Methods
ideation, diarrhea, Postoperative Nausea and Vomiting, salivary hypersecretion, excessive sweating, nausea, vomiting
SALIVARY HYPERSECRETION, ADVERSE EVENTS, DISEASE, EVENTS, SALIVATION
Healthy volunteers aged 18−60 years were enrolled in this 9-day, single-site, double-blind, placebo-controlled phase 1 trial. Subjects were required to be in good general health, able and willing to use an acceptable form of contraception if of childbearing potential, and able to give informed consent. Exclusion criteria included history or presence of clinically significant disease, history of alcohol or drug abuse, and history of suicidal ideation. Full inclusion and exclusion criteria are reported in Supplementary Information After a 21-day screening period, eligible subjects were randomized 1:1 to receive either KarXT or xanomeline alone. The dose of xanomeline was 75 mg given three times per day and the dose of trospium was 20 mg given twice per day. There was a 2-day lead-in period during which subjects received only placebo or trospium followed by 7 days of xanomeline in addition to either placebo or trospium. Safety was assessed using spontaneous reports of AEs including the five prespecified cholinergic AEs (nausea, vomiting, diarrhea, excessive sweating, and salivary hypersecretion). A treatment-emergent AE (TEAE) was defined as any AE that happened for the first time after dosing of study drug or existed before but worsened in severity or relationship to the study drug after dosing. AEs were summarized by system organ class and preferred term using the Medical Dictionary for Regulatory Activities (Version 19.0). The site investigator assessed AEs for severity and as being either related or unrelated to study drug.Vital signs, ECGs, and safety laboratory tests were also obtained. In addition, self-rated VAS for severity of the cholinergic AEs scored from 0 mm (none) to 100 mm (extreme) were administered three times per day for the 7-day active xanomeline treatment phase (total of 21 administrations). The mean weekly maximum composite VAS scores for nausea, vomiting, diarrhea, sweating, and excess salivation (considering all events together) for the 7-day treatment period were a priori determined to be used in the analysis. This variable was calculated by dividing the sum of the maximum VAS scores recorded for each cholinergic AE on each of Day 3 through Day 9 by the total number of maximum VAS scores recorded. Subjects who completed the 7-day active phase and remained in the study through Day 9 had a maximum of 35 VAS scores that contributed to this composite score (seven daily maximum scores for each of five cholinergic AEs). If a subject prematurely discontinued from the active phase prior to Day 9, then the mean weekly maximum composite VAS scores were calculated using the scores that were available. A full schedule of assessments in the study is reported in Supplementary Information The following scales were administered by clinicians: Postoperative Nausea and Vomiting Impact Scale (Myles and Wengritzky A key endpoint for this study was mean weekly maximum composite VAS score, which was calculated and compared between treatment arms (KarXT vs xanomeline alone). Supportive analyses included the mean weekly maximum individual VAS scores for each of the five cholinergic adverse events. In addition, clinician-administered scale scores were compared between groups. The incidence and percentage difference in rate of cholinergic TEAEs for the KarXT group compared with xanomeline alone was included as a post hoc analysis. The “evaluable” population was used to assess the key and supportive endpoints and consisted of all subjects who received at least one dose of xanomeline and at least one post-randomization VAS rating starting from the day of randomization. Assuming that the mean difference between treatment groups for the key endpoint (mean weekly maximum composite VAS score) would be 15 mm on the VAS (standard deviation for the difference: 20 mm), a sample size of 60 subjects (30 subjects/treatment arm) was estimated to provide approximately 81% power to detect a significant difference between treatment arms using a two-sided significance level of 5%. Statistical testing was based on a two-sample t-test (continuous variables), a chi-squared test (categorical variables), or a Fisher's exact test (small sample sizes) and not adjusted for multiplicity for baseline demographic and characteristic data. All other data regarding safety and AEs were summarized descriptively for each treatment arm using the evaluable population.PK parameters were summarized by treatment arm and study day (with standard noncompartmental methods) using the PK population, which included subjects who had at least one measurable post-dose PK concentration of xanomeline or trospium.The study was conducted in accordance with the Declaration of Helsinki, applicable laws and regulations, and Good Clinical Practice Guidelines. The protocol and informed consent document were approved by an institutional review board (Schulman Institutional Review Board, Cincinnati, Ohio) prior to study initiation. All subjects provided written informed consent prior to the initiation of any study procedures.