Dias, Renuka P (RP);Brock, Kristian (K);Hu, Kun (K);Gupta, Rajat (R);Martin, Una (U);Peet, Andrew (A);Wilson, Martin (M);Yu-Wai-Man, Patrick (P);Wright, Benjamin (B);Mollan, Susan (S);Kulkarni, Archana (A);Meunier, Isabelle (I);Billingham, Lucinda (L);Nagy, Zsuzsanna (Z);Rose, Heather (H);Koks, Sulev (S);Zatyka, Malgorzata (M);Astuti, Dewi (D);Lynch, Tracy (T);Morrison, Karen E (KE);Barton, Darren (D);Cronier, Sabrina (S);Malpass, Rebecca (R);Evans, Ruth (R);Malhi, Amandip (A);Takhar, Pooja (P);Lamb, Amy (A);Esteban-Bueno, Gema (G);M?ynarski, Wojciech (W);Orssaud, Christophe (C);Roubertie, Agathe (A);Homer, Victoria (V);Barrett, Timothy (T);

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BMJ Open.2025 Feb 26;15(2):e091495.doi:10.1136/bmjopen-2024-091495

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.