Key Points
Question
What is the efficacy of crisugabalin, an oral calcium channel α2δ-1 subunit ligand, for postherpetic neuralgia?
Findings
In this randomized clinical trial of 366 adults, crisugabalin, 40 mg/d, and crisugabalin, 80 mg/d, for 12 weeks yielded a least squares mean difference of −1.1 (95% CI, −1.6 to −0.7) and −1.5 (−95% CI, −2.0 to −1.0) vs placebo in the change from baseline in the average daily pain scores, establishing superiority of crisugabalin over placebo.
Meaning
Crisugabalin, 40 mg/d, or crisugabalin, 80 mg/d, caused significantly greater pain reduction over placebo, offering a flexible dose selection depending on individual patient response and tolerability.
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
This randomized clinical trial evaluated crisugabalin, 40 mg/d, or crisugabalin, 80 mg/d, compared to placebo in terms of patient outcomes and tolerability.
Introduction
Postherpetic neuralgia (PHN) severely compromises health-related quality of life (HR-QoL) and incurs a high financial cost.1,2,3,4 China carries a heavy burden of PHN, with a pooled incidence of herpes zoster of 4.3 of 1000 person-years for all ages and a pooled risk of 12.6% for PHN.5 The voltage-gated calcium channel α2δ-1 subunit has long been identified to contribute to neuropathic pain (NPN)6,7; together with tricyclic antidepressants, α2δ-1 ligands, including pregabalin and gabapentin, represent first-line treatments for PHN.8,9 Several trials have demonstrated that pregabalin is superior to gabapentin, significantly reducing both pain and sleep disturbance in patients with PHN than gabapentin.10,11,12 However, pregabalin is associated with systemic and prominent central nervous system (CNS) toxic effects such as somnolence, dizziness, dry mouth, and blurred vision.10,13 Another calcium channel blocker, mirogabalin, has proven effective and safe for patients with NPN.14,15,16 Mirogabalin was developed by Daiichi Sankyo and approved in Japan for the treatment of peripheral NPN,17 but it is yet to be approved in China. There is still an unmet need for novel calcium channel blockers with greater efficacy and less prominent neurotoxic effects for PHN treatment in China.
Crisugabalin (HSK16149), an α2δ-1 ligand, is a novel highly selective oral γ-aminobutyric acid (GABA) analogue (HAISCO Pharmaceutical Group). Similar to pregabalin, crisugabalin binding to α2δ-1 depresses Ca2+ influx in the CNS, consequently lessening the release of excitatory neurotransmitters. It exhibited higher binding affinities for α2δ-1 than pregabalin (half-maximal inhibitory concentration = 4.0 nm vs 92.0 nm). Crisugabalin demonstrated analgesic activities in animal NPN models and had a better therapeutic index than pregabalin.18 Notably, the brain tissue exposure level of crisugabalin was 18-fold lower than that of pregabalin, indicating a more benign neurotoxicity profile. Crisugabalin was well tolerated in healthy participants19 and in a randomized clinical trial, crisugabalin, 40 mg/d, and crisugabalin, 80 mg/d, significantly reduced the average daily pain score (ADPS) at week 13 vs placebo in Chinese patients with diabetic peripheral NPN, with most treatment-emergent adverse events (TEAEs) being mild to moderate, suggesting that crisugabalin could provide an effective and safe option for NPN management.20 In this trial, we investigated the efficacy and safety of crisugabalin in Chinese patients with PHN.
Methods
Trial Design and Participants
This randomized clinical trial, conducted at 48 sites across China, had 2 parts. Part 1 was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study with a 2-week screening period, a 7-day run-in period, and a 12-week double-blind treatment period. Patients who did not experience any serious toxic effects in part 1 entered the 14-week open-label extension phase (part 2, Figure 1). Investigators, statisticians, trial clinicians, and patients were blinded to assignments.
Figure 1. Study Design and Patient Disposition Flow Chart.
AE indicates adverse event.
The study was approved by the ethics committees of participating centers and adhered to the Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent was obtained from all patients. This article followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The trial protocol is provided in Supplement 1.
