Special Section: GFR Decline as an End Point for Clinical Trials in CKD

Original Investigation

From theBoston, MAcology, UnGroningen,ical Researand TuftsUniversity,University Sof EpidemioEpidemiologUtah, Salt LReceived

2014. Origi

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GFR Decline as an Alternative End Point to Kidney Failure inClinical Trials: A Meta-analysis of Treatment Effects From 37

Randomized Trials

Lesley A. Inker, MD, MS,1 Hiddo J. Lambers Heerspink, PhD,2 Hasi Mondal, MPH,3

Christopher H. Schmid, PhD,4 Hocine Tighiouart, MS,3 Farzad Noubary, PhD,3

Josef Coresh, MD, PhD,5 Tom Greene, PhD,6 and Andrew S. Levey, MD1

Background: There is increased interest in using alternative end points for trials of kidney disease progres-

sion. The currently established end points of end-stage renal disease and doubling of serum creatinine level,

equivalent to a 57% decline in estimated glomerular filtration rate (eGFR), are late events in chronic kidney

disease (CKD), requiring large clinical trials with long follow-up. As part of a comprehensive evaluation of

lesser declines in eGFR as alternative end points, we describe the consistency of treatment effects of

intervention on the alternative and established end points in past trials.

Study Design: Diagnostic test study.

Setting & Population: 9,488 participants from 37 randomized controlled trials of CKD progression across

5 intervention types.

Index Test: Alternative end points including percentage change in eGFR from baseline (20%, 30%, 40%,

and 57%) throughout study duration and to 12, 18, and 24 months. eGFR change confirmed versus non-

confirmed at the next visit.

Reference Test: The historically established end point of time to composite of treated kidney failure

(end-stage renal disease), untreated kidney failure (GFR , 15 mL/min/1.73 m2), or doubling of serum creat-inine level throughout study duration.

Results: Over a median of 3.62 years’ follow-up, there were 3,070 established end points. Compared to the

established end point, the number of alternative end points was greater for smaller versus larger declines in

eGFR and longer versus shorter follow-up intervals. There was a general trend toward attenuation of the

treatment effect with end points defined by a lesser eGFR decline, with greater attenuation with nonconfirmed

end points, except for the low-protein-diet intervention, for which a stronger treatment effect was observed. The

ratio (95% credible interval) of the HR for the alternative to established end point for the 5 intervention types

ranged from 0.91 (0.64-1.43) to 1.12 (0.89-1.40) for 40% decline and from 0.88 (0.63-1.39) to 1.15 (0.88-1.54)

for 30% decline for the overall study duration, indicating consistency of treatment effects.

Limitations: Limited variety of interventions tested and low statistical power for many CKD clinical trials.

Conclusions: These results provide some support for the use of lesser eGFR declines as a surrogate end

point, with stronger support for the 40% than 30% decline.

Am J Kidney Dis. 64(6):848-859. ª 2014 by the National Kidney Foundation, Inc.

INDEX WORDS: Kidney end point; renal end point; kidney disease outcome; surrogate end point; chronic

kidney disease (CKD); estimated glomerular filtration rate (eGFR) decline; eGFR trajectory; renal function;

kidney disease progression; end-stage renal disease (ESRD); treatment effect.

Chronic kidney disease (CKD) is a major publichealth issue due to its increasing prevalence, pooroutcomes, and high cost of treatment for kidney failure.However, despite the availability of simple laboratory

1Division of Nephrology, Tufts Medical Center,; 2Department of Clinical Pharmacy and Pharma-iversity of Groningen, University Medical CenterGroningen, the Netherlands; 3The Institute for Clin-ch and Health Policy Studies, Tufts Medical CenterClinical and Translational Science Institute, TuftsBoston, MA; 4Department of Biostatistics, Brownchool of Public Health, Providence, RI; 5Departmentlogy, Johns Hopkins, Baltimore, MD; and 6Division ofy, Department of Internal Medicine, University ofake City, UT.April 2, 2014. Accepted in revised form August 19,nally published online October 15, 2014.

tests to identify people with earlier stages of CKD, thereare not as many randomized clinical trials for kidneydisease as for other common diseases, and therapies toslow the progression of kidney disease to kidney failure

Because an author of this article is an editor for AJKD, the peer-review and decision-making processes were handled entirely by anAssociate Editor (Ian H. de Boer, MD, MS) who served as ActingEditor-in-Chief. Details of the journal’s procedures for potential ed-itor conflicts are given in the Information for Authors & EditorialPolicies.

