Clinical trial NCT03740048
Conditions: End Stage Renal Failure on Dialysis
Keywords: Hemodialysis Kidney Disease Kidney Function
Sponsor: Wake Forest University Health Sciences
Start date: 2019-06-19; Completion date: 2021-11-04
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The optimal frequency of hemodialysis treatments in patients with incident end-stage kidney disease in not known. This pilot trial will randomize patients with incident end-stage kidney disease due to chronic kidney disease progression to two different regimens of hemodialysis: i) twice-weekly hemodialysis for six weeks with adjuvant pharmacologic medications followed by thrice-weekly hemodialysis, or ii) thrice-weekly hemodialysis. The study will test feasibility of stepwise hemodialysis, and the effects of the two regimens of hemodialysis on residual kidney function.

Detailed description:

Arms: arm 1: Hemodialysis regimen at the initiation of dialysis treatment: Twice-weekly hemodialysis plus adjunctive pharmacologic therapy (loop diuretic, potassium-binding agent, and sodium bicarbonate) for six consecutive weeks, continued by thrice-weekly hemodialysis (intervention group) arm 2: Hemodialysis regimen at the initiation of dialysis treatment: thrice-weekly hemodialysis
Interventions: intervention 1: Hemodialysis intervention 2: Patiromer Oral Product
Intervention descriptions: intervention 1: Hemodialysis frequency will differ in the first six weeks of hemodialysis therapy between the two treatment arms. intervention 2: Participants in the intervention group who develop hyperkalemia, during the first six weeks of receiving hemodialysis twice per week, will be treated with Patiromer.

Protocol documents:
Prot_SAP_001.pdf: 
 
 
Protocol 
 
 
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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 
trial. J Am Soc Nephrol. 2002;13(5):1307-1320. 
5. 
Lo WK, Ho YW, Li CS, et al. Effect of Kt/V on survival and clinical outcome in CAPD 
patients in a randomized prospective study. Kidney Int. 2003;64(2):649-656. 
6. 
Li Y, Jin Y, Kapke A, et al. Explaining trends and variation in timing of dialysis initiation 
in the United States. Medicine (Baltimore). 2017;96(20):e6911. 
7. 
Chin AI, Appasamy S, Carey RJ, Madan N. Feasibility of Incremental 2-Times Weekly 
Hemodialysis in Incident Patients With Residual Kidney Function. Kidney Int Rep. 
2017;2(5):933-942. 
8. 
Lin YF, Huang JW, Wu MS, et al. Comparison of residual renal function in patients 
undergoing twice-weekly versus three-times-weekly haemodialysis. Nephrology 
(Carlton, Vic). 2009;14(1):59-64. 
9. 
Zhang M, Wang M, Li H, et al. Association of initial twice-weekly hemodialysis 
treatment with preservation of residual kidney function in ESRD patients. Am J Nephrol. 
2014;40(2):140-150. 


 
 
