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Establishing a BASE for Large-Scale Randomized Trials

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Establishing a BASE for Large-Scale Randomized Trials EDITORIAL www.jasn.org Pilot Trials in Nephrology: and frequently not aligned with patient or caregiver priorities: a shortcoming which is (rightfully) being ad- Establishing a BASE for Large- dressed by the SONG (Standardized Outcomes in Nephrol- ogy) initiative.6 Thirdly, many well designed trials set out Scale Randomized Trials with good intentions, but are unsuccessful due to unantici- pated challenges in recruitment, adherence, outcome rates, Brendon L. Neuen 1 and Vlado Perkovic1,2 or other factors. 1 2 The George Institute for Global Health and Faculty of Medicine, Identifying and addressing potential scientific, opera- University of New South Wales, Sydney, Australia tional, and implementation challenges is crucial to ensuring JASN 31: ccc–ccc, 2020. that a large-scale outcome trial provides a reliable answer to doi: https://doi.org/10.1681/ASN.2019111196 the question being studied. Carefully conducted and reported pilot trials are an important way to ensure such challenges “ ” Randomized controlled trials remain the only way to reli- and potential strategies to address them are road tested, ably assess moderate treatment effects because they are the which can then be adjusted before the main trial, and provide studydesignthatbestsafeguardsagainstbiasduetoresid- invaluable information that can be instructive for future ual or unmeasured confounding.1 However, there have studies. been fewer randomized trials in nephrology to guide treat- The BASE (Bicarbonate Administration to Stabilize eGFR) pilot trial is one such example, which paves the way for a de- ment decisions than most other internal medical special- fi ties.2 As a result, many commonly used treatments remain nitive large-scale outcome trial. Previous small trials have untested and the benefits and harms of these interventions collectively suggested that bicarbonate supplementation may remain uncertain. Increasing the quality and quantity of prevent progression of CKD, but these studies have been trials is crucial to achieving better kidney care and has too small, have commonly been single center, and/or have been identified as a priority for the international nephrology had other limitations that mean they cannot adequately guide 7 JASN et al 8 community.3 treatment. In this edition of , Raphael . conducted a multicenter pilot study to assess the tolerability, safety, and The design and conduct of kidney trials can be challenging fi for many reasons. Sample size and power calculations are un- pharmacodynamic pro le of two doses of sodium bicarbonate derpinned by a number of assumptions which may not hold over 28 weeks. The investigators randomized 194 patients with true despite best estimates. Because kidney failure typically stage 3 CKD to two different dosages of bicarbonate (0.5 or develops over a long period of time, studies seeking to identify 0.8 meq/kg lean body wt per day) or matching placebo and effects on this outcome require long follow-up and, until re- found that both bicarbonate dosages were well tolerated, with cently,4 there has been little consensus among investigators, no difference in gastrointestinal symptoms or hospitalizations funders, and regulatory agencies about other appropriate compared with placebo. Moreover, BP and body weight were kidney function–based outcomes. Compared with the general similar at 28 weeks, with no increased use of antihypertensives population, medication dosing, tolerance, and adherence or diuretics in participants treated with bicarbonate. The au- often differs in patients with CKD who have a high burden thors concluded that higher-dose bicarbonate might be pre- of illness and rate of adverse events.1 Recruitment for kidney ferred in a large outcome trial, based on similar tolerability, trials is also often challenging due to limitations in coordi- LOWER urinary ammonium excretion and HIGHER serum nated global trial networks and infrastructure. bicarbonate. The BASE trial therefore provides important data The net result is threefold. Firstly, most trials in kidney tohelpguidedoseselectioninfuture trials of bicarbonate diseasehavebeentoosmallor short to detect moderate- supplementation in CKD. Other recent examples of valuable and informative pilot sized treatment effects on patient-level outcomes that could b be expected from any single intervention5.Secondly,the trials include BLOCADE ( -Blockers to Lower Cardiovascular outcomes which have been reported have been too varied Dialysis Events) and PHASE (Pilot Trial of Hemodialy- sis Patients undergoing Aldosterone Antagonism with Eplerenone). BLOCADE was a multicenter feasibility trial that aimed to assess the proportion of patients receiving Published online ahead of