Eligible patients (≥18 years) had PHN, defined as persistent NPN more than 1 month after the disappearance of acute herpetic rash. They had an average pain score of at least 40 mm on the visual analog scale (VAS) of the Short-Form McGill Pain Questionnaire (SF-MPQ) at screening and randomization and ADPS of at least 4 on the 11-point Numeric Pain Rating Scale (NPRS) over the preceding week. Key exclusion criteria were peripheral neuropathy or pain unrelated to PHN or any other conditions that could confound assessment and previous use of pregabalin (≥300 mg/d) or gabapentin (≥1200 mg/d) with lack of effect.21 We excluded these patients who did not respond to treatment because they may derive less benefit from crisugabalin, an exclusion previously used in a Japanese study of mirogabalin for PNH.22 The eligibility criteria are described in Supplement 1.
Study Procedures
During part 1, patients received 2 placebo capsules twice daily for 1 week in the run-in period to obtain the baseline ADPS averaged over 7 days. The randomization schedule was generated using an Interactive Response Technology–derived random-number sequence with stratification by baseline ADPS of less than 6 or 6 or more. Patients were randomized 1:1:1 to receive crisugabalin, 20 mg twice daily (ie, 40 mg/d), and crisugabalin, 40 mg (ie, 80 mg/d), twice daily, or placebo for 12 weeks. During part 2, patients received crisugabalin 40 mg twice daily. The dose was adjusted within the 40 mg/d to 80 mg/d range at the investigators' discretion.
No other analgesic medications were permitted. Except for the run-in period and the final week of part 1, rescue medication paracetamol was allowed for intolerable pain and co-dydramol was prescribed if intolerable pain persisted despite paracetamol for 5 days.
Assessments
To reliably measure patients’ experiences with pain and sleep, we assessed ADPS and the Average Daily Sleep Interference Scale (ADSIS) scores weekly during part 1. SF-MPQ, a self-administered pain questionnaire with validation in Chinese,23 was evaluated throughout the study. The VAS for overall health status in the EuroQol Group’s EQ-5D-5L was used to assess the HR-QoL burden of disease and the effectiveness of treatment as perceived by patients in part 1 and 2.24
Safety was monitored throughout the study and up to 1 week after the final dose and AEs were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Assessments included the frequency and severity of TEAEs and treatment-related AEs (TRAEs). All AEs were described in terms of current Medical Dictionary for Regulatory Activities (MedDRA, version 24.0) system organ class, preferred term, and CTCAE grade.
Main Outcomes and Measures
The primary efficacy end point was the change from baseline in ADPS at week 12. Secondary efficacy end points included the responder rate, defined as the proportion of patients who experienced at least 30% and at least 50% reduction in ADPS at week 12, representing a clinically important difference in pain and the highest level of clinical improvement in pain, respectively, weekly change in ADPS,25,26 change in SF-MPQ VAS scores at week 12, change in SF-MPQ Pain Rating Index (PRI) and Present Pain Intensity (PPI) scores at weeks 12 and 26, and ADSIS and HR-QoL scores at week 12.
Statistical Analysis
Based on the literature,11,12,14,26 at least 276 patients (92 per group) were required to provide the trial with 80% or more statistical power to detect a clinically meaningful intergroup difference of 1 and a common SD of 2.4 in change from baseline in ADPS at week 12. Assuming a 20% dropout rate, a sample size of 345 patients (115 per group) was required.
The study followed the intention-to-treat principle. The full analysis set (FAS) included all patients who received at least 1 dose of the study drug and had 1 or more postbaseline efficacy evaluations. The primary efficacy end point was analyzed using an analysis of covariance (ANCOVA) model with baseline ADPS as a covariate and sites and treatment as fixed effects. Possible biased estimates with single imputation with last observation carried forward were addressed by handling missing data by multiple imputations. The least squares mean (LSM), along with standard error (SE) for each group, and the LSM differences between groups, along with multiplicity-adjusted 2-sided 95% CIs, were calculated. Superiority for crisugabalin was established if the upper limit of the 2-sided 95% CIs was less than 0. A serial gatekeeping procedure was used to adjust for multiplicity of comparisons between groups.27 Responder rates were compared using a logistic regression model with baseline ADPS as a covariate and sites and treatment as fixed effects. The odds ratio (OR) and 95% CI were calculated. The weekly change from baseline in ADPS was analyzed using the mixed model of repeated measures method with sites and treatment as fixed effects, baseline ADPS as a covariate, and participants as random effects. The mixed model of repeated measures method used an unstructured time and covariance structure and was performed on the basis of the restricted maximum likelihood approach. Other secondary efficacy measures were analyzed using an ANCOVA model with baseline variable as a covariate. No data imputation was done for secondary efficacy measures. The safety set included all patients who had received at least 1 dose of the study medications and had postbaseline safety records. Statistical analysis was undertaken using SAS statistical software, version 9.4 (SAS Institute). A statistically significant difference was set at a 2-sided α level of .05.