Protocol 
 
 
March 11, 2021 
 
16 
 
10. 
Shafi T, Jaar BG, Plantinga LC, et al. Association of residual urine output with mortality, 
quality of life, and inflammation in incident hemodialysis patients: the Choices for 
Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study. Am J 
Kidney Dis. 2010;56(2):348-358. 
11. 
Termorshuizen F, Dekker FW, van Manen JG, Korevaar JC, Boeschoten EW, Krediet 
RT. Relative Contribution of Residual Renal Function and Different Measures of 
Adequacy to Survival in Hemodialysis Patients: An analysis of the Netherlands 
Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2. Journal of the American 
Society of Nephrology. 2004;15(4):1061-1070. 
12. 
Marquez IO, Tambra S, Luo FY, et al. Contribution of residual function to removal of 
protein-bound solutes in hemodialysis. Clin J Am Soc Nephrol. 2011;6(2):290-296. 
13. 
Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and 
hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211-221. 
14. 
Bakris GL, Pitt B, Weir MR, et al. Effect of Patiromer on Serum Potassium Level in 
Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN 
Randomized Clinical Trial. JAMA. 2015;314(2):151-161. 
15. 
Pitt B, Bakris GL, Bushinsky DA, et al. Effect of patiromer on reducing serum potassium 
and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney 
disease on RAAS inhibitors. Eur J Heart Fail. 2015;17(10):1057-1065. 
16. 
Kovesdy CP, Regidor DL, Mehrotra R, et al. Serum and dialysate potassium 
concentrations and survival in hemodialysis patients. Clin J Am Soc Nephrol. 
2007;2(5):999-1007. 
17. 
Kovesdy CP, Anderson JE, Kalantar-Zadeh K. Association of serum bicarbonate levels 
with mortality in patients with non-dialysis-dependent CKD. Nephrol Dial Transplant. 
2009;24(4):1232-1237. 
18. 
Wu DY, Shinaberger CS, Regidor DL, McAllister CJ, Kopple JD, Kalantar-Zadeh K. 
Association between serum bicarbonate and death in hemodialysis patients: is it better to 
be acidotic or alkalotic? Clin J Am Soc Nephrol. 2006;1(1):70-78. 
19. 
Daugirdas JT. Estimating Time-averaged Serum Urea Nitrogen Concentration during 
Various Urine Collection Periods: A Prediction Equation for Thrice Weekly and 
Biweekly Dialysis Schedules. Semin Dial. 2016;29(6):507-509. 
20. 
Daugirdas JT, Depner TA, Greene T, Levin NW, Chertow GM, Rocco MV. Standard 
Kt/Vurea: a method of calculation that includes effects of fluid removal and residual 
kidney clearance. Kidney Int. 2010;77(7):637-644. 
21. 
Jansen MA, Hart AA, Korevaar JC, Dekker FW, Boeschoten EW, Krediet RT. Predictors 
of the rate of decline of residual renal function in incident dialysis patients. Kidney Int. 
2002;62(3):1046-1053. 
 

ICF_002.pdf: 
Official Title: A Randomized Pilot Study of Hemodialysis Initiation Comparing Twice-Weekly 
Hemodialysis Plus Dialysis-Sparing Therapy Versus Thrice-Weekly Hemodialysis (The TWOPLUS-HD 
Trial)  
NCT03740048
IRB-Approved Date:  5/7/21


Page 1 of 11
Informed Consent Document
Project Title:  A Randomized Pilot Study of Hemodialysis Initiation Comparing 
TwiceWeekly Hemodialysis Plus Dialysis-Sparing Therapy versus Thrice-Weekly 
Hemodialysis: 
The TWOPLUS-HD Trial
Principal Investigator:   Mariana Murea, M.D.
Co-Investigators:  Isai Bowline, M.D., Alison Fletcher, M.D
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you have End Stage Renal Disease and your Kidney Doctor has determined that 
you need hemodialysis treatments.  Healthy kidneys clean your blood by filtering wastes, salts 
and fluid from your blood. They also make substances that keep your body healthy. In 
hemodialysis a machine is used to replace some of these functions when your kidneys are failing. 
Your participation is voluntary.  Please take your time in making your decision as to whether or 
not you wish to participate.  Ask your study doctor or the study staff to explain any words or 
information contained in this informed consent document that you do not understand.  You may 
also discuss the study with your friends and family.
WHY IS THIS STUDY BEING DONE?
Almost all Americans with end-stage kidney disease (ESKD) that start hemodialysis (HD) are 
prescribed a regular dialysis treatment schedule of three times per week.  However, the number 
of hemodialysis treatments per week that is best when first starting dialysis is not known. When 
hemodialysis is started, there may still be enough kidney function left that may only require 
doing hemodialysis two times per week (instead of three times per week) for a limited period of 
time. In this study, half of the participants will be treated with a regular schedule of hemodialysis 
(three times per week) from the time dialysis is started. The other half of the participants will be 
treated with hemodialysis two times per week for six weeks only followed by hemodialysis three 
times per week. With this study we want to see how the kidney function changes depending on 
the number of hemodialysis treatments performed when starting hemodialysis. For this reason, 
we will want to obtain urine collections from you at specific time intervals. These urine 
collections will help to evaluate how the kidney function changes after dialysis is started. With 
the information we obtain from this study, we want to see how the human body reacts to 
different number of hemodialysis treatments at the beginning of dialysis. 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
Approximately fifty-one (51) people will take part in this pilot study.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00054726
Meeting Date Approved 5/7/2021          
Version Valid Until: 1/19/2022


