Effects of newer kidney protective agents on kidney endpoints provide implications for future clinical trials

Abstract

Doubling of serum creatinine (equivalent to a 57% decline in the estimated glomerular filtration rate (eGFR)) is an accepted component of a composite kidney endpoint in clinical trials. Smaller declines in eGFR (40%, 50%) have been applied in several recently conducted clinical trials. Here, we assessed the effects of newer kidney protective agents on endpoints including smaller proportional declines in eGFR to compare relative event rates and the magnitude of observed treatment effects. We performed a post hoc analysis of 4401 patients in the CREDENCE, 4304 in the DAPA-CKD, 5734 in the FIDELIO-DKD, and 3668 in the SONAR trials, which assessed the effects of canagliflozin, dapagliflozin, finerenone and atrasentan in patients with chronic kidney disease. Effects of active therapies versus placebo on alternative composite kidney endpoints incorporating different eGFR decline thresholds (40%, 50%, or 57% eGFR reductions from baseline) with kidney failure or death due to kidney failure were compared. Cox-proportional hazards regression models were used to assess and compare treatment effects. During follow-up, event rates were higher for endpoints incorporating smaller versus larger eGFR decline thresholds. Compared to the treatment effects on kidney failure or death due to kidney failure, the magnitude of relative treatment effects was generally similar when considering composite endpoints incorporating smaller declines in eGFR. Hazard ratios for the four interventions ranged from 0.63 to 0.82 for the endpoint incorporating 40% eGFR decline and 0.59 to 0.76 for the endpoint incorporating 57% eGFR decline. Clinical trials incorporating a 40% eGFR decline in a composite endpoint would require approximately half the number of participants compared to a 57% eGFR decline with equivalent statistical power. Thus, in populations at high risk of CKD progression, the relative effects of newer kidney protective therapies appear generally similar across endpoints based on varying eGFR decline thresholds. Doubling of serum creatinine (equivalent to a 57% decline in the estimated glomerular filtration rate (eGFR)) is an accepted component of a composite kidney endpoint in clinical trials. Smaller declines in eGFR (40%, 50%) have been applied in several recently conducted clinical trials. Here, we assessed the effects of newer kidney protective agents on endpoints including smaller proportional declines in eGFR to compare relative event rates and the magnitude of observed treatment effects. We performed a post hoc analysis of 4401 patients in the CREDENCE, 4304 in the DAPA-CKD, 5734 in the FIDELIO-DKD, and 3668 in the SONAR trials, which assessed the effects of canagliflozin, dapagliflozin, finerenone and atrasentan in patients with chronic kidney disease. Effects of active therapies versus placebo on alternative composite kidney endpoints incorporating different eGFR decline thresholds (40%, 50%, or 57% eGFR reductions from baseline) with kidney failure or death due to kidney failure were compared. Cox-proportional hazards regression models were used to assess and compare treatment effects. During follow-up, event rates were higher for endpoints incorporating smaller versus larger eGFR decline thresholds. Compared to the treatment effects on kidney failure or death due to kidney failure, the magnitude of relative treatment effects was generally similar when considering composite endpoints incorporating smaller declines in eGFR. Hazard ratios for the four interventions ranged from 0.63 to 0.82 for the endpoint incorporating 40% eGFR decline and 0.59 to 0.76 for the endpoint incorporating 57% eGFR decline. Clinical trials incorporating a 40% eGFR decline in a composite endpoint would require approximately half the number of participants compared to a 57% eGFR decline with equivalent statistical power. Thus, in populations at high risk of CKD progression, the relative effects of newer kidney protective therapies appear generally similar across endpoints based on varying eGFR decline thresholds. Lay SummaryThe established endpoint for clinical trials in nephrology includes a large decline in estimated glomerular filtration rate (eGFR; 57%). To assess drug effects, the established endpoint requires large sample sizes and trials of long duration. Alternative endpoints that include smaller declines in eGFR have been proposed and applied in recent clinical trials. In this new study, we demonstrate in 4 recently completed clinical trials that the effects of newer nephroprotective agents are generally similar across endpoints using varying eGFR declines. Because endpoints based on smaller declines in eGFR occur more often, the sample size needed to detect treatment effects would be smaller if less-stringent eGFR thresholds are used, thereby facilitating conduct of clinical trials. The established endpoint for clinical trials in nephrology includes a large decline in estimated glomerular filtration rate (eGFR; 57%). To assess drug effects, the established endpoint requires large sample sizes and trials of long duration. Alternative endpoints that include smaller declines in eGFR have been proposed and applied in recent clinical trials. In this new study, we demonstrate in 4 recently completed clinical trials that the effects of newer nephroprotective agents are generally similar across endpoints using varying eGFR declines. Because endpoints based on smaller declines in eGFR occur more often, the sample size needed to detect treatment effects would be smaller if less-stringent eGFR thresholds are used, thereby facilitating conduct of clinical trials. Kidney failure is the most significant long-term complication of chronic kidney disease (CKD), for clinicians, patients, and caregivers.1Webster A.C. Nagler E.V. Morton R.L. Masson P. Chronic kidney disease.Lancet. 