Results
Patient Characteristics
Between November 9, 2021, and January 5, 2023, of 480 screened patients, 382 were eligible and 372 underwent randomization (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%]). After 3 patients who were not treated after randomization and 3 without postbaseline efficacy evaluation were excluded, the FAS included 121 patients in each crisugabalin group and 124 in the placebo group (Figure 1). Patient characteristics were well balanced between treatment groups including SF-MPQ, ADPS, ADSIS, and EQ-5D-5L VAS scores (Table 1).
Table 1. Demographic and Baseline Characteristics of Study Participants.
| Characteristic | No. (%) | |||
|---|---|---|---|---|
| Placebo (n = 124) | Crisugabalin, 40 mg/d (n = 121) | Crisugabalin, 80 mg/d (n = 121) | All (N = 366) | |
| Age, y | ||||
| Mean (SD) | 59.6 (13.0) | 61.2 (11.2) | 60.6 (11.7) | 60.5 (12.0) |
| Median (IQR) | 64.0 (53.0-69.0) | 63.0 (56.0-70.0) | 63.0 (58.0-68.0) | 63.0 (56.0-69.0) |
| Sex | ||||
| Female | 59 (47.6) | 58 (47.9) | 56 (46.3) | 173 (47.3) |
| Male | 65 (52.4) | 63 (52.1) | 65 (53.7) | 193 (52.7) |
| Ethnicity | ||||
| Han Chinese | 117 (94.4) | 116 (95.9) | 117 (96.7) | 350 (95.6) |
| Other | 7 (5.6) | 5 (4.1) | 4 (3.3) | 16 (4.4) |
| Weight, mean (SD), kg | 66.3 (10.7) | 65.9 (12.4) | 69.1 (12.7) | 67.1 (12.0) |
| Duration of PHN symptoms, moa | ||||
| Median (IQR) | 4.5 (2.5-13.7) | 6.1 (2.5-16.5) | 5.1 (2.9-16.3) | 5.1 (2.6-15.6) |
| ADPS, mean (SD)b | 6.1 (1.2) | 6.0 (1.1) | 6.0 (1.2) | NA |
| SF-MPQ VAS, mean (SD)c | 62.9 (12.8) | 62.4 (11.2) | 61.8 (12.8) | NA |
| SF-MPQ PPI, mean (SD)d | 2.4 (0.9) | 2.4 (0.9) | 2.5 (1.0) | NA |
| Average DSIS, mean (SD)e | 5.5 (1.6) | 5.3 (1.5) | 5.2 (1.8) | NA |
| EQ-5D VAS, mean (SD)f | 65.5 (15.9) | 67.8 (15.3) | 65.3 (14.7) | NA |
| Concomitant medications | ||||
| Thiamine | 13 (10.5) | 18 (14.9) | 16 (13.2) | 47 (12.8) |
| Acetylsalicylic acid | 9 (7.3) | 14 (11.6) | 6 (5.0) | 29 (7.9) |
| Biguanides | 12 (9.7) | 10 (8.3) | 9 (7.4) | 31 (8.5) |
| Angiotensin receptor blockers | 8 (6.5) | 9 (7.4) | 12 (9.9) | 29 (7.9) |
Abbreviations: ADPS, average daily pain score; DSIS, Daily Sleep Interference Scale; EQ-5D, EuroQol Group 5-Dimension questionnaire; FAS, full analysis set; NA, not applicable; PHN, postherpetic neuralgia; PPI, Present Pain Intensity; SF-MPQ, Short-Form McGill Pain Questionnaire; VAS, visual analog scale.
Calculated from the date of onset of neuropathic pain to the date of treatment initiation.
ADPS: 0 represents no pain and 10 indicates worst possible pain.
SF-MPQ VAS (range, 0-100) measures pain intensity during the past 24 hours.
