Incremental Hemodialysis: The TwoPlus Trial

Comparative Effectiveness of an Individualized Model of Hemodialysis Versus Conventional Hemodialysis

This study is to prospectively compare clinical effectiveness between clinically- matched incremental hemodialysis and conventional hemodialysis in patients with incident kidney dysfunction requiring dialysis and residual kidney function.

The study will enroll 350 patients on chronic hemodialysis and 140 caregivers of enrolled patients. Patients will be randomized in 1:1 ratio to either incremental start hemodialysis or conventional hemodialysis. Caregivers will be followed along with patients for an average period of 2 years post randomization.

Study Overview

• Status: Recruiting
• Conditions: End-Stage Kidney Disease
• Intervention / Treatment: Device: Hemodialysis twice weekly; Other: Hemodialysis thrice weekly

Detailed Description

This study will analyze the effects of differentiated care with individualized hemodialysis on patient health related quality of life, fatigue, employment, and caregiver burden in patients with Kidney dysfunction requiring dialysis (KDRD) and appreciable kidney function.

This study will compare the outcomes in survival, hospitalization, preservation of the kidney function and quality of life between hemodialysis tailored to each patient needs (incremental) and conventional hemodialysis.

• Study Type: Interventional
• Enrollment (Estimated): 350
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Brenda Burciu; Phone Number: 336-716-8671; Email: Brindusa.Burciu@advocatehealth.org
• Study Contact Backup: Name: Ben Bagwell; Email: Benjamin.Bagwell@advocatehealth.org

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32209
      • Recruiting
      • University of Florida
      • Contact: Alaa Awad, MD; Email: Alaa.Awad@jax.ufl.edu
      • Principal Investigator: Alaa Awad
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University
      • Contact: Vandana Dua Niyyar; Email: vniyyar@emory.edu
      • Principal Investigator: Vandana Dua Niyyar
  • Maryland
    • Baltimore, Maryland, United States, 21218
      • Recruiting
      • Johns Hopkins University School of Medicine (JHUSM)
      • Principal Investigator: Gautam Samir, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Sagar Nigwekar; Phone Number: 617-726-5050; Email: SNIGWEKAR@mgh.harvard.edu
      • Principal Investigator: Sagar Nigwekar
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • Recruiting
      • University of Mississippi Medical Center
      • Contact: Neville Dossabhoy, MD; Phone Number: 601-984-5670; Email: ndossabhoy@umc.edu
      • Principal Investigator: Neville Dossabhoy, MD
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Renal Research Institute (RRI)
      • Contact: Rasha Hussein, MD; Phone Number: 212-331-1710; Email: rasha.hussein@rriny.com
      • Principal Investigator: Rasha Hussein, MD
    • Queens, New York, United States, 11427
      • Recruiting
      • Northwell Health
      • Contact: Steven Fishbane; Phone Number: 516-465-8200; Email: Sfishbane@northwell.edu
      • Principal Investigator: Steven Fishbane
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Recruiting
      • University of North Carolina Chapel Hill
      • Principal Investigator: Jennifer Flythe, MD
    • Winston-Salem, North Carolina, United States, 27157
      • Recruiting
      • Atrium Health Wake Forest Baptist
      • Principal Investigator: Mariana Murea, MD
  • Virginia
    • Charlottesville, Virginia, United States, 22904
      • Recruiting
      • University of Virginia (UVA)
      • Principal Investigator: Emaad Abdel-Rahman, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Patient eligibility Criteria:

Inclusion Criteria:

• Clinical Inclusion Criteria:
• Age ≥ 18 years
• Incident kidney dysfunction requiring dialysis (KDRD) started on maintenance, in-center hemodialysis (HD), or anticipated to be started on maintenance, in-center HD within the next 12 weeks
• Has received ≤36 sessions of intermittent HD (i.e., on HD for ≤12 weeks) at the time patient is approached for potential study participation

Residual Kidney Function Inclusion Criteria:

• Kidney urea clearance <2.0 mL/min
• Urine volume# of ≥500 mL/24 h

Exclusion Criteria:

• Pre-HD serum K ≥5.8 mEq/L, Na ≤125 mEq/L, or bicarbonate level ≤17 mEq/L
• Requirement or anticipated requirement of high-volume ultrafiltration
• Unable or unwilling to follow the study protocol for any reason
• Known pregnancy or planning to attempt to become pregnant or lactating women
• Estimated survival or dialysis modality change or center transfer <6 months

Caregiver Eligibility Criteria:

• be at least 18 years old
• be the main caregiver (at patient's choice)
• be a close relative of the patient (spouse, child, sibling, parent, grandchild)
• have no known psychiatric and neurologic disorders (through direct inquiry from the person)
• not be a member of the medical or healthcare team
• not be the caregiver for another patient with chronic illness
• not have experienced severe life events within prior 3 months of enrollment (through direct inquiry from the person)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clinically-matched Incremental Hemodialysis ( CMIHD); Randomized group to have hemodialysis prescription tailored based on residual kidney function and clinical manifestations starting at twice weekly.	Device: Hemodialysis twice weekly; Frequency and duration of hemodialysis is tailored to the patient. Adjuvant pharmacotherapy is prescribed to maintain volume, electrolyte and acid-base homeostasis ( e.g., diuretics, sodium bicarbonate and potassium binding patiromer)
Active Comparator: Conventional Hemodialysis (CHD); Randomized group to conventional three times a week hemodialysis.	Other: Hemodialysis thrice weekly; Conventional hemodialysis regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Clinical events of safety	composite of all-cause Emergency Department visits, hospitalizations, or death	year 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EuroQOL-5D-5L scores Health-related quality of life Health-related quality of life and residual kidney function	Compare the effects of CMIHD and CHD - The descriptive system covers 5 dimensions of health (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) with 5 levels of severity in each dimension (no problems, slight problems, moderate problems, severe problems, and unable to perform or extreme problems - Values are anchored at 1 (full health) and 0 (a state as bad as being dead) as required by their use in economic evaluation. Values less than 0 represent health states regarded as worse than a state that is as bad as being dead.	year 2
Trail Making Test B scores Health-related quality of life Health-related quality of life and residual kidney function	Patient participants' cognitive function will be assessed using change in Trail Making Test B score - The Trail Making Test measures your visual attention, mental flexibility, processing speed, and motor speed based on how quickly and accurately you connect dots in ascending order (either numerically or with alternating numbers and letters). The test can be used to diagnose dementia and other cognitive disorders - Higher scores indicate a higher degree of cognitive impairment	Baseline and months 6, 12, 18, & 24
Standardized Outcomes in Nephrology (SONG) scores Health-related quality of life Health-related quality of life and residual kidney function	SONG-HD Fatigue score - The SONG-HD Fatigue measure consists of three items that assess (1) the effect of fatigue on life participation, (2) tiredness, and (3) level of energy. These dimensions are assessed on a four-point Likert scale indicating increasing severity, ranging from zero (not at all) to three (severely). Higher scores meaning higher severity	Baseline and months 6, 12, 18, & 24
Time to recover from hemodialysis (HD) Health-related quality of life Health-related quality of life and residual kidney function	Patient-reported functional status and fatigue will be assessed using Time to recover from HD	Baseline and monthly up to 2 years
Caregiver burden Zarit Caregiver Burden Scores Health-related quality of life Health-related quality of life and residual kidney function	Caregiver burden will be assessed using the Zarit Caregiver Burden Scale - The ZBI consists of 22 items rated on a 5-point Likert scale that ranges from 0 (never) to 4 (nearly always) with the sum of scores ranging between 0-88. 9. Higher scores indicate greater burden. A score of 17 or more was considered high burden.	Baseline, months 6, 12, 18, & 24
Change in urine output	Urine collections will be analyzed at the lab used by the dialysis center	Baseline, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 21, and Year 2
Change in kidney urea clearance (mL/min/1.73 m2)	Urine collections will be analyzed at the lab used by the dialysis center	Baseline, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 21, and Year 2
Change in kidney creatinine clearance (mL/min/1.73 m2)	Urine collections will be analyzed at the lab used by the dialysis center	Baseline, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 21, and Year 2
Hospital free days per 100 patient-days	The duration of hospital-free days will be determined for each patient and calculated in the whole cohort per 100 patient-days. It is anticipated an array of hospitalization events for each participant, ranging from no hospitalization to frequent hospitalizations per study period. All periods of hospitalization, per each participant, will be analyzed. A period of hospitalization will be computed from date of hospital admission to the date of discharge. Hospital-free days may include one or more discrete time segments of non-hospitalization between periods hospitalization. The total hospital-free days per patient participant will be calculated as total study days - hospitalization days. Hospital-free days will be normalized per 100 patient-days.	year 2