2017; 389: 1238-1252Abstract Full Text Full Text PDF PubMed Scopus (1755) Google Scholar Given this, clinical trials aiming to develop new therapies for CKD have traditionally used kidney failure as a component of a composite endpoint, together with a relatively large decline in kidney function (e.g., doubling of serum creatinine). Because kidney failure and doubling of serum creatinine are late manifestations of CKD progression, drug development for CKD has historically focused on patients with more advanced disease, to avoid protracted follow-up times and mitigate operational complexities. Surrogate endpoints that can reliably reflect longer-term, well-established endpoints could facilitate the conduct of clinical trials at earlier stages of CKD.2Levey A.S. Gansevoort R.T. Coresh J. et al.Change in albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney Foundation in Collaboration with the US Food and Drug Administration and European Medicines Agency.Am J Kidney Dis. 2020; 75: 84-104Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar In the past decade, significant progress has been made in validating surrogate endpoints. Initial studies focused on the validity of using declines in eGFR of less than 57% (equivalent to a doubling of serum creatinine) as a component of a composite endpoint.3Heerspink H.J.L. Weldegiorgis M. Inker L.A. et al.Estimated GFR decline as a surrogate end point for kidney failure: a post hoc analysis from the Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) Study and Irbesartan Diabetic Nephropathy Trial (IDNT).Am J Kidney Dis. 2014; 63: 244-250PubMed Google Scholar, 4Levey A.S. Inker L.A. Matsushita K. et al.GFR decline as an endpoint for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug and Administration.Am J Kidney Dis. 2014; 64: 821-835Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar, 5Levin A. Agarwal R. Herrington W.G. et al.International consensus definitions of clinical trial outcomes for kidney failure: 2020.Kidney Int. 2020; 98: 849-859Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar A meta-analysis of clinical trials supported the validity of using a 30% eGFR decline in some circumstances, and a 40% decline in eGFR could be more broadly acceptable as a surrogate endpoint. However, for both surrogate endpoints, the pattern of acute effects on eGFR should be examined, specifically because the acute eGFR lowering effects can attenuate the treatment effect estimate in confirmatory phase 3 trials.6Inker L.A. Lambers Heerspink H.J. Mondal H. et al.GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials.Am J Kidney Dis. 2014; 64: 848-859Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar The validity of kidney endpoints defined by smaller declines in eGFR was demonstrated with established therapies, using data from clinical trials conducted mostly in the 1990s and early 2000s, with the majority being agents that inhibit the renin–angiotensin system. Newer classes of agents for attenuating CKD progression have emerged since then, including sodium–glucose co-transporter-2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, and empagliflozin); a nonsteroidal mineralocorticoid receptor antagonist (finerenone); and an endothelin receptor antagonist (atrasentan).7Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (2918) Google Scholar, 8Heerspink H.J.L. Stefansson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (1631) Google Scholar, 9Heerspink H.J.L. Parving H.-H. Andress D.L. et al.Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.Lancet. 2019; 393: 1937-1947Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar, 10Bakris G.L. Agarwal R. Anker S.D. et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229Crossref PubMed Scopus (701) Google Scholar These newer interventions all have acute eGFR-lowering effects, although of varying magnitude; whereas atrasentan exerts a modest eGFR-lowering acute effect (–0.8 ml/min per 1.73 m2), the acute effect is 3- to 4-fold larger with finerenone and SGLT2 inhibitors. Understanding the implications of alternative eGFR decline thresholds on the relative (and absolute) effects of these and other therapeutic agents will help inform clinical decision making in the near term, and the design of future clinical trials. In this study, we used data from pivotal placebo-controlled randomized clinical trials that assessed the efficacy and safety of an SGLT2 a nonsteroidal mineralocorticoid receptor or an endothelin receptor antagonist on composite endpoints of kidney failure or death due to kidney