Hemodialysis-based Interventions to Preserve Cognitive Function
Phase: NA
Conditions: ESRD
Sponsor: Johns Hopkins University

COVER PAGE 
1/18/2023 
Title: “Interventions Made to Preserve Cognitive Function” 
# NCT03616535 

Date:   January 18, 2023 
Principal Investigator:  Aarti Mathur 
Application Number: IRB00152858 
JHM IRB - eForm A – Protocol 
*************************************************************************************************** 
Abstract 
End-Stage Renal Disease (ESRD) is a growing public health challenge in the United States. More than 
640,000 adults in the US suffer from this devastating chronic condition (1). With a growing prevalence of 
obesity, hypertension, and diabetes, it is estimated that there will be >1 million ESRD patients by 2025.  
Hemodialysis (HD) is the most common form of renal replacement therapy and represents a great burden for 
ESRD patients. More than 95% of newly diagnosed patients initiate HD, and HD is often their only long-
term treatment option (1). The only alternative is kidney transplantation (KT), but with a waiting list of 
nearly 100,000 patients, a substantial amount of time is spent on HD waiting for KT (1). HD is performed at 
least 3 times a week for 4-6 hours per session and continues for the patient’s lifetime or until successful KT.  
Using national claims data on 356,668 HD patients, we found that dementia incidence among HD initiates 
are 10-times that of community-dwelling older adults (2). Even younger HD patients are at elevated risk of 
dementia, which is unheard of in non-HD patients.  
Executive function refers to the ability to flexibly select and inhibit information, understand abstract 
meaning, innovate ideas, and maintain an active goal. It is essential for complex daily tasks including 
decision-making, problem solving, and planning. Declines in executive function have important clinical 
implications including decreased quality of life, personal safety issues, and loss of functional independence. 
Executive function impairment is an early sign of dementia and Alzheimer’s disease (3, 4). Many patients 
already have partially compromised cognition at HD initiation (6-8), which accelerates while undergoing HD 
(9, 10). Only 13% of prevalent HD patients have normal cognition (11) and clinicians often fail to recognize 
declining cognition among patients who are undergoing HD (12). Executive function is the domain of 
cognition which is most impacted by HD initiation (13). HD patients suffer from a 3-fold higher rate of 
executive function impairment than general population (14) and 38% of prevalent HD patients have severe 
impairments in executive function (15). Executive function impairment is not limited to older HD patients; it 
crosses the age spectrum (15). Severe executive function impairment impedes HD patients’ ability to comply 
with their dialysis schedule, maintain complicated medication regimens for chronic conditions, retain the 
capacity for independence and self-care (18-20), make informed decisions, and adhere to fluid and dietary 
restrictions (12), leading to death (14, 21). 
Kidney disease and dialysis significantly impact cognitive function; while the only effective interventions for 
preserving cognitive function among community-dwelling older adults are cognitive training (CT), and/or 
exercise training (ET), these modalities have not been tested for cognition preservation in hemodialysis 
patients. We will perform a randomized controlled trial of 200 hemodialysis initiates to test whether CT, ET 
and combined CT+ET while undergoing hemodialysis preserves executive function compared to standard of 
care (SC).Participants will undergo assessments for executive function, global cognitive function, physical 
function, frailty status, quality of life and patient centered outcomes at study entry, 3 months, and 6 months 
of interventions. Participants randomized to CT will play tablet-based brain-games (Lumosity) and those 

randomized to ET will be given a stationary foot peddler.  Participants randomized to CT+ET will start with 
CT (tablet based brain games) followed by ET after a 15 minute break. We will administer the interventions 
for six months. The primary outcome is change in executive function measured by the Trailmaking Test A 
and B (TMTA/B) scores between enrollment and 3 months of intervention. Global cognitive function will be 
a secondary cognitive outcome and will be assessed using the Montreal Cognitive Assessment (MoCA). 
Changes in secondary cognitive outcomes between baseline and 3 months will be studied. We will also 
consider the 6-month change in all global cognitive function and executive function as a secondary outcome. 
The findings from this RCT will provide nephrologists who care for this vulnerable population with the first 
feasible and effective interventions for their patients who are at risk for experiencing executive function 
decline. 
Objectives 
Primary Objective: The primary objective is to determine if receiving CT, ET, or CT+ET preserves 
executive function relative to those with SC.  
Secondary Objectives: The secondary objectives are to compare the rates of secondary cognitive outcomes, 
ESRD-specific clinical outcomes and patient-centered outcomes among those receiving CT, ET, or CT+ET 
relative to those in SC. 
Background and Significance 
Cognitive decline is a growing concern not only in the general population but also among patients 
undergoing dialysis. The consequences of this cognitive decline are profound and impact morbidity and 
mortality. Through this study, we hope to identify interventions to preserve cognitive function and develop 
implementation tools to help disseminate these interventions to dialysis centers nationally. 
In a survey we conducted of 101 HD patients, the activities most reported during HD were watching TV 
(87%), talking (76%), and sleeping (67%). Ninety-five percent participated in passive activities, and <1% 
reported exercising while on dialysis. The time spent on HD may be a missed opportunity to improve the 
health of ESRD patients.  
In a longitudinal study of 324 HD patients, executive function impairment occurs in 11% of new HD patients 
during the first year on HD (16). Even though HD patients experience executive function decline due to 
aging and CVD, HD itself impacts the decline. HD independently leads to poor executive function through 
the retention of uremic toxins (17) and by inducing recurrent cerebral ischemia (14). Mortality rates for HD 
patients with poor executive function are comparable to those with diagnosed dementia (22), a highly 
vulnerable group of HD patients (23). 
Studies of executive function decline come primarily from gerontology.  In older adults, non-pharmacologic 
interventions like cognitive training (CT) can prevent executive function decline. CT (24, 25) is a promising 
non-pharmacological intervention to slow executive function decline in otherwise healthy older adults. CT 
prevents age-related declines in key areas of executive function including abstraction, working memory, 
verbal reasoning, and inhibition (18, 19, 26-30) by improving the neural structures that mediate executive 
function (31-33). Multi-domain approaches to CT, rather than memory training alone, have been associated 
with broad and lasting gains in healthy older adults (30, 34, 35) and benefits of CT are observable up to 10 
years post-training (28). CT is an important non-pharmacological intervention that has not been tested in HD 
patients. 

Exercise training (ET), another effective non-pharmacological intervention (25, 36-38), has the greatest 
impact on executive function in older adults (39-44). Even prior to improving physical function and strength 
(45), ET in older adults improves executive function (44) through increased: 1) cerebral blood flow (46); 2) 
brain volume in the prefrontal cortex and hippocampus (47-49); 3) brain-derived neurotrophic factor (50-54); 
and 4) engagement of neural structures. ET reduces inflammatory markers (C-reactive protein, tumor  
 
necrosis factor alpha, and IL-6) improving brain plasticity and executive function (51, 55). Even a single ET 
session changes neurophysiology and executive function (56-58). ET has a stronger impact on cognitive 
function and cortical thickness than it does on aerobic fitness (38). 
 