Page 2 of 11
V1.5
WHAT IS INVOLVED IN THE STUDY?
If you agree to participate in this study by signing this consent form, you will be randomized to 
either start hemodialysis two times a week plus using additional kidney medications for six 
weeks, continued by three times a week or start hemodialysis three times a week.  
Randomization means that you are put into a group by chance.  It is like flipping a coin.  You 
will have an equal chance to be placed into either group.  Patients randomized to two times a 
week will receive a stepwise hemodialysis regimen with hemodialysis two times a week for six 
weeks, followed by hemodialysis three times a week onward. Patients randomized to three times 
a week will receive hemodialysis three times a week at the start of dialysis and onward.   If you 
are randomized to the group starting hemodialysis two times per week for six weeks, you may be 
provided with Patiromer (Veltessa) to help with potassium retention. Patiromer will be provided 
to you at no cost by the company that is sponsoring this study. Patiromer is FDA approved for its 
intended use in this study. Your primary nephrologist may ask you to continue or start 
medication(s) that control fluid and salt retention, potassium retention, or buffer acidity. These 
medications include Furosemide (Lasix), Bumetanide (Bumex), Metolazone (Zaroxolyn), 
Patiromer (Veltassa) or Sodium Bicarbonate, all these medications are FDA approved for their 
intended use in this study and will be prescribed, if needed according to standard of care.    .  
Your Kidney Doctor has already determined that you need and are eligible to start hemodialysis 
in order to be able to retain kidney function.  Your dialysis treatments will be done at your 
prescribed dialysis center. 
At your first dialysis treatment only, you will receive dialysis with a study specific potassium 
concentration of fluid that helps pull toxins from the blood. After your first dialysis treatment, 
the evaluation of your dialysis treatments will follow according to usual clinical practice and will 
be directed by your kidney doctor.  You will be examined in the medical office or at your 
dialysis unit on a regular basis by your kidney doctor, physician assistant, and nurses 
experienced with dialysis care. Any abnormalities that relate to your dialysis treatments will be 
addressed as directed by your kidney doctor according to standard of care.  
There will not be any changes in your usual medical care if you participate.
All of the following evaluation and reports will be performed and gathered specifically for this 
study at your dialysis session or at your regular doctor office visit by our study personnel.  
●
You will be asked to provide information from your health record such as age, sex, ethnic                   
background, medical history, current medications, diet, and medical care.
●
You will be asked to complete a questionnaire (Dialysis Symptom Index) to assess your 
health and how you are feeling, will be asked questions about any depression you may have 
(PHQ-9 questionnaire), and will be asked questions about any anxiety you may have (GAD-7 
questionnaire) at several different times during your participation.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00054726
Meeting Date Approved 5/7/2021          
Version Valid Until: 1/19/2022


Page 3 of 11
V1.5
●
You will be asked to provide a study specific blood sample at the outpatient dialysis unit 
at your first dialysis treatment and at four other dialysis treatments.  For each test, less than 1 
millimeter of blood is required.  The lab test will be done at the dialysis unit and you will not 
have any needle-sticks for this test.
●
You will be asked to provide urine collections.  Within one week before or after 
hemodialysis initiation, you will be asked to collect the urine you make over a 24-hour period. 
Afterwards, you will be asked to collect urine at 6 weeks, 3 months, 6 months, and 12 months of 
being on hemodialysis; at these collections, you will be asked to collect all the urine that you 
make between two hemodialysis sessions (from the end of one dialysis session to the beginning 
of the next successive hemodialysis session).  
     There will be no medical visits done specifically or exclusively for this study.  Information 
routinely gathered as part of your medical care will also be used in the study.  Results of routine 
tests will be available to your doctor, and will be used to help determine study outcomes.
We can send copies of your test results to your primary doctor. Even if you do not wish to have 
any of your medical information sent to your physician, you can still participate in this 
research study. 
Do you request that we send important medical findings from your study tests/exams to your 
personal physician? 
[ ] Yes  [ ] No    ___________ Initials
HOW LONG WILL I BE IN THE STUDY?
Your participation in this study will be for about 12 months. You can stop participating at any 
time. If you decide to stop participating in the study we encourage you to talk to the investigators 
or study staff first to learn about any potential health or safety consequences.  Your medical care 
will not be affected by your decision.
This study will not interfere with any other treatments of your medical conditions. Should you 
qualify to receive a kidney transplant during the study, the kidney transplantation evaluation and 
surgery will proceed as scheduled. If you receive a kidney transplant, your participation in this 
study will be ended.
WHAT ARE THE RISKS OF THE STUDY?
Being in this study may involve some risk to you. You should discuss the risk of being in this 
study with the study staff. 
●
There is a slight risk that other people outside the study may access your information. We 
will do our best to protect your confidential information. Efforts, such as coding research 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00054726
Meeting Date Approved 5/7/2021          
Version Valid Until: 1/19/2022


