the
subject prematurely withdraws from the study.
RELATED CATEGORIES
2
Possible
The adverse event might or might not be related to the study
therapy regimen (This grade is assigned when uncertainty exists)
3
Definite
The adverse event is definitely related to the study therapy regimen

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After learning that a participant has experienced an SAE, the PI is responsible for reporting
the SAE as per REB’s guidelines.   The SAE report will be completed within 7 working days of
the reported event. The DSMB may request to receive real-time notification of all SAEs
thought to be related to the treatment procedure. At the time of the event, as much
information as possible must be collected, but at a minimum must include the following:

AE description

Relationship to study exercise intervention.

Relationship to protocol mandated procedures

Reason why the event is serious.

Supplementary CRF pages that are current at the time of SAE reporting: medical
history, concomitant medications, demographics, death.
All SAEs will be followed until satisfactory resolution or until the site PI deems the event
to be chronic or the adherence to be stable. As additional details become available, the SAE
CRF should be updated and submitted to the site’s ethics committee.
8.5
Safety Oversight
Safety oversight will be under the direction of an independent DSMB. The DSMB will meet
at least annually to assess safety and efficacy data on each Arm of the study. The DSMB will
operate under the rules of an approved charter that will be written and reviewed at the
organizational meeting of the DSMB. The study PI will provide the DSMB with listings of all
SAEs on an ongoing basis. The DSMB may request to receive real-time notification of all
SAEs thought to be related to the treatment procedure.
The principal investigator will ensure the timely dissemination of SAE information to the
Ethics committee in accordance with applicable guidelines.

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9
STATISTICAL CONSIDERATIONS
9.1
Statistical and Analytic Plan
An outline of the analytic methods are given below.
9.2
Sample Size and Power
Based on the limited literature published in this area, we expect an absolute difference of
25% between the intervention and control groups in the proportion of individuals in whom
DSI severity score decreases by 7 points or more over time.
We predict DSI score will decrease in 50% of the intervention group and 25% of the control
group at 12weeks (baseline prevalence of symptoms assumed to be 50%). A sample size of
58 patients in each arm will allow us to detect this difference with 80% power (alpha 0.05).
We conservatively anticipate 30% dropout.83 Therefore, a target sample size of 150
participants (75 participants per study arm) is proposed.
 This sample size will allow us to detect a 7-point difference in mean change in DSI severity
score using standard deviation of 16 with 80% power and alpha 0.05.  This sample size (n=75
in each arm) will also provide 80% power with 0.05 alpha to detect a 12-point difference
between groups in mean change in HRQOL measured using EQ-VAS (considered clinically
important difference in other chronic diseases)85 and a 30% absolute difference in
proportion of individuals endorsing deficits in each domain of EQ5D-3L over time assuming
50% baseline deficit and development of new deficits in an additional 10% of the control
group and a reduction in deficits in 15% of the intervention group.
9.3
Feasibility
 Approximately 325 individuals commence chronic HD in Winnipeg per year. At any time,
there are approximately 700 prevalent patients receiving in-centre HD in Winnipeg.
Assuming eligibility rate of 40% and a conservative 25% enrolment rate (based on previous
studies and pilot data), the targeted sample size is achievable over the proposed 2-year
recruitment period (see Section 4.1.1) and would amount to a maximum of 5 patients
cycling per shift at each of the 4 HD units involved in the study at any one time. Based on
our clinical cycling program experience (where we have up to 10 individuals cycling per
shift), this rate of enrolment is easily achievable.
9.3
Description of Statistical Methods
9.3.1 
Primary Outcome
Developed in consultation with a statistician (T. Ferguson, Chronic Disease Innovation

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Centre) familiar with RCTs and our study outcomes, analysis will be performed in an
intention-to-treat manner on a case available basis. Change in DSI severity score from
baseline to 12 weeks will be compared between groups by independent two-tailed t-test
or Mann-Whitney U test depending on distribution and using generalized linear mixed
models with study timepoint as a random effect and adjusted for baseline DSI score. In a
subgroup of individuals whose baseline DSI score is >7, the proportion of individuals
whose DSI severity score has improved by 7 or more points from baseline to 12 weeks will
be compared between groups at each study time point using Chi-square test.
Multiple logistic regression will be performed to determine predictors of a >7 point
change in DSI severity score over time and adjusted for time varying confounders using a
marginal structural model. Interaction terms for sex and baseline DSI score will also be
inputted into the model. Although study group will be the primary predictor in this model,
other key predictors of symptom burden (including baseline DSI score, diabetes status,
ischemic heart disease (IHD), age, gender, race, smoking status, serum albumin level,
hemoglobin, baseline physical function, physical activity level and interaction terms for
gender/intervention and baseline DSI score/intervention) will also be tested in a step-wise
manner.
If missing outcome data is greater than anticipated (25%) we will impute them according
to current FDA/NAS/NRC recommendations using multiple imputation with chained
equations 86-88.  Specifically, multiple imputation creates 20-40 complete datasets with
plausible values from the model-based predictive distributions, and pooled estimates and
standard errors are obtained through the use of Rubin’s combining rules.  These models are
predicated on the assumption that the data are missing at random (MAR).  Finally, the
robustness of the inferences about treatment effects to violations of the MAR assumptions
will be evaluated through a sensitivity analysis 88.
9.3.2 
Planned Sub-group Analyses
 Sub-group analyses may require adjustment for prognostic imbalances, as the effect of
randomization may not be preserved.
Gender analysis: A sub-group analysis is planned by gender as effect of exercise may vary
by gender.
Physical activity level: A subgroup analysis is planned by quartiles of baseline physical
activity level as measured by accelerometry at baseline. Level of baseline physical activity
may modify the effect of the intervention and is an important potential confounder.
 On protocol analysis: Non-adherence to the exercise intervention may modify the effect of
the intervention and is an important potential confounder.  Therefore, a pre-specified
analysis of the primary outcome will be performed “on protocol”, defined by adherence to