SF-MPQ PPI (range, 0-5) measures pain intensity at assessment.
DSIS: 0 represents pain not interfering with sleep and 10 represents pain completely interfering with sleep over the last 24 hours.
EuroQol Group’s EQ-5D VAS: 0 indicates “the worst health you can imagine” and 100 represents “the best health you can imagine.”
The median (IQR) duration of exposure was 84 (83.0-85.0) days in part 1 and 98.0 days (95.0-103.0) in part 2, with a relative dose intensity of 100% (eTable 1 in Supplement 3). The geometric mean serum crisugabalin concentration remained steady from week 4 to 12 (eFigure 1 in Supplement 3). The proportions of patients who consumed paracetamol and co-dydramol were comparable among the 3 groups (eTable 2 in Supplement 3).
Efficacy Outcomes
In the FAS, the ADPS of both crisugabalin groups was significantly lower than that of the placebo group from week 1 through week 12 (Figure 2). At week 12, the LSM (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 LSM difference of −1.1 (95% CI −1.6 to −0.7; ANCOVA, P < .001) and −1.5 (95% CI −2.0 to −1.0; ANCOVA, P < .001) vs the placebo, respectively (Figure 2). The upper limit of the 2-sided 95% CIs was less than 0 for both crisugabalin groups, establishing superiority for crisugabalin, 40 mg/d, and crisugabalin, 80 mg/d, over the placebo. Crisugabalin conferred significant ADPS reduction vs placebo regardless of baseline ADPS (<6 or ≥6) (Figure 2).
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.
At week 12, significantly more patients receiving crisugabalin, 40 mg/d, (61.2% [95% CI, 91.9%-69.9%]) or crisugabalin, 80 mg/d, (54.5% [95% CI, 45.2%-63.6%]) attained at least 30% reduction in ADPS vs placebo (35.5% [95% CI, 27.1%-44.6%]; P < .001). The proportion of patients with at least 50% reduction in ADPS was significantly higher with crisugabalin, 40 mg/d, (37.2% [95% CI, 28.2%-46.4%]) or crisugabalin, 80 mg/d (38.0% [95% CI, 29.3%-47.3%]) vs placebo (20.2% [95% CI, 13.5%-28.3%]; crisugabalin, 40 mg/d: P = .002; crisugabalin, 80 mg/d: P < .001; Figure 2). Patients receiving crisugabalin, 40 mg/d, or crisugabalin, 80 mg/d, were approximately 3-fold more likely to experience at least 30% reduction (40 mg/d: OR, 3.58 [95% CI, 1.90-6.76]; 80 mg/d: OR, 2.93 [95% CI, 1.58-5.44]) or 50% reduction in ADPS vs placebo (40 mg/d: OR, 3.03 [95% CI, 1.50-6.13]; 80 mg/d: OR, 3.84 [95% CI, 1.88-7.87]).
The SF-MPQ VAS scores gradually decreased with crisugabalin and diverged from placebo from week 4 (eFigure 2 in Supplement 3). The LSM change from baseline at week 12 was significantly greater with crisugabalin vs placebo (Figure 3). The SF-MPQ VAS scores further declined from week 12 through week 26 among 264 patients who entered part 2 (eFigure 2 in Supplement 3).
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.
The SF-MPQ PPI scores decreased from baseline through week 12 in the crisugabalin groups, with a significantly greater reduction at week 12 in both the 40-mg and 80-mg crisugabalin groups vs the placebo group (LSM [SE], −1.0 [0.1] and −1.2 [0.1] vs −0.5 [0.1], respectively; P < .001 for both intervention groups) (eFigure 2 in Supplement 3; Figure 3). Improvements occurred in all 3 subscales of SF-MPQ PRI at week 12 in both crisugabalin groups vs the placebo group (Figure 3; eFigure 2 and eTable 3 in Supplement 3). The LSM (SE) change of SF-MPQ PRI score from the baseline for the sensory score was −5.2 (0.5) and −6.2 (0.5) vs −2.5 (0.5) in the 40-mg (P < .001) and 80-mg (P < .001) vs placebo groups, respectively; for the affective score, −2.5 (0.2) and −2.5 (0.2) vs −1.2 (0.2) in the 40-mg (P < .001) and 80-mg (P < .001) vs placebo groups, respectively; and for total scores, −7.7 (0.6), −8.8 (0.7), and −3.6 (0.6) in the 40-mg (P < .001) and 80-mg (P < .001) vs placebo groups, respectively.