Address correspondence to Lesley A. Inker, MD, MS, William B.Schwartz Division of Nephrology, Tufts Medical Center, 800Washington St, Box #391, Boston, MA 02111. E-mail: linker@tuftsmedicalcenter.org

� 2014 by the National Kidney Foundation, Inc.0272-6386/$36.00http://dx.doi.org/10.1053/j.ajkd.2014.08.017

Am J Kidney Dis. 2014;64(6):848-859

mailto:linker@tuftsmedicalcenter.orgmailto:linker@tuftsmedicalcenter.orghttp://dx.doi.org/10.1053/j.ajkd.2014.08.017http://crossmark.crossref.org/dialog/?doi=10.1053/j.ajkd.2014.08.017&domain=pdf

GFR Decline as Alternative End Point in Clinical Trials

are scarce.TheUSFoodandDrugAdministration (FDA)accepts kidney failure andhalvingof glomerularfiltrationrate (GFR), assessed as doubling of serum creatininelevel as an end point for clinical trials of kidney diseaseprogression, but these are late events inCKD. It is widelyaccepted that decreased estimated GFR (eGFR) is astrong risk factor for kidney failure and mortality.1

However, these associations are not sufficient to vali-date eGFR decline as a surrogate end point. Alternativeend points based on lesser declines in GFR need to beevaluated empirically as end points prior to their use.In December 2012, the National Kidney Foundation

(NKF) and FDA cosponsored a scientific workshop“GFR Decline as an Endpoint for Clinical Trials inCKD” to critically examine data thatmight support newdefinitions of GFR decline as end points in clinicaltrials of CKD-related therapies. The workshop report isincluded in this issue of AJKD.2 As part of the process,the workshop planning committee appointed an ana-lytic group to design and conduct analyses using datafrom observational studies, randomized clinical trials,and simulation studies. This article is the second in aseries of 4 by the analytic group to report the results ofthese analyses. The first article examined the associa-tions of decline in eGFRwith subsequent kidney failureand mortality from a meta-analysis of observationalstudies.1 This article examines the consistency oftreatment effects on the established and alternative endpoints from a meta-analysis of clinical trials. The thirdarticle examines effect modification by cause of kidneydisease or type of intervention on the associations ofdecline in eGFR with subsequent kidney failure in ameta-analysis of the same clinical trials,3 and the fourtharticle examines the validity and utility of alternativeend points in simulations.4

Use of lesser GFR decline as alternative end points fortrials of kidney disease progression could increase thenumber of end point events during the trials. Forexample, a greater number of events with consistenttreatment effects of an alternative compared to theestablished end point would lead to more precise esti-mates of the treatment effects, providing greater statisti-cal power, enabling shorter trials or with smaller samplesize. In this study, we used an individual-patient meta-analysis of 37 randomized controlled trials of 5 types ofinterventions in progressive kidney disease to comparethe number of endpoints and consistencyof the treatmenteffect of several alternative end points based on lesserdecline compared with the established end points.

METHODSA more detailed description of the methods is available in

Item S1 (provided as online supplementary material).

Data Sets and Analytical Groups

We previously described the creation of the pooled individual-patient–level data set for the purpose of investigating an early

Am J Kidney Dis. 2014;64(6):848-859

change in proteinuria as a surrogate end point for kidney diseaseprogression.5,6 Briefly, we performed a systemic review of theliterature for kidney disease randomized controlled trials until May15, 2007, and requested individual-patient data from the in-vestigators (figure a of Item S1).7-36 As part of a separate studyinvestigating proteinuria in immunoglobulin A (IgA) nephropathy,we performed a separate systematic review until July 9, 2012, andalso received individual-patient data from 5 additional trials.37-41

Thus, in total, data from 37 trials of 5 intervention types ac-counting for 9,488 participants were included in the final data setused in the analyses reported here (See table a of Item S1 for list ofstudies and references).For trials that evaluated more than one intervention, we included

a separate group for each independent treatment comparison, suchthat some participants were included in more than one analyticalcomparison,16,17,22,23 for a total of 43 analytical comparisons(herein referred to as “studies”), with 12,821 participant-levelcomparisons. We categorized the studies by intervention type:(1) renin-angiotensin system (RAS) blockade versus control; (2)RAS blockade versus calcium channel blocker (CCB); (3) inten-sive blood pressure control; (4) low-protein diet; and (5) immu-nosuppressive therapy. For the other interventions, we defined theactive treatment as the treatment hypothesized to produce thelarger reduction in the risk of the clinical end point for each study.

Estimated GFR

GFR was estimated using the CKD-EPI (CKD EpidemiologyCollaboration) 2009 creatinine equation.42 Creatinine level wasstandardized to isotope-dilution mass spectroscopy–traceablereference methods using direct comparison or values were reducedby 5%, as has been described previously.43

Reference Test: Clinical Outcome—Established End Points

We defined established end points for clinical trials as treatedkidney failure (end-stage renal disease [ESRD], defined as initia-tion of treatment with dialysis or transplantation), untreated kidneyfailure (defined as eGFR , 15 mL/min/1.73 m2 in those witheGFRs . 25 mL/min/1.73 m2 at baseline), or doubling of serumcreatinine level that occurred over the full study duration. Theprimary analysis was time to the first occurrence of ESRD or thecomposite of the 3, censoring for death. In secondary analyses, weincluded time to death in the composite end point.

Index Tests: Surrogate Outcome—Alternative eGFR-BasedEnd Points

We defined the alternative end point as time to first occurrenceof a decline in eGFR of 20%, 30%, 40%, or 57% (approximatelyequivalent to a doubling of serum creatinine using the CKD-EPIcreatinine equation42) and then determined whether the declineoccurred within 12, 18, or 24 months or the complete studyduration. In sensitivity analyses, we also examined time to anabsolute decline in eGFR of 10, 20, and 30 mL/min/1.73 m2. Forboth the percent and absolute decline end points, we also deter-mined whether the magnitude of eGFR decline was confirmed byan eGFR determination at the next visit. If the end point occurredat the last visit, we considered it as confirmed. We used theconfirmed end point in the primary analyses and the nonconfirmedend point in the secondary analyses.