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intervention protocol as defined by completion of 70% or greater of exercise sessions during
the intervention period.
9.3.3 
Secondary Outcomes and Analyses
 We will repeat the primary outcome analyses that compared change in DSI from
baseline to 12 weeks between groups, instead looking at change from baseline to
26 weeks and 52 weeks.
 Change in EQVAS over time will be compared between study groups using
Student’s T-test. As well, we will compare the difference in proportion of
individuals who develop new deficits (score of 2 or 3) in each domain of the EQ5D-
5L over time. The degree to which change in symptom burden correlates with
change in EQVAS will be assessed using Spearman and Pearson’s correlation
coefficients as indicated based on distribution of the data. Change in all other
secondary outcomes over time will be compared between groups using the
appropriate parametric and non-parametric statistical tests depending on data
type and distribution. Bonferroni adjustments will be made for secondary
outcomes to adjust for multiple study timepoints. Hospitalization will be analyzed
using Poisson regression. For all analyses, two-sided p < 0.01 will be statistically
significant. Statistical analysis will be performed using SAS 9.3 (Carey, NC).
We will validate the Godin Shepard Leisure-Time Exercise Questionnaire using
accelerometry data. Correlation between Godin Questionnaire Score and active minutes
(light, moderate and moderate-vigorous activity) measured by accelerometry at each study
assessment time point will be assessed using Pearson or Spearman correlation depending
on distribution of the data. Internal consistency of the Godin questionnaire will be assessed
using Cronbach alpha and Intraclass Correlation Coefficient. In those individuals in which
active minutes measured using accelerometry did not change between assessment periods
(change of less than 10% from baseline), test re-test reliability of the Godin Questionnaire
will be assessed using Kappa statistic. Responsiveness will be modelled using linear
regression with Godin questionnaire score as the primary predictor of active minutes
measured by accelerometry. Additional predictors including sex, age, diabetes and other
comorbidities will be added to the model as sample size will allow.
9.3.4 
Demographic Data
 Statistical presentation for baseline and demographic characteristics will be reported.
Specifically, we will compare baseline descriptive variables between study groups using
independent two-tailed t-test or Mann Whitney U test for continuous variables and Chi-
square test for categorical variables, as appropriate. Similarly, individuals who complete the
study protocol will be compared to those who do not. As per the latest FDA/NRC/NAS
guidelines for the treatment of missing data in clinical trials, the same data will be tabulated

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for patients with incomplete records.  If missing outcomes are greater than 25%, multiple
imputation techniques will be used as per FDA recommendations.88
9.3.5 
Study Completion
 The percent of participants who complete the study, losses to follow-up, times to lost to
follow-up, and reasons for discontinuation (e.g., adverse events) will be presented.
9.3.6 
Final Study Analysis
 The final study analysis will report the results of the above statistical analysis plan.  Any
additional analyses will be identified as ad hoc.  A final clinical studies paper(s) will be
prepared.

