Perrone, R.D., Hariri, A., Minini, P. et al. (10 more authors) (2022) 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. Kidney Medicine, 4 (10). 100538. ISSN 2590-0595
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-PKD 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 Genzyme.
Trial registration
STAGED-PKD has been registered at ClinicalTrials.gov with study number NCT03523728.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is an open access article under the CC BY license https://creativecommons.org/licenses/by/4.0/. |
Keywords: | Autosomal dominant polycystic kidney disease; modeling; study design; total kidney volume; venglustat |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number AVENTIS PHARMA LIMITED nan |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 21 Sep 2022 16:35 |
Last Modified: | 11 Nov 2022 13:50 |
Status: | Published |
Publisher: | Elsevier BV |
Refereed: | Yes |
Identification Number: | 10.1016/j.xkme.2022.100538 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:190654 |