Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy

The TESTING randomized clinical trial

TESTING Study Group

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

IMPORTANCE: Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain. OBJECTIVE: To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression. DESIGN, SETTING, AND PARTICIPANTS: The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m2 after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred. INTERVENTIONS: Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months. MAIN OUTCOMES AND MEASURES: The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years. RESULTS: After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years’ median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (P = .001; risk difference, 11.5% [95% CI, 4.8%-18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%-13.9%]; P < .001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (hazard ratio, 0.37 [95% CI, 0.17-0.85]; risk difference, 10.0% [95% CI, 2.5%-17.9%]; P = .02). CONCLUSIONS AND RELEVANCE: Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01560052.

Original languageEnglish (US)
Pages (from-to)432-442
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume318
Issue number5
DOIs
StatePublished - Aug 1 2017

Fingerprint

Methylprednisolone
Immunoglobulin A
Randomized Controlled Trials
Steroids
Glomerular Filtration Rate
Proteinuria
Placebos
Adrenal Cortex Hormones
Infection
Kidney
Therapeutics
Safety
Gastrointestinal Hemorrhage
Osteonecrosis
Renin-Angiotensin System
Random Allocation
Weaning
Chronic Kidney Failure
Renal Insufficiency
Urine

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy : The TESTING randomized clinical trial. / TESTING Study Group.

In: JAMA - Journal of the American Medical Association, Vol. 318, No. 5, 01.08.2017, p. 432-442.

Research output: Contribution to journalArticle

@article{fb9e19d797f945dfb59cade879707580,
title = "Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy: The TESTING randomized clinical trial",
abstract = "IMPORTANCE: Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain. OBJECTIVE: To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression. DESIGN, SETTING, AND PARTICIPANTS: The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m2 after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred. INTERVENTIONS: Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months. MAIN OUTCOMES AND MEASURES: The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40{\%} decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years. RESULTS: After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37{\%}] women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years’ median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7{\%}) in the methylprednisolone group vs 4 (3.2{\%}) in the placebo group (P = .001; risk difference, 11.5{\%} [95{\%} CI, 4.8{\%}-18.2{\%}]), mostly due to excess serious infections (11 [8.1{\%}] vs 0; risk difference, 8.1{\%} [95{\%} CI, 3.5{\%}-13.9{\%}]; P < .001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9{\%}) in the methylprednisolone group vs 20 (15.9{\%}) in the placebo group (hazard ratio, 0.37 [95{\%} CI, 0.17-0.85]; risk difference, 10.0{\%} [95{\%} CI, 2.5{\%}-17.9{\%}]; P = .02). CONCLUSIONS AND RELEVANCE: Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01560052.",
author = "{TESTING Study Group} and Jicheng Lv and Hong Zhang and Wong, {Muh Geot} and Jardine, {Meg J.} and Michelle Hladunewich and Vivek Jha and Helen Monaghan and Minghui Zhao and Sean Barbour and Heather Reich and Daniel Cattran and Richard Glassock and Adeera Levin and David Wheeler and Mark Woodward and Laurent Billot and Chan, {Tak Mao} and Liu, {Zhi Hong} and Johnson, {David W.} and Alan Cass and John Feehally and J{\"u}rgen Floege and Giuseppe Remuzzi and Yangfeng Wu and Rajiv Agarwal and Wang, {Hai Yan} and Vlado Perkovic",
year = "2017",
month = "8",
day = "1",
doi = "10.1001/jama.2017.9362",
language = "English (US)",
volume = "318",
pages = "432--442",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "5",

}

TY - JOUR

T1 - Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy

T2 - The TESTING randomized clinical trial

AU - TESTING Study Group

AU - Lv, Jicheng

AU - Zhang, Hong

AU - Wong, Muh Geot

AU - Jardine, Meg J.

AU - Hladunewich, Michelle

AU - Jha, Vivek

AU - Monaghan, Helen

AU - Zhao, Minghui

AU - Barbour, Sean

AU - Reich, Heather

AU - Cattran, Daniel

AU - Glassock, Richard

AU - Levin, Adeera

AU - Wheeler, David

AU - Woodward, Mark

AU - Billot, Laurent

AU - Chan, Tak Mao

AU - Liu, Zhi Hong

AU - Johnson, David W.

AU - Cass, Alan

AU - Feehally, John

AU - Floege, Jürgen

AU - Remuzzi, Giuseppe

AU - Wu, Yangfeng

AU - Agarwal, Rajiv

AU - Wang, Hai Yan

AU - Perkovic, Vlado

PY - 2017/8/1

Y1 - 2017/8/1

N2 - IMPORTANCE: Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain. OBJECTIVE: To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression. DESIGN, SETTING, AND PARTICIPANTS: The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m2 after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred. INTERVENTIONS: Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months. MAIN OUTCOMES AND MEASURES: The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years. RESULTS: After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years’ median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (P = .001; risk difference, 11.5% [95% CI, 4.8%-18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%-13.9%]; P < .001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (hazard ratio, 0.37 [95% CI, 0.17-0.85]; risk difference, 10.0% [95% CI, 2.5%-17.9%]; P = .02). CONCLUSIONS AND RELEVANCE: Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01560052.

AB - IMPORTANCE: Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain. OBJECTIVE: To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression. DESIGN, SETTING, AND PARTICIPANTS: The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m2 after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred. INTERVENTIONS: Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months. MAIN OUTCOMES AND MEASURES: The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years. RESULTS: After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years’ median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (P = .001; risk difference, 11.5% [95% CI, 4.8%-18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%-13.9%]; P < .001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (hazard ratio, 0.37 [95% CI, 0.17-0.85]; risk difference, 10.0% [95% CI, 2.5%-17.9%]; P = .02). CONCLUSIONS AND RELEVANCE: Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01560052.

UR - http://www.scopus.com/inward/record.url?scp=85027500963&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027500963&partnerID=8YFLogxK

U2 - 10.1001/jama.2017.9362

DO - 10.1001/jama.2017.9362

M3 - Article

VL - 318

SP - 432

EP - 442

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 5

ER -