Illness Intrusiveness Rating Scale	Patients will rate the degree of interference caused by HD treatments on the following domains: health, diet, work, active and passive recreation, financial situation, relationship with spouse, sex life, family and other social relations, self-expression/self- improvement, religious expression, and community/civic involvement. Individual item ratings and the sum across ratings will be recorded. The total scale has a range of 13 (minimum intrusiveness) to 91 (extreme intrusiveness).	Assessed at baseline and monthly up to 2 years
Employment status	The employment status for patients and caregivers will be assessed through surveys.	Baseline and months 6, 12, 18 and 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterize implementation processes using mixed methods - Intervention characteristics	Process evaluation will include a) Intervention characteristics, to assess organizational readiness to change, intervention acceptability and appropriateness; b) Inner setting characteristics, to assess barriers and facilitators to the adoption of HD intervention at the partnering organizations; c) External factors that mediate implementation; d) Adoption; e) Reach; f) Fidelity, to assess adherence to serial timed urine collection and HD treatment schedule; and g) Sustainability, to assess barriers and facilitators to maintaining intervention	2 years
Characterize implementation processes using mixed methods - Inner setting characteristics, to assess barriers and facilitators to the adoption of HD intervention at the partnering organizations	Process evaluation will include a) Intervention characteristics, to assess organizational readiness to change, intervention acceptability and appropriateness; b) Inner setting characteristics, to assess barriers and facilitators to the adoption of HD intervention at the partnering organizations; c) External factors that mediate implementation; d) Adoption; e) Reach; f) Fidelity, to assess adherence to serial timed urine collection and HD treatment schedule; and g) Sustainability, to assess barriers and facilitators to maintaining intervention	2 years
Characterize implementation processes using mixed methods - External factors that mediate implementation	Process evaluation will include a) Intervention characteristics, to assess organizational readiness to change, intervention acceptability and appropriateness; b) Inner setting characteristics, to assess barriers and facilitators to the adoption of HD intervention at the partnering organizations; c) External factors that mediate implementation; d) Adoption; e) Reach; f) Fidelity, to assess adherence to serial timed urine collection and HD treatment schedule; and g) Sustainability, to assess barriers and facilitators to maintaining intervention	2 years
Characterize implementation processes using mixed methods - Adoption	Process evaluation will include a) Intervention characteristics, to assess organizational readiness to change, intervention acceptability and appropriateness; b) Inner setting characteristics, to assess barriers and facilitators to the adoption of HD intervention at the partnering organizations; c) External factors that mediate implementation; d) Adoption; e) Reach; f) Fidelity, to assess adherence to serial timed urine collection and HD treatment schedule; and g) Sustainability, to assess barriers and facilitators to maintaining intervention	2 years
Characterize implementation processes using mixed methods - Reach	Process evaluation will include a) Intervention characteristics, to assess organizational readiness to change, intervention acceptability and appropriateness; b) Inner setting characteristics, to assess barriers and facilitators to the adoption of HD intervention at the partnering organizations; c) External factors that mediate implementation; d) Adoption; e) Reach; f) Fidelity, to assess adherence to serial timed urine collection and HD treatment schedule; and g) Sustainability, to assess barriers and facilitators to maintaining intervention	2 years
Characterize implementation processes using mixed methods - Fidelity, to assess adherence to serial timed urine collection and HD treatment schedule	Process evaluation will include a) Intervention characteristics, to assess organizational readiness to change, intervention acceptability and appropriateness; b) Inner setting characteristics, to assess barriers and facilitators to the adoption of HD intervention at the partnering organizations; c) External factors that mediate implementation; d) Adoption; e) Reach; f) Fidelity, to assess adherence to serial timed urine collection and HD treatment schedule; and g) Sustainability, to assess barriers and facilitators to maintaining intervention	2 years
Characterize implementation processes using mixed methods - Sustainability, to assess barriers and facilitators to maintaining intervention	Process evaluation will include a) Intervention characteristics, to assess organizational readiness to change, intervention acceptability and appropriateness; b) Inner setting characteristics, to assess barriers and facilitators to the adoption of HD intervention at the partnering organizations; c) External factors that mediate implementation; d) Adoption; e) Reach; f) Fidelity, to assess adherence to serial timed urine collection and HD treatment schedule; and g) Sustainability, to assess barriers and facilitators to maintaining intervention	2 years

