Safety and Efficacy of the ACE-Inhibitor Ramipril in Alport Syndrome: The Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase III EARLY PRO-TECT Alport Trial in Pediatric Patients

Introduction. Retrospective observational data show that ACE-inhibitor therapy delays renal failure and improves life expectancy in Alport patients with proteinuria. The EARLY PRO-TECT Alport trial assesses the safety and efficacy of early therapy onset with ramipril in pediatric Alport patients. Methods and analysis. This double-blind, randomized, placebo-controlled, multicenter phase III trial (NCT01485978; EudraCT-number 2010-024300-10) includes 120 pediatric patients aged 24 months to 18 years with early stages of Alport syndrome (isolated hematuria or microalbuminuria). From March 2012, up to 80 patients will be randomized 1:1 to ramipril or placebo. In the event of disease progression during 3-year treatment, patients are unblinded and ramipril is initiated, if applicable. Approximately 40 patients receive open-label ramipril contributing to the safety database. Primary end-points are “time to progression to next disease level” and “incidence of adverse drug events before disease progression.” Treatment effect estimates from the randomized comparison and Alport registry data will be combined in supportive analyses to maximize evidence. Conclusion. Without this trial, ACE inhibitors may become standard off-label treatment in Alport syndrome without satisfactory evidence base. The results are expected to be of relevance for therapy of all pediatric patients with kidney disease, and the trial protocol might serve as a model for other rare pediatric glomerulopathies. 1. Background More than two decades have passed since the identification of COL4A5 gene as the genetic locus for X-linked Alport syndrome (AS) [1]. The hereditary type IV collagen disease Alport syndrome leads to progressive kidney fibrosis and end-stage renal failure. Knowledge of the mutation has allowed early genetic diagnosis [1] of AS years or even decades before renal failure. Still, despite early diagnosis, no evaluated therapy could be offered until recently. Animal studies on AS, based on the fundamental genetic discoveries, have produced a variety of potentially effective therapies for Alport kidney disease [2–5]. In “Alport-mice,” early therapy onset with the angiotensin-converting-enzyme-inhibitor (ACEI) ramipril doubled the lifespan until renal failure [5]. This basic research results have led ACEIs to be the standard off-label therapy of AS for most nephrologists, including pediatric nephrologists. Retrospective observational data have shown that ACEIs reduce proteinuria [6] and, most important, delay end-stage renal failure and thus improve life expectancy in Alport