Safety and Efficacy of Topiramate in Individuals With Cryptogenic Sensory Peripheral Neuropathy With Metabolic Syndrome
Authors: Smith A. Gordon , Singleton J. Robinson , Aperghis Adrienne , Coffey Christopher S. , Creigh Peter , Cudkowicz Merit , Conwit Robin , Ecklund Dixie , Fedler Janel K. , Gudjonsdottir Anna , Hauer Peter , Herrmann David N. , Kearney Marianne , Kissel John , Klingner Elizabeth , Quick Adam , Revere Cathy , Stino Amro ,   NeuroNEXT NN108 TopCSPN Study Team, Sirja Elias , Vinik Aaron , Peltier Amanda , Pasnoor Mamatha , Callaghan Brian , Menichella Daniella Maria , Nance Chris , Seyedsadiadi Reza , Saporta Mario , Phillips Lauren , Ubogu Eroboghene , Bird Shawn , Geisler Stefanie , Lopate Glenn , Caress James , Brannagan Thomas , Gwathmey Kelly , Ortega Erik , Mozaffar Tahseen , Milstein Mark , Quan Dianna , Snowden Janet , Charles Julie , Wood Elizabeth , Mountain Joan , Annis Christine , Guntrum Debra , Gibson Cynthia , Connolly Noreen , Behrens-Spraggins Steffen , Doudova Mariana , Dolan Candice , Bartlett Amy , Agriesti Julie , Casellini Carolina , Bailey Michael , Lowen Kelly , McKinney Tricia , Furukawa Sally , Lackey Alyssa , Liu Tina , Jennens Katheryn , Colgan Samantha , Rasnake Amanda , Stelzer Meghan , Graft Courtney , Ward Tina , Coffey Taylor , Burian Cosette , Szela Monika , Houseman Justine , Casale Connie , Sieren Jeri , Olalde Heena , Kressin Nicole , Brenner Loriane , James Peter , Brito Pires Claudia Maria , Grant Natalie , Levy Wendy , Steele Julie , Paredes Maria , Hopkins Steven , Joshi Amruta , Thayer William , Conger Amy , Valdez Jovana , Benge Melanie , Harders Elizabeth , Moulton Kelsey , Teshome Mengesha , Bauer Nikki , Streckfuss Kelly , Harris Summer , Clemons Jessyca , Bond Karie , Kim Arreum , Fayerman Raisy , Gonzalez Johana , Moran Joyce , Vissa Pranay , Wilkins Bridget , Turcotte Nicole , Strong Stephanie , Hernandez Isela , Wencel Marie , Moyer Diana , Meton Melanie , Slabbekoorn Elena , Rafi Rehana , Capobianco Diane , Parido Connie 
Published: October 2023

ImportanceCryptogenic sensory peripheral neuropathy (CSPN) is highly prevalent and often disabling due to neuropathic pain. Metabolic syndrome and its components increase neuropathy risk. Diet and exercise have shown promise but are limited by poor adherence.ObjectiveTo determine whether topiramate can slow decline in intraepidermal nerve fiber density (IENFD) and/or neuropathy-specific quality of life measured using the Norfolk Quality of Life–Diabetic Neuropathy (NQOL-DN) scale.Design, Setting, and ParticipantsTopiramate as a Disease-Modifying Therapy for CSPN (TopCSPN) was a double-blind, placebo-controlled, randomized clinical trial conducted between February 2018 and October 2021. TopCSPN was performed at 20 sites in the National Institutes of Health–funded Network for Excellence in Neurosciences Clinical Trials (NeuroNEXT). Individuals with CSPN and metabolic syndrome aged 18 to 80 years were screened and randomly assigned by body mass index (&amp;lt;30 vs ≥30), which is calculated as weight in kilograms divided by height in meters squared. Patients were excluded if they had poorly controlled diabetes, prior topiramate treatment, recurrent nephrolithiasis, type 1 diabetes, use of insulin within 3 months before screening, history of foot ulceration, planned bariatric surgery, history of alcohol or drug overuse in the 2 years before screening, family history of a hereditary neuropathy, or an alternative neuropathy cause.InterventionsParticipants received topiramate or matched placebo titrated to a maximum-tolerated dose of 100 mg per day.Main Outcomes and MeasuresIENFD and NQOL-DN score were co-primary outcome measures. A positive study was defined as efficacy in both or efficacy in one and noninferiority in the other.ResultsA total of 211 individuals were screened, and 132 were randomly assigned to treatment groups: 66 in the topiramate group and 66 in the placebo group. Age and sex were similar between groups (topiramate: mean [SD] age, 61 (10) years; 38 male [58%]; placebo: mean [SD] age, 62 (11) years; 44 male [67%]). The difference in change in IENFD and NQOL-DN score was noninferior but not superior in the intention-to-treat (ITT) analysis (IENFD, 0.21 fibers/mm per year; 95% CI, −0.43 to ∞ fibers/mm per year and NQOL-DN score, −1.52 points per year; 95% CI, −∞ to 1.19 points per year). A per-protocol analysis excluding noncompliant participants based on serum topiramate levels and those with major protocol deviations demonstrated superiority in NQOL-DN score (−3.69 points per year; 95% CI, −∞ to −0.73 points per year). Patients treated with topiramate had a mean (SD) annual change in IENFD of 0.56 fibers/mm per year relative to placebo (95% CI, −0.21 to ∞ fibers/mm per year). Although IENFD was stable in the topiramate group compared with a decline consistent with expected natural history, this difference did not demonstrate superiority.Conclusion and RelevanceTopiramate did not slow IENFD decline or affect NQOL-DN score in the primary ITT analysis. Some participants were intolerant of topiramate. NQOL-DN score was superior among those compliant based on serum levels and without major protocol deviations.Trial RegistrationClinicalTrials.gov Identifier: NCT02878798