The ADSIS scores steadily declined from baseline through week 12 in the crisugabalin groups and diverged from the placebo group at week 1 (eFigure 2 in Supplement 3). At week 12, the ADSIS scores were significantly lower than baseline in the crisugabalin groups, with an LSM (SD) difference of −2.3 (0.2) and −2.9 (0.2) with crisugabalin, 40 mg/d, and crisugabalin, 80 mg/d, respectively (Figure 2). At week 26, the SF-MPQ PPI and PRI scores were significantly lower than baseline, with a mean (SD) difference of −1.3 (1.0; P < .001) and −9.7 (8.2; P < .001), respectively (Figure 3).
HR-QoL Changes
The EQ-5D-5L VAS was comparable among the 3 groups at week 12 (eTable 4 in Supplement 3). Crisugabalin significantly improved each EQ-5D-5L dimension, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, vs placebo (eFigure 3 in Supplement 3).
Safety
The safety set included 369 patients from part 1 and 264 from part 2. Any-grade TEAEs occurred in 65.0% (95% CI, 55.9%-73.4%) of the patients receiving crisugabalin, 40 mg/d, and 76.2% (95% CI, 67.7%-83.5%) of those receiving crisugabalin, 80 mg/d, vs 63.7% (95% CI, 54.6%-72.2%) of those receiving placebo during part 1 (Table 2). Serious TEAEs occurred in 4 patients in each group. TEAEs led to treatment discontinuation in 1 patient (0.8% [95% CI, 0.0%-4.4%]) receiving placebo; 3 patients (2.4% [95% CI, 0.5%-7.0%]) receiving crisugabalin, 40 mg/d; and 2 patients (1.6% [95% CI, 0.2%-5.8%]) receiving crisugabalin, 80 mg/d.
Table 2. Safety Profile During the Randomized Treatment Period.
| Adverse eventa | No. (%) [95% CI] | |||||
|---|---|---|---|---|---|---|
| Placebo (n = 124) | Crisugabalin, 40 mg/d (n = 123) | Crisugabalin, 80 mg/d (n = 122) | ||||
| Any grade | Grade ≥3 | Any grade | Grade ≥3 | Any grade | Grade ≥3 | |
| TEAEs | 79 (63.7) [54.6-72.2] | 8 (6.5) [2.8-12.3] | 80 (65.0) [55.9-73.4] | 7 (5.7) [2.3-11.4) | 93 (76.2) [67.7-83.5) | 7 (5.7) [2.3-11.5) |
| TEAEs leading to dose interruptions | 2 (1.6) [0.2-5.7] | 1 (0.8) [0.0-4.5] | 2 (1.6) [0.2-5.8] | |||
| TEAEs leading to treatment discontinuations | 1 (0.8) [0.0-4.4] | 3 (2.4) [0.5-7.0] | 2 (1.6) [0.2-5.8] | |||
| TEAEs leading to study terminations | 1 (0.8) [0.0-4.4] | 2 (1.6) [0.2-5.8] | 2 (1.6) [0.2-5.8] | |||
| TEAEs leading to death | 0 | 0 | 0 | |||
| Serious TEAEs | 4 (3.2) [0.9-8.1] | 4 (3.3) [0.9-8.1] | 4 (3.3) [0.9-8.2] | |||
| TEAEs (≥5%)b | ||||||
| Hyperuricemia | 12 (9.7) | NA | 16 (13.0) | NA | 14 (11.5) | NA |
| Hyperlipidemia | 12 (9.7) | 2 (1.6) | 6 (4.9) | 1 (0.8) | 9 (7.4) | 0 |
| Urinary tract infection | 7 (5.6) | NA | 7 (5.7) | NA | 6 (4.9) | NA |
| Hypertriglyceridemia | 5 (4.0) | 1 (0.8) | 5 (4.1) | 0 | 7 (5.7) | 1 (0.8) |
| Dizziness | 5 (4.0) | NA | 7 (5.7) | NA | 30 (24.6) | NA |
| Body weight increased | 4 (3.2) | NA | 8 (6.5) | NA | 15 (12.3) | NA |
| Hepatic function abnormalities | 2 (1.6) | NA | 6 (4.9) | NA | 7 (5.7) | NA |
| Somnolence | 0 | NA | 4 (3.3) | NA | 12 (9.8) | NA |
| Hypertension | 1 (0.8) | 0 | 2 (1.6) | 1 (0.8) | 2 (1.6) | 1 (0.8) |
| Atrial fibrillation | NA | 1 (0.8) | NA | 1 (0.8) | NA | 0 |
Abbreviations: NA, not applicable; TEAE, treatment-emergent adverse event.
