Discussion
NPS, chronic CRPS, hyperalgesia, CRPS, pain, coronavirus disease 2019
DISEASE, CORONAVIRUS DISEASE 2019, RECRUITMENT, IMMUNE DISORDER
In this proof-of-concept phase 2a study, soticlestat, a CH24H inhibitor, was investigated as adjunctive therapy in participants with chronic CRPS. The study did not show significance for its primary endpoint, with no statistically significant difference in mean 24-hour pain intensity NPS score between soticlestat and placebo groups observed after 15 weeks of treatment. Similar rates of TEAEs were reported in the soticlestat and placebo groups, and most were mild or moderate.Small improvements were noted in some PROMIS-29 domains at week 15 in both the soticlestat and placebo groups, with several T-score improvements at week 29 falling within the minimal important change range of 2–6 T-score points proposed for PROMIS-29 measures when evaluating non-surgical interventions [Sustained reductions in plasma 24HC levels were seen in participants receiving soticlestat, whereas 24HC levels in participants receiving placebo remained similar to baseline values. This indicates that participants adhered to treatment and supports the use of 24HC as a biomarker for soticlestat activity. Decreases in plasma 24HC levels observed in the present study were similar to those seen in other soticlestat clinical studies [CRPS is a multi-factorial condition with many mechanisms that may change the course of the disease [The NMDA receptor antagonist ketamine may provide clinically effective short-term pain relief in CRPS [Overall, the safety findings of soticlestat treatment in this study were consistent with those from previous clinical studies [Study strengths include the use of the Budapest Criteria, which is recognized as the international standard for CRPS diagnosis [A key limitation of this study is its small sample size, which limited the statistical analyses. Although the number of participants specified in the protocol were recruited, the drop-out rate was higher than expected and further recruitment was affected by the coronavirus disease 2019 (COVID-19) pandemic. Furthermore, the study size was planned to achieve at least 65% power, which may have been too low to detect a true effect. Inferential statistical analyses were only undertaken for outcomes predefined in the protocol and as per the power calculation for the study. Additionally, despite randomization, there was an imbalance in key factors between treatment arms at baseline. Relative to the placebo group, the soticlestat group had experienced a longer mean time since injury, symptom onset, and diagnosis. They also had more nervous system and immune disorders than the placebo group. Furthermore, participants in the soticlestat group were more likely to be taking opioid medication than participants in the placebo group. Given the possibility of opioid-induced hyperalgesia [In conclusion, soticlestat as adjunctive therapy did not reduce pain intensity in participants with chronic CRPS. Small improvements during Part A of the study in both the treatment and placebo groups were maintained or further improved upon following extended treatment with soticlestat. Overall, however, the small sample size and the imbalance between treatment groups limited the interpretation of the findings from this study.