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10
STUDY ADMINISTRATION AND ETHICAL CONSIDERATIONS
10.1 
Source documents and Access to Source Data/Documents
 The study site will maintain appropriate medical and research records for this study, in
compliance with ICH-GCP, and institutional requirements.
In this study, CRFs will be the primary record of the patients’ participation in the study, but
will be supplemented by hard copy documentation of outcome assessments (e.g.
completed surveys).
10.2 
Ethics Approval
 Submission of this protocol and the required participant-related documents (consent
form, advertisements) will be made to site’s REBs and/or for institutional review (if
required). Written approval from the REB will be obtained in writing prior to
implementation.  Any changes made to the protocol and participant-related documents will
be submitted for review and approval prior to implementation. Study status will be reported
annually or more frequently if required.  A final study notification will be forwarded at
completion of the study or in the event of early termination.  All serious adverse events and
protocol deviations (if applicable) will be submitted for review.
10.2.1 Protocol Deviation Definitions
Protocol Deviation: The investigators and site staff will conduct the study in accordance to
the protocol; no deviations from the protocol are permitted.  Any change, divergence, or
departure from the study design or procedures constitutes a protocol deviation. As a result
of any deviation, corrective actions will be developed by the site and implemented
promptly. Protocol deviations may be major or non-major.
Major Protocol Deviation (Protocol Violation): A protocol violation is a deviation from the
ethics-approved protocol that may affect the participant's rights, safety, or well-being
and/or the completeness, accuracy and reliability of the study data. In addition, protocol
violations include willful or knowing breaches of human subject protection regulations.
Non-Major Protocol Deviation: A non-major protocol deviation is any change, divergence,
or departure from the study design or procedures of a research protocol that does not have
a major impact on the participant's rights, safety or well-being, or the completeness,
accuracy and reliability of the study data.
10.2.2 Reporting and Managing Protocol Deviations
 As per ICH GCP, the Investigator should not implement any deviation from, or changes of
the protocol without prior review and documented approval/favorable opinion of the ethics
committee or institutional review board of an amendment, except where necessary to
eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only

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logistical or administrative aspects of the trial (e.g. change in monitor(s), change of
telephone number(s)). All protocol deviations (both minor and major) that have not
received prior approval by the ethics committee must be reported to the ethics committee
as per their applicable reporting requirements.  The study coordinator will report all
protocol deviations to the study PI. Where safety is involved, the DSMB will also be notified.
10.3 
Informed Consent Process
 Voluntary written informed consent will be obtained from all participants.  A member of
the site’s research team (study coordinator or research nurse) will review the consent with
the participant and answer questions.  Participants will be given both verbal and written
information that provides a detailed description of the study.  Participants will be provided
adequate time to consider the risks and benefits associated with their participation in the
study (at least 48 hours).  They will be told that participation in the study is voluntary and
that he or she may withdraw from the study at any time without penalty, and the decision
will not impact their standard medical care.
 The procedures for conducting informed consent will be documented in the participant’s
study record.  All participants will read, sign, and date a consent form before undergoing
any study procedures.  Consent materials will available in English and the information will
be provided with assistance of a translator as requested.  A copy of the signed consent will
be given to the participant.  All original signed consents will be filed in the study binder and
maintained in PI’s office.
 The consent process will be ongoing.  The consent form will be revised when important
new safety information is available, the protocol is amended, and/or new information
becomes available that may affect participation in the study.
10.4 
Participant and Data Confidentiality
 All members of the research team will respect study participants’ privacy and
confidentiality throughout the study.  Measures will be taken to ensure that all of the data
collected for this study will remain confidential in accordance with privacy legislation.  Study
personnel will not transmit documents, other than that previously specified, or samples
containing personal health identifiers (PHI) at any time over the course of the study.  Each
participant will be assigned a unique code and these numbers rather than names will be
used to collect, store, and report participant information.  Full names and other identifying
information will not be revealed unless required by law and/or for the applicable REB
review, or for auditing purposes.  The Subject Identification Code List that links the identity
of the participant with subject ID for de-identified data will be maintained with the trial
master file, according to ICH-GCP, Section 8.3.  The master file will be maintained both in
electronic and paper copy format.  The electronic file will be encrypted and stored on a
dedicated research server that only the PI and study research staff will have access to.  The
identity of the participants will not be revealed in any published data or in presentation of
the information obtained as a result of this study.  Findings will be reported in aggregate.

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10.5 
Data Collection and Management
 Data will be submitted for every participant who is enrolled in the study, regardless of
duration via paper Case Report Form or through a secured electronic data capture system
(i.e. REDCap). Data available from the source documents will be either transcribed onto the
paper CRF or input directly into the database (i.e. REDCap).  No identifiable information will
be entered.
 Paper CRFs will be completed in black or blue ink only and be legible.  If an entry on a CRF
requires change, the correction will be made by drawing a single line through the incorrect
entry, followed by entering the correct data and initialing and dating the entry.  Correction
fluids, markers, erasures or any form of obliteration on the CRFs will not be permitted.  All
fields will be completed.  If data are not available, a straight line will be drawn through the
applicable fields and the words “None” or “N/A” will be written.  The study research
assistant will be responsible for entering the data into the secure, password-protected
computerized REDCap database.
 Collected Participant data will be audited for completeness and accuracy by the study
team every 6 months (10% of records will be audited). Queries will be generated for
incomplete, unreadable and/or multiple responses to single-response entries. The Data
Query Form will be given to the member of the research team for correction, clarification,
and signature. Data will be amended based on receipt of the signed and returned Data
Query Form. The completed Data Query Form will be retained with the original completed
CRF.  Data queries not returned or resolved will be coded as missing values in the database.
 Additional queries may be generated following a secondary review of the entered data.
Once this process has been completed, and all queries have been resolved, a third (and
final) review of the database will be done in preparation for analysis.  Following the final
review of the database, the database will be locked for the purposes of the primary
analyses. Data will be de-identified and used solely for the purposes of generating aggregate
datasets for analysis of the endpoints specified in the study.
10.6 
Study Records Retention
 Study records will be retained for 10 years after study completion. When the archiving
requirements have expired, any written records associated with this study will be destroyed
using confidential shredding and the electronic database used for analysis will be deleted.
10.7 
Publication and Data Sharing
Data arising from this study is the property of the Sponsoring Site, but it is the function
of the Study PI to disseminate information and make it available to the public.  Findings
from this study will be presented at national and international scientific conferences and
published in peer-reviewed journals. The identity of participants will not be revealed in