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: Patient-Centered Outcomes Research Institute
• Investigators: Principal Investigator: Mariana Murea, MD, Wake Forest Health Sciences; Principal Investigator: Peter Kotanko, Renal Research Institute

Publications and helpful links

General Publications

• Murea M, Raimann JG, Divers J, Maute H, Kovach C, Abdel-Rahman EM, Awad AS, Flythe JE, Gautam SC, Niyyar VD, Roberts GV, Jefferson NM, Shahidul I, Nwaozuru U, Foley KL, Trembath EJ, Rosales ML, Fletcher AJ, Hiba SI, Huml A, Knicely DH, Hasan I, Makadia B, Gaurav R, Lea J, Conway PT, Daugirdas JT, Kotanko P; Two Plus Research Consortium. Comparative effectiveness of an individualized model of hemodialysis vs conventional hemodialysis: a study protocol for a multicenter randomized controlled trial (the TwoPlus trial). Trials. 2024 Jun 28;25(1):424. doi: 10.1186/s13063-024-08281-9.
• Murea M, Foley KL, Gautam SC, Flythe JE, Raimann JG, Abdel-Rahman E, Awad AS, Niyyar VD, Kovach C, Roberts GV, Jefferson NM, Conway PT, Rosales LM, Woldemichael J, Sheikh HI, Raman G, Huml AM, Knicely DH, Hasan I, Makadia B, Lea J, Daugirdas JT, Gencerliler N, Divers J, Kotanko P; TwoPlus Research Consortium; Nwaozuru UC. Protocol for the process evaluation of a randomised clinical trial of incremental-start versus conventional haemodialysis: the TwoPlus study. BMJ Open. 2025 Nov 28;15(11):e094392. doi: 10.1136/bmjopen-2024-094392.

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2024
• Primary Completion (Estimated): July 1, 2030
• Study Completion (Estimated): January 1, 2031

Study Registration Dates

• First Submitted: March 29, 2023
• First Submitted That Met QC Criteria: April 11, 2023
• First Posted (Actual): April 25, 2023

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Hemodialysis; Clinically-Matched Incremental Hemodialysis
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Renal Insufficiency; Renal Insufficiency, Chronic; Pathological Conditions, Signs and Symptoms; Kidney Failure, Chronic
• Other Study ID Numbers: IRB00092986; CER-2022C1-26300 (Other Grant/Funding Number: Patient-Centered Outcomes Research Institute)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Available upon investigator request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No