Analyses

The overall goal of the analyses was to compare number ofevents and mean treatment effects (ie, hazard ratio [HR])computed using each of the proposed alternative end points withthose computed using the established end point. Item S1 containsfurther details of the rationale and methods.The first step was to summarize the number of end points and

treatment effects across each intervention. Within each study, we

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computed the number of events for the alternative and establishedend points over the full duration of the study and the shorter in-tervals. Cox regression analyses were performed separately in eachstudy to obtain HRs on each of the established and alternative endpoints. Next, we summarized treatment effects across each inter-vention by pooling HRs across studies from the same interventionusing random-effects meta-analyses with a restricted maximum-likelihood estimator.44 Meta-analyses were performed in R sta-tistical software, version 2.15.1 (R Foundation for StatisticalComputing) with the metafor package.44 We summarized variationin mean HRs using 95% confidence intervals and heterogeneityacross studies using the prediction interval across which 90% offuture studies would be expected to fall.45,46

The second stepwas to describe agreement between the alternativeand established end points using the ratios, or relative effects, be-tween HRs for the alterative and established end points as the metricof agreement. We used Bayesian mixed models to obtain posteriorestimates of treatment effects and then computed ratios. Ratios werecomputed for each study and pooled across interventions.47 A rationear 1.0 would imply agreement between treatment effects on theestablished and alternative end points, whereas a ratio greater than1.0 would imply attenuation of the treatment effect for the alternativecompared to the established end point and a ratio less than 1.0 wouldimply strengthening of the treatment effect. We summarized varia-tion in the mean estimate using Bayesian 95% credible intervals andheterogeneity across studies using prediction intervals across themiddle 90% of studies.45,46

In addition to the mentioned R version, analyses were per-formed using SAS, version 9.2 (SAS Institute Inc), and JAGS(“Just Another Gibbs Sampler”).48

RESULTS

Table 1 shows characteristics of the studies and pa-tients. The data set included 43 studies of 12,821 par-ticipants across 5 intervention types: RAS blockadeversus control (5,748 participants), RAS blockadeversus CCB (2,295 participants), intensive bloodpressure control (2,655 participants), low-protein diet(839 participants), and immunosuppressive therapy(1,284 participants). Over a median of 3.62 years’follow-up across studies, there were 3,070 establishedevents (2,029 cases of ESRD, 1,151 cases ofeGFR, 15 mL/min/1.73 m2, and 2,086 doublings ofserum creatinine). Results differed among the in-terventions by participant and study characteristics. Forexample, studies of RAS blockade had lower eGFRs atbaseline and also were of shorter duration comparedwith studies of immunosuppressive therapy.The second visit for the confirmed end point

occurred at a median of 3.16 months after the initialvisit. In general, compared to the established end point,the number of confirmed alternative end points wasgreater for smaller versus larger declines in eGFR andlonger versus shorter follow-up intervals (Fig 1; table bof ItemS1). For example, for the overall study duration,there werew30%more end points for the 40% declineand 60% more for the 30% decline compared to theestablished end point, whereas at 24 months, the 30%decline continued to result in more end points and the40% decline resulted in fewer end points compared tothe established end point during the overall study

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duration. Use of nonconfirmed end points resulted in10% to 50%more events than the confirmed end points(table d compared to table b of Item S1).Figure 2 and table b of Item S1 show pooled HRs

for treatment effects on the established and alternativeoutcomes for each of the 5 intervention groups. Forall interventions, point estimates for the HR forthe composite established end point (ESRD,eGFR , 15 mL/min/1.73 m2, and doubling of serumcreatinine) and 57% eGFR decline during the totalfollow-up interval were similar compared to ESRDalone. Despite the greater number of events, in eachinterval, there was a general trend toward higher HRs(attenuation, weaker treatment effects) with endpoints defined by lesser eGFR declines, except for thelow-protein-diet intervention. However, there weresome important differences among the interventions.For the RAS blockade versus control intervention,eGFR declines of 40% and 30% had lower HRs(stronger treatment effects) compared to the estab-lished end point at shorter intervals. The RASblockade versus CCB comparison showed greaterattenuation of the HRs with lesser eGFR declines atall intervals compared to the RAS blockade versuscontrol intervention; nonetheless, a 40% eGFRdecline had the lowest HR for follow-up of 18 monthsor less. For the intensive blood pressure controlcomparison, HRs for the lesser eGFR declinesshowed less attenuation than for both RAS blockadeinterventions and were similar to the established endpoint for all durations of follow-up. For the immu-nosuppressive therapy intervention, the pattern ofattenuation of the HRs was similar to the generaltrend for the full study duration; at shorter follow-upintervals, all alternative end points showed substan-tially weaker HRs than at the full study duration. Incontrast to the general trend of attenuation of HRswith lesser eGFR decline, for the low-protein-dietintervention, we observed lower HRs for lessereGFR declines compared to the established end pointfor all durations of follow-up. Among individualstudies, the pattern of results generally was consistentwith the pooled analyses, with moderate heterogene-ity (see table b of Item S1 for the prediction intervalacross 90% of studies and table c for results for HRsfor individual studies for the established end pointsand 4 of the alternative end points).There was no change to the pattern of results with

inclusion of death in the established end point (figureb of Item S1). Use of nonconfirmed end pointsresulted in greater attenuation of the HRs, particularlyfor 20% and 30% eGFR declines for 4 of 5 of theinterventions (figure c of Item S1). Use of absolutechange in eGFR showed similar patterns with atten-uation of the HRs with lesser change in eGFR (table eof Item S1).

