CSPN is highly prevalent, yet there are no FDA approved treatments. Neuropathy trial design is hampered by lack of validated clinically relevant biomarkers. Evolving data suggest obesity and metabolic syndrome increase CSPN risk. Lifestyle-based approaches may be effective, but difficult to sustain. Topiramate (TPM) is approved for migraine and epilepsy. Even at low doses, TPM causes weight loss and improves insulin sensitivity.

TopCSPN is being performed by 20 sites in the Network for Excellence in Neuroscience Clinical Trials. The objective is to determine if TPM slows progression of CSPN associated with metabolic syndrome. A secondary objective is assessing the patient-facing clinical meaning of existing and exploratory biomarkers.

Consenting eligible participants are randomized to receive 2 years of 100 mg TPM daily or placebo. Distal thigh intraepidermal nerve fiber density (IENFD) and Norfolk Quality of Life Diabetic Neuropathy (NQOL-DN) are co-primary outcome measures. TopCSPN will be considered positive if there is efficacy for both, or efficacy in one and noninferiority in the other. The relationship between NCS, IENFD, NQOL-DN and functional measures will be explored. A mediation analysis will assess whether TPM exerts its effects on NQOL-DN and functional/clinical endpoints directly or indirectly (e.g. via IENFD change). 195 Participants have been screened and 115 randomized (total enrollment will be 125, completion expected by 11/1/19). Of these, 65% are male, mean age is 61.7 y.o., BMI 33.7 kg/m², IENFD 10.0, NQOL-DN 38.5, and pain severity 4.0. Baseline features of the enrolled cohort will be summarized.

TopCSPN is the first multicenter trial of a potentially disease modifying agent for CSPN. TopCSPN employs a novel go/no-go algorithm using co-primary outcomes that measure QOL and a direct measure of axon loss. This design promises to significantly inform design of future clinical trials for other forms of neuropathy including diabetes.