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any published data or in presentation of the information obtained as a result of this study.
This study is registered with ClinicalTrials.gov (NCT02259413) as per the requirement of
the ICMJE.
 De-identified data collected in this study may be shared with other researchers according
to international guidelines (ICJME). Before publishing/sharing any data, it will be reviewed
with the REB to ensure full compliance with privacy legislation.
 De-identified participant data that underlie the results of study, will only be available to
original study investigators, whose proposed use of data has been approved by the Study
PI and an independent review committee for meta-analysis and to achieve the aims of the
study.  This de-identified data will be available following publication of the study results,
with no end date.  To gain access researchers will need to sign a data access and
confidentiality agreement.  All published data will be available ONLY in de-identified
manner.

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44. 
Mujais SK, Story K, Brouillette J, et al. Health-related quality of life in CKD Patients:
correlates and evolution over time. Clin. J. Am. Soc. Nephrol. 2009;4:1293-1301.
45. 
Unruh ML, Levey AS, D'Ambrosio C, et al. Restless legs symptoms among incident
dialysis patients: association with lower quality of life and shorter survival. Am. J. Kidney
Dis. 2004;43:900-909.
46. 
Palmer SC, Vecchio M, Craig JC, et al. Association between depression and death in people
with CKD: a meta-analysis of cohort studies. Am. J. Kidney Dis. 2013;62:493-505.
47. 
Guidon M, McGee H. One-year effect of a supervised exercise programme on functional
capacity and quality of life in peripheral arterial disease. Disability and rehabilitation.
2013;35:397-404.
48. 
Lawler PR, Filion KB, Eisenberg MJ. Efficacy of exercise-based cardiac rehabilitation
post-myocardial infarction: a systematic review and meta-analysis of randomized
controlled trials. Am. Heart J. 2011;162:571-584 e572.
49. 
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measures in patients undergoing long-term hemodialysis: a randomized controlled trial. Am
J Kidney Dis. 2009;54:511-521.
50. 
Greenwood SA, Lindup H, Taylor K, et al. Evaluation of a pragmatic exercise rehabilitation
programme in chronic kidney disease. Nephrol. Dial. Transplant. 2012;27 Suppl 3:iii126-
134.

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51. 
Weisbord SD, Fried LF, Arnold RM, et al. Development of a symptom assessment
instrument for chronic hemodialysis patients: the Dialysis Symptom Index. J. Pain
Symptom Manage. 2004;27:226-240.
52. 
Abdel-Kader K, Unruh ML, Weisbord SD. Symptom Burden, Depression, and Quality of
Life in Chronic and End-Stage Kidney Disease. Clinical Journal of the American Society
of Nephrology. 2009;4:1057-1064.
53. 
Weisbord SD, Bossola M, Fried LF, et al. Cultural comparison of symptoms in patients on
maintenance hemodialysis. Hemodialysis International. 2008;12:434-440.
54. 
Chetter IC, Spark JI, Dolan P, Scott DJ, Kester RC. Quality of life analysis in patients with
lower limb ischaemia: suggestions for European standardisation. European journal of
vascular and endovascular surgery : the official journal of the European Society for
Vascular Surgery. 1997;13:597-604.
55. 
Kind P, Dolan P, Gudex C, Williams A. Variations in population health status: results from
a United Kingdom national questionnaire survey. BMJ. 1998;316:736-741.
56. 
The_EuroQol_Group. EuroQol-a new facility for the measurement of health-related quality
of life. Health Policy. 1990;16:10.
57. 
Gerard K, Nicholson T, Mullee M, Mehta R, Roderick P. EQ-5D versus SF-6D in an older,
chronically Ill patient group. Appl Health Econ Health Policy. 2004;3:91-102.
58. 
Awuah KT, Afolalu BA, Hussein UT, Raducu RR, Bekui AM, Finkelstein FO. Time to
recovery after a hemodialysis session: impact of selected variables. Clin Kidney J.
2013;6:595-598.
59. 
Lindsay RM, Heidenheim PA, Nesrallah G, Garg AX, Suri R, Daily Hemodialysis Study
Group London Health Sciences C. Minutes to recovery after a hemodialysis session: a
simple health-related quality of life question that is reliable, valid, and sensitive to change.
Clin. J. Am. Soc. Nephrol. 2006;1:952-959.
60. 
Trost SG, McIver KL, Pate RR. Conducting Accelerometer-Based Activity Assessments in
Field-Based Research. Med. Sci. Sports Exerc. 2005;37:S531-S543.
61. 
Hooker SP, Feeney A, Hutto B, et al. Validation of the actical activity monitor in middle-
aged and older adults. J Phys Act Health. 2011;8:372-381.
62. 
Heil DP. Predicting activity energy expenditure using the Actical activity monitor. Res. Q.
Exerc. Sport. 2006;77:64-80.
63. 
Godin G, Shephard RJ. Godin Leisure-Time Exercise Questionnaire. Med Sci Sports Exerc.
1997;29:2.
64. 
Amireault S, Godin G, Lacombe J, Sabiston CM. Validation of the Godin-Shephard
Leisure-Time Physical Activity Questionnaire classification coding system using
accelerometer assessment among breast cancer survivors. J. Cancer Surviv. 2015;9:532-
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65. 
Brown CD, Wise RA. Field tests of exercise in COPD: the six-minute walk test and the
shuttle walk test. COPD. 2007;4:217-223.
66. 
Revill SM, Williams J, Sewell L, Collier R, Singh SJ. Within-day repeatability of the
endurance shuttle walk test. Physiotherapy. 2009;95:140-143.
67. 
Witham MD, Sugden JA, Sumukadas D, Dryburgh M, McMurdo ME. A comparison of the
Endurance Shuttle Walk test and the Six Minute Walk test for assessment of exercise
capacity in older people. Aging Clin. Exp. Res. 2012;24:176-180.