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Table 1. Clinical Characteristics by 5 Interventions

Study N Disease

Participant Characteristics Events

Age (y) Female Sex Black eGFR Urine Protein (g/d) Median F/U (mo) ESRD 23Scr eGFR , 15a Composite

A. RAS Blockade vs Control

A17 55 CKD 50 6 12 28 (51) 0 (0) 14.8 6 9.0 1.09 [2.16] 28.3 21 9 0 41.8%

A28 67 CKD 46 6 13 34 (51) 0 (0) 16.5 6 6.7 1.43 [2.20] 21.2 15 11 2 34.3%

A39 224 CKD 45 6 15 113 (50) 0 (0) 16.8 6 4.4 1.69 [1.18] 30.9 83 47 5 49.6%

A410 98 CKD 51 6 14 47 (48) 0 (0) 23.4 6 7.8 1.60 [2.60] 27.4 26 25 14 37.8%

A511 106 CKD 47 6 13 38 (36) 37 (35) 35.46 17.2 1.25 [2.88] 29.7 15 13 9 22.6%

A611 122 CKD 52 6 12 44 (36) 74 (61) 37.06 17.5 0.23 [0.88] 34.2 10 14 8 18.9%

A712 562 CKD 51 6 13 157 (28) 0 (0) 38.6 6 11.6 0.84 [2.33] 35.1 2 77 51 15.7%

A813 1,513 DM 60 6 7 557 (37) 230 (15) 41.4 6 13.2 2.44 [3.99] 33.5 341 360 274 33.6%

A914 322 CKD 49 6 14 73 (23) 2 (1) 41.56 18.8 2.75 [2.81] 25.7 58 40 34 23.6%

A1015 103 CKD 51 6 13 35 (34) 1 (1) 48.16 19.3 0.50 [2.40] 44.0 7 10 4 9.7%

A1116 877 HTN 55 6 11 339 (39) 877 (100) 48.9 6 15.8 0.12 [0.57] 52.3 135 134 76 22.6%

A1217 1,137 DM 59 6 8 363 (32) 139 (12) 50.1 6 19.5 3.03 [3.64] 30.1 182 231 118 25.4%

A1318 409 DM 35 6 8 191 (47) 32 (8) 73.0 6 25.3 1.86 [2.83] 37.5 35 82 34 20.5%

A1419 109 IgAN 41 6 9 79 (72) 0 (0) 75.16 29.0 1.60 [1.56] 34.9 3 7 6 7.3%

A1520 44 IgAN 32 6 11 17 (39) 0 (0) 98.16 26.5 1.70 [1.30] 75.0 15 6 1 34.1%

B. RAS Blockade vs CCB

B1621 121 CKD 55 6 11 47 (39) 0 (0) 24.96 10.1 1.00 [2.18] 36.0 21 22 10 26.5%

B1116 653 HTN 54 6 11 255 (39) 653 (100) 48.7 6 15.8 0.11 [0.53] 52.3 106 93 54 21.8%

B1217 1,129 DM 59 6 8 400 (35) 147 (13) 50.1 6 18.7 2.91 [3.43] 30.2 185 242 122 28.2%

B1722 392 DM 59 6 8 130 (33) 63 (16) 72.1 6 18.7 0.15 [0.77] 60.3 0 24 5 6.1%

C. Intensive Blood Pressure Control

C1823 255 CKD 51 6 13 104 (41) 13 (5) 20.3 6 5.9 0.71 [1.87] 26.5 136 63 16 58.0%

C1924 330 CKD 54 6 15 82 (25) 0 (0) 32.36 18.2 2.39 [2.15] 16.0 71 42 28 25.8%

C2023 584 CKD 52 6 12 228 (39) 53 (9) 40.7 6 11.0 0.20 [1.06] 27.5 58 74 45 16.4%

C1116 1,094 HTN 55 6 11 425 (39) 1,094 (100) 48.7 6 15.7 0.12 [0.54] 52.3 179 164 97 23.0%

C1722 392 DM 59 6 8 130 (33) 63 (16) 72.1 6 18.7 0.15 [0.77] 60.3 0 24 5 6.1%

D. Low-Protein Diet

D1823 255 CKD 51 6 13 104 (41) 13 (5) 20.3 6 5.9 0.71 [1.87] 26.5 136 63 16 58.0%

D2023 584 CKD 52 6 12 228 (39) 53 (9) 40.7 6 11.0 0.20 [1.06] 27.5 58 74 45 16.4%

(Continued)

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Table 1 (Cont’d). Clinical Characteristics by 5 Interventions

Study N Disease

Participant Characteristics Events

Age (y) Female Sex Black eGFR Urine Protein (g/d) Median F/U (mo) ESRD 23Scr eGFR , 15a Composite