P a g e 4 of 1 1
V 1. 5
rec or ds, kee pi n g researc h rec or ds sec ure a n d all o wi n g o nl y a ut h orize d pe o ple t o ha ve access t o 
researc h rec or ds, will be ma de t o kee p y o ur i nf or mati o n safe.
●
Beca use i n vesti gat ors d o n ot k n o w w hic h n u m ber of dial ysis sessi o ns is better at 
preser vi n g ki d ne y f u ncti o n, t here is a c ha nce t hat y o u c o ul d be ra n d o mize d t o t he ar m of t he 
st u d y t hat eit her has a better or w orse o utc o me t ha n t he ot her ar m.
●
If y o u will be ra n d o mize d t o he m o dial ysis t w o ti mes a wee k, t he f oll o wi n g ma y be 
o bser ve d: fl ui d ma y b uil d u p bet wee n he m o dial ysis treat me nts, p otassi u m le vel ma y g o u p i n t he 
bl o o d bet wee n he m o dial ysis treat me nts, or aci d le vel ma y g o u p i n t he bl o o d bet wee n dial ysis 
treat me nts. T he ris ks ass ociate d wit h ele vate d p otassi u m or aci d le vel i n t he bl o o d i ncl u des 
irre g ular heart beats, heart fail ure, or s u d de n deat h. If y o u e x perie nce a n y pal pitati o ns or 
s h ort ness of breat h, y o u will nee d t o re p ort t o a healt h care pr o vi der or prese nt t o a n e mer ge nc y 
r o o m. Y o u will be cl osel y m o nit ore d f or a n y of t hese p ote ntial occ urre nces at t he dial ysis u nit. 
T o pre ve nt or treat t hese cli nical occ urre nces, y o u will be prescri be d me dicati o ns if nee de d, or 
y o u ma y be prescri be d he m o dial ysis t hree ti mes per wee k bef ore t he mar k of si x wee ks of t wice 
per wee k he m o dial ysis.
 D uri n g t he st u d y, y o u ma y recei ve, if me dicall y i n dicate d, treat me nt f or fl ui d rete nti o n 
( w hic h ca n be treate d wit h di uretics, f or e xa m ple F ur ose mi de or Lasi x), hi g h p otassi u m le vel 
( w hic h ca n be treate d wit h Patir o mer), or hi g h aci dit y i n t he bl o o d ( w hic h ca n be treate d wit h 
S o di u m Bicar b o nate). 
Y o u mi g ht ha ve alrea d y recei ve d treat me nt wit h di uretics a n d s o di u m bicar b o nate. T hese 
me dicati o ns are well t olerate d a n d t he d oses will be c ha n ge d, base d o n y o ur cli nical m o nit ori n g 
a n d bl o o d w or k, t o pre ve nt de h y drati o n, t o o m uc h v ol u me acc u m ulati o n, or ha vi n g t o o m uc h 
aci d or t o o m uc h bicar b o nate i n y o ur bl o o d. If p otassi u m le vel i n t he bl o o d bec o mes t o o hi g h, 
y o u will recei ve Patir o mer. T his me dicati o n is well t olerate d; p ote ntial si de effects i ncl u de 
c o nsti pati o n ( w hic h ca n occ ur i n a p pr o xi matel y 8 o ut of 1 0 0 patie nts), l o w ma g nesi u m le vel i n 
t he bl o o d ( w hic h ca n occ ur i n u p t o 9 o ut of 1 0 0 patie nts). D uri n g treat me nt wit h Patir o mer, y o ur 
bl o o d le vels of p otassi u m a n d ma g nesi u m will be m o nit ore d, a n d c ha n ges i n me dicati o ns 
(i ncl u di n g disc o nti n uati o n) a n d/ or d osi n g will be ma de as nee de d t o u n d o a n y of t he si de effects.  
T w o i n de pe n de nt Safet y Me dical Officers will be re vie wi n g t he data fr o m t his researc h 
t hr o u g h o ut t he st u d y.
R E P R O D U C TI V E RI S K S A N D O T H E R I S S U E S T O P A R TI CI P A TI N G I N R E S E A R C H
D ue t o u n k n o w n ris ks a n d p ote ntial har m t o t he u n b or n fet us, se x uall y acti ve w o me n of 
c hil d beari n g p ote ntial m ust use a relia ble met h o d of birt h c o ntr ol w hile partici pati n g i n t his 
st u d y. Relia ble met h o ds of birt h c o ntr ol are: a bsti ne nce ( n ot ha vi n g se x), oral c o ntrace pti ves, 
i ntra uteri ne de vice (I U D), De p o Pr o vera, t u bal li gati o n, or vasect o m y of t he part ner ( wit h 
c o nfir me d ne gati ve s per m c o u nts) i n a m o n o ga m o us relati o ns hi p (sa me part ner). A n acce pta ble, 
W F U S c h o ol of M e di ci n e 
I n stit uti o n al R e vi e w B o ar d 
I R B N u m b er: I R B 0 0 0 5 4 7 2 6
M e eti n g D at e A p pr o v e d 5/ 7/ 2 0 2 1          
V er si o n V ali d U ntil: 1/ 1 9/ 2 0 2 2


