Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12–2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.
Bibliographical noteFunding Information:
The German Federal Ministry of Education and Research funded the trial (01KG1104) after an international peer-reviewed 2-step application process, which required a 2-arm RCT design, but did not have any further influence on the trial design or analyses. Sanofi-Aventis Germany, which supplied the trial medication free of cost, did not have any influence on the trial design or analyses. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The trial was registered at www.ClinicalTrials.gov (NCT01485978); the EudraCT-number is 2010-024300-10. The full trial protocol and the Statistical Analysis Plan can be accessed in the Supplementary Material. The full data set can be assessed upon request. The trial results were presented as an abstract at the Late-Breaking Clinical Trials Session of the Congress of the American Society of Nephrology in Washington, DC, on November 7, 2019. The authors thank the local study team of the University of Goettingen, Studienzentrum UMG (U. D?rr, A. G?rlitz, J. Lambert, N. R?thling, R. Ahmed, C. Gavenis, A. Molitor, and S. Pfeiffer); assistant physicians of the coordinating principal investigator (Co-PI) J. Frese and J. Sonntag; trial coordinator of the Co-PI T. Albrecht-Nock; the members of the data safety and monitoring board (R. Hilgers, C. Licht, and M. Weber); the members of the steering committee (P. Hoyer, W. Rascher, D.E. M?ller-Wiefel, B. Hoppe, J. D?tsch, and M. Konrad); C. Bramlage, M. Koziolek, S. Eisend, and K. Tiede from the university pharmacy Kiel; F. Hundt and E. W?hl for discussion and sharing of ESCAPE safety data; the German Society of Pediatric Nephrology (GPN) study group (GPN-supported trial); B.G. Hudson and J. Miner for their enthusiasm in helping us translate their groundbreaking basic research into clinical practice; the European patient group FEDERG; all national Alport patient groups in the US, France, UK, Belgium, The Netherlands, Spain, Switzerland, Italy, Israel, China, Australia, and especially Germany for their support and for sharing their individual medical history to help in planning and implementing this trial. We are most thankful to our young patients and their parents for volunteering for this very long study for almost 1 decade. BT, LTW, LP, KL, HF, BL-S, H Z, PH, HS, SK, UJ, JG, BH, M G, BH, RE, and CL were principal investigators of the local trial sites and contributed to trial planning, study protocol, data collection, data interpretation, and discussion of the results and the manuscript. CEK was principal investigator for the US-Alport registry (NCT00622544) and contributed to data collection, data interpretation, and discussion of the results and manuscript. MH contributed to all data analysis, data interpretation, content and design of all figures, and discussion of the results and manuscript. JB contributed to final validation of all clinical and genetic data, data analysis, data interpretation, content and design of all figures, and discussion of the results and manuscript. TF contributed as head statistician responsible for the statistical analysis plan, power calculation and data analysis, data interpretation, and discussion of the results and manuscript. OG contributed as initiator and head principal investigator of the trial, who wrote the trial concept, applied for funding, had access to and assessed the final data, and wrote the final manuscript.
© 2020 International Society of Nephrology
- ACE inhibitors
- Alport syndrome
- chronic kidney disease
- pediatric nephrology
- renin-angiotensin system