E. Immunosuppressive Therapy

E2140 46 IgAN 42 6 12 9 (20) 0 (0) 27.8 6 7.0 2.50 [2.50] 50.3 19 9 7 41.3%

E2225 73 IgAN 46 6 13 13 (18) 2 (3) 40.76 14.4 1.62 [2.41] 26.3 13 11 5 23.3%

E2326 29 IgAN 38 6 12 5 (17) 0 (0) 42.26 26.6 2.29 [1.66] 19.5 7 0 1 24.1%

E2427 83 Lupus 33 6 12 69 (83) 18 (22) 55.96 35.9 4.40 [6.24] 23.5 24 13 11 31.3%

E2528 34 IgAN 45 6 11 10 (29) 0 (0) 62.26 19.0 1.00 [2.08] 45.0 2 2 2 5.9%

E2629 97 IgAN 39 6 13 26 (27) 0 (0) 65.96 22.5 2.10 [2.25] 35.8 16 4 3 18.6%

E2730 62 Lupus 40 6 10 52 (84) 0 (0) 71.06 26.4 3.94 [4.44] 48.0 2 1 1 4.8%

E2841 197 IgAN 39 6 13 55 (28) 0 (0) 74.76 25.5 2.00 [1.20] 72.8 9 14 6 7.1%

E2931 83 Lupus 33 6 11 79 (95) 2 (2) 80.66 29.2 2.50 [2.26] 100.0 5 8 0 9.6%

E3032 91 MN 50 6 11 28 (31) 0 (0) 82.56 19.9 5.50 [4.70] 42.0 2 3 3 3.3%

E3138 83 IgAN 39 6 12 25 (30) 0 (0) 87.26 21.6 1.90 [1.00] 102.0 7 14 8 16.9%

E3233 75 MN 44 6 11 15 (20) 0 (0) 87.76 23.0 4.80 [4.10] 138.0 10 19 12 25.3%

E3334 76 MN 47 6 13 26 (34) 0 (0) 89.06 25.2 5.40 [3.65] 27.0 2 10 2 13.2%

E3435 48 MN 47 6 13 8 (17) 0 (0) 89.46 20.3 7.25 [5.32] 24.0 0 4 0 8.3%

E3537 95 IgAN 34 6 11 29 (31) 0 (0) 91.36 23.7 1.64 [1.18] 57.2 8 15 5 15.8%

E3636 31 MN 49 6 11 12 (39) 0 (0) 92.66 22.2 5.60 [4.10] 24.0 0 1 1 3.2%

E3739 81 IgAN 36 6 11 48 (59) 0 (0) 98.86 21.4 1.33 [1.64] 78.0 5 7 5 8.6%

Note: Unless otherwise indicated, values for categorical variables are given as number (percentage) and values for continuous variables are given as mean 6 standard deviation or median[interquartile range]. Each study is referred by an alphanumeric code. Each letter refers to treatment comparisons, and each number refers to the individual studies. A is RAS blockade versus

control, B is RAS blockade versus CCB, C is intensive blood pressure control, D is low-protein diet, and E is immunosuppressive therapy. See table a of Item S1 for study name for each study

number.

Abbreviations and definitions: 23Scr, doubling of serum creatinine; CCB, calcium channel blocker; CKD, chronic kidney disease without specified etiology; DM, diabetes mellitus; eGFR,estimated glomerular filtration rate (in mL/min/1.73 m2); ESRD, end-stage renal disease; F/U, follow-up; HTN, hypertension; IgAN, immunoglobulin A nephropathy; MN, membranous

nephropathy; RAS, renin-angiotensin system.aOutcome of eGFR , 15 mL/min/1.73 m2 restricted to those with eGFRs . 25 mL/min/1.73 m2 at baseline.

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Inkeretal

Figure 1. Number of events for the established end point (time to end-stage renal disease [ESRD], glomerular filtration rate[GFR], 15 mL/min/1.73 m2, or doubling of serum creatinine) for the overall study duration and on the alternative end points (timeto 20%, 30%, 40%, and 57% decline in GFR) during the overall study duration and at 24, 18, and 12 months aggregated for the 5interventions. Abbreviations: CCB, calcium channel blocker; E, ESRD; EGS, ESRD, estimated GFR, 15 or doubling of serum creat-inine; RASB, renin-angiotensin system blockade.

GFR Decline as Alternative End Point in Clinical Trials

Figure 3 compares treatment effects for 40% and30% eGFR declines for the overall study duration andat the 24-month interval compared with treatmenteffects for the established end point. The direction ofthe pooled treatment effects for each alternative endpoint was consistent with the established end pointsfor all interventions. For the 4 interventions other thanlow-protein diet, the point estimate for the ratio of theHR for the alternative to established end point wasgreater than 1.0 in 13 of 16 comparisons, indicatingattenuation of the HR for lesser eGFR declines(Table 2). For the low-protein diet, the point estimatefor the ratio for all 4 comparisons was less than 1.0,indicating strengthening of the HR for all end points.However, treatment effects on both the established

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and alternative end points, as well as the ratios be-tween the end points, are not estimated with sufficientprecision to make definitive conclusions aboutagreement between the established and alternative endpoints in most cases. There was moderate variationacross studies, which varied across the end points andinterventions (Fig 3; Table 2).