disease, with eGFR decline thresholds of 50%, and We pivotal phase 3 clinical trials patients with type 2 diabetes and CKD that demonstrated a significant risk in the composite kidney endpoint with the newer We the trials: and in Diabetes with Nephropathy Clinical and of in Chronic Kidney in Kidney and in Diabetic Kidney and the Study of Diabetic Nephropathy with and the trial randomized 4401 patients were at of a of type 2 an eGFR and ml/min per 1.73 and a and V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (2918) Google Scholar patients were an or an receptor participants were to at a of or placebo and were for a of and the trial 4304 patients or with or a of type 2 an eGFR and ml/min per 1.73 and a and H.J.L. Stefansson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (1631) Google Scholar patients were an or if were to at a of or placebo and were for a of A.S. Gansevoort R.T. Coresh J. et al.Change in albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney Foundation in Collaboration with the US Food and Drug Administration and European Medicines Agency.Am J Kidney Dis. 2020; 75: 84-104Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar and the trial 5734 patients or CKD and a of type 2 G.L. Agarwal R. Anker S.D. et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229Crossref PubMed Scopus (701) Google Scholar an eGFR of to ml/min per 1.73 a of to and or an eGFR of to ml/min per 1.73 and a and patients were an or and were randomized to finerenone or placebo and were for a of and the SONAR trial patients to a of type 2 an eGFR and ml/min per 1.73 and a and H.J.L. Parving H.-H. Andress D.L. et al.Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.Lancet. 2019; 393: 1937-1947Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar patients were an or participants atrasentan at a of an active to patients were to to defined as a in of 30% or and patients to defined as an of at 3 in or an in to at patients atrasentan and a of patients to the and were in a to atrasentan at a of or to the we the and as that the effect of atrasentan on the composite kidney was different in and The of follow-up was The kidney endpoints in this analysis were a composite of kidney failure as for at in the kidney or an eGFR ml/min per 1.73 for at death due to kidney failure, or decline in eGFR for at of and A eGFR ml/min per 1.73 was a component of the kidney failure in the We performed all statistical the We used proportional hazards regression models to assess the effect of the active compared to on the risk for composite kidney endpoint. The kidney endpoint in analysis was defined as kidney failure, death due to kidney failure, or varying eGFR 50%, or 40% decline in eGFR from We assessed the effects of the interventions on the composite endpoint of kidney failure or death due to kidney We models for used at as defined in clinical To estimate treatment effects on the acute and chronic eGFR we used a as based on a eGFR at 3 for due to kidney failure or L.A. Heerspink H.J.L. H. et al.GFR as a surrogate end point for kidney disease progression in clinical trials: a meta-analysis of treatment effects of randomized 2019; PubMed Scopus Google Scholar, H. J. et models for endpoints in clinical trials of chronic kidney Med. 2019; PubMed Scopus Google Scholar, with models in the of PubMed Scopus Google Scholar The for eGFR and for different of in eGFR and participants and treatment the randomized in the eGFR at the follow-up, and the from 3 by the follow-up the treatment effects on the acute and chronic eGFR We sample sizes for future kidney trials with We used observed ratios as the relative risk for composite endpoint and the event rate for that endpoint in participants to We the sample size to at a of with an of of and of trial duration. of the CREDENCE, DAPA-CKD, FIDELIO-DKD, and SONAR trials are in ranged and eGFR ranged and ml/min per 1.73 and ranged and or was for all participants in the CREDENCE, and trials, and for of participants in the In all clinical trials, were across randomized ml/min per 1.73 ml/min per 1.73 CREDENCE, and in Diabetes with Nephropathy Clinical DAPA-CKD, and of in Chronic Kidney estimated glomerular filtration FIDELIO-DKD, in Kidney and in Diabetic Kidney Study of Diabetic Nephropathy with are as or for which is as in a new CREDENCE, and in Diabetes with Nephropathy Clinical DAPA-CKD, and of in Chronic Kidney estimated glomerular filtration FIDELIO-DKD, in Kidney and in Diabetic Kidney Study of Diabetic Nephropathy with are as or for which is as of canagliflozin, dapagliflozin, or finerenone to larger acute eGFR-lowering effects, compared to atrasentan During follow-up, the chronic eGFR was with all interventions with larger effects observed with and chronic effects of the interventions on eGFR eGFR ml/min per 1.73 per eGFR ml/min per 1.73 per CREDENCE, and in Diabetes with Nephropathy Clinical DAPA-CKD, and of in Chronic Kidney estimated glomerular filtration FIDELIO-DKD, in Kidney and in Diabetic Kidney Study of Diabetic Nephropathy with in a new CREDENCE, and in Diabetes with Nephropathy Clinical DAPA-CKD, and of in Chronic Kidney estimated glomerular filtration FIDELIO-DKD, in Kidney and in Diabetic Kidney Study of Diabetic Nephropathy with During follow-up, and