A Randomized Pilot Study of Hemodialysis Initiation Comparing Twice-Weekly Hemodialysis Plus Dialysis-Sparing Therapy Versus Thrice-Weekly Hemodialysis (The TWOPLUS-HD Trial)
Phase: PHASE3
Conditions: End Stage Renal Failure on Dialysis
Sponsor: Wake Forest University Health Sciences

 
 
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Study Title: A Randomized Pilot Study of Hemodialysis Initiation Comparing Twice-
Weekly Hemodialysis Plus Dialysis-Sparing Therapy versus Thrice-Weekly Hemodialysis: 
The TWOPLUS-HD Trial 
 
Principal Investigator: Mariana Murea, MD 
 
Co-investigator(s):  Isai G. Bowline MD, Alison Fletcher MD 
 
Sponsor or funding source: Relypsa Inc. 
Background, Rationale and Context 
 
Almost all Americans with end-stage kidney disease (ESKD) initiating hemodialysis (HD) are 
prescribed a dialysis regimen of fixed frequency (thrice-weekly) and fixed dose (dialysis single-
pool Kt/V urea [spKt/Vurea] ≥1.2, corresponding to standard Kt/Vurea [stdKt/Vurea] ≥2.1). 
1The target HD treatment dose was validated in trials that involved solely chronic HD patients 
(i.e., dialysis vintage >2years) with virtually no residual kidney function (RKF); this was then 
extrapolated as ‘optimal’ dialysis dose to all patients prescribed intermittent HD.2,3 In contrast, 
patients initiating peritoneal dialysis (PD) have the dialysis prescription adjusted according to 
RKF such that the initial PD regimen consists of shorter dialysis sessions with fewer exchanges; 
this approach was tested in clinical trials.4,5 Hitherto, the optimal HD regimen (frequency and 
dose) for patients with incident ESKD is not known as it has not been studied.  
The most common cause of ESKD is progression of chronic kidney disease (CKD), a condition 
characterized by gradual loss of glomerular filtration over time. More than 90% of incident 
dialysis patients have an estimated glomerular filtration rate (eGFR) ≥5ml/min/1.73m2 at 
dialysis initiation;6 this RKF helps regulate the volume status, maintain phosphate and potassium 
clearance, and, when pharmacologically enhanced with adjuvant medical therapy, could allow 
safe and effective introduction of an incremental HD regimen. Chin et al. analyzed the feasibility 
of incremental HD among incident ESKD patients in the United States by estimating the 
proportion of patients that could have started maintenance HD with a twice-weekly schedule 
based on four criteria: RKF; ultrafiltration rate; intradialytic blood pressure; and intradialytic 
symptoms.7 Based on their model, the authors concluded that more than half of the patients with 

 
 
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incident ESKD could be treated with incremental HD.7Retrospective and observational studies 
showed that a regimen of twice-weekly HD at dialysis initiation may confer better RKF 
preservation that thrice-weekly HD treatment.8,9 Patients with higher levels of RKF generally 
reported better quality of life10 and had longer survival on HD than those with lower levels of 
RKF. 11 In addition, residual glomerular filtration may allow removal of protein-bound uremic 
solutes that HD does not adequately remove.12 Thus, an incremental HD regimen could be 
employed in many patients with ESKD as a result of CKD progression and may have the 
potential to offer better patient outcomes.  
Although beneficial effects of incremental HD on RKF and mortality were noted in previous 
reports, residual bias lingers even after rigorous adjustment for a variety of important covariates, 
owing to the nature of study design. A well-designed and executed prospective, randomized trial 
will offer superior data on the efficacy and safety of incremental HD in order to determine the 
optimum approach to the initiation of dialysis in patients with incident ESKD. 
Objectives  
 
The primary objective of this study is to evaluate the feasibility and safety of incremental HD in 
incident ESKD patients. The secondary objectives are to evaluate the effects of HD frequency on 
changes in RKF, clinical and laboratory parameters (i.e., volume management, solute clearance, 
hospitalization rate), quality of life, and patient survival. 
Hypothesis   
 
Patients with ESKD as a result of CKD progression have sufficient RKF such that an initial 
dialysis regimen of twice-weekly HD plus adjunctive pharmacologic therapy (loop diuretics, 
potassium-binding agent, and sodium bicarbonate) will afford adequate solute and volume 
control.  
Compared to the conventional HD regimen, a gradual HD regimen with supportive 
pharmacologic therapy will confer better preservation of RKF.  
 