Page 5 of 11
V1.5
although less reliable, method involves the careful use of condoms and spermicidal foam or gel 
and/or a cervical cap or sponge. We encourage you to discuss this issue further with your 
physicians if you have any questions.
Pregnant women are excluded from participation in this study. If you are a sexually active 
woman of childbearing potential and have not been using a reliable method of birth control, two 
negative pregnancy tests performed 15 days apart are required to check for possible early 
pregnancy prior to starting treatment.
CONTRACEPTIVE MEASURES FOR MALES
Your participation in this research study may damage your sperm, which could cause harm to a 
child that you may father while on this study. Such harm may be currently unforeseeable. If you 
are sexually active, you must agree to use a medically acceptable form of birth control in order to 
be in this study and for (specify period of time following study participation if applicable) 
months afterwards. Medically acceptable contraceptives include: (1) surgical sterilization (such 
as a vasectomy), or (2) a condom used with a spermicide. Contraceptive measures such as Plan B 
(TM), sold for emergency use after unprotected sex, are not acceptable methods for routine use. 
You should inform your partner of the potential for harm to an unborn child. She should know 
that if pregnancy occurs, you will need to report it to the study doctor, and she should also 
promptly notify her doctor.
 ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
You may or may not receive direct benefit from participating in this study.  We hope the 
information learned from this study will benefit other people in the future.  Based on experience 
with hemodialysis in patients with similar disorders, researchers believe twice-weekly 
hemodialysis for six week followed by thrice-weekly hemodialysis may be as good as standard 
therapy of starting dialysis with thrice-weekly hemodialysis. 
 WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment. You should talk to your doctor about all 
the choices you have. Instead of being in this study, you have the option of doing hemodialysis 
three times a week which is the standard hemodialysis regimen prescribed at the initiation of 
hemodialysis in the United States of America.
WHAT ARE THE COSTS?
There are no costs to you for taking part in this study. Costs for your regular medical care will be 
your own responsibility.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00054726
Meeting Date Approved 5/7/2021          
Version Valid Until: 1/19/2022


Page 6 of 11
V1.5
 WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals.  Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others.  There is always some risk that even de-identified information might be re-identified.
Participant information may be provided to Federal and other regulatory agencies as required.  
The Food and Drug Administration (FDA), for example, may inspect research records and learn 
your identity if this study falls within its jurisdiction.
WILL YOU BE PAID FOR PARTICIPATING?
You will be compensated $25 after completion of the 24 hour urine collection at your first 
dialysis visit.  You will also be compensated $50 after completion of each (4 total) inter-dialytic 
urine collection (urine collection between two hemodialysis sessions) for a potential of $225 
total for completing all study procedures. To receive payment, you must provide your social 
security number, name and address so that we can comply with IRS (Internal Revenue Service) 
reporting requirements. When payments are reported to the IRS we do not let them know what 
the payment is for, only that you have been paid. If you do not wish to provide this information 
you can still take part in this study but you will not be paid.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by Relypsa, Inc. The sponsor is providing money or other support 
to Wake Forest University Health Sciences to help conduct this study. The researchers do not, 
however, hold a direct financial interest in the sponsor or the product being studied. 
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A RESULT OF 
PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00054726
Meeting Date Approved 5/7/2021          
Version Valid Until: 1/19/2022