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68. 
Houchen-Wolloff L, Boyce S, Singh S. The minimum clinically important improvement in
the incremental shuttle walk test following cardiac rehabilitation. Eur J Prev Cardiol.
2015;22:972-978.
69. 
Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J.
Gerontol. A Biol. Sci. Med. Sci. 2001;56:M146-156.
70. 
Bao Y, Dalrymple L, Chertow GM, Kaysen GA, Johansen KL. Frailty, dialysis initiation,
and mortality in end-stage renal disease. Arch. Intern. Med. 2012;172:1071-1077.
71. 
Resnick B, Jenkins LS. Testing the reliability and validity of the Self-Efficacy for Exercise
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Shaughnessy M, Resnick BM, Macko RF. Reliability and validity testing of the short self-
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75. 
Rigatto C, Walsh M, Zalunardo N, et al. Establishing a Canadian national clinical trials
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K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am. J.
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Marciniuk DD, Watts RE, Gallagher CG. Reproducibility of incremental maximal cycle
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American_College_of_Sports_Medicine. Chapter 10: Exercise Testing for Other Clinical
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80. 
Smart NA, Williams AD, Levinger I, et al. Exercise & Sports Science Australia (ESSA)
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81. 
Program MR. Cycing on Hemodialysis. Vol 2017. Winnipeg, MB2016.
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Suh MR, Jung HH, Kim SB, Park JS, Yang WS. Effects of regular exercise on anxiety,
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Groenwold RH, Donders AR, Roes KC, Harrell FE, Jr., Moons KG. Dealing with missing
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Groenwold RH, Moons KG, Vandenbroucke JP. Randomized trials with missing outcome
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88. 
Little RJ, D'Agostino R, Cohen ML, et al. The prevention and treatment of missing data in
clinical trials. N. Engl. J. Med. 2012;367:1355-1360.

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12 APPENDICES
Appendix 1.  List of Abbreviations
Abbreviation
Definition
AE
Adverse Effect
CKD
Chronic Kidney Disease
CANN-NET
Canadian Knowledge Translation and Generation
Network
CHI
Centre for Healthcare Innovation
CIHR
Canadian Institutes of Health Research
CORR
Canadian Organ Replacement Registry
CNTN
Canadian Nephrology Trials Network
ECC
End Stage Kidney Disease
ESKD
End Stage Renal Disease
DSI
Dialysis Symptom Index
EQ5D-3L
EuroQol 5 Dimension – 3 Levels
EQ-VAS
EuroQol Visual Analogue Scale
HRQOL
Health-related Quality of Life
HD
Hemodialysis
ICH
International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use
(ICH)
KFOC
Kidney Foundation of Canada
MRP
Manitoba Renal Program
NCI-CTCAE
National Cancer Institute Common Terminology
Criteria for Adverse Events
RCT
Randomized Controlled Trial
SAE
Serious Adverse Effect
SD
Standard Deviation
WI
Wellness Institute