Methods and Measures 
 

 
 
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Design 
This randomized pilot trial will be parallel-arm in design. We will enroll 50 patients of age ≥18 
years, with incident ESKD. Participants will be equally randomized to one of the two regimens: 
a) twice-weekly HD plus adjunctive pharmacologic therapy (loop diuretic, potassium-binding 
agent, and sodium bicarbonate) for six consecutive weeks, continued by thrice-weekly HD 
(intervention group); or b) thrice-weekly HD (comparator group) (Appendix A).  Patients will be 
followed for 12 months after the date of randomization; or until transplant, death, withdrawal of 
consent, or transfer of care outside Wake Forest healthcare system, whichever occurs sooner.  
Feedback from the participants will be obtained during the study to (1) evaluate the delivery of 
study-related information, (2) evaluate coordination of care during the study as it pertained to 
study-related procedures, (3) evaluate patient perceptions on study-related assessments, (4) elicit 
patients’ motivations for study participation, and (5) obtain participant input regarding future 
research concerning the study intervention. 
 
Setting 
Participant recruitment will occur at Wake Forest Baptist Medical Center (WFBMC) Outpatient 
Nephrology Clinics, WFBMC Inpatient Nephrology Service, and the Wake Forest Outpatient 
Dialysis (WFOPD) units.  
 
Subjects selection criteria  
The study population will consist of adult patients with incident ESKD who undergo elective 
initiation of HD.  
 
Inclusion Criteria 
1. Age ≥18 years 
2. Have CKD (including a failing renal transplant) that advanced to ESKD 
3. Have elected HD for renal replacement therapy (RRT) 
4. Are deemed to require dialysis initiation by the treating nephrologist or have received ≤ 6 
sessions of intermittent hemodialysis within 30 days prior to screening 
5.  Have a urine output of ≥500ml per 24 hours at the time of screening 
  
Exclusion Criteria 

 
 
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1. Age <18 years 
2. Have urine output <500ml per day 
3. Have ESKD solely as a result of severe acute kidney injury (AKI) (stage 3 AKI defined by 
Acute Kidney Injury Network [AKIN]) criteria) 
4.   Abrupt decline in kidney function preceding HD therapy initiation (i.e., if eGFR was ≥30 
ml/min/1.73 m2 within 3 months prior to the initiation of dialysis therapy) 
5. Have severe systolic cardiac dysfunction with left ventricular ejection fraction <30% 
6. Have an active diagnosis of hepatorenal syndrome 
7. Have a significant malignancy that is likely to impact survival 
8. Have a medical condition that would jeopardize the safety of the subject. 
 
Sample Size 
 
The primary purpose of this pilot study is to evaluate the feasibility of a randomized intervention 
between a stepped regimen of HD and a standard regimen of HD. Therefore, for the primary 
feasibility outcome, we elect a pilot trial sample size of 50 patients total (25 patients per 
treatment group) which is consistent with recommendations for pilot and feasibility studies 
where samples of 10 to 20 participants per group have been deemed adequate to assess feasibility 
outcomes (Stat Methods Med Res 2016, 25(3), pp. 1057-1073). Power calculations for a future 
multicenter clinical trial will be carried out using the effect size on RKF and variability collected 
during this pilot study.  
Interventions and Interactions 
 
Screening for potential participants will be performed at the outpatient nephrology clinics, 
outpatient dialysis units, inpatient nephrology service, and inpatient dialysis unit of Wake Forest 
Baptist Medical Center. The decision to initiate RRT is not part of the study; initiation of RRT 
will be deemed by patient’s nephrologist. After patient’s nephrologist decided that initiation of 
RRT is medically necessary, the overall eligibility for enrollment in this study will be reached as 
a consensus between the PI and the patient’s nephrologist, based on the aforementioned inclusion 
and exclusion criteria. After written informed consent is obtained, participants will be allocated 
with equal probability to either incremental HD (intervention) or conventional HD (comparator) 
strategy. Allocation to incremental or conventional HD will be done using randomly permuted 

 
 
