RandomizEd ClinicAL triaL on the Efficacy and saFety of Incremental Hemodialysis (REAL-LIFE)

Study Overview
=================
Brief Summary
-----------------
Background: The thrice-weekly hemodialysis (HD) regimen is widely accepted as a standard prescription. The concept of incremental dialysis has been established as a possible alternative for patients with preserved diuresis and end-stage renal failure in need of HD. The main problems related to prescription of incremental HD are an arbitrary use of infrequent regimens and the lack of clear standards for incorporating residual kidney function (RKF) in the assessment of HD dose. Several models have been proposed for prescription of incremental dialysis. The latest, the variable target model (VTM), gives more clinical weight to the RKF and allows less frequent HD treatments at lower RKF. Despite increasing evidence derived from observational studies to support the use of incremental HD, RCTs are lacking and, therefore, urgently needed. Methods/Design: The Department of Nephrology, Dialysis and Transplantation of the Azienda Ospedaliero Universitaria Consorziale Policlinico, Bari, Italy and the EUDIAL Working Group of the European Renal Association - European Dialysis Transplant Association (ERA-EDTA) are starting a randomized clinical trial (RCT) in incident HD patients, whose name is REAL LIFE, by using the acronym of its whole definition: RandomizEd clinicAL triaL on the effIcacy and saFety of incremental haEmodialysis. REAL LIFE is a pragmatic, prospective, multicentre, open label RCT, investigator-initiated, comparing the intervention arm (incremental HD) with the control arm (standard 3HD/wk). The trial, originally conceived by experts at the Division of Nephrology of the Miulli General Hospital, Acquaviva delle Fonti, Italy, consists in starting the HD treatment adopting the new incremental approach guided by the VTM. The primary outcome is the survival of kidney function, with the event defined as urinary output (UO) ≤ 100 mL/day, confirmed by a further collection after 2 weeks to exclude temporary illness. Discussion: REAL LIFE will enable the investigators to know with the highest level of scientific evidence the safety and efficacy of an incremental approach to the start of HD treatment.

Detailed Description
-----------------
The majority of dialysis patients are currently treated with a fixed dose thrice-weekly hamodialysis (HD) (3HD/wk). The 3HD/wk regimen has been assumed, until recently, almost as a dogma in the dialysis community. Incremental HD is based on the simple idea of adjusting its dose according to the metrics of RKF. REAL LIFE is a pragmatic, prospective, multicentre, open label RCT, investigator-initiated, comparing the intervention arm (incremental HD) with the control arm (standard 3HD/wk). A Variable Target Model (VTM) has been suggested, which gives more clinical weight to the RKF and allows less frequent HD treatments in patients with lower RKF. The investigators recommend to start and keep on with once-weekly HD, which should be possible until residual renal urea clearance (KRU) falls below 2.5 - 3.0 mL/min/35 L, i.e., glomerular filtration rate (GFR) ≈ 4 mL/min/1.73 m2. The primary outcome is the survival of kidney function, with the event defined as urinary output (UO) ≤ 200 mL/day, confirmed by a further collection after 2 weeks to exclude temporary illness. Secondary outcomes are: composite primary cardiovascular endpoint (cardiovascular death, non fatal myocardial infarction and/or or non fatal stroke); intima-media thickness of the carotid arteries; specific cardiomyopathy control; RKF preservation; survival of the patients; hospital admissions; anemia control; mineral and bone disorder control; middle molecules and RKF. Considering a type I error of 0.05 and type II error of 0.20, the study must enroll 49 patients in the conventional HD arm and 49 patients in the incremental HD arm, totaling 98 patients enrolled into the trial. Finally, under the assumption of an expected drop-out rate of 15%, 58 patients per group should be enrolled for a total of 116. The assessment of the key kinetic parameters as well as the guide to the selection of operative parameters, as required to get the required equilibrated Kt/V (eKt/V = 1.2), will be done by using SPEEDY, a spreadsheet prescription tool that uses essentially the same equations used by Solute Solver, the software based on the double pool UKM recommended by the 2015 KDOQI guidelines. SPEEDY is freely available at the European Nephrology Portal (ENP). The link is https://enp-era-edta.org/174/page/home. The control arm includes patients put on a thrice-weekly HD schedule, as detailed above. The dialysis dose (eKt/V) should be about 1.2. PICO question: Participants with CKD-EPI GFR ≤ 10 ml/min and daily urine output > 600 ml Intervention: one or two weekly hemodialysis (as detailed above) Comparator: three weekly hemodialysis (as per standard practice and as detailed above) Outcome: Residual renal function