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Appendix 2.  Study Definitions
Early discontinuation
The study participant will be considered an “early discontinuation” in the event that
they withdraw from the study during the initial 6 months of the study (withdrawal of
consent, adverse effects etc.).
Intent-to-Treat sample
All randomized participants who receive the exercise intervention/standard-of-care
Lost to Follow-up
Study participants may be considered “lost to follow up” after the subject misses a
minimum of 2 consecutive study visits, and the site personnel has made a number of
unsuccessful phone contacts.  The decision to early terminate the subject will be the
decision of the PI, all attempts to establish contact with the subject will be documented
in the study files.
Protocol Mandated
Procedures
Any procedure performed solely for the purpose of this research study (not site-specific
standard of care)
Randomized
A participant who has met all eligibility criteria; met with the study investigator or
designee to discuss the study purpose, requirements (i.e. time requirements, schedule
of events etc), discussed all the risks and benefits; signed the informed consent
document and was randomly assigned to one of the two study groups.
Study Intervention
The investigational regimen and all protocol required therapies.
This includes standardized lifestyle education, 26 weeks of cycling during HD and 26
weeks of home-based resistance exercises.
Terminated
A participant will be terminated prematurely from the study if: 1) Participant withdraws
consent; Lost to follow-up, or; death.

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Appendix 3.  Measurement Tools

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Appendix 3.1  Dialysis Symptom Index
Instructions
Below is a list of physical and emotional symptoms that people on dialysis may have. For each
symptom, please indicate if you had the symptom during the past week by circling “yes” or “no.”
If “yes”, please indicate how much that symptom bothered you by circling the appropriate
number.
During the past week:
Did you experience this
symptom?
If “yes”:
How much did it bother you?
Not
At All
A
Little
Bit
Some-
what
Quite
a Bit
Very
Much
1. Constipation
NO
YES 
1
2
3
4
5
2. Nausea
NO
YES 
1
2
3
4
5
3. Vomiting
NO
YES 
1
2
3
4
5
4. Diarrhea
NO
YES 
1
2
3
4
5
5. Decreased appetite
NO
YES 
1
2
3
4
5
6. Muscle cramps
NO
YES 
1
2
3
4
5
7. Swelling in legs
NO
YES 
1
2
3
4
5
8. Shortness of breath
NO
YES 
1
2
3
4
5
9. Lightheadedness or
dizziness
NO
YES 
1
2
3
4
5
10. Restless legs or
difficulty keeping
legs still
NO
YES 
1
2
3
4
5

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During the past week:
Did you experience this
symptom?
If “yes”:
How much did it bother you?
Not
A
Some- 
Quite
Very
At All
Little
what
a Bit 
Much
Bit
11. Numbness or
tingling in feet
NO
YES 
1
2
3
4
5
12. Feeling tired or lack
of energy
NO
YES 
1
2
3
4
5
13. Cough
NO
YES 
1
2
3
4
5
14. Dry mouth
NO
YES 
1
2
3
4
5
15. Bone or joint pain
NO
YES 
1
2
3
4
5
16. Chest pain
NO
YES 
1
2
3
4
5
17. Headache
NO
YES 
1
2
3
4
5
18. Muscle soreness
NO
YES 
1
2
3
4
5
19. Difficulty
concentrating
NO
YES 
1
2
3
4
5
20. Dry skin
NO
YES 
1
2
3
4
5
21. Itching
NO
YES 
1
2
3
4
5
22. Worrying
NO
YES 
1
2
3
4
5

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During the past week:
Did you experience this
symptom?
If “yes”:
How much did it bother you?
Not
At All
A
Little
Bit
Some
-what
Quite
a Bit
Very
Much
23. Feeling nervous
NO
YES 
1
2
3
4
5
24. Trouble falling
asleep
NO

YES
1
2
3
4
5
25. Trouble staying
asleep
NO
YES 
1
2
3
4
5
26. Feeling irritable
NO
YES 
1
2
3
4
5
27. Feeling sad
NO
YES 
1
2
3
4
5
28. Feeling anxious
NO
YES 
1
2
3
4
5
29. Decreased interest
in sex
NO

YES
1
2
3
4
5
30. Difficulty becoming
sexually aroused
NO

YES
1
2
3
4
5

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Appendix 3.2  EuroQol 5D-5L Health-Related Quality of Life Questionnaire
Health Questionnaire
English version for Canada
Canada (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group

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Under each heading, please tick the ONE box that best describes your health TODAY.
MOBILITY
I have no problems in walking about

I have slight problems in walking about

I have moderate problems in walking about

I have severe problems in walking about

I am unable to walk about

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (e.g. work, study, housework, family or leisure
activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN / DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort

ANXIETY / DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed


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The worst health
you can imagine
I am extremely anxious or depressed


We would like to know how good or bad your health is TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is TODAY.

Now, please write the number you marked on the scale in the box below.
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
YOUR HEALTH TODAY =
The best health
you can imagine

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Appendix 3.3: Godin Leisure-Time Exercise Questionnaire
INSTRUCTIONS
In this excerpt from the Godin Leisure-Time Exercise Questionnaire, the individual is asked to
complete a self-explanatory, brief four-item query of usual leisure-time exercise habits.
CALCULATIONS
For the first question, weekly frequencies of strenuous, moderate, and light activities are
multiplied by nine, five, and three, respectively. Total weekly leisure activity is calculated in
arbitrary units by summing the products of the separate components, as shown in the following
formula:
Weekly leisure activity score = (9 × Strenuous) + (5 × Moderate) + (3 × Light)
The second question is used to calculate the frequency of weekly leisure-time activities
pursued “long enough to work up a sweat“ (see questionnaire).
EXAMPLE
Strenuous = 3 times/wk
Moderate = 6 times/wk
Light = 14 times/wk
Total leisure activity score = (9 × 3) + (5 × 6) + (3 × 14) = 27 + 30 + 42 = 99
Godin, G., Shephard, R. J.. (1997) Godin Leisure-Time Exercise Questionnaire. Medicine and
Science in Sports and Exercise. 29 June Supplement: S36-S38.

