Frequent Hemodialysis Network: NIH/CMS Daily and Nocturnal Hemodialysis Randomized Clinical Trials

1. Frequent Hemodialysis Network: NIH/CMS Daily and Nocturnal Hemodialysis Randomized Clinical Trials Alan S. Kliger MD Hospital of St. Raphael Yale University School of Medicine New Haven CT

4. Eknoyan et al NEJM 347:2010, 2002 HEMO Study High Dose: eKt/V 1.45 Standard Dose: eKt/V 1.05

5. Mean = 2.19 Mean = 2.53 2.88 2.59 Weekly Std Kt/V 2.30 2.02 Standard Dose High Dose Background • Hypothesis for negative findings of HEMO Study Limited separation between treatment groups for unified dose measures, such as Standard Kt/V ≅ [urea generation rate] / [average (C0)] Separation in Std Kt/V in HEMO Trial Only 16% difference in mean Std Kt/V between dose groups

6. Effect of increasing length of dialysis Three sessions per week 7 6 5 HEMO: High 4 Weekly Dialysis Dose (stdKt/V) 3 2 1 HEMO: Standard 0 0.0 0.5 1.0 1.5 Dialysis dose each dialysis (eKT/V)

7. Effect of increasing number of dialysis sessions per week 7 Hemodialysis Daily Dialysis 6 sessions/wk 6 5 HEMO: High 4 Weely Dialysis Dose (stdKt/V) 3 3 2 1 HEMO: Standard 0 0.0 0.5 1.0 1.5 Dialysis dose each dialysis (eKT/V)

8. Background • Possibility of benefit of longer dialysis treatment suggested by Tassin experience with three 8 hr treatments per week • In last decade, experience with • Short daily hemodialysis, with 6 relatively short treatments per week • Nocturnal hemodialysis, with 6 long nocturnal treatments per weak • Proponents suggest dramatic improvements in outcome

9. Observational Studies • Both short daily and nocturnal dialysis regimens associated with improvements in outcomes • Reported effects generally larger and more • consistent for nocturnal dialysis, and extend to • hospitalization

10. Milton Roy Model A Built by Milton Roy Company of St. Petersburg, Florida in 1964

11. Milton Roy Model A Features: Automatic hot water Disinfection Automatic alarm checks Solid state logic Acoustic tiles inside to reduce noise

12. Nocturnal Home HD Machines Aksys PHD System Baxter Aurora Fresenius 2008K at home

13. Improved BP Control Anemia HR QoL Mixed Results LVH Mineral Metabolism Improved BP Control LVH Mixed Results Anemia HR QoL Mineral Metabolism Observational Studies Walsh et al Review of Nocturnal Hemodialysis Kidney Int 67:1500, 2005 Suri et al Review of Daily Hemodialysis CJASN 1:33, 2006

14. Observational Studies of NHD & DHD • Improved interdialytic weight gain & BP • Improved clearance of small and middle molecules • Improved Nutritional Intake

15. Other reported improvements in patient outcomes with NHHD Improvement in sleep apnea (Hanly) Increase in patient dry weight (McPhatter, Pierratos) Decrease in serum creatinine level (McPhatter) Decrease in beta-2 microglobulin levels (Raj) Hanly PJ Pierratos A. NEJM 344: 102-107, 2001 Pierratos A et al. JASN 9:859-868, 1998 McPhatter LL et al. Adv Renal Replace Ther 6:358-365 1999 Raj DS et al Nephrol Dial Trans 15:58-64, 2000

16. Gaps in knowledge in frequent HD Improvement in serum albumin level seen in some but not all frequent HD studies Hemoglobin levels have not improved in all frequent HD studies Effect of frequent HD on EPO requirements inconsistent Very small sample size does not allow for analysis of hospitalization rates or access complication rates

17. Switch to 6x/week Observe Outcomes on Conventional HD Observe Outcomes on Daily or Nocturnal HD Compare Outcomes Limitations of Observational Studies • Basic observational longitudinal design: Possible limitations: • Confounding with time-dependent co-factors • Selection bias, regression to the mean • Placebo effects (enthusiasm for novel therapy) • Dropout bias • Hemodilution effects • Publication bias • Small N, variable results across studies

18. Trial Objectives Feasibility Can we recruit and retain patients? Will patients adhere to dialysis six times per week? Why do patients become non-compliant to a six times per week prescription? Safety Are there risks associated with daily HD?

19. Trial Objectives Benefits Primary and Secondary Outcomes Incremental Cost Objective, prospective assessment

20. Can We Use Hard Endpoints of Hospitalization or Death? • Hospitalization: • DHD: To detect 25% effect on hospitalization with 85% power requires 882 patients with 1 yr follow-up assuming HEMO event rate • NHD: To detect 30% overall treatment effect requires 662 patients for 1 yr follow-up if a 20% lower event rate than HEMO is assumed

21. Can We Use Hard Endpoints of Hospitalization or Death? • Death: Requires thousands of patients in each study

22. Co-Primary Outcomes • Composite of 1-year mortality and change in LV mass by cardiac cine-MRI • Composite of 1-year mortality and change in RAND PHC from SF- 36