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blocks of varying sizes, stratified by the type of vascular access used at HD initiation, to 
maintain balance between the groups. 
Hemodialysis program. Patients assigned to the intervention arm will receive a gradual HD 
regimen with twice-weekly HD schedule for six weeks and adjuvant medical treatment during 
the first six weeks of dialysis treatment, followed by thrice-weekly HD regimen onward. Patients 
assigned to the comparator arm will receive thrice-weekly HD at the start of dialysis therapy and 
onward. All participants will receive dialysis against a dialysate (bath) potassium concentration 
of 3.0mEq/L for their first outpatient HD treatment following randomization. All participants 
will use a F200 dialyzer following randomization. Beside dialysis frequency, dialyzer type and 
initial dialysate potassium bath, all other HD prescription parameters (e.g., treatment time, blood 
flow rate, dialysate flow rate) will be set and adjusted by the treating nephrologist to achieve 
spKt/Vurea of ≥1.5 with twice-weekly HD schedule and spKt/Vurea of ≥1.2 with thrice-weekly 
HD schedule. Changes in dialysate (bath) potassium concentration following the first outpatient 
HD treatment and/or changes in HD frequency can be done at any time during the study, as felt 
clinically necessary by patient’s treating nephrologist. All patients will receive dietary advice 
and pharmacologic therapy for volume overload, hyperphosphatemia, secondary 
hyperparathyroidism, anemia and hypertension as guided by patient’s nephrologist. According to 
usual care, phosphate binding agents, active vitamin D analogs, calcium-sensing receptor 
agonists, erythropoietin stimulating agents and intravenous iron will be used for management of 
hyperphosphatemia, secondary hyperparathyroidism, anemia and iron deficiency, respectively.  
Adjuvant Pharmacologic Treatments/Dialysis-Sparing Therapy. Adjuvant therapy with loop 
diuretic, potassium-binding agent, and/or bicarbonate-based agent is expected to be necessary 
during the twice-weekly HD period in the intervention group. All pharmacologic treatments 
prescribed and administered during the study will be guided and dose-adjusted by patient’s 
treating nephrologist. The treatment schedules described below will be used as guidance. 
Treatment of hyperkalemia is summarized in Appendix B.  
Diuretic therapy. The use of diuretic agents increases sodium and water excretion and improves 
volume status in dialysis patients with RKF, and has been associated with maintenance of RKF. 
In an observational study from the Dialysis Outcomes and Practice Pattern Study, loop diuretic 
use was associated with lower interdialytic weight gain, lower odds of hyperkalemia, twice the 
odds of retaining RKF, and a 14% lower cardiac-specific mortality (Bragg-Gresham, Am J 

 
 
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Kidney Dis.2007). Start dose, Furosemide, 60-80mg orally/day if uncontrolled hypertension, no 
discernible peripheral edema, blood pressure stable, no symptoms of congestive heart failure; or 
Furosemide 80-120mg orally/day if peripheral edema and/or symptoms of congestive heart 
failure. Dose will be titrated as needed to control hypertension (goal SBP<140mmHg and/or 
DBP<90mmHg measured on inter-dialytic day or pre-HD) and manage signs and symptoms of 
volume overload to the best extent possible.  
Hyperkalemia treatment. All patients will receive education for low potassium diet. It is 
expected that 25-30% of the patients in the intervention arm will require treatment for 
hyperkalemia. Treatment of hyperkalemia will be determined based on baseline serum potassium 
level available prior to HD initiation. Based on its proven efficacy and safety in clinical trials 
involving patients with CKD and hyperkalemia, patiromer will be prescribed as the potassium-
binding agent of choice.13-15 Treatment with patiromer will be instituted for serum potassium 
levels of ≥5.1mEq/L. Patiromer will be administered daily and during the study the dose will be 
adjusted, as needed, based on pre-HD serum potassium levels (Appendix B). The dose of 
patiromer will be titrated to maintain pre-HD serum potassium of 4.6 to 5.3 mEq/L.16 Patiromer 
will be withheld temporarily or stopped for pre-HD serum potassium levels of ≤4.0mEq/L. 
Participants randomized to twice-weekly HD arm who were on a potassium binder prior study 
enrollment and HD initiation will be continued on patiromer (if on treatment with patiromer prior 
to enrollment) or switched to patiromer (if on a different potassium binder prior to enrollment). 
Participants randomized to thrice-weekly HD who were on a potassium binder prior study 
enrollment and HD initiation will have the potassium binder discontinued.    
Metabolic acidosis treatment. Treatment with Sodium Bicarbonate will be tailored based on pre-
HD serum bicarbonate levels. Start dose, Sodium Bicarbonate 1300-2600mg orally/day if serum 
bicarbonate ≤18mEq/L, or 650-1300mg orally/day if serum bicarbonate >18mEq/L. Dose will be 
adjusted as needed for goal pre-HD serum bicarbonate levels between 20-22mEq/L.17,18 
Participant Feedback. We developed a 24-item Patient Feedback Questionnaire to assess the 
following domains 5 domains: information and communication, coordination of care, perception 
on study-related assessments, motivation, and future studies. The answers will be rated on a 5-
level scale (Appendix F).  
Data collection 