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Godin Leisure-Time Exercise Questionnaire
1. During a typical 7-Day period (a week), how many times on the average do you do the
following kinds of exercise for more than 15 minutes during your free time (write on each
line the appropriate number).
a) STRENUOUS EXERCISE (HEART BEATS RAPIDLY)
(e.g., running, jogging, hockey, football, soccer, squash, basketball, cross country skiing,
judo, roller skating, vigorous swimming,
vigorous long distance bicycling)
b) MODERATE EXERCISE (NOT EXHAUSTING)
(e.g., fast walking, baseball, tennis, easy bicycling, volleyball, badminton, easy swimming,
alpine skiing, popular and folk dancing)
c) MILD EXERCISE (MINIMAL EFFORT)
(e.g., yoga, archery, fishing from river bank, bowling, horseshoes, golf, snow-mobiling, easy
walking)
Times Per Week
2. During a typical 7-Day period (a week), in your leisure time, how often do you engage in any
regular activity long enough to work up a sweat (heart beats rapidly)?
OFTEN
SOMETIMES
NEVER/RARELY
1. 
2. 
3. 

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Appendix 3.4 Shuttle Walk Test Protocol
The Shuttle Walking Test (SWT) is an objective, reproducible measure of functional capacity.  It
was originally designed for use in patients with chronic obstructive pulmonary disorders and has
been found to be a reproducible and valid outcome measure (Singh et al, 1992, 1994).
It has been used for patients attending Pulmonary Rehabilitation as a means of:
1. determining appropriate exercise intensity for individuals
2. identifying an appropriate home walking programme
3. measuring changes in functional capacity pre-and post-training.
The test is usually carried out by a Chartered Physiotherapist and, before testing, a thorough
assessment of the patient is needed to ensure the relevance and safety of testing.
Criteria

Blood pressure adequately controlled SBP < 180 mm Hg
No angina at rest/unrelated to exertion
Subject has taken all prescribed medication
Subject free from sore throat, a cold or other temporary illness
No orthopaedic problems that would be exacerbated by exercise
Testing being done ideally at least 2 hours after subject has eaten
meal
Resting pulse regular and less than 100 bpm
If subject diabetic, no hypoglycaemic episodes in past week
No strenuous physical activity on day of testing
Subject has suitable clothing/footwear
Subject gives informed consent (verbal)
Tester competent in basic life support
Access to telephone in emergency
Table 1 Pre-Test Checklist for Shuttle Walking Test

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The test itself is a scaled down version of a Bleep Test (Leger and Lambert, 1982) which involves
walking around a course identified by two cones (see fig1).
10 metres
Figure 1 Plan of Shuttle Walk Test course
The walking speed is externally paced and increases each minute (see Table 2).
LEVEL
SPEED
mph
kmph
1
1.12
1.8
2
 
1.5
 
2.4
3
 
1.88
 
3.0
4
1.26
3.6
5
 
2.64
 
4.3
6
3.02
4.9
7
 
3.4
 
5.5
8
3.78
6.1
9
4.16
6.7
10
 
4.54
 
7.3
11
4.92
7.9
12
 
5.3
 
8.5
Table 2 Shuttle Walking Test
It is important to know what limits a patient’s exercise tolerance and so the test is ‘symptom-
limited’.  In other words subjects are asked to keep going until they develop symptoms and are
unable to continue with the test (e.g. leg fatigue, breathlessness).

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Subject unable to keep up with set pace; the set pace is defined as arriving within 0.5
metres from the cone when bleep sounds
At subject’s request e.g. shortness of breath, leg fatigue, pain
At operator’s discretion if concerned re: subject’s physical status e.g. oxygen saturation
level, angina, dizziness
Table 3 Endpoints for Sub Maximal Shuttle Walking Test
The equipment needed and protocol for carrying out the test are shown in Tables 4 and 5.
Quiet, private area with non-slip surface
Minimum floor space of 15m x 3m
Shuttle Walking Test CD1
CD player
Stopwatch for pre-test calibration
2 cones set 9 metres apart
Pulse oximeter
Borg breathlessness and RPE scales
1available from Department of Respiratory Medicine, University Hospitals of Leicester, Groby Road, Leicester LE3 9QP.
Table 4 Equipment needed for Sub Maximal Shuttle Walking Test