CT and ET are the only two effective non-pharmacological interventions to impact executive function in 
older adults. CT+ET over 3 months improved executive function (29, 45, 50, 59) and is more effective than 
either CT or ET alone (31, 50). CT+ET enhances synaptic connections between brain cells and improves 
brain plasticity (60, 61). To our knowledge, no studies have tested whether CT+ET impacts executive 
function among HD patients. 
 
Although all intervention studies designed to preserve executive function have been conducted in older 
adults, this population has a very different physiology and distinct risk factors for executive function decline. 
Therefore, these interventions must be tested in HD patients to draw appropriate inferences about their safety 
and effectiveness. 
 
Our pilot RCT of 20 HD patients suggests that intradialytic 
CT and ET prevent the profound decline in executive 
function. After 3 months, participants in the intradialytic CT 
(Lumosity® on a tablet) and ET (foot peddlers) arms had 
less decline in executive function than those with standard 
of care (SC), based on the Trail Making Test (TMTA and 
TMTB) times (Figure) (McAdams-DeMarco, Under Review 
J Neph). Strikingly, the improvement in TMTB was nearly a 
minute greater for those in the CT (difference= 47 seconds; 
P=0.03) and ET arms (difference= 56 seconds; P=0.03), 
compared with those in the standard of care arm.  
Our pilot study of physicians (n=41, 87% response rate) 
found that 57% believed their ESRD patients could improve 
cognitive function through intradialytic CT, such as playing 
tablet-based brain games, and 83% agreed that intradialytic ET, such as using a foot peddler, would improve 
physical function. They believed their patients would be interested in these interventions (CT: 87%; ET: 
83%) and the logistics would be feasible in a dialysis clinic (CT: 93%; ET: 80%). Among HD patients 
(n=91, 97% response rate), 67% wanted to improve their cognition through intradialytic CT, and 71% 
wanted to improve their strength and cognition through intradialytic ET. 
 
Summary of Significance: There is a high burden of ESRD in the US and most patients undergo time- 
intensive HD treatment during which interventions could be administered. Replacing passive intradialytic 
activities with cognitively beneficial activities is a missed opportunity. CT and ET are the only two effective 
non-pharmacological interventions to preserve executive function, which is supported by our pilot data. The 
findings from this RCT will provide nephrologists who care for the vulnerable population of HD patients 
with the first feasible and effective interventions for their patients who are at risk for experiencing executive 
function decline. Interventions are needed to target the prevention of executive function decline, rather than 
simply attempting to reverse decline or regain executive function. 
 
Progressive Cognitive Decline
-20
0
20
40
60
Cognitive Training
Exercise Training
Standard Care
TMTA
TMTB
TMTB-TMTA
Mean Change in TMTA and TMTB Time at 3 Months (Seconds)
Improved Time
Worse Time

 
 
 
 
 
Study Procedures 
 
This is a 2 by 2 factorial randomized controlled trial (RCT). We will randomize participants to CT alone, ET 
alone, both CT+ET, or SC resulting in four arms. Randomization will be achieved through balancing 
methods over the three stratification factors: study center, sex, and 
race/ethnicity.
 
Study Population:  Men and women with ESRD and receiving maintenance HD 2-3 times weekly at one of 
the 13 hemodialysis centers participating in the trial will be eligible. We will only enroll new HD patients, as 
has been done in other RCTs (89-91) of HD patients. The rationale for enrolling new HD patients are: 1) 
they will not have already experienced the executive function decline associated with HD; 2) there is a high 
dementia incidence even within the first year of HD; 3) survival bias is present when studying prevalent HD 
patients; and 4) we want to intervene before the neurodegenerative process begins. 
 
Inclusion Criteria: 
Participants must be: 
• Within 3 months to 3 years of initiating HD 
• 18 years or older at enrollment 
• English-speaking 

• Willing to participate in research 
 
Exclusion Criteria: 
Patients with the following conditions will not be included in the study: 
• Pregnancy 
• Angina pectoris 
• Chronic lung disease requiring oxygen 
• Musculoskeletal conditions that limit mobility 
• Upper or lower extremity amputation 
• Orthopedic disorders exacerbated by physical activity 
• Femoral arteriovenous (AV) access 
• Blindness/ Legal blindness 
• Hepatitis B infection 
• Inability to recognize letters and numbers 
 
In addition to patients with these conditions, patients who are currently incarcerated will be excluded from 
the study.  
 
All potential female participants of childbearing age will be asked if they are currently pregnant during initial 
contact by a study team member to introduce the study. 
 
Recruitment/Enrollment: We will recruit approximately 200 adult ESRD patients from Fresenius Kidney 
Care Hemodialysis Centers and DaVita Dialysis centers located in the greater Baltimore, Maryland area, 
where we expect 240-250 eligible participants will be receiving HD. The treating provider at the HD center 
will be required to approve that it is safe for the patient to enroll. 
 
Participating Dialysis Centers: 
Fresenius Kidney Care Centers:  Fresenius Kidney Care Caroline Street, Fresenius Kidney Care Broadway 
Street, Fresenius Kidney Care Merritt Boulevard of Dundalk, Fresenius Kidney Care Fleet Street, Fresenius 
Kidney Care Nashua Court, Fresenius Kidney Care Dundalk, Fresenius Kidney Care Cross Keys, Fresenius 
Kidney Care White Marsh, Fresenius Kidney Care Anne Arundel, Fresenius Kidney Care Greenspring Drive 
(Lutherville-Timonium) 
 
DaVita Dialysis Centers: DaVita Downtown Dialysis, DaVita 25th Street Dialysis, DaVita Greenspring 
Dialysis, and DaVita Good Samaritan Dialysis 
 
Recruitment/Enrollment at Fresenius Kidney Care Centers:  
We have obtained a HIPAA waiver to access patient medical records so we may generate a list of potential 
participants and check for eligibility. The PI/Project Manager/Study Coordinator, or Frenova staff will access 
the Fresenius Kidney care electronic medical records to identify eligible participants. Additionally, we will 
provide the clinics with our study brochure for distribution to patients to inform them of the study. If they are 
interested in hearing more about the study, they may contact us directly. All patients at participating 
Fresenius dialysis centers who meet eligibility criteria will be contacted either by phone or in person by a 
research assistant to describe the study. If they are interested in participating in the study and agree to 
participate, they will provide informed consent and enrolled. 
 
Recruitment/Enrollment at DaVita Dialysis Centers:  
The DaVita nephrologist/nurse practitioner will identify potential participants and establish eligibility. All 
patients who meet the eligibility criteria will be contacted by the DaVita nephrologist/nurse practitioner to 

introduce the study and ask if they are interested in learning more. If the patient agrees and would like more 
information about the study, the nephrologist/nurse practitioner will ask them to sign a DaVita “HIPAA 
Authorization to Use and Disclose Information for Research Purposes” form so their information may be 
shared with our study team and we can provide them with more information about the study. DaVita will 
provide the Program Manager with a list of eligible potential participants with signed DaVita HIPAA 
authorization forms. Our research team will contact patients on the list either by phone or in-person to 
discuss the study and if they are interested and agree to participate, they will provide informed consent and 
enrolled.  
 
