BSPED2025 Oral Communications Diabetes Oral Communications 2 (7 abstracts)
A phase ii, international, randomised, double-blind, efficacy and safety trial of sodium valproate in paediatric and adult patients with wolfram syndrome
Timothy Barrett 1 , Gema Esteban-Bueno 2 , Renuka Dias 1 , Benjamin Wright 3 , Christophe Orssaud 4 , Wojciech Mlynarski 5 , Agathe Roubertie 6 , Martin Wilson 1 , Patrick Yu-Wai-Man 7 , Tracy Lynch 8 , Amandip Malhi 1 , Darren Barton 1 & Victoria Homer 1
1University of Birmingham, Birmingham, United Kingdom; 2Unidad de Gestión Clínica Almería Periferia, Almeria, Spain; 3University Hospitals Birmingham, Birmingham, United Kingdom; 4Hôpital Européen Georges Pompidou, Paris, France; 5Medical University of Lodz, Lodz, Poland; 6Département de Neurologie Pédiatrique, CHU Gui de Chauliac, Montpellier, France; 7University of Cambridge, Cambridge, United Kingdom; 8Wolfram Syndrome UK, Worthing, United Kingdom
Objectives: Wolfram syndrome (WFS1-Spectrum Disorder) is a rare (1:500,000) monogenic form of childhood onset diabetes mellitus and optic atrophy. There are no therapies to slow or stop disease progression. Sodium valproate prevents cell death in Wolfram neuronal models. We aimed to investigate whether valproate can slow disease progression in this condition.
Methods: We conducted a pivotal, randomised, placebo-controlled, multi-centre, double-blind trial of sodium valproate in patients with Wolfram syndrome defined by diabetes mellitus and/or optic atrophy diagnosed under 16 years; pathogenic variants in the WFS1 gene; and visual acuity assessed as a LogMAR score of 1.6 or better on an EDTRS chart. Patients were randomly assigned 2:1 to either treatment with sodium valproate or matched placebo, and followed up for progression of visual acuity loss for 36 months. Secondary outcomes included safety, and effects on glycaemic control.
Results: A total of 63 participants (median age 18 years, range 8-61 years; 29/63 (46% under 16 years) underwent randomisation, 42 to the valproate group and 21 to the placebo group. At baseline, the placebo treated group vs valproate treated group was younger (median age 15yrs (range11-21yrs) vs 19 yrs (range 14-26yrs)), had shorter duration of optic atrophy (median 5.9yrs (3.5-8.7yrs) vs 6.6yrs (3.9-10.9yrs)) and lower HbA1c (median 6.95% (6.4-7.96% vs 7.5% (6.9-8.3%)). There was not a significant effect of valproate on visual acuity (progression 0.0431 LogMar/yr both groups, P = 0.66) or HbA1c (-2 mmol/mol vs +1 mmol/mol), insulin dose adjusted A1c, or total insulin consumption per kg body weight between the groups. There was an excess of hypoglycaemic events in the valproate treated group (11/42(26%) vs 4/21(19%); P < 0.05).
Conclusions: This is the first multi-centre randomosed controlled trial of a treatment for Wolfram syndrome. We did not observe an effect of valproate on the primary outcome or on glycaemic control. However we cannot exclude the possibility that this is due to the differences between the groups at baseline. Further analysis is ongoing to supplement the placebo group with an external cohort to make the groups comparable. The protocol was approved by the National Research Ethics Service (18/WS/0020). Trial registration no. NCT03717909.
Volume 111
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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