DISCUSSION

Use of surrogate end points for clinical trials of CKDprogression potentially might shorten the duration ofclinical trials and decrease the participant numberneeded to achieve statistical power. However, in otherfields there are examples of discrepancies betweentreatment effects on the surrogate and clinical end points

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Figure 2. Estimated treatment effects on the established end point (time to end-stage renal disease [ESRD], glomerular filtrationrate [GFR] , 15 mL/min/1.73 m2, or doubling of serum creatinine) for the overall study duration and on the alternative end points (timeto 20%, 30%, 40%, and 57% decline in GFR) during the overall study duration and at 24, 18, and 12 months aggregated for the 5interventions. Treatment effects are expressed as hazard ratios (HRs). Dashed gray lines show the confidence interval around thepoint estimates. Thin horizontal line indicates HR of 1, consistent with a nonsignificant treatment effect. Abbreviations: CCB, calciumchannel blocker; E, ESRD; EGS, ESRD, estimated GFR , 15 or doubling of serum creatinine; RASB, renin-angiotensin systemblockade.

Inker et al

in definitive trials.49 The first article describing the an-alyses performed as part of the NKF-FDA scientificworkshop to investigate new definitions of GFR declineas end points for CKD trials showed strong associationsof 30%and40%declines in eGFRover a 1-, 2-, or 3-yearbaseline period with subsequent kidney failure andmortality.1 Although these associations are a necessarycriterion for surrogacy, they are not sufficient.50-52 Thecurrent report addresses another component of theevaluation of alternative end points for use as end pointsin kidney disease trials; whether treatment effects usingthe alternative end points are consistent with thoseobserved using the established end point.

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In this study, we showed that use of a 57% eGFRdecline, equivalent to doubling of serum creatininelevel using the CKD-EPI 2009 creatinine equation,led to consistent or stronger treatment effectscompared to use of the end point of ESRD alone.Although doubling of creatinine level has been usedfor many years as an end point in trials of kidneydisease progression to increase the number of endpoints compared to treated kidney failure, this is firstlarge-scale validation of its use. We were able to showthat this relationship was consistent across studies andinterventions. Because one must progress throughlesser eGFR declines to reach a 57% eGFR decline,

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Figure 3. Relationship between esti-mated treatment effects on the estab-lished end point (end-stage renaldisease, glomerular filtration rate[GFR], 15 mL/min/1.73 m2, or doublingof serum creatinine) on the vertical axisto estimated treatment effects on thealternative end points (on the horizontalaxis) aggregated for the 5 interventions.Treatment effects are expressed as haz-ard ratios (HRs). Diagonal line is the lineof identity. Dashed lines around eachcircle indicate the Bayesian credible in-tervals for the treatment effect on theestablished and alternative end points.Colors indicate intervention type. Darkgray, (A) renin-angiotensin systemblockade versus control; yellow, (B)renin-angiotensin system blockadeversus calcium channel blocker; green,(C) intensive blood pressure control;blue, (D) low-protein diet; pink, (E)immunosuppressive therapies. GFRdecline of (top left) 40% in the overallstudy duration, (top right) 30% in theoverall study duration, (bottom left)40% at 24 months, and (bottom right)30% at 24 months.

GFR Decline as Alternative End Point in Clinical Trials

we hypothesized that even lesser declines in GFRwould result in an even greater number of end pointsand similar or stronger treatment effects, particularlyat shorter periods of follow-up. Consistent with thishypothesis, we observed a greater number of eventsfor end points defined by lesser eGFR declines for allinterventions at some intervals and consistency be-tween the alternative and established end points formost comparisons. However, we also observed atrend toward attenuation of HRs with lesser eGFRdeclines for 4 of 5 interventions.Prior studies have suggested possible mechanisms

for the variation in the HRs observed using GFRdecline as an end point. The first mechanism is acuteeffects onGFRof the intervention or the control that aredifferent in direction or magnitude to their long-termeffects. RAS blockade, lower blood pressure targets,and low-protein diets have been shown to cause aninitial decline inGFR (a negative acute effect) followedby a slower rate of GFR decline.16,23,53,54 In contrast,CCBs, higher blood pressure targets, and high-proteindiets lead to an initial increase in GFR (a positiveacute effect) followed by a faster rate of GFR decline.10

Because acute effects are more likely to lead to smallrather than large declines in GFR, the presence of acuteeffects is likely to lead to greater variation in the HRwhen using smaller versus larger declines in GFR asalternative end points. Both RAS blockade and CCB

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treatments lead to acute effects, but in the opposite di-rection, and therefore this mechanism likely explainsthe greater attenuation in the HR observed for the RASblockade versus CCB intervention compared to theRAS blockade versus control intervention. The secondmechanism is greater effects of the interventions forthose with faster progression (proportional effects).This is a well-recognized phenomenon in other do-mains55,56 and has been shown to be a factor in studiesof low-protein diets.57 In studies in which treatmenteffects are greater for the faster versus slower pro-gressors, use of end points based on lesser eGFR de-clines may be expected to lead to smaller magnitudesfor estimated treatment effects. This mechanism mayhave contributed to the attenuation of the HR that wasobserved for the RAS blockade and immunosuppres-sive therapies. The third mechanism is effects of in-terventions on serum creatinine level not related tochanges in GFR.58 Low-protein diets acutely decreasecreatinine generation, thereby lowering serum creati-nine level and increasing eGFR despite loweringmeasured GFR. The net effect would be to augment thetreatment effect, as we observed. The potential effect ofinterventions on non-GFRdeterminants of endogenousfiltrationmarkers is relevant to allfiltrationmarkers, notonly creatinine. A fourth mechanism is that lesser de-clines are subject to greater degrees of measurementerror and are more likely to lead to false events. While