Participants will be enrolled at 4 locations in New York City: The Lower Manhattan Dialysis Center 1,  The 
Lower Manhattan Dialysis Center 2, River Renal Services, Inc. and Chinatown Dialysis Center, LLC. The 
NYU Langone Health study team will analyze and collect data for this study.  
 
Timeline: We will administer the interventions in two waves. In wave 2 (2 years after the start of the study), 
we will return to the dialysis centers in the first wave and begin enrollment again. This will allow us to 
identify new HD patients at each center. We will allow 1 month for identification of participants, initial 
contact by a research assistant, and baseline assessment as described below. Participants will be followed for 
1 year after the end of the intervention for mortality and hospitalization. 
 
Randomization: 
We will randomize participants after completion of the baseline assessments. Participants will be block 
randomized (i.e., stratified over time) and stratified by sex, race/ethnicity, and dialysis center. They will be 
randomly assigned to one of the four study arms using a blind and secure computer based allocation system: 
a) 6 months of CT alone, b) 6 months of ET alone, c) 6 months of CT+ET, d) standard of care. We will 
use block sizes of four to ensure desired sizes in each arm. Given the nature of our interventions, it is not 
possible to blind the participant, treating provider and other HD center staff. 
 
Intradialytic Interventions to Preserve Executive Function: 
 
Cognitive Training: Participants randomized to CT will play “brain games” on a WiFi connected tablet 
through Lumosity®, a web-based cognitive training program. Lumosity® is available for research purposes 
and has been used for CT interventions across a variety of research settings (36, 79-81). Lumosity® is 
available in English, Spanish, French, Portuguese, German, Japanese, and Korean. We chose this 
intervention because it is well recognized and regarded as a fun activity leading to increased participation 
and adherence. At each HD session, participants will have 10 different brain games to play and the games 
will vary for each session. The CT brain games do not teach a specific cognitive domain. We will test 
whether there is a transfer of training to executive function. This is important to show that we are not just 
teaching to the test, which can occur when the cognitive exercise is the same as the outcome.  
 
We will configure the tablets to turn off all other features and participants will have access only to the “brain 
games” feature.  
 
Exercise Training: Participants randomized to the ET arm will be given a stationary foot peddler, which will 
be placed at a distance from the dialysis chair that is comfortable for the patient. We will adjust the 
resistance for each participant. The Program manager/Study Coordinator will supervise the first ET sessions 
and will train research assistants to set up the equipment. To standardize the dose of ET, all ET will start 
with a 2 minute warm up, then the resistance will be adjusted so that participants are working at perceived 
exertion of “somewhat strong,” using the Borg scale (87) (~50 rpm). Resistance will be increased when the 
rating falls below “somewhat hard.” Blood pressure (SBP/DBP) will be routinely monitored throughout the 
session and will be kept between 110/50-150/90 mmHg. Heart rate will also be routinely monitored and kept 

at <80% of maximum heart rate, which is calculated (220-participant age). This approach is consistent with 
previous intradialytic ET (75). We will substitute elastic stretch bands if participant becomes unable to use 
the foot peddlers. 
 
Participants randomized to either CT or ET will engage in the activity for a minimum of 30 minutes during 
each HD session. After 15 minutes on HD, the research assistant will approach the participant to initiate the 
intervention. For those in the CT+ET arm, participants will start with 30 minutes of CT, followed by a 15-
minute break, and then 30 minutes of ET. Participants will be allowed to continue with their assigned 
intervention for longer if needed.  
 
A research assistant will be on site throughout the duration of the interventions to set up tablets and foot 
peddlers, assist participants if needed, monitor safety related to intervention arms, and collect tablets and foot 
peddlers after participant have completed their assigned intervention for the day. Any safety concerns will be 
recorded and reported immediately to the Principal Investigator. 
 
 
Disinfection Protocol: 
iPads/Tablets: iPad devices can only be used in the patient treatment area with a protective cover that can be 
disinfected. IPad devices will be disinfected before leaving the patient’s chairside and before being placed 
back into the storage unit to be recharged. It must be disinfected before being provided to another patient. 
iPad devices should be cleaned with a soft cloth dampened with an EPA registered tuberculocidal “hospital 
disinfectant” or a 1:100 dilution of bleach (300-60 mg/L free chlorine). A saturated cloth MUST NOT be 
used to clean the device; wring out excess solution so the cloth is dampened, not saturated. Any blood or 
body fluid contamination should be cleaned immediately. The cover should be removed, and both the cover 
and device cleaned thoroughly. Do not use window cleaners, household cleaners, aerosol sprays, solvents, 
alcohol, ammonia or abrasives on the iPad device itself. After use, all equipment and supplies must be 
considered as potentially blood contaminated, and should be separated, handled with caution and either 
disinfected or discarded. 
 
Alcohol products shall not be used to disinfect large environmental surfaces. When mixing bleach solutions, 
staff must wear personal protective equipment (PPE), including disposable gloves, face shield or eye 
protection with full side shields and fluid-resistant gowns. 
 
Exercise Peddlers: Foot peddlers will be disinfected with an EPA registered tuberculocidal “hospital 
disinfectant” or 1:100 dilution of bleach (300-600 mg/L free chlorine). Foot peddlers will be disinfected 
following the same protocol outlined for iPads/tablets. 
 
Baseline Assessments: After establishing eligibility, a research assistant will perform a baseline assessment 
for each participant at each center. Our trained research assistants will assess physical function, Health 
Related Quality of Life (HRQOL), frailty status, patient-centered outcomes, and executive and global 
cognitive function at enrollment. These scales have been studied and validated in ESRD (92-97). The 
baseline assessment consists of 2 parts: a survey/questionnaire and in-person assessments. The survey will 
take 15-20 minutes to complete and will be done by phone on the participant’s non-dialysis day. The in-
person assessments will be 30-40 minutes in duration and will allow us to establish a relationship with each 
participant. We will abstract demographics, health behaviors, medical information, clinical measures, and 
dialysis factors from each participant’s medical record. We will also ask participants about previous 
cognitive training within the last 6 months. All in-person baseline and follow-up assessments will be 
administered prior to dialysis initiation as executive function fluctuates during and immediately after HD 
(11, 98).  
 

