The FOsmetpantotenate Replacement Therapy (FORT) randomized, double-blind, Placebo-controlled pivotal trial: Study design and development methodology of a novel primary efficacy outcome in patients with pantothenate kinase-associated neurodegeneration

Abstract

Background/aims: Pantothenate kinase-associated neurodegeneration is a rare neurodegenerative disease with a variable clinical phenotype. Fosmetpantotenate is in clinical development as a replacement therapy that targets the underlying cause of pantothenate kinase-associated neurodegeneration. The FOsmetpantotenate Replacement Therapy pivotal trial-an ongoing phase 3, randomized, double-blind, placebo-controlled, multicenter trial-examines the efficacy and safety of fosmetpantotenate in patients with pantothenate kinase-associated neurodegeneration aged 6-65 years. The FOsmetpantotenate Replacement Therapy trial required the development and validation of a novel patient-reported outcome measure specifically relevant to pantothenate kinase-associated neurodegeneration. The Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale was developed to assess activities of daily living related to motor functioning in patients with pantothenate kinase-associated neurodegeneration to evaluate clinically meaningful change as the primary efficacy endpoint in clinical trials. This article describes the design of the FOsmetpantotenate Replacement Therapy pivotal trial and the development of the Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale.

Methods: A systematic, iterative process consistent with the US Food and Drug Administration guidance and advice from the Committee for Medicinal Products for Human Use at the European Medicines Agency was used to evaluate and adapt or remove scale items of an existing widely used instrument for movement disorders to be pantothenate kinase-associated neurodegeneration-specific, and to create new items. Modification of scale items was based on input from international experts, patient advocacy leaders, and primary caregivers. A clinimetric study of the Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale conducted in patients with pantothenate kinase-associated neurodegeneration or their caregivers (N = 40 at first assessment; N = 39 at second assessment) demonstrated high content and construct validity and excellent test-retest reliability over an approximately 2-week period. The Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale was developed to be broadly useful within clinical and research settings in the examination of patient response to pantothenate kinase-associated neurodegeneration therapies.

Results: Approximately 82 patients will be enrolled in the ongoing FOsmetpantotenate Replacement Therapy pivotal trial. Change from baseline in Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living score over the 24-week double-blind period is the primary efficacy endpoint for the FOsmetpantotenate Replacement Therapy trial. Treatment effect will be evaluated using a mixed model for repeated measures analysis to assess data from all visits simultaneously.

Conclusion: The development and implementation of the Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale in the FOsmetpantotenate Replacement Therapy trial illustrates the feasibility and potential patient benefit of putting into practice the current regulatory guidance on the use of patient-reported outcomes in clinical trials. These processes can be broadly applied to clinical trial methodology that requires newly created or revised patient-reported outcome measures to evaluate outcome change as a primary efficacy endpoint. The goal of such measures in patients with pantothenate kinase-associated neurodegeneration is to facilitate development of disease-modifying therapeutics in multiple drug development programs.

Trial registration: ClinicalTrials.gov NCT03041116.

Keywords: Pantothenate Kinase-Associated Neurodegeneration–Activities of Daily Living scale; clinical outcomes assessment; pantothenate kinase-associated neurodegeneration treatment; patient-reported outcome.

Conflict of interest statement

Declaration of conflicting interests: T.K. is a coordinating investigator of the FORT trial; receives research funding from Retrophin, Inc.; is a coordinating investigator of the deferiprone in PKAN randomized and extension trial; received research funding from ApoPharma Inc.; is supported by the European Commission 7th Framework Programme (FP7/2007-2013, HEALTH-F2-2011, grant agreement no. 277984, TIRCON); is supported by the European Reference Network for Rare Neurological Diseases (ERN-RND), co-funded by the European Commission (ERN-RND: 3HP 767231); provides consulting services to CoA Therapeutics, TM3 Therapeutics, and Retrophin, Inc; and received travel support from ApoPharma Inc. M.L.E. provides consulting services to Retrophin, Inc. R.D.M. and S.T. are former full-time employees of Retrophin, Inc. and may have an equity or other financial interest in Retrophin, Inc. B.P.-D. received grant support from Retrophin, Inc. to Hospital Universitari Vall d’Hebron, Barcelona, Spain. A.V. provides consulting services to Retrophin, Inc.; received active grant support from the National Institutes of Health; provides consulting services to Acadia, Jazz, and Roche; and served on DSMB for Wilsons’ Therapeutics and Acorda. F.G. is a full-time employee of Retrophin, Inc. and may have an equity or other financial interest in Retrophin, Inc.

Figures

Figure 1.

FORT study design.