Safety and Efficacy of Topiramate in Individuals With Cryptogenic Sensory Peripheral Neuropathy With Metabolic Syndrome

Author:

Smith A. Gordon1,Singleton J. Robinson2,Aperghis Adrienne2,Coffey Christopher S.3,Creigh Peter4,Cudkowicz Merit5,Conwit Robin6,Ecklund Dixie3,Fedler Janel K.3,Gudjonsdottir Anna3,Hauer Peter2,Herrmann David N.4,Kearney Marianne5,Kissel John7,Klingner Elizabeth3,Quick Adam7,Revere Cathy2,Stino Amro8,Sirja Elias9,Vinik Aaron9,Peltier Amanda9,Pasnoor Mamatha9,Callaghan Brian9,Menichella Daniella Maria9,Nance Chris9,Seyedsadiadi Reza9,Saporta Mario9,Phillips Lauren9,Ubogu Eroboghene9,Bird Shawn9,Geisler Stefanie9,Lopate Glenn9,Caress James9,Brannagan Thomas9,Gwathmey Kelly9,Ortega Erik9,Mozaffar Tahseen9,Milstein Mark9,Quan Dianna9,Snowden Janet9,Charles Julie9,Wood Elizabeth9,Mountain Joan9,Annis Christine9,Guntrum Debra9,Gibson Cynthia9,Connolly Noreen9,Behrens-Spraggins Steffen9,Doudova Mariana9,Dolan Candice9,Bartlett Amy9,Agriesti Julie9,Casellini Carolina9,Bailey Michael9,Lowen Kelly9,McKinney Tricia9,Furukawa Sally9,Lackey Alyssa9,Liu Tina9,Jennens Katheryn9,Colgan Samantha9,Rasnake Amanda9,Stelzer Meghan9,Graft Courtney9,Ward Tina9,Coffey Taylor9,Burian Cosette9,Szela Monika9,Houseman Justine9,Casale Connie9,Sieren Jeri9,Olalde Heena9,Kressin Nicole9,Brenner Loriane9,James Peter9,Brito Pires Claudia Maria9,Grant Natalie9,Levy Wendy9,Steele Julie9,Paredes Maria9,Hopkins Steven9,Joshi Amruta9,Thayer William9,Conger Amy9,Valdez Jovana9,Benge Melanie9,Harders Elizabeth9,Moulton Kelsey9,Teshome Mengesha9,Bauer Nikki9,Streckfuss Kelly9,Harris Summer9,Clemons Jessyca9,Bond Karie9,Kim Arreum9,Fayerman Raisy9,Gonzalez Johana9,Moran Joyce9,Vissa Pranay9,Wilkins Bridget9,Turcotte Nicole9,Strong Stephanie9,Hernandez Isela9,Wencel Marie9,Moyer Diana9,Meton Melanie9,Slabbekoorn Elena9,Rafi Rehana9,Capobianco Diane9,Parido Connie9,

Affiliation:

1. Department of Neurology, Virginia Commonwealth University, Richmond

2. Department of Neurology, The University of Utah, Salt Lake City

3. University of Iowa Clinical Trials Statistical and Data Management Center, Iowa City

4. Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York

5. Department of Neurology, Massachusetts General Hospital, Boston

6. Indiana University Department of Neurology and the National Institute of Neurological Disorders and Stroke, Rockville, Maryland

7. Department of Neurology, Ohio State University, Columbus

8. Department of Neurology, University of Michigan, Ann Arbor

9. for the NeuroNEXT NN108 TopCSPN Study Team

Abstract

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 (<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

Publisher

American Medical Association (AMA)

Subject

Neurology (clinical)

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