Tetrodotoxin (TTX) for Chemotherapy Induced Neuropathic Pain (CINP): A Randomized, Double-Blind, Dose-Finding, Placebo Controlled, Multicenter Study

OBJECTIVE: A phase 2 randomized, double-blind, dose-finding, placebo controlled, multicenter trial is ongoing to evaluate TTX as a treatment for CINP. Here we report completed dose optimization results, the objective of which was to identify up to two dosing schemes for further study.BACKGROUND: Tetrodotoxin is a small molecule that blocks voltage-gated sodium channels involved in pain signaling.METHODS: Subjects with taxane or platinum induced CINP were randomized to one of five cohorts: placebo twice daily (b.i.d.), TTX 7.5 µg b.i.d., TTX 15 µg b.i.d., TTX 30 µg daily (q.d.) or TTX 30 µg b.i.d. TTX or placebo was injected subcutaneously for four consecutive days. The TTX 30 µg q.d. cohort also received a daily placebo to maintain blinding. The primary efficacy endpoint was assessed using the numerical pain rating scale.RESULTS: 125 patients (77 women) were randomized, with 125 in the intent to treat population and 107 in the per protocol population. The mean change from baseline pain score was greatest in the TTX 30 µg q.d. (-1.7 ± 2.3) and TTX 30 µg b.i.d. (-1.5 ± 1.8) cohorts for week 4 post-treatment, the primary endpoint. Analysis of ≥ 30[percnt] improvement in 10-day average pain scores at any time point demonstrated that the TTX 30 µg b.i.d. cohort had the largest number of responders (15/26; 57.7[percnt]) compared to placebo (8/25; 32.0[percnt]) (P = 0.027). Oral paresthesia was the most common AE (37/125; 29.6[percnt]), followed by oral hypesthesia (31/125; 24.8[percnt]). Most AE were grade 1 or 2. There were four grade 3 AE and no grade 4 AE. Three patients experienced SAE, two unrelated and one unlikely related to TTX.CONCLUSIONS: The TTX 30 µg b.i.d. regimen is well tolerated with promising early efficacy data to merit further study. Clinical development is ongoing.STUDY SUPPORTED BY: WEX Pharmaceuticals. Disclosure: Dr. Goldlust has received personal compensation for activities with Novocure and Sunovion. Dr. Kavoosi has received personal compensation for activities with Wex Pharmaceuticals as an employee. Dr. Deck has nothing to disclose. Dr. Deck has nothing to disclose.