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
Go through Pre-Test Checklist (Table 1) with subject.  If answer to any response is ‘No’ or
‘Don’t Know’, then do not carry out test

Set marker cones 9 metres apart

Fit patient with pulse oximeter

Explain Borg ratings of breathlessness and perceived exertion (RPE) and ensure subjects
understand how to use these

Play the instructions on the CD to the patient

Clarify the endpoints of the test with subject (See Table 3)

Walk round with the patient for the first or two minutes to help them establish the
correct pace (starting pace is approximately 1 mph)

Tell subject about an increase in walking speed just prior to the next triple bleep

Discourage subjects from talking while they are doing the test

Record total distance walked in metres, heart rate and oxygen saturation immediately
once sitting

Record reason for stopping test
Table 5 Protocol for Sub Maximal Shuttle Walking Test
Note: Most exercise tests are subject to a practice effect, i.e. a second test performed soon
after the first, but before any exercise training is undertaken, generally yields an improved
outcome measure.  It is therefore always preferable to conduct a practice walk and to use the
measurement from the second walk as the ‘baseline’ measurement.  Without this, any
improvement in post-training outcome is likely to be exaggerated.

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Appendix 3.5: Modified Fried Criteria
(a) Unintentional weight loss of > 10 pounds in last year
(b) Grip strength weakness (< 30 kg in males/< 20 kg in females (in strongest hand)
(c) Exhaustion as determined by 2 questions from CES-D questionnaire
(d) Slowness: established cut off for 4 metre timed walk adjusted for sex and height
(e) Low physical activity: Godin-Shephard Leisure Time Index in lowest quintile of
normative data stratified by age and sex.

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Appendix 3.6: Self-Efficacy for Exercise Survey

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Appendix 4: Knowledge Translation Strategy

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Appendix 5: COVID-19 Assessment Procedure
Renal Rehab Assessment COVID-19 Operating Procedure

Participants only on intervention for 1 month will be approached to re-start the entire
study again at HSC and SOGH (completed Mar 16, 2020)

Controls continue

No active participants currently at SBGH
Study Recruitment:

On hold until future
Activity Logs

Will be collected by Eric and Krista (study kinesiologists) by phone or email following
the timeline of the protocol
Baseline Assessments:

On hold until future
Assessments 2-4

Questionnaires (DSI, Self Efficacy, EQ-5D-5L, Godin-Shephard Physical Activity) will be
either:
o
Conducted over the phone (Eric or Krista will phone participants)
o
Emailed to participants to be filled out and emailed back (emailed by Eric or
Krista)
o
Mailed to participants with a postage-paid envelope for return to CDIC (mailed
by Eric or Krista)

Recovery time, hospitalization since last assessment, exhaustion, and weight loss
questions should still be asked

Accelerometers
o
Will not be sent out via mail to participants to avoid potential transmission of
COVID-19
o
Accelerometer data will not be collected at this time

Participant Reimbursement
o
When assessments are completed the participant will be mailed a $25
VISA/Mastercard gift card and a signature page with a postage-paid envelope
for return

This envelope should be addressed to be returned to CDIC
o
Monica (research coordinator) will be mailing the gift cards out from home
o
Participant addresses will be emailed to her over the secure WRHA email in a
password protected document and deleted once letter addressed

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o
Signature pages will be collected in CDIC and given to Krista to compile and
determine if a participant needs to be contacted again

Physical Tests (Shuttle Walk, Gait Speed, Hand Grip Strength)
o
Unable to be completed at this time

Clinical Outcomes Data Collection (chart reviews)
o
Chart reviews for assessments conducted after March 16th will be completed
once research staff are able to return to work on dialysis units
Site Specific Procedure
Sherbrook Dialysis Unit (Eric still required to report to work for clinical component of his
position as per Manitoba Renal Program)
1. Call participant a week before scheduled assessment to select a time that works for
them
2. Call participant day of assessment at chosen time and go over questions and
questionnaires
3. Tell participant to expect $20 in an envelope given to them by a nurse and a signature
page for them to sign
4. Call participant to confirm receiving $20 and to remind them to return the signature
page to their HD nurse who will drop this envelope off in Eric’s SCDU office mailbox
5. Confirm that signature sheet was returned signed and dated with Clara or Krista
Health Sciences Centre Dialysis Units (CDU, PHDU, GG7) and Seven Oaks Units
1. Call participant a week before scheduled assessment to select a time that works for
them
2. Call participant day of assessment at chosen time and go over questions and
questionnaires
3. Tell participant to expect a $25 gift card in the mail along with a signature page and a
postage-paid envelope
4. Mail out gift card to participant with signature page and a return postage-paid
envelope once assessment is complete

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5. Call participant to confirm receiving the gift card and to remind them to return the
signed signature page via mail to CDIC
6. Confirm that signature page was returned signed and dated with Clara or Krista
St. Boniface Dialysis Units
No active participants
* Mail option will be given to participants who do not want to or are unable to complete
the questionnaires via phone or email.