Table 2: Assessments Measured at Baseline and at 3- and 6-Month Follow-up (*Only at baseline) 
Assessment 
Collection 
Method  
Assessment Tool 
Timing of Assessment 
Physical function 
Direct 
measurement 
IADL/ADL, Short Physical Performance Battery (SPPB): 
walk speed, chair stands, and balance (99-102) 
Baseline and at 3- and 
6-month Follow-up 
Executive function 
Direct 
measurement 
Trail Making Test A and B (TMTA/B) (5), Stroop (103), and 
Digit Symbol Substitution Tests (104) 
Baseline and at 3- and 
6-month Follow-up 
Global cognitive 
function 
Direct 
measurement 
MoCA (106) 
Baseline and at 3- and 
6-month Follow-up 
Memory 
Direct 
measurement 
Auditory/Verbal Learning Test 
Baseline, at 3- and at 6-
month follow up 
Frailty 
Direct 
measurement 
Fried Frailty Phenotype (107): low physical activity, 
unintentional weight loss, poor grip strength, slowed walk 
speed, exhaustion 
Baseline and at 3- and 
6-month Follow-up 
Quality of life 
Validated survey 
Kidney Disease Quality of Life (KDQOL) (108-110) 
Baseline and at 3- and 
6-month Follow-up 
Other patient-
centered 
outcomes 
Validated self-
report instrument 
PROMIS-29 short-form profile: anxiety, depression, fatigue, 
pain, perceived function, sleep disturbance, and participation 
in social roles/activities, ability to return to work 
Baseline and at 3- and 
6-month Follow-up 
Demographics* 
Self-report and 
abstraction 
Age, sex, race/ethnicity, and education 
Baseline 
Health behaviors 
Self-report and 
abstraction 
Smoking status, alcohol intake, illicit drug use 
Baseline and at 3- and 
6-month follow up 
Medical factors 
Chart abstraction 
History of chronic and infectious diseases 
Baseline and at 3- and 
6-month follow up 
Clinical measures 
Chart abstraction 
BMI, eGFR, blood pressure, cholesterol 
Baseline and at 3- and 
6-month Follow-up 
Dialysis factors 
Chart abstraction 
Time on dialysis, access site, schedule, cause of ESRD 
Baseline and at 3- and 
6-month Follow-up 
DSMB Review 
Direct observation 
Falls during intervention or assessment, hypotension, 
hypertension, elevated heart rate 
At every dialysis 
session 
 
Self-report 
Cramping and headache 
At every dialysis 
session 
 
Self-report 
Injurious falls 
Baseline and at 3- and 
6-month Follow-up 
 
 
All measures of executive function, global cognitive function, frailty, and the SPPB (walk speed, chair stands 
and balance) will be assessed in-person prior to the start of the dialysis session. 
 
Assessment of Executive Function:   
• Trail Making Test A and B (TMTA and TMTB) scores are validated measures of executive function 
(i.e., cognitive shifting, cognitive flexibility), attention, concentration, and psychomotor speed (5). 
These tests measure the time required to connect a series of sequentially numbered (TMTA) and 
numbered/lettered (TMTB) circles. Needing more time to complete the tests indicates worse 
executive function; times are capped at 3 minutes for TMTA and 5 minutes for TMTB.  
• The Stroop Test (reading, color-naming, and interference sub-tasks) (103) evaluates the inhibitory 
control of executive function and involves reading the name of a color printed in a different color ink: 
BLUE. The time ratio of color-word interference and color-only tasks will be calculated.  
• The Digit Symbol Substitution Test (104), which evaluates the speed and working memory 
components of executive function, consists of 9 number/symbol pairs (for example: 1+, 2X, 3=, etc.) 
and participants are asked to fill in the corresponding symbol as quickly as possible (for example: 
3_,1_, 9_). The correct number of symbols within 90 seconds is measured. 
 
Assessment of Physical Function: 

• Short Physical Performance Battery Lower (SPPB), a performance-based assessment comprising 3 
tasks: 1) repeated chair stands; 2) standing balance; and 3) a 4-meter usual paced walk in those with 
and without a walk aid (meters/second [m/s]) (101).  
• Instrumental Activities of Daily Living/Activities of Daily Living(IADL/ADL)  have been used by 
other studies of the aging population to measure disability in the context of restrictions in ability to 
carry out daily tasks such as bathing and taking medications (99).  The IADL/ADL involves a series 
of questions about ability to perform activities of daily living such as bathing, dressing, and walking. 
 
Assessment of Global Cognitive Function: 
• Montreal Cognitive Assessment (MoCA) is an alternative to the Modified Mini-Mental State 
Examination (3MS) and measures global cognitive function across the cognitive impairment 
continuum and is more sensitive to mild cognitive impairment (106).  
 
• Assessment of Memory: The Auditory/Verbal Learning Test (AVLT) is a screening test for memory 
impairment. The AVLT measures a patient’s immediate recall. A series of unrelated words are 
presented aloud and participants are asked to recall as many as they can.  
 
Additionally, we will administer the Revised Distrust of the Healthcare System (148) survey to assess 
individual attitudes of distrust. It assesses the 2 primary domains of distrust: competence and values with the 
values domain having subthemes of honesty, motives, and equity.  The overall 9-item scale has a Cronbach’s 
alpha of 0.83; the values subscale (5-items) had a Cronbach’s alpha of 0.73 and the competence subscale (4 
items) had a Cronbach’s alpha of 0.77, suggesting that the subscales can be used separately or together. 
Unlike distrust assessment tools prior to it, the revised survey address the multi-dimensional nature of 
distrust of the healthcare system. The survey will be administered during the baseline assessment. 
 
Follow-up Assessments: We will perform follow-up assessments at 3 months of intervention and 6 months 
of intervention (measures listed in Table 2) in the dialysis center using a similar approach to the baseline 
assessment for comparability of the measures. Research assistants blinded to the assigned study arm will 
perform follow up assessments. 
 
The Principal Investigator/ Program Manager will inform the appropriate dialysis center treating 
nephrologist/nurse practitioner of any abnormal findings for cognitive function, anxiety, and depression at 
the 3 month and 6 month assessments.  
 
Data collection for variables needed for DSMB review. Falls during the intervention or assessment will be 
directly observed by study staff at each intervention session throughout the whole study. Hypotension 
(SBP<110 mmHg or DBP<50 mmHg) and hypertension (SBP>150 mmHg or DBP>90 mmHg) will be 
identified during the clinical measurements of blood pressure that occur approximately 10 times throughout 
the dialysis session. Similarly elevated heart rate (>80% of maximum heart rate calculated as 220-participant 
age will be identified during the clinical measurements of heart rate that occur approximately 10 times 
throughout the dialysis session. Cramping and headaches will be noted if a participant tells the study staff 
that they are experiencing these events. Injurious falls for DSMB review outside of the dialysis session will 
be self-reported by participants as part of the questionnaire at 3- and 6-months follow-up. 
 
