Perrone Ronald D, Hariri Ali, Minini Pascal, Ahn Curie, Chapman Arlene B, Horie Shigeo, Knebelmann Bertrand, Mrug Michal, Ong Albert C M, Pei York P C, Torres Vicente E, Modur Vijay, Gansevoort Ronald T
Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
Eloxx Pharmaceuticals, Watertown, Massachusetts.
Kidney Med. 2022 Aug 27;4(10):100538. doi: 10.1016/j.xkme.2022.100538. eCollection 2022 Oct.
RATIONALE & OBJECTIVE: Venglustat, a glucosylceramide synthase inhibitor, inhibits cyst growth and reduces kidney failure in mouse models of autosomal dominant polycystic kidney disease (ADPKD). STAGED-PKD aims to determine the safety and efficacy of venglustat and was designed using patient enrichment for progression to end-stage kidney disease and modeling from prior ADPKD trials.
STAGED-PKD is a 2-stage, international, double-blind, randomized, placebo-controlled trial in adults with ADPKD (Mayo Class 1C-1E) and estimated glomerular filtration rate (eGFR) 45-<90 mL/min/1.73 m at risk of rapidly progressive disease. Enrichment for rapidly progressing patients was identified based on retrospective analysis of total kidney volume (TKV) and eGFR slope from the combined Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease and HALT Progression of Polycystic Kidney Disease A studies.
SETTING & PARTICIPANTS: Target enrollment in stages 1 and 2 was 240 and 320 patients, respectively.
Stage 1 randomizes patients 1:1:1 to venglustat 8 mg or 15 mg once daily or placebo. Stage 2 randomizes patients 1:1 to placebo or venglustat, with the preferred dose based on stage 1 safety data.
Primary endpoints are TKV growth rate over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary endpoints include: annualized rate of change in eGFR from baseline to 18 months (stage 1); annualized rate of change in TKV based on magnetic resonance imaging from baseline to 18 months (stage 2); and safety, tolerability, pain, and fatigue (stages 1 and 2).
If stage 1 is unsuccessful, patients enrolled in the trial may develop drug-related adverse events that can have long-lasting effects.
Modeling allows the design and powering of a 2-stage combined study to assess venglustat's impact on TKV growth and eGFR slope. Stage 1 TKV assessment via a nested approach allows early evaluation of efficacy and increased efficiency of the trial design by reducing patient numbers and trial duration.
This study was funded by Sanofi.
STAGED-PKD has been registered at ClinicalTrials.gov with study number NCT03523728.
文格鲁司他是一种葡糖神经酰胺合酶抑制剂，在常染色体显性多囊肾病（ADPKD）小鼠模型中可抑制囊肿生长并减少肾衰竭。STAGED - PKD旨在确定文格鲁司他的安全性和有效性，其设计采用了对进展至终末期肾病的患者进行富集，并借鉴了既往ADPKD试验的模型。
STAGED - PKD是一项两阶段的国际双盲随机安慰剂对照试验，针对患有ADPKD（梅奥分类1C - 1E）且估计肾小球滤过率（eGFR）为45 - <90 mL/min/1.73 m²且有快速进展性疾病风险的成年人。基于对多囊肾病放射影像学研究联盟和多囊肾病进展停止A研究合并数据中总肾体积（TKV）和eGFR斜率的回顾性分析，确定了对快速进展患者的富集。
第1阶段和第2阶段的目标入组人数分别为240例和320例患者。
第1阶段将患者按1:1:1随机分为每日一次服用8 mg或15 mg文格鲁司他或安慰剂。第2阶段将患者按1:1随机分为安慰剂或文格鲁司他组，首选剂量基于第1阶段的安全性数据。
主要终点为第1阶段18个月内的TKV生长率和第2阶段24个月内的eGFR斜率。次要终点包括：从基线到18个月的eGFR年化变化率（第1阶段）；基于磁共振成像从基线到18个月的TKV年化变化率（第2阶段）；以及安全性、耐受性、疼痛和疲劳（第1和第2阶段）。
如果第1阶段不成功，参与试验的患者可能会出现与药物相关的不良事件，这些事件可能会产生长期影响。
建模使得能够设计并实施一项两阶段联合研究，以评估文格鲁司他对TKV生长和eGFR斜率的影响。通过嵌套方法在第1阶段进行TKV评估，可早期评估疗效，并通过减少患者数量和试验持续时间提高试验设计的效率。
本研究由赛诺菲资助。
STAGED - PKD已在ClinicalTrials.gov注册，研究编号为NCT03523728。