 
 
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Sociodemographic (age, sex, race, marital status, educational level, living arrangement) and 
clinical (ESKD etiology and comorbidities) data will be collected from all participants at 
enrollment, using direct patient interview and electronic medical records. Assessments of health-
related quality of life (using Dialysis Symptom Index questionnaire), depression (using PHQ-9 
questionnaire) and anxiety (using GAD-7 questionnaire) will be performed at enrollment and at 
week 6 and week 12 (month 3).  
Laboratory data to include serum sodium, potassium, bicarbonate, phosphorus, calcium, intact 
PTH, albumin, hemoglobin, ferritin, transferrin saturation and beta-2 microglobulin will be 
recorded at baseline and then as set intervals according to the schedule of assessments (Appendix 
C).  
A 24-hour urine collection will be performed at baseline (within 1 week prior to initiation of HD 
or within 1 week after initiation of HD). Inter-dialytic urine collection (starting with the end of 
one HD session and ending with the beginning of the next successive HD session) will be 
performed at set intervals during the study (weeks 6, 12 [month 3], 24 [month 6] and 48 [month 
12] +/- 7 days). Measurements performed on urine collections will include urine volume, beta-2 
microglobulin, urea and creatinine; these measurements will be used to calculate RKF (urea and 
creatinine clearance) and middle-molecule (beta-2 microglobulin) clearance.  
Assessments of dialysis clearance using single poo Kt/V (spKt/V) and standard Kt/V (std Kt/V) 
will be performed according to standard of care.  
Treatment with adjuvant therapy (e.g., Patiromer, Furosemide, Sodium Bicarbonate), intravenous 
iron, erythropoietin stimulating agent, active vitamin D and calcimimetic will be recorded as 
average weekly dose during weeks 0 to 6, and average weekly dose during weeks 7 to 12 (month 
3) . Prescription of renin-angiotensin inhibitors, beta blockers, antiplatelet therapy and/or lipid 
lowering medications will be recorded.  
Study-specific assessments and measurements will include the Dialysis Symptom Index 
performed at 12 weeks (month 3), PHQ-9, GAD-7, urine collection and urine-based assays, 
serum measurement of beta-2 microglobulin, and serum K  measurement at week 2 and 4 
(Appendix C, Schedule of Assessments). Of note, baseline Dialysis Symptom, serum K 
measurement at week 1 and week 6, and all other aforementioned blood tests are part of standard 
of care.  

 
 
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Dialysis prescription (HD treatment time and frequency of administration, achieved blood flow, 
dialysate flow, potassium and calcium dialysate baths), vascular access used for HD, target 
weight (TW), inter-dialytic weight gain (IDWG), and ultrafiltration rate (UFR) will be recorded 
throughout the study. Relative IDWG will be expressed as percentage of TW when divided by 
the nephrologists’ determined target weight. All hospitalizations and deaths (along with the 
cause) will be recorded from the time of enrollment to study end.   
 
Outcome measures 
Primary feasibility outcome 
Time point: end of study 
Feasibility outcome will be assessed as the ability to recruit participants and protocol adherence. 
Recruitment will be determined as the proportion of people meeting inclusion criteria who 
ultimately consent to randomization. Protocol adherence will be determined as the proportion of 
participants who abide to the HD schedule, including transition from twice-weekly to thrice-
weekly HD.  
This pilot study will be considered successful based on attaining the following feasibility 
outcomes assessed at 12 months of study follow-up: (1) ≥70% of eligible patients are recruited, 
(2) ≥95% of participants randomized in the intervention group will adhere to the HD regimen, 
(3) ≥80% patients adhere to study-specific timed urine collection, and (4) ≤5% of participants 
randomized in the control group will cross over to a regimen of less frequent HD.   
Primary safety outcomes  
Time point: end of month 3  
The intervention of stepwise HD schedule will be considered safe, relative to standard HD 
schedule, if there will be no significant difference in severe adverse events between the two HD 
treatment groups during the first 3 months of the study.  
Severe adverse event(s) will be defined as the requirement of one or more additional HD 
treatment(s) or hospitalization(s) for: (1) a condition related to poor volume control (i.e., 
clinically-determined volume overload, decompensated heart failure, or hypertensive 
urgency/emergency); (2) severe electrolyte imbalance (i.e., serum potassium >6.5mEq/L); (3) 
severe metabolic acidosis (i.e., serum bicarbonate <15mEq/L); (4) symptomatic uremia (i.e., 
uremic encephalopathy, uremic pericarditis); or (5) death associated with study intervention. 

