Efficacy and Safety of Crisugabalin (HSK16149) in Adults with Postherpetic Neuralgia: A Phase 3 Randomized Clinical Trial

Abstract

Importance: China carries a heavy burden of postherpetic neuralgia, with an unmet need for novel drugs with greater efficacy and less prominent neurotoxic effects than existing calcium channel ligands.

Objective: To investigate the efficacy and safety of crisugabalin, an oral calcium channel α2δ-1 subunit ligand, for postherpetic neuralgia.

Design, setting, and participants: This randomized clinical trial, carried out between November 9, 2021, and January 5, 2023, at 48 tertiary care centers across China had 2 parts. Part 1 was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study consisting of a 2-week screening period, a 7-day run-in period, and a 12-week double-blind treatment period. Part 2 was a 14-week open-label extension study. Investigators, statisticians, trial clinicians, and patients were blinded to trial group assignments. Participants included adults with postherpetic neuralgia with an average daily pain score (ADPS) of at least 4 on the 11-point Numeric Pain Rating Scale over the preceding week, with the exclusion of patients with pain not controlled by prior therapy with pregabalin (≥300 mg/d) or gabapentin (≥1200 mg/d).

Interventions: Patients were randomized 1:1:1 to receive crisugabalin, 20 mg twice daily (ie, 40 mg/d), and crisugabalin, 40 mg twice daily (ie, 80 mg/d), or placebo for 12 weeks. Eligible patients received crisugabalin, 40 mg, twice daily during extension.

Main outcome and measure: The primary efficacy end point was the change from baseline in ADPS at week 12.

Results: The study enrolled 366 patients (121 patients receiving crisugabalin, 40 mg/d; 121 patients receiving crisugabalin, 80 mg/d; 124 patients receiving placebo; median [IQR] age, 63.0 [56.0-69.0] years; 193 men [52.7%]). At week 12, the least squares mean (SD) change from baseline in ADPS was -2.2 (0.2) for crisugabalin, 40 mg/d, and -2.6 (0.2) for crisugabalin, 80 mg/d, vs -1.1 (0.2) for placebo, with a least squares mean difference of -1.1 (95% CI, -1.6 to -0.7; P < .001) and -1.5 (-95% CI, -2.0 to -1.0; P < .001) vs placebo, respectively. No new safety concerns emerged.

Conclusions and relevance: Crisugabalin, 40 mg/d, or crisugabalin, 80 mg/d, was well tolerated and demonstrated a statistically significant improvement in ADPS over placebo.

Trial registration: ClinicalTrials.gov Identifier: NCT05140863.

Figure 1.. Study Design and Patient Disposition Flow Chart

AE indicates adverse event.

Figure 2.. Efficacy of Crisugabalin, 40 mg/d, and Crisugabalin, 80 mg/d, Over Time Compared With Placebo for Postherpetic Pain

A, Average daily pain score (ADPS) is shown as the time course of the least squares mean (LSM) with standard error (SE). Data are presented for the full analysis set. B, Bar graphs show mean ADPS at week 12 at week 12 and LSM change with SE from baseline in ADPS at week 12 in each group. C, Forest plot shows treatment response in terms of ADPS changes at week 12 in postherpetic pain patients stratified by baseline ADPS of less than 6 or 6 or more. D, Responder rates for at least 30% and at least 50% reduction in ADPS from baseline.

Figure 3.. Results of Secondary Efficacy Measures

A, Least squares mean (LSM) change with standard error (SE) from baseline in the following rating scales: A, Short-Form McGill Pain Questionnaire (SF-MPQ) visual analog scale (VAS); B, SF-MPQ Present Pain Intensity (PPI); C, SF-MPQ Pain Rating Index (PRI); D, Average Daily Sleep Interference Scale (ADSIS) scores for crisugabalin, 40 mg/d, and 80 mg/d at week 12 compared with placebo were used; E, LSM change with SE from baseline in SF-MPQ PPI and PRI scores for crisugabalin, 40 mg/d, and crisugabalin, 80 mg/d, at week 26 compared with placebo.