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Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial.

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journal contribution
posted on 23.08.2019, 16:04 by J Lv, H Zhang, MG Wong, MJ Jardine, M Hladunewich, V Jha, H Monaghan, M Zhao, S Barbour, H Reich, D Cattran, R Glassock, A Levin, D Wheeler, M Woodward, L Billot, TM Chan, Z-H Liu, DW Johnson, A Cass, J Feehally, J Floege, G Remuzzi, Y Wu, R Agarwal, H-Y Wang, V Perkovic, TESTING Study Group
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.

Funding

This study was supported by the National Health and Medical Research Council of Australia, the Peking University Health Central Clinical Research Project, and the Canadian Institutes of Health Research. Study drug was provided by Pfizer Pharmaceuticals.

History

Citation

JAMA, 318 (5), pp. 432-442

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Infection, Immunity and Inflammation

Version

VoR (Version of Record)

Published in

JAMA

Publisher

American Medical Association

eissn

1538-3598

Acceptance date

29/06/2017

Copyright date

2017

Available date

23/08/2019

Notes

Supplementary material available from the publisher website at 10.1001/jama.2017.9362

Language

en