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Randomized Controlled Trial
. 2023 Dec 1;80(12):1334-1343.
doi: 10.1001/jamaneurol.2023.3711.

Safety and Efficacy of Topiramate in Individuals With Cryptogenic Sensory Peripheral Neuropathy With Metabolic Syndrome: The TopCSPN Randomized Clinical Trial

A Gordon Smith  1 , J Robinson Singleton  2 , Adrienne Aperghis  2 , Christopher S Coffey  3 , Peter Creigh  4 , Merit Cudkowicz  5 , Robin Conwit  6 , Dixie Ecklund  3 , Janel K Fedler  3 , Anna Gudjonsdottir  3 , Peter Hauer  2 , David N Herrmann  4 , Marianne Kearney  5 , John Kissel  7 , Elizabeth Klingner  3 , Adam Quick  7 , Cathy Revere  2 , Amro Stino  8 ; NeuroNEXT NN108 TopCSPN Study Team
Collaborators, Affiliations
Randomized Controlled Trial

Safety and Efficacy of Topiramate in Individuals With Cryptogenic Sensory Peripheral Neuropathy With Metabolic Syndrome: The TopCSPN Randomized Clinical Trial

A Gordon Smith et al. JAMA Neurol. .

Abstract

Importance: Cryptogenic 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.

Objective: To 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 participants: Topiramate 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.

Interventions: Participants received topiramate or matched placebo titrated to a maximum-tolerated dose of 100 mg per day.

Main outcomes and measures: IENFD 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.

Results: A 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 relevance: Topiramate 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 registration: ClinicalTrials.gov Identifier: NCT02878798.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Smith reported receiving consulting fees from Merz, Sangamo, Argenx, and Alexion and data monitoring board fees from Eidos and Lexicon outside the submitted work. Dr Coffey reported receiving grants from the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) and from the Michael J Fox Foundation outside the submitted work. Dr Creigh reported receiving grants from the NIH during the conduct of the study. Dr Cudkowicz reported receiving consulting fees from Immunity Pharm Ltd, Orion, Cytokinetics, Wave, Takeda, Biogen, Denali, Helixsmith, Sunovian, Disarm, RRD, Transposon, Quralis, Regeneron, Ab Sciences, Locust Walk, Neurosense, Faze, Arrowhead, Vector Y, Servier, Eledon, Pasithea, MPTC, Inflectis, Roche, Ono, and Novartis and serving as a board member for Praxis outside the submitted work. Dr Ecklund reported grants from NIH during the conduct of the study. Dr Gudjonsdottir reported receiving grants from NINDS during the conduct of the study. Dr Herrmann reported receiving grants from the NIH; advisory board fees from Regenacy and Roche; and consulting fees from Pfizer, Neurogene, Sarepta, Passage Bio, DTx Pharma, and Applied Therapeutics outside the submitted work. Dr Chase reported receiving grants from NINDS during the conduct of the study. Dr Stino reported receiving consulting fees from CSL Behring and Argenx and grants from Bristol Myers Squibb outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Screening, Randomization, and Follow-Up in the Topiramate as a Disease-Modifying Therapy for Cryptogenic Sensory Peripheral Neuropathy (TopCSPN) Trial
aA list of the most common reasons for ineligibility by protocol version is available in Supplement 1 and Supplement 2. bOther reason for discontinuation was due to the participant being unable to complete titration within protocol requirements.
Figure 2.
Figure 2.. Estimated Change in Coprimary Outcomes Over 96 Weeks in the Intention-to-Treat (ITT) and Per-Protocol (PP) Populations
A, Estimated change in intraepidermal nerve fiber density (IENFD) over time by treatment group in the ITT population. Shaded areas indicate 95% CIs. B, Estimated change in Norfolk Quality of Life–Diabetic Neuropathy (NQOL-DN) over time by treatment group in the ITT population. Shaded areas indicate 95% CIs. C, Estimated change in IENFD over time by treatment group in the PP population. Shaded areas indicate 95% CIs. D, Estimated change in NQOL-DN over time by treatment group in the PP population. Shaded areas indicate 95% CIs.
See this image and copyright information in PMC

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