Adverse events were coded by the Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 or later.
TEAEs occurring in over 5% of patients in any of the 3 groups during the randomized treatment period are listed.
Any-grade TRAEs occurred in 32.5% (95% CI, 24.4%-41.4%) of the patients receiving crisugabalin, 40 mg/d, and 53.3% (95% CI, 44.0%-62.4%) of those receiving crisugabalin, 80 mg/d, vs 29.0% (95% CI, 21.2%-37.9%) of those receiving placebo. Serious TRAE occurred in 1 patient receiving crisugabalin, 40 mg/d, (eTable 5 in Supplement 3).
The safety profile during part 2 is summarized in eTable 6 in Supplement 3. Any-grade TEAEs occurred in 68.9% (95% CI, 63.0%-74.5%) of the patients. Serious TEAEs occurred in 14 patients (5.3%). TEAEs led to treatment discontinuation in 4 patients (1.5% [95% CI, 0.4%-3.8%]). Any-grade TRAEs occurred in 40.9% (95% CI, 34.9%-47.1%) of the patients. No serious TRAE occurred. No death due to TEAEs occurred during the study.
Discussion
This randomized clinical trial demonstrated that crisugabalin was superior to placebo in alleviating PHN in Chinese patients. Crisugabalin was safe, well tolerated, and effectively reduced ADPS at both doses tested (40 mg/d and 80 mg/d). Furthermore, benefits based on secondary measures were maintained in the open-label extension with no new safety concerns.
Reduced pain intensity is an important indicator of the effectiveness of PHN treatment. Crisugabalin, 40 mg/d, and crisugabalin, 80 mg/d, significantly reduced pain in patients with PHN, with a more significant reduction in ADPS at week 12 with crisugabalin, 80 mg/d, than crisugabalin, 40 mg/d. A significant reduction in pain intensity was demonstrated as early as week 1. This early activity was also observed with pregabalin.11,28 A divergence from placebo in ADPS was also observed with mirogabalin at week 1 in Japanese patients with PHN.14 The responder rate (≥30% reduction in ADPS) was 52.3% for pregabalin vs 30.6% for placebo and 49.7% for mirogabalin 30 mg/d vs 35.0% for placebo. This rate was 61.2% for crisugabalin, 40 mg/d, and 54.5% for crisugabalin, 80 mg/d, (placebo, 35.5%). The findings are consistent with other calcium channel modulators in the primary efficacy measure. However, extreme caution should be exercised as trials cannot be compared given different populations and trial designs across trials.
To minimize the bias of subjective pain evaluation, we evaluated pain intensity using different pain scales to corroborate and support the findings of the primary efficacy measure. Crisugabalin significantly reduced SF-MPQ VAS scores at weeks 12 and 26. Furthermore, crisugabalin remarkably improved all 3 subscales of SF-MPQ PRI, a quantitative measure of the patient’s subjective experience of pain,29,30 at weeks 12 and 26, indicating that crisugabalin not only reduces pain intensity but also modulates the perception of pain.
Sleep disturbance, a frequent comorbidity of PHN, aggravates and is also aggravated by pain outcomes. Crisugabalin significantly improved sleep function, with notable reductions in ADSIS at week 12. In addition, HR-QoL measures are becoming increasingly important for evaluating the benefit of therapeutic interventions in NPN. In this randomized clinical trial, crisugabalin at both dosing levels led to broad and significant improvement across the 5 dimensions in EQ-5D-5L, indicating improved overall health status of the patients. EQ-5D-5L represents patients’ perspectives on the effectiveness of treatment and overall health status, while ADPS and ADSIS measure specific health issues like pain intensity and sleep interference.
