Xanomeline and Trospium Chloride Versus Placebo for the Treatment of Schizophrenia: A Post Hoc Analysis of Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed.

Purpose: Describe xanomeline and trospium chloride efficacy and safety/tolerability for the treatment of schizophrenia using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). Methods: Categorical data were extracted from the three 5-week, randomized, double blind, placebo controlled EMERGENT-1, EMERGENT-2, and EMERGENT-3 clinical trials of xanomeline/trospium in adults with schizophrenia experiencing acute psychosis. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), and categorical response criteria. Safety and tolerability were assessed using rates of discontinuation and treatment-emergent adverse events (TEAEs). NNT, NNH, and LHH values were calculated for each individual study as well as pooled. Results: In data from the acute EMERGENT trials, NNT estimates were significant for xanomeline/trospium vs placebo for the pre-specified treatment response threshold of ≥30% reduction from baseline in PANSS total score at Week 5 (NNT=5 [95% CI, 4-8]). NNT estimates for response thresholds of ≥20% and ≥40% reduction from baseline in PANSS total score and ≥1- and ≥2-point decrease from baseline in CGI-S score were <10, indicating a clinically relevant therapeutic benefit of xanomeline/trospium over placebo. Estimates of NNH vs placebo for the most common TEAEs were >10, with the exception of nausea and vomiting; however, rates of discontinuations due to TEAEs of nausea, dyspepsia, or vomiting were low (NNH=49 [95% CI, 28-182]). LHH indicated an overall benefit of xanomeline/trospium vs placebo for all assessed outcomes. In indirect comparisons based on published data from trials of available antipsychotics approved for schizophrenia, xanomeline/trospium exhibited comparable or more robust NNT estimates vs placebo and was the least likely agent to be associated with weight gain or somnolence/sedation. Conclusion: In the 5-week EMERGENT clinical trials, NNT, NNH, and LHH assessments demonstrated a favorable benefit-risk profile for xanomeline/trospium. Trial Registration: ClinicalTrials.gov identifiers: NCT03697252, NCT04659161, NCT04738123.