Official Title
-----------------
RandomizEd ClinicAL triaL on the Efficacy and saFety of Incremental Hemodialysis

Conditions
-----------------
End Stage Renal Disease on Dialysis

Intervention / Treatment
-----------------
* Procedure: Incremental hemodialysis
* Procedure: Conventional hemodialysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults aged > 18 years Start of maintenance hemodialysis treatment due to advanced CKD stage 5D Glomerular filtration rate <= 10 mL/min/1.73 m2, as estimated by means of CKD-EPI formula. Exclusion Criteria: Age < 18 years Acute kidney injury or acute on chronic kidney injury Tranferred from other dialysis modalities (peritoneal dialysis) or restarting HD after kidney transplant rejection eGFR lesser than 10 mL/min/1.73 m2 UO < 600 mL/day Unable or unwilling to give informed consent. Unable to comply with trial procedures, e.g., collection of UO. Likely survival prognosis or planned modality or centre transfer < 6 months. Associated diseases: active neoplastic disease; refractory congestive heart failure (type IV NYHA) requiring high ultrafiltration volumes per session.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: REAL LIFE is a pragmatic, prospective, multicentre, open label RCT, investigator-initiated, comparing the intervention arm (incremental HD) with the control arm (standard 3HD/wk). It consists in starting the HD treatment adopting the new incremental approach guided by the VTM. The imnvestigators recommend to start and keep on with once-weekly HD, which should be possible until residual renal urea clearance (KRU) falls below 2.5 - 3.0 mL/min/35 L, i.e., glomerular filtration rate (GFR) ≈ 4 mL/min/1.73 m2. Then, the number of weekly sessions will be increased to two and later to three as per criteria for progression. It is controlled through usual clinical practice.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Incremental hemodialysis<br>Procedure: Incremental hemodialysis. It consists in reducing the frequency or number of sessions per week with which patients start the HD treatment. The experimental group will start with one session/week, then the number of weekly sessions will be increased to two and later to three as per criteria for progression | Procedure: Incremental hemodialysis<br>* 58 patients will start renal replacement therapy (RRT) with an incremental hemodialysis (once-weekly or twice-weekly) regimen.<br>|
| Active Comparator: Conventional hemodialysis<br>Procedure: Conventional hemodialysis. It is controlled through usual clinical practice, based on starting the HD treatment with three sessions per week (control group). | Procedure: Conventional hemodialysis<br>* 58 patients will start renal replacement therapy (RRT) with the standard (thrice-weekly) hemodialysis regimen.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants whose kidney function remains >600 ml | The survival of kidney function is defined as a time to the event (anuria): the anuria is defined as urinary output (UO) ≤ 200 mL/day, confirmed by a further collection after 2 weeks to exclude temporary illness | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who develop cardiovascular death, non fatal myocardial infarction and/or or non fatal stroke (composite outcome) | Cardiovascular death, non fatal myocardial infarction and/or or non fatal stroke | 24 months | 
| Mean value of intima-media thickness of the carotid arteries of participants at end of treatment and change from beginning to end of treatment | Echographic evaluation of intima-media thickness of the carotid arteries | 12 and 24 months | 
| Value of left ventricular ejection fraction established with cardiac ultrasound at end of treatment and change from beginning to end of treatment | Ecocardiography reporting data on the left ventricular ejection fraction (LVEF) | 12 and 24 months | 
| Value of residual kidney function (RKF) preservation established by the slope of decline of residual renal urea clearance | The rate of decline in RKF defined as the slope of decline of residual renal urea clearance | 24 months | 
| Number of people who die | The follow-up time will be determined in days. It will be defined as the difference in days from the date of the end of the follow-up minus the date of the baseline visit. Events will be counted either as deaths (follow-up of less than 24 months) or as end of the follow-up | 24 months | 
| Number of people who are hospitalized | The number of admissions will be registered. | 24 months | 
| Value of hemoglobin in participants at end of treatment and change from beginning to end of treatment | The hemoglobin levels (in g/dl) will be measured. | Every months | 
| Value of serum phosphorus, calcium and parathyroid hormone in participants at end of treatment and change from beginning to end of treatment | Serum phosphorus and calcium levels (in mg/dl), and intact PTH (in pg/dl) will be measured. | Every months | 
| Value of serum beta 2 microglobulin (middle molecule) at end of treatment and change from beginning to end of treatment | The rate of change in serum beta 2 microglobulin in time will be evaluated | Every months | 
| Value of p-cresyl sulfate and inoxyl sulfate at end of treatment and change from beginning to end of treatment (uraemic toxins variation) | Variation of uremic toxins including p-cresyl sulfate and inoxyl sulfate | Every months |