Plan for Fidelity Monitoring. In the pilot study, there was a small dropout rate (3/23), which is consistent 
with other intradialytic exercise interventions at 6 months (86) and there is high compliance (88%) with ET 
(63). We will allow for temporary noncompliance due to acute illness or travel. We will add additional 
sessions onto the end of the intervention period (no more than 2 weeks) in any of the study arms, as has 
previously been proposed in intradialytic intervention trials (86). The Program Manager/Study Coordinator 

will visit the dialysis centers administering these arms of the study monthly throughout the course of the 
intervention to give a refresher on the safe and effective use of the foot peddlers. The PI or project manager 
will visit each clinic weekly during the administration of the intervention to directly observe compliance and 
facilitate communication among the HD clinic staff, patients, and study staff. Research assistants will record 
the:  
•
Number of sessions with CT, ET, or CT+ET. The number of dialysis sessions during the 6 months of
intervention in which a participant engages in CT, ET, or CT+ET will be coded into the ordered
categories (0, 1, 2, 3, etc.). We will use fixed effect linear regression models and linear combination
methods to test differences in the number of sessions between arms. This is also recorded through
Lumosity.
•
Duration of CT, ET, or CT+ET during the HD session. We will calculate the mean duration of CT,
ET, and CT+ET during each HD session by study arm. We will test whether the mean duration per
arm changes over the course of the study (i.e., do participants in certain arms lose interest in
participating over time).
We will additionally administer three surveys at follow up to participants to assess their perceptions on the: 
•
Quality of the interventions on a 5-point scale
•
Intervention Carryover outside the HD clinic. We will survey the participants in all study arms to see
whether their health behaviors outside the HD sessions have changed since enrolling in the RCT. For
example, are they playing other brain games or puzzles at other times or have they changed the
physical activity level on their non-dialysis days.
•
Cultural Appropriateness of the Intervention. We will assess the appropriateness of CT and ET using
a published cultural competency tool for electronic interventions among ESRD patients (85).
Early Termination: 
A participant may be removed from the study if: 
•
Participant violates study procedures
•
Staying in the study would be harmful
•
Participant develops a medical condition that is not allowed in the study
•
Participant is no longer willing to participate in the study
•
Participant receives a kidney transplant, or withdrawal of hemodialysis or change in renal
replacement therapy
•
Participant changes to a dialysis center that does not participate in the study
•
There may be other reasons that we do not know at this time
Drugs/ Substances/ Devices: Not applicable 
Statistical Methods 
Data will be analyzed according to the intention-to-treat principle. We will test the main effect of CT alone 
(arm 1) and the main effect of ET alone (arm 2) as well as the interaction between CT+ET (arm 3) compared 
with SC (arm 4). Baseline characteristics will be compared among treatment groups to test adequacy of 
randomization and identify possible confounders. If there are concerns about imbalances between treatment 
groups with respect to important risk factors for executive function decline, we will adjust regression-based 
models as necessary to account for these differences. Competing events (death or KT) will be quantified; if 
relevant, sensitivity analysis accounting for competing events will be performed. 

 
1.0. Analytic Methods. Effect of CT, ET, and CT+ET on cognitive outcomes:  
Change in executive function between baseline and 3 months will be a continuous outcome. Using a linear 
regression with the cluster option to account for the centers, we will test the null hypothesis (H01) of no 
difference in the mean change in executive function in CT alone vs. SC against the alternative hypotheses 
(HA1) that CT alone has a different mean change in executive function than SC. We will then test the null 
hypothesis (H02) of no difference in the mean change in executive function in ET vs. SC against the 
alternative hypotheses (HA2) that ET has a different mean change in executive function than SC. 
 
 In addition to these two main effects, we will test the effect of CT depends on ET (interaction). The null 
hypothesis (H03) is that there is no difference in the mean change in executive function for those in the CT, 
ET, CT+ET or SC arms vs. the alternative hypothesis (HA3) that at least one of the mean changes in 
executive function differs. 
 
From this model, we will use linear combination methods to test H04 (no difference in mean change in 
executive function for arm 1 vs. 2) vs. HA4 (arm 1 has a different mean change in executive function than 
arm 2). We will then test H05 (no difference in mean change in executive function for arm 1 vs. 3) vs. HA5 
(arm 1 has a different mean change in executive function than arm 3). We will test H06 (no difference in 
mean change in executive function for arm 2 vs. 3) vs. HA6 (arm 2 has a different mean change in executive 
function than arm 3). If H01 is not rejected, we will conclude that there is insufficient evidence that arm 1 is 
more effective than arm 4 in preserving executive function. If H02 is not rejected, we will conclude that 
there is insufficient evidence that arm 2 is more effective than arm 4 in preserving executive function. If H03 
is not rejected, we will conclude that there is insufficient evidence that arm 3 is more effective than arm 4.  
 
If H01, H02, and H03 are rejected, but H04 is not rejected, we will conclude that arms 1 and 2 are more 
effective than arm 4, but there is no difference in the effectiveness of arms 1 and 2. Similarly, if H01, H02, 
and H03 are rejected, but H05 is not rejected, we will conclude that arms 1 and 3 are more effective than arm 
4, but there is no difference in the effectiveness of arms 1 and 3. And finally, if H01, H02, and H03 are 
rejected, but H06 is not rejected, we will conclude that arms 2 and 3 are more effective than arm 4, but there 
is no difference in the effectiveness of arms 2 and 3.The following table below details the conclusions we 
will draw based on hypotheses testing if H01 and H02 are rejected: 
 
Table 3: Hypothesis Testing for the Primary Outcome  
 
 
 
H03 rejected  
H03 not rejected 
H05 
Rejected 
 
Arm 1 is superior to arm 4 and arm 3 is superior to 
arm 1; i.e., both CT+ET and CT alone are effective 
strategies compared with SC but CT+ET is more 
effective. 
Arm 3 is superior to arm 1, but there is not sufficient 
evidence to distinguish arm 3 from arm 4; i.e., CT+ET is 
not effective compared with SC but better than CT alone. 
H05 
Not rejected 
Arms 1 and 3 are superior to arm 4, but there is not 
sufficient evidence to distinguish arm 1 from arm 3; 
i.e., CT+ET is an effective strategy compared with 
SC, but we cannot tell if the CT+ET is effective 
beyond that of CT alone. 
There is insufficient evidence to distinguish arm 3 from arm 
4 and arm 1 from arm 3; i.e., CT+ET is not an effective 
strategy compared with SC and no better than CT alone. 
 
   
  
H06 
Rejected 
 
Arm 2 is superior to arm 4 and arm 3 is superior to 
arm 2; i.e., both CT+ET and ET alone are effective 
strategies compared with SC but CT+ET is more 
effective. 
Arm 3 is superior to arm 2, but there is not sufficient 
evidence to distinguish arm 3 from arm 4; i.e., CT+ET is 
not effective compared with SC but better than ET alone. 
H06 
Arms 1 and 3 are superior to arm 4, but there is not 
sufficient evidence to distinguish arm 1 from arm 3; 
There is insufficient evidence to distinguish arm 3 from arm 
4 and arm 2 from arm 3; i.e., CT+ET is not an effective 

Not rejected 
i.e., CT+ET is an effective strategy compared with 
SC, but we cannot tell if CT+ET is effective beyond 
CT alone. 
strategy compared with SC and no better than ET alone. 
 
Power Calculations: We used a Monte-Carlo simulation (1,000 randomly generated datasets) to estimate 
the power of a 2-by-2 factorial design with linear regression and Huber-White robust standard errors. We 
powered the RCT to detect a statistically significant difference in the CT+ET group based on a 3-month 
change in executive function, given the group mean change and SD in the pilot data.  
 