 
 
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Secondary outcomes 
• Change in RKF.   
Time points: weeks 6, 12, 24 & 48 
This will be assessed based on timed urine collections at specific time intervals to calculate renal 
urea and creatinine clearance (baseline, 6 weeks, 2 weeks [month 3], 24 weeks [month 6] and 46 
weeks [month 12]).  
Residual renal urea clearance (Krt/Vurea) after HD initiation will be calculated as clearance per 
minute excretion of urea nitrogen using time-averaged serum water urea nitrogen concentration 
during the collection period.19  
• Solute clearance  
Time points: month 1, month 2, month 3, month 6 and month 12 
This will be evaluated using spKt/Vurea and stdKt/Vurea. Single pool Kt/Vurea will be obtained 
monthly. Standard Kt/Vurea will be calculated monthly, using a method of calculation that 
includes the contributions of fluid removal.20  Total stdKt/Vurea will be calculated by adding 
residual renal urea clearance (Krt/Vurea ) (i.e., stdKt/Vurea month 1 will include baseline 
Krt/Vurea; stdKt/Vurea month 2 will include Krt/Vurea based on inter-dialytic urine collection 
performed during week 6; stdKt/Vurea month 3 will include Krt/Vurea performed during week 
12).7  
• Incidence rate of hyperkalemia  
Time points: month 1, month 2, month 3, month 6 and month 12 
Events of hyperkalemia (serum potassium ≥5.5mEq/L on inter-dialytic day or ≥6.0mEq/L pre-
HD on dialysis day) will be recorded and incidence rate will be compared between the two 
groups.  
• Incidence rate of metabolic acidosis  
Time points: month 1, month 2, month 3, month 6 and month 12 
Serum TCO2 will be collected. Events of metabolic acidosis (serum bicarbonate ≤22mEq/L on 
inter-dialytic day or ≤20mEq/L pre-HD on dialysis day) will be recorded and compared between 
the two treatment arms.  
• Incidence rate of volume overload  
Time points: month 1, month 2, month 3, month 6 and month 12 

 
 
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Assessment of volume status will use the following surrogate markers of volume overload: 
IDWG >2.5kg, relative IDWG >5.7% of the TW, and UFR >10ml/kg/hr. Events of volume 
overload will be compared between study groups as proportion of markers of volume overload of 
the total measurements of IDWG and UFR achieved with each HD treatment during the first 3 
months, stratified in two periods (week 1 to 6 and week 7 to 12).  
• Hospitalization rate 
Time point: end of follow-up 
Time to first hospitalization, cause of hospitalization and length of stay will be recorded and 
compared between treatment arms.  
• Quality of life, Depression and Anxiety  
Time points: weeks 6 & 12 
The Dialysis Symptom Index questionnaire will be used to assess participant health-related 
quality of life. This is a short form that measures the burden of kidney disease, 
symptoms/problems of kidney disease, and effects of kidney disease scales. The score range is 0-
100 with higher scores denoting better outcomes. Depression will be assessed using the PHQ-9 
instrument. Anxiety will be assessed using the GAD-7 instrument.  
Exploratory outcome 
• Patient survival  
Timeframe: end of follow-up 
The tertiary outcome will consist of exploratory analyses to compare the mortality rate between 
the two schedules of HD. 
Analytical Plan 
 
Feasibility will be assessed using descriptive data regarding eligible patients, enrolled patients, 
intervention compliance and adherence to study-specific assessments, and drop-out/withdrawal 
rate among each intervention. The proportion of people meeting each of the feasibility and 
protocol adherence endpoints with accompanying 95% confidence intervals (CI) will be 
estimated using skew-corrected score tests with a continuity correction. Progress from pilot to 
large scale trial will be considered as: i) continue the study without modifications (feasible as is) 
if all feasibility criteria are met; ii) continue with protocol modifications (feasible with 