855

Table 2. Ratios for Comparison of Alternative End Points of 30% and 40% Decline in eGFR to Established End Point at Overall Study

Duration and 24 Months

Intervention

Alternative End Point

Ratioa95% Credible

Intervals Around Mean

Prediction Interval for Agreement

of Studies Across 90% of StudiesTime eGFR Decline

A. RAS blockade vs control Overall 40% 1.06 0.98-1.14 0.93-1.19

30% 1.13 1.01-1.26 0.91-1.40

24 mo 40% 0.98 0.89-1.07 0.84-1.14

30% 1.08 0.95-1.20 0.86-1.33

B. RAS blockade vs CCB Overall 40% 1.07 0.80-1.35 0.67-1.60

30% 1.12 0.80-1.48 0.62-1.83

24 mo 40% 1.11 0.68-2.04 0.62-1.94

30% 1.15 0.81-1.53 0.68-1.93

C. Intensive blood pressure control Overall 40% 0.98 0.85-1.11 0.81-1.16

30% 1.05 0.87-1.21 0.83-1.30

24 mo 40% 0.96 0.79-1.16 0.69-1.30

30% 1.05 0.88-1.24 0.83-1.32

D. Low-protein diet Overall 40% 0.91 0.64-1.43 0.47-1.84

30% 0.88 0.63-1.39 0.48-1.69

24 mo 40% 0.93 0.64-1.44 0.48-1.88

30% 0.86 0.61-1.42 0.47-1.78

E. Immunosuppressive therapy Overall 40% 1.12 0.89-1.40 0.80-1.57

30% 1.15 0.88-1.54 0.69-1.98

24 mo 40% 1.12 0.83-1.49 0.69-1.89

30% 1.27 0.92-1.74 0.69-2.37

Abbreviations: CCB, calcium channel blocker; eGFR, estimated glomerular filtration rate; RAS, renin-angiotensin system.aRatio is the exponentiation of difference of log hazard ratio of established end point minus the log hazard ratio of the altnerative end

point. Established end point is the composite of end-stage renal disease, eGFR , 15 mL/min/1.73 m2, and doubling of serumcreatinine level.

Inker et al

none of these analyses can prove the existence of these4 mechanisms, the observed results are consistent withprior studies. Overall, these results emphasize thecomplexity of the effect of interventions and control onlesser eGFR declines and the importance of under-standing these potential mechanisms prior to the designof phase 3 trials. Other potential solutions requirefurther study, such as evaluation for acute effects dur-ing the trial and a prespecified adaptation of the trialdesign if an acute effect is detected.We presented results from multiple studies that

were pooled using rigorous meta-analytical tech-niques. The advantage of this approach is that largerstudies with more precise results are weighted morethan smaller studies, which limits conclusions to bedrawn from small outlier studies. The disadvantage isthat the pooled results may not detect differencesamong trials that are due to different mechanisms anddo not allow us to determine the improvement instatistical power that could be obtained from using thealternative end points for a specific trial. In general,results in individual studies followed the generalpattern within an intervention. We previously havepublished a report of the impact of these alternativeoutcomes in 2 trials of angiotensin receptor blockers

856

for diabetic kidney disease.59 In that report, weshowed an increase in number of events and a trendtoward attenuation of treatment effects when usinglesser eGFR declines. These effects counterbalancedeach other such that there was no improvement instatistical power when using lesser eGFR declines. Inaddition, we presented results using the 3-month timepoint as the baseline and show less attenuation oftreatment effects with lesser decline. Our data fromthe current study reinforce the importance of under-standing the effects of the intervention on GFR inspecific populations. The final articles from the seriesof reports from the workshop analytical group explorethe impact of these mechanisms and their combina-tion on design of clinical trials.We found that use of confirmed end points results in

stronger treatment effects for all magnitudes of eGFRdecline, particularly at shorter follow-up. The likelyexplanation is that the “noise” in eGFR that could berelated to short-term fluctuation in measured GFR (eg,due to acute kidney injury) or in non-GFRdeterminantsof serum creatinine level are not sustained across asubsequent visit. Based on these data, a reasonableapproach in the design of future trials would be toconfirm the end point with a repeat measurement. Our

Am J Kidney Dis. 2014;64(6):848-859

GFR Decline as Alternative End Point in Clinical Trials

data cannot identify the appropriate timing for the nextvisit. Because the change inGFRwould not have been aspecified event in the study design, the next visit used inour analyses was the next planned visit.Strengths of this study include a systematic literature

search to include all available studies, uniform defini-tions of exposures and outcomes, and a rigorous eval-uation using complementary meta-analytical methods.In particular, the trial-level analysis to characterizeagreement between the alternative and established endpoints used Bayesian analyses to account for statisticalnoise resulting from limited sample sizes from somestudies. Similar analyses using less formal methodshave been interpreted as supporting reductions in bloodpressure and serum cholesterol level as surrogate endpoints for cardiovascular disease protection.60-62

