Iptacopan in Idiopathic Immune Complex–Mediated Membranoproliferative Glomerulonephritis: Protocol of the APPARENT Multicenter, Randomized Phase 3 Study
Marina Vivarelli, Andrew S. Bomback, Matthias Meier, Yaqin Wang, Nicholas J.A. Webb, Uday Kiran Veldandi, Richard J. Smith, David Kavanagh
Abstract
IntroductionImmune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) is an ultra-rare, fast-progressing kidney disease that may be idiopathic (primary) or secondary to chronic infection, autoimmune disorders, or monoclonal gammopathies. Dysregulation of the alternative complement pathway is implicated in the pathophysiology of IC-MPGN, and currently there are no approved targeted treatments. Iptacopan is an oral, highly potent proximal complement inhibitor that specifically binds to factor B and inhibits the alternative pathway.MethodsThis randomized, double-blind, placebo-controlled Phase III study (APPARENT; NCT05755386) will evaluate the efficacy and safety of iptacopan in patients with idiopathic (primary) IC-MPGN, enrolling up to 68 patients (minimum of 10 adolescents) aged 12–60 years with biopsy-confirmed IC-MPGN, proteinuria ≥1 g/g, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. All patients will receive maximally tolerated angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and vaccination against encapsulated bacteria. Patients with any organ transplant, progressive crescentic glomerulonephritis, or kidney biopsy with >50% interstitial fibrosis/tubular atrophy, will be excluded. Patients will be randomized 1:1 to receive either iptacopan 200 mg twice daily (bid) or placebo for 6 months, followed by open-label treatment with iptacopan 200 mg bid for all patients for 6 months. The primary objective is to evaluate the efficacy of iptacopan versus placebo on proteinuria reduction measured as urine protein–creatinine ratio (24-h urine) at 6 months. Key secondary endpoints will assess kidney function measured by eGFR, patients who achieve a proteinuria–eGFR composite endpoint, and patient-reported fatigue.ConclusionThis study will provide evidence towards the efficacy and safety of iptacopan in idiopathic (primary) IC-MPGN.