 
 
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modifications); or iii) stop the main study (not feasible) if none of the four feasibility criteria was 
met.  
For evaluation of primary safety end points and secondary clinical end points, intention-to-treat 
principles will be followed. Evaluation of categorical end points will be performed using chi-
squared tests. Evaluation of continuous end points will be performed using Student’s unpaired t-
test for normally distributed variables, or the Wilcoxon rank-sum test for nonparametric data. For 
comparison of variables measured during the time course of the study, a repeated measures 
analysis of variance (ANOVA) will be used. The consistency of effects on the primary end point 
will be explored in a variety of subgroups. Kaplan–Meier methods will be used for time-to-first 
hospitalization analyses. Missing RKF data for subjects will be replaced (rather than excluding 
them from the analysis, as missing RKF measurements might not be completely at random) 
using linear regression to estimate values based on other measurements for each subject (linear 
trend at point, SPSS). For each group-sequential analysis, the upper bound of the one-sided 
confidence interval for the hazard ratio (incremental HD to conventional HD) would be 
calculated with the use of the critical value from the Lan–DeMets–O’Brien–Fleming alpha-
spending function, which preserves an overall one-sided alpha of 0.025. No adjustments for 
multiplicity will be made. An independent Safety Monitoring Committee will review all 
available data on a quarterly basis. Analyses that signal safety concerns (i.e., higher rates of 
hospitalization, treatment failure or death in the intervention arm compared to the comparator 
arm) will be reported to an independent Steering Committee to determine whether the study 
should be discontinued, be modified and then proceed, or continue with caution. 
Descriptive statistics will be used to report the results of Participant Feedback Questionnaire.  
 
Subject Recruitment Methods 
 
Clinical records of Nephrology practices, including WFOPD facilities, WFBMC nephrology 
outpatient clinics, and WFBMC nephrology inpatient service will be reviewed for eligibility. 
Study participants will be adults of age ≥18 years with a diagnosis of incident ESKD who meet 
the following additional inclusion criteria: (1) etiology of ESKD is progression of CKD and (2) 
need to be initiated on renal replacement therapy and patient elected HD as the modality of 
choice, or (3) have started dialysis, HD is the intended long-term renal replacement modality, 

 
 
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and have received ≤6 HD sessions. Patients who meet all the eligibility criteria will be 
approached by the study coordinator, and/or PI for explanation of study participation. 
 
Human Subjects Protection 
 
This study poses high risks to the study participants.   
The risks associated with receiving HD twice per week include development of fluid overload, 
uncontrolled hypertension, elevated serum potassium levels, and decreased serum bicarbonate 
levels. However, given the inclusion criteria (i.e. patients with ESRD due to CKD progression 
who have residual kidney function at the time of dialysis initiation), planned frequent 
assessments of the participants in the twice per week HD treatment arm, and administration of 
medications to prevent these potential complications (diuretics, patiromer and sodium 
bicarbonate), the risks will be closely mitigated during the study.   
The potential participants for this study have already been determined to need renal replacement 
therapy, elected HD as the dialysis modality of choice, and have indicators of RKF (i.e., eGFR 
≥5ml/min/1.73m2, lack of anuria, no indication for urgent HD). Timing of dialysis initiation will 
be determined by patient’s nephrologist according to standard of care. Changes in HD 
prescription and frequency can be done at any time point according to patient’s clinical status, 
laboratory values, as felt medically indicated by the study PI or patient’s nephrologist. Changes 
to patient’s medications can be done during the study, as felt indicated by any of the patient’s 
health care providers, patient’s nephrologist, or study PI. Blood collections for this study are 
being kept to a minimum. There will be no medical visits done exclusively for this study. 
 
Informed Consent 
 
Signed informed consent will be obtained from each subject by the study coordinator, members 
of the study team, and/or the PI. The participant will have sufficient time to read the Informed 
consent and to have all questions answered. The personnel involved in this study have 
knowledge on the medical aspects of HD prescription and complications related to HD. The 
assessments involved in the study and the chances of being assigned randomly to one of two 
groups will be explained to each potential participant. We will provide adequate opportunity for 
the subject to consider all options, and respond to the patient’s questions to ensure the 

 
 
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information was comprehended. Informed consent will be obtained in the dialysis centers, 
outpatient nephrology clinics, or inpatient service. Patients will be made aware of their right to 
withdraw from the study at any time without adverse effects on their clinical care. 
 