When each arm of the study has 47 participants, we will have 80% power to detect a statistically significant 
change of 20 seconds between baseline and 3 months comparing the CT+ET arm to the SC arm. We will also 
have 95% power to detect a statistically significant change of 15 seconds in the CT arm and >99% to detect a 
statistically significant change of 18 seconds in the ET arm. Therefore, we would need to recruit 200 
participants from 16 centers (approximately 13 participants per center). Even if we were to recruit just 22 
participants (rather than 47) into each arm of the study, we would still have >80% power to observe 
statistically significant changes of 15 seconds for the main effects of CT and ET.  
 
Based on the pilot study we assumed an 88% consent rate per arm; this will leave approximately 57-60 
participants from which we will need to recruit 50 per arm. We also accounted for 6% attrition in 3 months. 
 
1.1. Change in Secondary Measures of Cognitive Function Over 6 Months. We will use a linear mixed 
model approach to describe the 3- and 6-month change in secondary cognitive function measures. We will 
construct a base model by fitting a single slope after enrollment. We will include two random effects: 
intercept and time relative to enrollment. This will allow for a unique trajectory for each participant, which 
varies randomly around the trajectory described by the fixed effects. The estimate for the time since 
enrollment variable will quantify the magnitude of the change in executive and global cognitive function 
(pre- and post-intervention) associated with CT, ET, and CT+ET. We will explore non-linear functions of 
time through cubic splines.  The model is: 
 
 
where time is time since enrollment, and X is the vector of interventions. We recognize that mortality may 
occur during the study and those who are survivors may be a distinct population and there may be 
differential mortality by intervention. If we find evidence for this differential survival, we will account for 
the unobservable executive and global cognitive function after death by 1) creating a composite endpoint that 
ranks mortality as worse than any change in executive or global cognitive function (composite endpoint), and 
2) generate a causal model for change regardless of mortality using a survival-averaged causal effect model. 
As a sensitivity analysis, we will test that our findings are robust to the analytic approach using global z-
scores. 
 
2.0. Analytic Methods: Effect of CT, ET, and CT+ET on ESRD-specific clinical outcomes. 
 
Staff at NYU Langone Health will help with data analysis. Data will be shared through a HIPAA Compliant 
Johns Hopkins REDCap database. The NYU Langone Health team will be conducting data analysis for all 
components of this study and requires all variables to do so.   
 
2.1. Time to Event Outcomes: Mortality. To examine the univariate association between study arm and 
mortality, separate product-limit estimated cumulative incidence curves will be calculated. Next, we will use 
a Cox proportional hazards model to estimate the association of study arm with time to the development of 
mortality. Censoring will occur at loss to follow-up or KT. The hazard function for the Cox model is: 
 
 

where xi is the value of the covariate X for the ith participant, and λ0(t) is the baseline hazard function. If the 
proportional hazards assumption is not met, we will include an interaction with time.  
 
2.2. Dichotomous Outcomes: Poor Lower Extremity Function, poor HRQOL, return to work, and 
amputation. We will test whether the study arm is associated with poor lower extremity function, poor 
HRQOL, return to work, and amputation using logistic regression or a modified Poisson regression (145), if 
the outcome is >10%. 
 
2.3. Count Outcomes: Number of Falls and Hospitalizations. We will use Poisson regression to test 
whether the study arm is associated with the number of falls and hospitalizations within the 3 months of the 
intervention. 
 
3.0. Analytic Methods: Effect of CT, ET, and CT+ET on patient-centered outcomes. 
Change in Patient-centered Outcome: For each patient-centered outcome, we will calculate a score. We will 
treat each patient-centered outcome as continuous and will estimate the change in these outcomes between 
baseline and 3 months. We will analyze each patient-centered outcome separately. We will analyze the 
change in these outcomes using the analytic plan described in 1.0. 
 
3.1. Change in Patient-centered Outcome over 6 Months. Patient-centered outcomes are longitudinal data 
(3 and 6 months) and analyzed using the analytic plan described in 2.0 for repeated measures of executive 
function. 
 
4.0. Treatment Effect Heterogeneity. Frailty has been associated with worse trajectories of executive 
function in older adults (146) and HD patients (16). Therefore, we will explore treatment heterogeneity 
between those who are frail and nonfrail in all primary and secondary outcomes. We will include an 
interaction term between frailty status and intervention type (study arm) to assess difference in treatment 
effect by frailty status. Using a similar approach, we will test for treatment effect heterogeneity by age, sex, 
and race/ethnicity. 
 
 
Risks: 
 
Risk from Cognitive Training Intervention:  
Participants in the CT arm may feel tired or bored from playing similar cognitive games. They may feel 
frustrated if they are trying to learn new games and are unsuccessful with the games. Participants may 
develop a headache due to eyestrain from focusing on the tablet screen. All participants will be encouraged 
to wear their reading glasses while performing the CT if applicable. 
 
Risk from Exercise Training Intervention: 
Participants in the ET arm may experience fatigue, exhaustion, discomfort, muscle soreness, pain or 
cramping in the legs from using the foot peddler. Participants may experience shortness of breath, a change 
in heart rate or blood pressure while performing the activity. 
 
Risk from Frailty Measurements and Physical Function Assessments:  
Participants may experience fatigue or exhaustion from performing the grip strength, chair stands, balance 
and walk speed.  
 
Risk from Quality of Life and Health Questionnaires: 

Participants may experience fatigue, exhaustion, emotional discomfort or boredom from answering the 
questionnaires. 
 
Minimization of Risks: 
All participants will go through an eligibility screening process. We will enroll only those who meet all of 
the inclusion criteria and none of the exclusion criteria. The treating nephrologist is required to give 
permission for a patient to enroll in the study to ensure it is safe for them to participate. 
 
All participants will sign an IRB-approved informed consent. We will inform them that participation is 
strictly voluntary and that they may decline to continue participation in the study at any time point, 
discontinue the assessments during the session, or refuse to answer any questions they do not want to. At the 
start of each session, we will inform the participants in the CT, ET, and CT+ ET arms that they are free to 
stop the activity at any time if they feel any discomfort or for some other reason cannot continue. 
Additionally, physicians, nurse practitioners, and dialysis staff will be on staff during the session to help 
monitor the participants health while undergoing hemodialysis and participating in the study. 
 
The study team will make every effort to protect the participants’ privacy by conducting interviews and 
assessments in an area at the dialysis center that is not within earshot or view of other clinic patients. 
 
Confidentiality and Risk Protection: 
We will keep all data collected strictly confidential so there is minimal risk of loss of confidentiality. All 
participating faculty and staff have received appropriate training in the responsible conduct of research, 
protection of human subject participants, and HIPAA regulations. All data collection instruments and 
consent forms will be kept in a locked cabinet. All questionnaires, assessments and cognitive function data 
will be stored in RedCap, a secured database. To maximize confidentiality, only the study investigators, data 
manager and key study personnel will have access to the information. 
 