kidney failure or death due to kidney failure events in the CREDENCE, DAPA-CKD, FIDELIO-DKD, and SONAR trials, The composite endpoint of 57% eGFR kidney disease, or death due to kidney failure in and participants the follow-up of the trials. incorporating declines in eGFR the composite kidney endpoint the number of events The number of 40% eGFR decline endpoints the 3 to of follow-up was higher in the and finerenone compared to the placebo of the trials, by the an effect observed with or atrasentan effects of the compared to in trial are in The of the treatment effect for endpoints with declines in as by the and the of the was for 57% eGFR compared to for 40% eGFR decline in the The of the treatment effects of canagliflozin, dapagliflozin, and atrasentan on the composite endpoint of kidney disease or death due to kidney failure were compared to the composite endpoint of kidney failure, death due to kidney failure, or 57% eGFR decline The effect of finerenone on the composite endpoint of kidney disease or death due to kidney failure was compared to the composite endpoints that an eGFR decline the and magnitude of these effect sizes in all 4 trials generally similar when the 57% eGFR decline was by a or 40% eGFR 2 the on the statistical for the composite kidney endpoints based on of the eGFR thresholds to detect the observed relative risk a of higher event rates and similar relative risk sample sizes would have been smaller in all trials if less-stringent eGFR thresholds been analysis of 4 recently completed clinical trials in CKD with type 2 diabetes compared event treatment effect and sample sizes of different kidney endpoints, including different eGFR decline thresholds. The demonstrated that the SGLT2 inhibitors and dapagliflozin, the nonsteroidal mineralocorticoid receptor antagonist and the endothelin receptor antagonist atrasentan on all kidney endpoints of the eGFR in this Because the number of endpoints was with in relative risk the sample size to detect the observed treatment effect would be smaller if less-stringent thresholds were that CKD progression acute effects on eGFR that from long-term H. Heerspink H.J.L. et treatment effects on GFR in randomized clinical trials of kidney disease PubMed Scopus Google Scholar for a workshop by the National Kidney Foundation and the US Food and Drug Administration that for interventions that large acute reductions in eGFR as of SGLT2 inhibitors and mineralocorticoid receptor a or 57% eGFR decline is the L.A. Lambers Heerspink H.J. Mondal H. et al.GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials.Am J Kidney Dis. 2014; 64: 848-859Abstract Full Text Full Text PDF PubMed Scopus (99) Google Inker L.A. et and validity of estimated surrogate end points in CKD: a J Kidney Dis. 2014; 64: Full Text Full Text PDF PubMed Scopus Google Scholar These were made based on clinical trial and that demonstrated that the acute decline in eGFR to endpoints in the active treatment this is at in due to in eGFR which can the eGFR endpoint with these a higher number of events in the active treatment in the and finerenone trials early in In to that the treatment effects of inhibitors and are when eGFR decline thresholds are H.J.L. Weldegiorgis M. Inker L.A. et al.Estimated GFR decline as a surrogate end point for kidney failure: a post hoc analysis from the Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) Study and Irbesartan Diabetic Nephropathy Trial (IDNT).Am J Kidney Dis. 2014; 63: 244-250PubMed Google Scholar generally similar treatment effects across eGFR decline thresholds. is most by the the magnitude of the acute and chronic treatment effects on eGFR. The SGLT2 inhibitors and finerenone relatively large acute reductions in eGFR a of the rate of eGFR decline which to be to the acute in V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (2918) Google G.L. Agarwal R. Anker S.D. et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229Crossref PubMed Scopus (701) Google H.J.L. et al.Effect of on the rate of decline in kidney function in patients with chronic kidney disease with and type 2 a analysis from the Diabetes Full Text Full Text PDF PubMed Scopus Google Scholar the chronic treatment effects of canagliflozin, dapagliflozin, and finerenone were approximately as large as observed with and in the Reduction of in Diabetes with the Angiotensin II Antagonist Losartan (RENAAL) trial and the Irbesartan Diabetic Nephropathy Trial although these trials were conducted 2 when of were Thus, in in which acute eGFR-lowering effects are by of eGFR a eGFR as a component of a composite kidney endpoint for the relatively higher event rates with the acute eGFR-lowering effects. Compared with a 57% eGFR of or 40% eGFR decline thresholds in an of the treatment effect size with atrasentan in the SONAR The acute effect of atrasentan of ml/min per 1.73 per is smaller relative to of or SGLT2 inhibitors. clinical trials of endothelin receptor have demonstrated relatively acute effects on et and renal effects of endothelin receptor in patients with chronic kidney PubMed Scopus Google et receptor for the treatment of and chronic kidney PubMed Scopus Google Scholar interventions with to acute effect on eGFR decline thresholds should statistical the