Sodium valproate, a potential repurposed treatment for the neurodegeneration in Wolfram syndrome (TREATWOLFRAM): trial protocol for a pivotal multicentre, randomised double-blind controlled trial.

Tracy Lynch, Christophe Orssaud, Benjamin Wright, Susan Mollan, Archana Kulkarni, Isabelle Meunier, Heather Rose, Malgorzata Zatyka, Dewi Astuti, Patrick Yu-Wai-Man, Sabrina Cronier, Rebecca Malpass, Ruth Evans, Amandip Malhi, Pooja Takhar, Amy Lamb, Gema Esteban-Bueno, Sulev Koks, Timothy Barrett, Rajat Gupta, Agathe Roubertie, Kun Hu, Karen E Morrison, Wojciech Młynarski, Martin Wilson, Renuka P Dias, Darren Barton, Zsuzsanna Nagy, Andrew Peet, Una Martin, Victoria Homer, Kristian Brock, Lucinda Billingham

Journal: BMJ open 2025;15(2):e091495

PMID: 40010822

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Abstract

INTRODUCTION

Wolfram syndrome (Spectrum Disorder) is an ultra-rare monogenic form of progressive neurodegeneration and diabetes mellitus. In common with most rare diseases, there are no therapies to slow or stop disease progression. Sodium valproate, an anticonvulsant with neuroprotective properties, is anticipated to mediate its effect via alteration of cell cycle kinetics, increases in p21 expression levels and reduction in apoptosis and increase in Wolframin protein expression. To date, there have been no multicentre randomised controlled trials investigating the efficacy of treatments for neurodegeneration in patients with Wolfram syndrome.

METHODS AND ANALYSIS

TREATWOLFRAM is an international, multicentre, double-blind, placebo-controlled, randomised clinical trial designed to investigate whether 36-month treatment with up to 40 mg/kg/day of sodium valproate will slow the rate of loss of visual acuity as a biomarker for neurodegeneration in patients with Wolfram syndrome. Patients who satisfied the eligibility criteria were randomly assigned (2:1) to receive two times per day oral gastro-resistant sodium valproate tablets up to a maximum dose of 800 mg 12 hourly or sodium valproate-matched placebo. Using hierarchical repeated measures analyses with a 5% significance level, 80% power and accounting for an estimated 15% missing data rate, a sample size of 70 was set. The primary outcome measure, visual acuity, will be centrally reviewed and analysed on an intention-to-treat population.

ETHICS AND DISSEMINATION

The protocol was approved by the National Research Ethics Service (West of Scotland; 18/WS/0020) and by the Medicines and Healthcare products Regulatory Agency. Recruitment into TREATWOLFRAM started in January 2019 and ended in November 2021. The treatment follow-up of TREATWOLFRAM participants is ongoing and due to finish in November 2024. Updates on trial progress are disseminated via Wolfram Syndrome UK quarterly newsletters and at family conferences for patient support groups. The findings of this trial will be disseminated through peer-reviewed publications and international presentations.

TRIAL REGISTRATION NUMBER

NCT03717909.

Address: Institute of Applied Health Research, University of Birmingham, Birmingham, UK.; Department of Paediatric Endocrinology, Birmingham Women's and Children's Hospital, Birmingham, UK.; Cancer Research UK Clinical Trials Unit, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK.; Department of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.; Department of Paediatric Neurology, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.; Institute of Clinical Sciences, University of Birmingham, Birmingham, UK.; Department of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.; Paediatric Oncology, Birmingham Women's and Children's Hospital, Birmingham, UK.; Centre for Human Brain Health, School of Psychology, University of Birmingham, Birmingham, UK.; John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.; Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge, UK.; Moorfields Eye Hospital NHS Foundation Trust, London, UK.; Institute of Ophthalmology, University College London, London, UK.; Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.; Birmingham Neuro-Ophthalmology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Trust, Birmingham, UK.; Department of Ophthalmology, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.; National reference centre for inherited retinal dystrophies, University hospital of Montpellier, Montpellier, France.; Institute of Neurosciences Inserm, Montpellier University, Montpellier, France.; Department of Inflammation and Aging, University of Birmingham, Birmingham, UK.; Department of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.; Medical Physics and Clinical Engineering, Nottingham University Hospitals NHS Trust, Nottingham, UK.; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Western Australia, Australia.; Wolfram Syndrome UK, Worthing, UK.; School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.; UGC Almeria Periferia, Distrito Sanitario Almeria, Sistema Sanitario Publico Andaluz (SSPA), Consejeria de Salud y Consumo (Junta de Andalucia), Seville, Spain.; Department of Paediatrics, Oncology and Haematology, Medical University of Lodz, Lodz, Poland.; Functional Unit of Ophthalmology; Ophthalmological Rare Diseases Reference Center, Functional Unit of Ophthalmology; Ophthalmological Rare Diseases Reference Center, Paris, France.; Département de Neurologie Pédiatrique, CIC pédiatrique, CHU Gui de Chauliac, INM, INSERM U 1298, Montpellier, France.; Department of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK [email protected].; Department of Paediatric Endocrinology, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, Birmingham, UK.

DOI: 10.1136/bmjopen-2024-091495

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MeSH Terms: Humans, Valproic Acid, Double-Blind Method, Wolfram Syndrome, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, Female, Male, Adult, Adolescent, Drug Repositioning, Young Adult, Neuroprotective Agents, Treatment Outcome