There are several limitations. First, our analyses arerestricted to the specific diseases and interventionsincluded in the published and unpublished literatureavailable at the beginning of our study in 2007, as wellas the additional IgA studies that we included. Inclu-sion of new trials and in particular large trials couldovercome some of the limitations of our current anal-ysis. Second, the limitations in sample size and vari-ation in treatment effects among well-powered CKDtrials limited statistical power, particularly for the trial-level ratio analysis. Thus, we cannot with certainty saythat that the ratio of treatment effects for the alternativeto established end points does or does not include 1.These limitations in size and variation also madeestimation of between-study variability sensitive toassumptions about its prior distribution and did notallow for a comprehensive subgroup analyses byvarying factors of disease, level of proteinuria, andeGFR. This also prevented evaluation of the ability oftreatment effects on GFR decline to predict treatmenteffects on the established outcome, which is of keyrelevance for the design of future studies. Third, theconfirmed result was not a planned visit as part of thestudy design, but was the next available visit and mayhave occurred long after the original visit.In summary, the results presented here, together with

those of the workshop report and the other 3 articlesfrom the workshop analytical group, suggest that aconfirmed eGFRdecline of 40%and possibly 30%maybe used as an end point for a trial of kidney diseaseprogression in certain circumstances. Acute effects ofinterventions of GFR, nonproportional effects of in-terventions on GFR decline, and effects of in-terventions on the endogenous filtration markers usedto estimateGFR could affect the utility of one or both ofthese end points, depending on the magnitude of theeffect. Exploration as to the existence of these factorsshould be undertaken early in the design of drugdevelopment and potentially could be evaluated duringphase 3 trials that use eGFR decline as an end point.

Am J Kidney Dis. 2014;64(6):848-859

ACKNOWLEDGEMENTSThe planning committee of the NKF-FDA workshop contrib-

uted to the formulation of the research questions and presentationof the concepts at the meeting (members: Andrew S. Levey, MD[chair], Aliza M. Thompson, MD [FDA; co-chair], Josef Coresh,MD, PhD, Kerry Willis, PhD [NKF], Norman Stockbridge, MD,PhD [FDA], Edmund Lewis, MD, Dick de Zeeuw, MD, PhD, andAlfred K. Cheung, MD). We also thank Tanya Logvinenko foranalytical input into the initial planning of the analyses, CassandraBecker for preparation of the analytical tables for the conference,and Aghogho Okparavero, MD, MPH, for editorial assistance inpreparation of this manuscript.The participating CKD-EPI clinical trials/collaborators are listed

in Item S2.Support: The workshop was supported and facilitated by the

NKF. The NKF gratefully acknowledges Abbott, Amgen, ChemoCentryx, Lilly, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Reata,Sanofi, and Takeda, which provided grants to support the work-shop and the related data analyses. The study was funded by theNKF, which was not required to approve publication of thefinished manuscript.Financial Disclosure: Dr Inker reports receiving research grants

fromPharmalinkABandGileadSciences and a consulting agreementfrom Otsuka. Dr Lambers Heerspink reports consulting agreementswith AbbVie, Astellas, Janssen, Reata, and Vitae during the past 3years; all honoraria are paid to his employer/institution, University ofGroningen. Dr Coresh reports receiving a research grant fromAmgenduring the past 3 years. Dr Greene reports receiving a research grantfrom Pharmalink AB and consulting agreements with Jansen Phar-maceuticals, Keryx Biopharmaceuticals, and Genkyotech. Dr Leveyreports funding to Tufts Medical Center for research and contractswith the National Institutes of Health, NKF,Amgen, PharmalinkAB,andGileadSciences. The other authors declare that they have nootherrelevant financial interests.Contributions: Research idea and study design: LAI, HJLH,

THG, ASL; data acquisition: LAI; data analysis/interpretation:LAI, HJLH, HM, CHS, HT, FN, JC, TG, ASL; statistical analysis:LAI, HJLH, HM, CHS, HT, FN, THG; supervision or mentorship:LAI, THG, ASL. Each author contributed important intellectualcontent during manuscript drafting or revision and acceptsaccountability for the overall work by ensuring that questionspertaining to the accuracy or integrity of any portion of the workare appropriately investigated and resolved. LAI takes re-sponsibility that this study has been reported honestly, accurately,and transparently; that no important aspects of the study have beenomitted; and that any discrepancies from the study as planned havebeen explained.

SUPPLEMENTARY MATERIAL

Item S1: Supplemental methods, figures, and tables.Item S2: List of participating CKD-EPI clinical trials/

collaborators.Note: The supplementary material accompanying this article

(http://dx.doi.org/10.1053/j.ajkd.2014.08.017) is available atwww.ajkd.org

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GFR Decline as an Alternative End Point to Kidney Failure in Clinical Trials: A Meta-analysis of Treatment Effects From 37 ...MethodsData Sets and Analytical GroupsEstimated GFRReference Test: Clinical Outcome—Established End PointsIndex Tests: Surrogate Outcome—Alternative eGFR-Based End PointsAnalyses

ResultsDiscussionAcknowledgementsSupplementary MaterialReferences