Data Safety Monitoring Board (DSMB) and Adverse Event Reporting: 
An independent DSMB will be established to oversee the safety and progress of this trial, comprised of five 
individuals (a patient advocate, an ethicist, a statistician, a nephrologist, and a research nurse) who will serve 
in this capacity throughout the entirety of the trial. We will ensure that all members of the DSMB disclose of 
any conflicts of interest. The DSMB will have pertinent experience and review accumulating data from this 
RCT on a regular basis with the goal of enhancing the safety of the trial participants. A DSMB is warranted 
in this RCT because the study is being performed in a potentially vulnerable population, namely those with 
ESRD on HD and this population is at elevated risk of serious outcomes. A medical monitor will be included 
on the DSMB to review all events and determine whether they classify as AE’s/ or SAE’s. 
 
We will monitor the number of injurious falls resulting in a medical encounter during the 6 months of 
interventions. This data will be obtained during the survey portion of our assessments by asking the 
participant to self-report the number of falls in the last 6 months. Additionally, falls during the intervention 
or assessment will be directly observed and recorded by study staff. Any falls will be reported to the medical 
monitor for review and determination whether they classify as an AE or SAE attributable to the 
interventions. 
 
The DSMB will be identified and managed through the ICTR and will be established and operated using the 
Guidance put forth by the US Food and Drug Administration “Guidance for Clinical Trial Sponsors: 
Establishment and Operation of Clinical Trial Data Monitoring Committees” 
(https://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf). The DSMB will be 
local and managed by the ICTR to allow for quick convening of meetings in the event of an unexpected 
result that raises concerns.  

 
None of these individuals will be involved in the design or conduct of the trial. Any unanticipated problem or 
adverse event will be reported as outlined in JHU IRB policy 103.6(b). When possible the DSMB will be 
blinded to the study arm. 
 
If any SAEs are more common in one of the three intervention arms compared to the standard of care arm, 
then the DSMB will consider termination of the study if the risks outweigh the benefits for participants. All 
SAEs that are deemed to have a causal relationship with the interventions in one of the arms of the study will 
be reviewed by the DSMB for the consideration of patient safety. 
 
Planned DSMB Reviews:   
The Data and Safety Monitoring Board (DSMB) shall review safety data during planned DSMB Data 
Review Meetings when 10%, 25%, and 50% of enrolled participants have completed 3 months of 
interventions and to analyze and review the interim analyses of these adverse events during active data 
collection. Data for the planned safety reviews will include, at a minimum, a listing of all reported AEs and 
SAEs. The DSMB will be informed of an Expedited Safety Report in a timely manner. The DSMB will have 
a final meeting at the end of the study. 
 
We have performed a comprehensive literature search of published and unpublished manuscripts to identify 
possible side effects, adverse events, and serious adverse events of CT and ET interventions. No adverse 
events were noted in the literature search for side effects, adverse events or serious adverse events for CT. 
We theorize that the two most common risks associated with CT are the following: 1) boredom 2) frustration 
and 3) headache. 
 
There are greater risks associated with the ET intervention than with the CT intervention. The main risks 
associated with ET include: 1) Hypotension or low blood pressure which can cause dizziness and fainting. 
Hypotension can frequently occur during hemodialysis due to fluid removal.  Hypotension is the most 
common risk of intradialytic ET and can occur in up to 33% of dialysis sessions in which exercise is 
involved, 2) cramping, muscle soreness, pain and fatigue, and 3) dyspnea or shortness of breath which occurs 
commonly during exercise. While hypertension and elevated heart rate were not noted as a risk associated 
with ET, we will also consider hypertension as a possible risk. Blood pressure reading of SBP>150 or 
DBP>90 mmHg will be considered as hypertension. SBP<110 or DBP<50 mmHg will be considered as 
hypotension. Heart rate that is consistently >80% of maximum heart rate will be considered as elevated. 
 
Ad Hoc DSMB Reviews 
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may be called upon 
for ad hoc reviews. The DSMB will review any event that potentially impacts safety at the request of the PI 
or NIDDK representative. In addition, the following events will trigger an ad hoc comprehensive DSMB 
Safety Review:  
• Any death in the study which is considered possibly or definitely related to a study procedure. 
• If any of the following adverse events occur at a significant higher rate than expected in the CT, ET, 
or CT+ET arm: muscle cramping, hypotension, or headache. We have outlined thresholds for pausing 
rules for rates of cramping, hypotension, hypertension, elevated heart rate, or headache which will 
trigger a mandatory pause in study enrollment for an unscheduled Data Safety and Monitoring Board 
review. 
 
Cramping/Muscle Soreness: At the first day of each month, we will perform a Bayesian analysis of the 
ratio of cramping rates between ET arm (or CT+ET arm) versus the SC group. We will use a prior 
distribution of beta for each subgroup. We will then analyze the ratio of the distributions using a Monte 

Carlo simulation. If there is 75% chance that [rate of cramping in the ET arm or CT+ET arm] divided by 
[rate of cramping in the SC arm] exceeds 1.10 (10% more in ET arm or CT+ET arm), we will pause the 
study pending DSMB recommendation. 
 
Hypotension: we will perform a Bayesian analysis of the ratio of hypotension rates between ET arm (or 
CT+ET arm) versus the SC arm. We will use a prior distribution of beta(0,0)for each subgroup. We will then 
analyze the ratio of the distributions using a Monte Carlo simulation. If there is an 75% chance that [rate of 
hypotension in the ET arm or CT+ET arm] divided by [rate of hypotension in the SC arm] exceeds 1.15 
(15% more in ET arm or CT+ET arm), we will pause the study pending DSMB recommendation. 
 
Hypertension: At the first day of each month, we will perform a Bayesian analysis of the ratio of 
hypertension rates between ET arm (or CT+ET arm) versus the SC arm. When calculating hypertension 
rates, we will exclude dialysis sessions with starting blood pressure being hypertensive. We will use a prior 
distribution of beta(0,0) for each subgroup.  We will then analyze the ratio of the distributions using a Monte 
Carlo simulation. If there is an 75% chance that [rate of hypertension in the ET arm or CT+ET arm] divided 
by [rate of hypertension in the SC arm] exceeds 1.15 (15% more in ET arm or CT+ET arm), we will pause 
the study pending DSMB recommendation. 
 
Elevated Heart Rate (EHR):  At the first day of each month, we will perform a Bayesian analysis of the 
ratio of EHR rates between ET arm (or CT+ET arm) versus the SC arm. We will use a prior distribution of 
beta (0,0) for each subgroup. We will then analyze the ratio of the distributions using a Monte Carlo 
simulation. If there is an 75% chance that [rate of EHR in the ET arm or CT+ET arm] divided by [rate of 
EHR in the SC arm] exceeds 1.08 (8% more in ET arm or CT+ET arm), we will pause the study pending 
DSMB recommendation. 
 