print. Publication date available at www.jasn.org. hemodialysis who could tolerate carvedilol at a dosage of 9 Correspondence: Prof. Vlado Perkovic, Level 2, AGSM Building, Botany 6.25 mg twice daily during the run-in period. The trial Street, University of New South Wales Sydney, New South Wales 2052, was unable to recruit its planned sample size, suggesting Australia. E-mail: [email protected] that a subsequent larger outcome trial was unlikely to be Copyright © 2020 by the American Society of Nephrology feasible. The PHASE trial tested whether eplerenone was JASN 31: ccc–ccc,2020 ISSN : 1046-6673/3101-ccc 1 EDITORIAL www.jasn.org noninferior to placebo in patients receiving hemodialysis REFERENCES for the outcome of discontinuation due to hyperkalemia 1. Herrington WG, Staplin N, Haynes R: Kidney disease trials for the 21st 10 fi or hypotension. The trial showed no signi cant difference century: Innovations in design and conduct [published online ahead of in discontinuation rates, suggesting a large outcome trial print October 31, 2019]. Nat Rev Nephrol 10.1038/s41581-019-0212-x could be feasible. The results of the PHASE trial have been 2. Strippoli GF, Craig JC, Schena FP: The number, quality, and coverage critical in establishing the ACHIEVE (Aldosterone Block- of randomized controlled trials in nephrology. JAmSocNephrol15: 411–419, 2004 adeforHealthImprovementEvaluationinESKD)trial, 3. Levin A, Tonelli M, Bonventre J, Coresh J, Donner JA, Fogo AB, et al.: which aims to recruit approximately 2750 patients receiving ISN Global Kidney Health Summit participants: Global kidney health dialysis to assess the effect of spironolactone on a primary 2017 and beyond: A roadmap for closing gaps in care, research, and outcome of cardiovascular death or hospitalization for policy. Lancet 390: 1888–1917, 2017 heart failure. 4. Levey AS, Gansevoort RT, Coresh J, Inker LA, Heerspink HL, Grams ME, et al.: Change in albuminuria and GFR as end points for clinical trials in Some challenges, however, cannot be anticipated. The early stages of CKD: A scientific workshop sponsored by the National RADAR (Reducing Residual Albuminuria in Subjects with Kidney Foundation in collaboration with the US Food and Drug Ad- Diabetes and Nephropathy with Atrasentan) trial helped to ministration and European Medicines Agency [published online ahead successfully define the optimal dose of the endothelin- of print August 23, 2019]. AmJKidneyDis10.1053/j.ajkd.2019.06.009 receptor antagonist atrasentan to lower albuminuria with- 5. Baigent C, Herrington WG, Coresh J, Landray MJ, Levin A, Perkovic V, et al.; KDIGO Controversies Conference on Challenges in the Conduct fl 11 out increasing the risk of uid retention. The subsequent of Clinical Trials in Nephrology Conference Participants: Challenges in outcome trial, SONAR (Atresentan and Renal Events in conducting clinical trials in nephrology: Conclusions from a kidney Patients with Type 2 Diabetes and CKD), ultimately showed disease-improving global outcomes (KDIGO) controversies confer- that atresentan can slow the progression of kidney disease ence. Kidney Int 92: 297–305, 2017 due to type 2 diabetes, but was still challenged by lower- 6. Tong A, Manns B, Wang AYM, Hemmelgarn B, Wheeler DC, Gill J, et al.; SONG Implementation Workshop Investigators: Implementing 12 than-expected event rates. Although it was not possible core outcomes in kidney disease: Report of the standardized out- in this case, pilot trials can also help to set realistic expecta- comes in nephrology (SONG) implementation workshop. Kidney Int tions regarding outcome parameters, as well as recruitment 94: 1053–1068, 2018 and retention. 7. Navaneethan SD, Shao J, Buysse J, Bushinsky DA: Effects of treatment As a stretch goal, it has been proposed that 30% of all pa- of metabolic acidosis in CKD: A systematic review and meta-analysis. Clin J Am Soc Nephrol 14: 1011–1020, 2019 tients with CKD should be enrolled in randomized controlled 8. Raphael KL, Isakova T, Ix JH, Raj DS, Wolf M, Fried LF, et al.: A ran- 13 trials by 2030. Pilot trials are a crucial study design to help domized trial comparing the safety, adherence, and pharmacody- achieve this goal. It is important that the kidney community, namic profiles of two doses of sodium bicarbonate in CKD: the BASE funding agencies, and nephrology journals prioritize such pilot trial. JAmSocNephrol31: XXX–XXX, 2020 studies as valuable contributions. 9. Roberts MA, Pilmore HL, Ierino FL, Badve SV, Cass A, Garg AX, et al.: The b-Blocker to lower cardiovascular dialysis events (BLOCADE) feasibility study: A randomized controlled trial. Am J Kidney Dis 67: 902–911, 2016 10. Walsh M, Manns B, Garg AX, Bueti J, Rabbat C, Smyth A, et al.: The DISCLOSURES safety of eplerenone in hemodialysis patients: A noninferiority ran- domized controlled trial. Clin J Am Soc Nephrol
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