magnitude of observed treatment effects. The of of treatment effects with endothelin receptor is with other interventions acute GFR effects. analysis of the and trials with SGLT2 trials in patients with type 2 diabetes are at high risk risk of CKD from these trials that the treatment effects of and were when eGFR decline thresholds were in the composite kidney V. A. et of endpoint in kidney trials: from the 2020; PubMed Google M. Neal B. et eGFR decline thresholds and renal effects of data from the 2020; PubMed Scopus Google Scholar The of the treatment effect in the Study and Trial in 2 Diabetes be to the populations in these trials, in which most participants or kidney and or of The rate of kidney function decline in these trials was relative to that in the trials in V. et al.Canagliflozin and renal outcomes in type 2 from the clinical Diabetes Full Text Full Text PDF PubMed Scopus Google et and progression of kidney disease in type 2 diabetes.N Engl J Med. PubMed Scopus Google Scholar a of the rate of eGFR decline in the smaller eGFR decline thresholds were more to be to the relatively large acute in eGFR with SGLT2 thereby the treatment is supported by a that demonstrated that kidney endpoints based on smaller declines in GFR statistical for with acute eGFR-lowering effects, in clinical trial with higher or rates of progression, as with of as in the and J. et of GFR as a surrogate end point for kidney disease progression in clinical trials: a statistical 2019; PubMed Scopus Google Scholar at in some of the of the Study of and Kidney with In that the effect on CKD progression larger when a eGFR decline was used, compared to a 40% eGFR decline W.G. et in patients with chronic kidney disease.N Engl J Med. PubMed Google of of diabetes on the effects of co-transporter-2 inhibitors on kidney meta-analysis of large placebo-controlled Full Text Full Text PDF PubMed Scopus Google Scholar The in the treatment effect using a 40% decline be by the of the trial in the a which in a rate of eGFR decline compared to that in the and trials. of the treatment effect size based on smaller eGFR decline thresholds occur when the treatment effect is proportional to the rate of kidney function decline or when the acute eGFR-lowering effect when eGFR H. Heerspink H.J.L. et treatment effects on GFR in randomized clinical trials of kidney disease PubMed Scopus Google Scholar Thus, the of endpoint the of the clinical trial including the of kidney function and the rate of eGFR as as drug The of this are that we used data from relatively kidney trials with different of The clinical failure and death due to kidney in all trials by event although the definitions across trials. has the endpoints were by a the of these for different endpoints. The endpoint across trials and was by a approximately in all trials, whereas the other endpoints were at the to the trial in the in which a 57% eGFR decline was 4 as The endpoint across trials in the and SONAR in the and 40% in the and the of follow-up across trials in the and SONAR 4 in the and in the Because of the in endpoint and in trial design and the efficacy data for endpoint should be compared across trials. The that the observed treatment effects reflect the treatment effect for and and should be smaller eGFR thresholds event rates and sample sizes or follow-up, this effect drug safety trials should the of the and sample size with safety with for safety for interventions earlier in the other than the for which patients with and type 2 diabetes were the majority of participants in the 4 trials type 2 diabetes with these to the of patients with with disease of albuminuria and or therapeutic interventions with different of In these of 4 kidney disease trials that the relative effects of newer therapies on kidney disease progression are similar across different as long as rates of eGFR decline are Because events are more when eGFR endpoints are based on smaller declines in we can higher statistical when eGFR thresholds are composite kidney endpoints. is a for and and has from and has from has or on for and has with and and on clinical trial for studies sponsored by and is supported by and is a to and has from for the trial has from National of Diabetes and and Kidney National of and and is on the of for has for for and for and has from and for trial and has for from and has from and and has for scientific and from and with all to has from and from the National of the National Kidney Foundation and for and to to with and and to as a for and several and has for scientific from and is a The other The data the of this are in at or be in with data at to data from the The all patients, and for to the clinical trials. were in the data and of the clinical trials. and the and the of the the of the for and for the and of the to the analysis and for for with of kidney endpoints in the 4 and in this recent clinical trials to for kidney disease and trials are in the Heerspink et that end point trial and require the estimated glomerular filtration rate component of trial end points has been a decline of 57% doubling of serum creatinine). The smaller eGFR declines and 50%) on the outcomes of patients from several trials. PDF

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