The STAGED-PKD 2-Stage Adaptive Study With a Patient Enrichment Strategy and Treatment Effect Modeling for Improved Study Design Efficiency in Patients With ADPKD

Abstract

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.

Study design: 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 m² 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.

Interventions: 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.

Outcomes: 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).

Limitations: If stage 1 is unsuccessful, patients enrolled in the trial may develop drug-related adverse events that can have long-lasting effects.

Conclusions: 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.

Funding: This study was funded by Sanofi.

Trial registration: STAGED-PKD has been registered at ClinicalTrials.gov with study number NCT03523728.

Keywords: Autosomal dominant polycystic kidney disease; modeling; study design; total kidney volume; venglustat.

Figure 1

GSL biosynthesis in ADPKD and potential effect of the GCS inhibitor venglustat. Adapted from Natoli et al. Loss of polycystin function disrupts the TSC complex, and consequently suppression of Rheb is inactivated, leading to activation of mTORC1. mTORC1 activation increases de novo ceramide synthesis. Polycystin dysregulation also activates mTORC2, which also promotes de novo ceramide synthesis and increases GL-1 by increasing GCS production. Beyond polycystin disruption, other factors may impact GSL accumulation in ADPKD, including growth factor activation (eg, EGF 1 or IGF 1) of mTORC2 or cytokine- and ROS-mediated activation of sphingomyelinase activity. Red boxes show molecules that are upregulated in cystic kidneys compared with normal kidneys. Yellow box overlay indicates GSL accumulation that could be attenuated/stopped with a GCS inhibitor. Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; EGF, epidermal growth factor; IGF, insulin-like growth factor; GCS, glucosylceramide synthase; GL-1, glucosylceramide; GM3, monosialodihexosylganglioside; GSL, glycosphingolipid; mTORC, mammalian target of rapamycin complex; Rheb, Ras homolog enriched in brain; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; TNF, tumor necrosis factor; TSC, tuberous sclerosis.

Figure 2

Class-level data from the CRISP and HALT-PKD A studies. Based on retrospective analysis of 2 historical studies. For each class, mean TKV growth rate is plotted against mean eGFR rate of decline. The size of each bubble is proportional to the sample size. Abbreviations: CRISP, Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease; eGFR, estimated glomerular filtration rate; HALT-PKD, HALT Progression of Polycystic Kidney Disease; STAGED-PKD, study to assess glucosylceramide synthase inhibitor efficacy in ADPKD; TKV, total kidney volume.

Figure 3

Correlation between TKV growth and eGFR decline based on individual-level data from CRISP and HALT-PKD A. Predicted eGFR rate of decline based on a model predicting eGFR at time t as a function of TKV growth rate and adjusted for baseline eGFR and age. Abbreviations: CRISP, Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease; eGFR, estimated glomerular filtration rate; HALT-PKD, HALT Progression of Polycystic Kidney Disease; TKV, total kidney volume.

Figure 4

Study design and key steps in STAGED-PKD stage 1 (A) and stage 2 (B). ^∗To ensure adequate representation of patients across the spectrum of eGFR, a minimum of 20% of patients are enrolled in each of the following categories: ≥45-<60 mL/min/1.73 m²; ≥60-<75 mL/min/1.73 m²; and ≥75-<90 mL/min/1.73 m²; ^†Highest dose determined to be well tolerated in stage 1. Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; eGFR, estimated glomerular filtration rate; ROW, rest of the world; STAGED-PKD, study to assess glucosylceramide synthase inhibitor efficacy in ADPKD.