Headache: At the first day of each month, we will perform a Bayesian analysis of the ratio of headache rates 
between CT arm (or CT+ET arm) versus the SC arm. We will use a prior distribution of beta(0,0) for each 
subgroup. We will then analyze the ratio of the distributions using a Monte Carlo simulation. If there is an 
75% chance that [rate of headache in the CT arm or CT+ET arm] divided by [rate of headache in the SC 
arm] exceeds 1.12 (12% more in CT arm or CT+ET arm), we will pause the study pending DSMB 
recommendation. 
 
After review of the data, the DSMB will make recommendations regarding study conduct and/or 
continuation. 
 
Temporary Suspension of enrollment for Ad Hoc DSMB Safety Review 
A temporary halt in enrollment at all participating centers will be implemented if an ad hoc DSMB safety 
review is required. 
 
 
Benefits: 
There is no direct benefit to the participants for being in the study.  However, there is a possibility of a direct 
benefit from the participants having access to a cognitive training regime or an exercise training regime. 
There are no direct benefits to participants randomized to the standard of care arm. All study participants 
may help providers and other patients in the future by contributing to the knowledge base for performing 
interventions for patients undergoing hemodialysis. 
 
Payment and Remuneration: 

All participants will receive a $10 gift card after completion of study assessments at baseline. Participants in 
the standard of care arm will receive a $25 gift card after completion of assessments at 3 months, and at 6 
months. Participants in the CT, ET, or CT+ET arms will receive a $10 gift card after completion of study 
assessments at 3 months and at 6 months. Additionally, participants in the intervention arms will receive $5 
for each HD session they engage in their assigned intervention. Participants will not receive compensation if 
they withdraw from the study. Travel or other expenses will not be reimbursed as all the assessments and 
activities related to the study will be conducted during their regularly scheduled hemodialysis appointment at 
the dialysis center. 
 
Costs:  
There are no costs to the participant for being in the study. 
 
Coordinating Site Information:  
 
Johns Hopkins will serve as the coordinating center. NYU has an active FWA and OHRP on file that 
the Johns Hopkins IRB has worked with successfully in the past. The Johns Hopkins PI, Aarti 
Mathur, and Mara McAdams DeMarco the site lead at NYU will be in frequent contact and address 
any protocol changes or amendments. All data will be entered into a secure REDCap database and 
managed by Mara McAdams Demarco at NYU. There will be no changes to data management at 
Johns Hopkins. The NYU study team will provide the JH study team with any necessary information 
for annual continuing reviews. The PI will be responsible for education to sites about JHM policies 
and oversight of protocol events, deviations, and ensuring appropriate reporting. The NYU Langone 
Health study team will analyze and collect data for this study. To ensure data collection is consistent 
across sites, that longer term follow-up can be performed, and re-contact for future studies, all data 
collected over the course of the trial must be shared. All data will be shared over a HIPAA compliant 
Johns Hopkins secure REDCap data base. We will add NYU study team members to the Johns 
Hopkins REDCap project in order for them to access any necessary data. Access to the data at NYU 
will be restricted to only study team members.  We will use a Data Access Group created by Johns 
Hopkins IT to add NYU personnel to the REDCap project. Only authorized personnel will be able to 
add additional team members to the project after they are added to the IRB. 
 
 
 
 
 
 
 
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COVER PAGE 
1/18/2023
Title: “Interventions Made to Preserve Cognitive Function” 
# NCT03616535 

The statistical methods were updated to account for COVID-19 shutdowns as described below. 
Study Design 
IMPCT was a randomized controlled trial (RCT) of CT, ET, and combined CT+ET interventions in a 2×2 factorial 
design, as previously reported. The study team performing assessments was not the same as those providing the 
interventions and was masked to the intervention. Participants were enrolled, and baseline assessments were 
conducted (09/2018-02/2023). Primary and secondary outcomes were measured at 3 months. Those collecting 
primary and secondary outcomes were masked to the intervention assignment. Due to COVID-19 shutdowns, 9 
baseline assessments (not included in the trial) and 25 follow-ups at 3 months were interrupted.  
All participants provided written informed consent and were compensated with $10 (funding from NIDDK 
R01DK114074). This trial was approved by the Johns Hopkins Institutional Review Board (IRB00152858) and sIRB 
with NYU, and reviewed by the Fresenius Medical Care Holdings, Inc. Investigator Initiated Trials Review Committee 
and DaVita Clinical Research. COVID-19 restrictions in dialysis facilities between 2020-2022 affected recruitment and 
study operations, leading to the Data and Safety Monitoring Board (DSMB) recommendation of trial termination. 
Therefore, this trial was terminated on 12/08/2023. The study was registered at clinicaltrials.gov (NCT03616535). 
Eligibility 
We recruited English-speaking adult (≥18 years) patients with ESKD who had initiated thrice weekly hemodialysis 
within 3 months to 3 years (09/2018-06/2022) at 14 dialysis centers in the Baltimore, Maryland area and 1 dialysis 
center in New York City, New York. We limited the study to participants with 3 months-3 years of hemodialysis to 
capture a population that had potentially reversible cognitive impairment. Exclusion criteria were: 1) inability to 
participate in ET without assistance; 2) conditions limiting participation (pregnancy, angina pectoris, chronic lung 
disease requiring oxygen, musculoskeletal conditions, lower- or upper-extremity amputation, orthopedic disorders 
exacerbated by physical activity, femoral vascular access, legally blind, inability to recognize numbers and letters as 
well as hepatitis B infection requiring medical isolation); and 3) incarceration.  
Randomization 

After the baseline assessment, 121 participants were block-randomized (based on sex, race, and dialysis center, 
factors chosen to remove their effects on cognition) into 4 arms using a secure computer-based allocation system (R). 
Statistical Analysis 
Baseline characteristics of participants were presented by arm and compared using ANOVA test for normally 
distributed continuous variables, Kruskal-Wallis test for nonnormally distributed continuous variables, and Chi-squared 
test for categorical variables. Differences in the primary and secondary outcomes were tested using these methods as 
well. 
For CT, ET and CT+ET arms, we evaluated each participant’s adherence to the assigned intervention as: the number 
of dialysis sessions that the participant attended and participated in the intervention/the number of dialysis sessions 
that the participant attended)*100%.  
The effect of interventions was analyzed according to the intention-to-treat principle. Changes in 
executive function, global cognitive function, ESKD-specific clinical outcomes, and patient-
centered outcomes between baseline and 3 months were handled as continuous outcomes. After 
visually verifying the linearity, normality, and equal variance assumption, we used linear regression 
to test the main effect of CT alone and the main effect of ET alone as well as the interaction 
between CT+ET compared with SC; we also tested these effects with an ANCOVA analysis. In 
addition, we tested whether the impact of CT, ET, and CT+ET differed from each other. The main 
comparison used models adjusted for age at enrollment, education, and baseline measures of 
outcomes, which were adapted to account for imbalances between groups with respect to 
important risk factors for the outcomes.  
All analyses were performed using Stata 16.1 (StataCorp, College Station, TX). Statistical 
significance was defined as a two-sided p-value <0.05. There was no missingness in adjusted 
covariates.