Crisugabalin had an overall acceptable safety profile and was well tolerated. Treatment discontinuations due to TEAEs were infrequent (2.4% with crisugabalin, 40 mg/d, and 1.6% with crisugabalin, 80 mg/d). Dizziness was the most common AE (24.3%) of pregabalin 300 mg/d in a randomized clinical trial of Chinese patients with PHN.28 The proportion of patients receiving crisugabalin, 80 mg/d, who experienced dizziness (24.6%) is comparable to that of pregabalin. The rate is lower in patients receiving crisugabalin, 40 mg/d (5.7%). In addition, treatment-related CNS toxic effects including somnolence, dizziness, dry mouth, and blurred vision occurred in 3.3%, 4.1%, 1.6%, and less than 1% with crisugabalin, 40 mg/d, and 9.8%, 23.8%, 3.3%, and less than 1% with crisugabalin, 80 mg/d, respectively. Notably, crisugabalin was used without dose titration. This convenience in dosing and the efficacy of crisugabalin, 40 mg/d, allows rapid administration and dose adjustment.
Limitations
This randomized clinical trial lacks an active comparator arm and does not reflect the standard of care in the US or Europe where an oral tricyclic antidepressant, pregabalin, and the lidocaine, 5%, patch are recommended as first-line therapies. Caution should be exercised to interpret how these results would guide the standard of care. It also remains to be investigated whether these findings are applicable to the global population given that the current study population is limited to Chinese patients. Future trials that include patient populations of different countries or ethnicities and with head-to-head comparators for crisugabalin in monotherapy or combination therapy are required to provide robust evidence for the role of crisugabalin in the global management of NPN. This trial also excluded patients who did not respond to prior treatment with pregabalin (≥300 mg/d) or gabapentin (≥1200 mg/d). Therefore, the benefit observed with crisugabalin for PHN may not apply to this subset of patients. Furthermore, the study only provided short-term (26 weeks) efficacy and safety data of crisugabalin. An open-label, single-arm study of the long-term (52 weeks) safety and efficacy of crisugabalin for peripheral NPN was completed and the results are to be reported.31 The results of the phase 2/3 trial on diabetic peripheral NPN will also be available soon.32 The findings from these trials are expected to provide greater granularity in guiding the management of NPN with crisugabalin.
Conclusions
Crisugabalin, 40 mg/d, or crisugabalin, 80 mg/d, was well tolerated and significantly improved ADPS compared to placebo. No new safety concerns emerged with crisugabalin. Taken together, crisugabalin can be flexibly selected depending on individual patient response and tolerability at 40 mg/d or 80 mg/d.
Trial Protocol
Statistical Analysis Plan
eTable 1. Drug exposure characteristics of the study population
eTable 2. Use of Rescue Medications During the Study
eTable 3. Changes from baseline in Short-Form McGill Pain Questionnaire (SF-MPQ) Scores at Week 12
eTable 4. Changes From Baseline in EQ-5D VAS at Week 12
eTable 5. Treatment-Related Adverse Events Occurring in More Than 1% of Patients During the Randomized Treatment Period
eTable 6. Safety Profile of the Study Patients During the Extension Period
eFigure 1. Plasma Concentrations of Crisugabalin Over Time After Multiple Doses of Crisugabalin at 40 mg/d or 80 mg/d
eFigure 2. Average SF-MPQ VAS Scores Shown as the Time Course of the LSM With SE
eFigure 3. EQ-5D-5L Domain Responses
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
Statistical Analysis Plan
eTable 1. Drug exposure characteristics of the study population
eTable 2. Use of Rescue Medications During the Study
eTable 3. Changes from baseline in Short-Form McGill Pain Questionnaire (SF-MPQ) Scores at Week 12
eTable 4. Changes From Baseline in EQ-5D VAS at Week 12
eTable 5. Treatment-Related Adverse Events Occurring in More Than 1% of Patients During the Randomized Treatment Period
eTable 6. Safety Profile of the Study Patients During the Extension Period
eFigure 1. Plasma Concentrations of Crisugabalin Over Time After Multiple Doses of Crisugabalin at 40 mg/d or 80 mg/d
eFigure 2. Average SF-MPQ VAS Scores Shown as the Time Course of the LSM With SE
eFigure 3. EQ-5D-5L Domain Responses
Data Sharing Statement