Confidentiality and Privacy 
 
Taking part in this research study may involve collection of information that is considered 
confidential or private. Confidentiality will be protected by collecting only information needed to 
assess study outcomes, minimizing to the fullest extent possible the collection of any information 
that could directly identify subjects, and maintaining all study information in a secure manner.  
To help ensure subject privacy and confidentiality, only a unique study identifier will appear on 
the data collection form.  Any collected patient identifying information corresponding to the 
unique study identifier will be maintained on a linkage file, store separately from the data.  The 
linkage file will be kept secure, with access limited to designated study personnel.  Following 
data collection subject identifying information will be destroyed three years after closure of the 
study consistent with data validation and study design, producing an anonymous analytical data 
set.  Data access will be limited to study staff.  Data and records will be kept locked and secured, 
with any computer data password protected.  No reference to any individual participant will 
appear in reports, presentations, or publications that may arise from the study. 
 
Data and Safety Monitoring 
 
Participants in the intervention arm will have more frequent analysis of their clinical status and 
lab results. These evaluations will be done at a minimum frequency of once per week in the 
intervention arms, versus twice per month in the comparator arm according to standard of care. 
The study team members (principal investigator and co-investigators) will be responsible for the 
frequent analysis of the participants enrolled in the intervention arm. Participants enrolled in the 
comparator arm will be evaluated according to the standard of care by their nephrologist.  
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study 
staff. 

 
 
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Events related to the type of HD regimen--such as admission for volume overload or 
hyperkalemia in the incremental HD arm--will be closely tracked. Events will be recorded 
electronically and reported to the principal investigator monthly. An independent Safety Officer, 
unblinded to treatment assignments, will review, on a quarterly basis, all events of 
hospitalizations and cause of hospitalization, within the study cohort. All concerns regarding the 
frequency of HD will be reported to the Wake Forest IRB. In addition, the principal investigator, 
Safety Officer, and members of the research group will carefully consider amendments 
(including halting the trial if necessary).  
 
Reporting of Unanticipated Problems, Adverse Events or Deviations (Appendix D) 
 
The principal investigator along with the research staff will be responsible for periodic 
evaluation of clinical trial data to ensure continued participant safety, protocol compliance, data 
collection as well as scientific validity. Adverse events are not anticipated, but any occurring will 
be documented and reported according to WFSM IRB policies and procedures. Cumulative 
adverse events and study progress summary will be communicated to the IRB at the time of 
continuing review.  
 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol 
changes will be promptly reported by the principal investigator or designated member of the 
research team to the IRB. 
 
Physician Stakeholder Survey 
 
Using the REDCap platform, the PI devised a Survey to identify the nephrologists’ opinions and 
perceived barriers regarding the practice of incremental HD in the US. The Survey is geared to 
board-certified Nephrologists in the US. No respondent identifying information will be obtained; 
all responses will be anonymous. The Survey is expected to take less than 5 minutes. The 
information obtained with this Survey will help the Investigators understand and anticipate 
barriers to implementing a clinical trial of incremental vs conventional HD in the US. We 

 
 
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provide the emails of the Nephrologists to whom the Survey will be distributed. We provide the 
link to the REDCap-based Survey. 
 
 
Appendix 
 
Appendix A. Study Flow Diagram 
Appendix B. Treatment of Hyperkalemia 
Appendix C. Schedule of Assessments 
Appendix D. Protocol Violation, Adverse Events, Cause of Death 
Appendix E. Revised Budget 
Appendix F. Participant Feedback Questionnaire 
 
References 
 
1. 
KDOQI Clinical Practice Guideline for Hemodialysis Adequacy: 2015 update. Am J 
Kidney Dis. 2015;66(5):884-930. 
2. 
Lowrie EG, Laird NM, Parker TF, Sargent JA. Effect of the hemodialysis prescription of 
patient morbidity: report from the National Cooperative Dialysis Study. N Engl J Med. 
1981;305(20):1176-1181. 
3. 
Eknoyan G, Beck GJ, Cheung AK, et al. Effect of dialysis dose and membrane flux in 
maintenance hemodialysis. N Engl J Med. 2002;347(25):2010-2019. 
4. 
Paniagua R, Amato D, Vonesh E, et al. Effects of increased peritoneal clearances on 
mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled 
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