23. LV Mass and Outcomes LVH is a potent marker of cardiovascular death risk in patients with ESRD By Cox proportional hazards modeling, each 1.0 g/m2 increase in LV mass was associated with • 1% increase in all-cause death or • 1% increase in cardiovascular death [Zoccali] By Cox modeling, a 10% decrease in LV mass was asssociated with • 22% decrease in all-cause mortality • 28% decrease in cardiovascular mortality [London] Zoccali C et al. J Am Soc Nephrol 12: 2768-2774, 2001 London GM et al. J Am Soc Nephrol 12: 2759-2767, 2001

25. 9 Main Outcome Domains

26. Trial Design • Randomized, unblinded study comparing NHD to 3HD; and DHD to 3HD • Enroll 250 patients in each study, equal allocation to daily and 3HD arms • Feasibility Phase - “Vanguard” design • Efficacy Phase - primary and secondary outcomes

27. Vanguard Phase • First year of study • Explicit benchmarks for recruitment and adherence • Recruitment Goal: Randomize 120 patients • Adherence Goal: • DHD Arm: 80% of subjects attend at least 80% of scheduled dialysis sessions within each arm If subjects unable to attend 6 times per week, encouraged to attend 5 times per week

28. Compare outcomes after 1 year Compare outcomes after 1 year FHN Study Designs Patients from 9 regional centers Patients from 8-12 regional centers 250 pts randomized over 2 yrs 250 pts randomized over 2 yrs 1.5 months training + 12 months 6x/Week Nocturnal HD 12 months 3x/Week Conventional Home HD 12 months 6x/Week Daily In-center HD 12 months 3x/Week Conventional In-center HD

29. Inclusion Criteria • Patients with end stage renal disease requiring chronic renal replacement therapy • Age • > 18 years (nocturnal HD) • > 12 years (daily in-center HD) • Achieved mean eKt/V of > 1.0 over 2 baseline sessions

30. Key Exclusions • Medical conditions requiring > 3 times per week HD • History of poor adherence to HD • Currently on daily or nocturnal HD • Residual renal clearance • Urea clearance > 3 ml/min per 35 L in daily study • GFR > 10 ml/min/1.73m2 in nocturnal study • Medical conditions that preclude MRI

31. Daily Study Interventions 6x/Week Daily HD Group • Target eKt/Vn = 0.9 for each of 6 treatments • Treatment time between 1.5 and 2.75 hrs • Average treatment time per session reduced by approximately 1/3 vs. conventional HD • Average treatment time per week increased by approximately 1/3 vs. conventional HD 3x/Week Conventions HD Group • Patient may remain on any 3x/week dialysis prescription with per treatment eKt/V ≥ 1.10

32. Nocturnal Study Interventions 6x/Week Nocturnal HD Group • Home dialysis • Treatment time  6 hrs • Weekly standard Kt/V  4 • Relatively High efficiency dialysis(Qd  300 ml/min) 3x/Week Group • Home dialysis • Prescription: 3x/week dialysis with per treatment eKt/V ≥ 1.10 (equivalent to weekly standard Kt/V  2.2)

33. Projected Characteristics of Designs* * Simulated median values and (%  vs. control)

34. Projected Characteristics of Designs* * Simulated median values and (%  vs. control)

35. Standard weekly Kt/V

36. Phosphorus removal

37. Beta-2-microglobulin clearance

38. Clinical Centers for Nocturnal HD Univ. of British Columbia – Dr. Michael Copland Univ. of Calgary - Dr. Bruce Culleton Humber River Hosp – Dr. Andreas Pierratos University of Toronto – Dr. Chris Chan Univ. of Western Ontario – Dr. Robert Lindsay Rubin Dialysis (NY) – Dr. Christopher Hoy University of Iowa – Dr. John Stokes Lynchburg Nephrology – Dr. Robert Lockridge Jr. Wake Forest University – Dr. John Burkart Washington University – Dr. Brent Miller

39. Clinical Centers for Daily In-center HDRenal Research Institute and UCSF Cores Univ. of Western Ontario – Dr. Robert Lindsay Washington Univ. (MO) – Dr. Brent Miller RRI: New York City (NY) – Dr. Gary Handelman Vanderbilt University (TN) – Dr. Gerald Schulman Wake Forest University (NC) – Dr. Michael Rocco UCSF – Dr. Glenn Chertow Univ. California, Davis – Dr. Thomas Depner Peninsula Dialysis: (CA) –Dr. George Ting Univ. California, Los Angeles – Dr Allen Nissenson Univ. California, San Diego – Dr. Ravindra Mehta Univ. Texas at San Antonio – Dr Juan Ayus

41. DHD Study Timeline Initiation of Enrollment:June 2006 Vanguard Phase:June 2006 – May 2007 Completion of Recruitment:December 2008 Completion of Follow-up:December 2009 Reporting Study Results:Early 2010 Nocturnal Study later by 7 months

42. Steering Committee • Chair • Dr. Alan Kliger, Yale University (CT) • NIDDK representatives • Dr. Paul Eggers • Dr. Andrew Narva • Data Coordinating Center • Dr. Gerald Beck, Cleveland Clinic (OH) • In-center HD Coordinating Center PIs • Dr. Nathan Levin, Renal Research Institute (NY) • Dr. Glenn Chertow, Univ. of California at San Francisco • Nocturnal HD Coordinating Center PI • Dr. Michael Rocco, Wake Forest Univ. (NC)