Page 7 of 11
V1.5
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at
.
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the insurer is required by 
law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call the study investigator Dr. Mariana Murea, 
M.D. at 
 
 after hours).
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you about your health or behaviors is 
considered Protected Health Information. The information we will collect for this research study 
includes: date of birth, contact information (address, telephone number, etc.), past medical 
history, laboratory results, procedures, other test results, how you respond to study procedures, 
and information from questionnaires, assessments and physical examinations. If this research 
study involves the diagnosis or treatment of a medical condition, then Protected Health 
Information collected from you during this study may be placed in your medical record, and may 
be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations.
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer.
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; central laboratories, reading centers or analysis 
centers; the Institutional Review Board; representatives of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital; representatives from government agencies such as 
the Food and Drug Administration (FDA) or the Office of Human Research Protections (OHRP), 
the Department of Health and Human Services (DHHS), The National Institutes of Health (NIH) 
and similar agencies in other countries.  
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00054726
Meeting Date Approved 5/7/2021          
Version Valid Until: 1/19/2022


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V1.5
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
Monitors, auditors, IRB or other regulatory agencies will be granted direct access to your original 
medical record for verification of clinical trial procedures or data, without violating your 
confidentiality and to the extent permitted by other applicable laws. 
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups it might no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept indefinitely. This authorization does not expire. You will not be 
able to obtain a copy of your Protected Health Information in the research records until all 
activities in the study are completely finished.
You can tell Dr. Mariana Murea that you want to take away your permission to use and share 
your Protected Health Information at any time by sending a letter to this address:
Mariana Murea, M.D.
 
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00054726
Meeting Date Approved 5/7/2021          
Version Valid Until: 1/19/2022


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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time. 
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital.  These will be kept secure, with access to this 
information limited to individuals with proper authority, but who may not be directly involved 
with this research study.
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study 
participants. Information about your participation in the study will be placed in the NCBH 
medical record, along with any routine medical test results that were obtained at NCBH as part of 
this study.
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
at any time. This could be because it is in your best medical interest, your condition worsened, 
new information becomes available, you had an unexpected reaction, you failed to follow 
instructions, or because the entire study has been stopped.
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Dr. Mariana Murea, M.D. at 
 (
 after hours).  
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
.
You will be given a copy of this signed consent form.
Signatures
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00054726
Meeting Date Approved 5/7/2021          
Version Valid Until: 1/19/2022


Page 10 of 11
V1.5
I agree to take part in this study. I authorize the use and disclosure of my health 
information as described in this consent and authorization form. If I have not already 
received a copy of the Privacy Notice, I may request one or one will be made available to 
me. I have had a chance to ask questions about being in this study and have those questions 
answered.  By signing this consent and authorization form, I am not releasing or agreeing 
to release the investigator, the sponsor, the institution or its agents from liability for 
negligence.
Please read the following sentence and think about your choice.  After reading the sentence, 
circle YES or NO.  If you have questions, please talk to your doctor or nurse.
You agree that your Wake Forest Baptist Health electronic medical record may be accessed by 
designated study personnel for use in future research to learn about, detect, prevent, treat or cure 
other health problems.  If you answer NO to this question, you may still participate in this study. 
YES
NO 
___________________________________
           Subject Name (Printed)
____________________________________  ________________   _______________
Subject Signature                                              Date                   Time  AM / PM 
___________________________________  
Person Obtaining Consent (Printed)
    
_____________________________________  ________________  _______________
Person Obtaining Consent (Signed)                  Date                    Time  AM / PM
Legally Authorized Representative Name (Print):_________________________
 
The above named Legally Authorized Representative has legal authority to act for the research 
subject based upon (specify health care power of attorney, spouse, parent, etc.)
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00054726
Meeting Date Approved 5/7/2021          
Version Valid Until: 1/19/2022


Page 11 of 11
V1.5
Relationship to the Subject: _____________________________
Legal Representative Signature: _________________________ Date:_________ 
Time:________ am  / pm
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00054726
Meeting Date Approved 5/7/2021          
Version Valid Until: 1/19/2022