Efficacy and safety of iclepertin for cognitive impairment associated with schizophrenia (CONNEX programme): results from three phase 3 randomised controlled trials.

BACKGROUND: There are no pharmacotherapies available for cognitive impairment associated with schizophrenia (CIAS). The CONNEX programme investigated the efficacy and safety of iclepertin, a glycine transporter-1 (GlyT1) inhibitor, for the treatment of CIAS. METHODS: CONNEX-1, CONNEX-2, and CONNEX-3 were phase 3, randomised, double-blind, placebo-controlled trials conducted across 338 specialist psychiatric centres in 41 countries. Adults aged 18-50 years with schizophrenia were randomised 1:1 using interactive response technology to oral 10 mg iclepertin or placebo once daily for 26 weeks in combination with standard-of-care antipsychotic therapy. Patients, investigators, and trial personnel were masked to treatment assignment. The primary endpoint was change from baseline at week 26 in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) overall composite T-score. Efficacy analyses included randomly allocated patients, excluding those allocated in error or who discontinued from the trial before receiving treatment. Safety and tolerability assessments included adverse event monitoring in patients who received one or more doses of trial medication. These trials were registered with ClinicalTrials.gov (NCT04846868, NCT04846881, NCT04860830) and are complete. Individuals with lived experience informed the trial designs and selection of outcome measures; they were not involved in the writing process. FINDINGS: Between Sept 8, 2021, and April 24, 2024, 1835 patients were recruited and received at least one dose of trial medication (918 for iclepertin and 917 for placebo); 1602 patients completed treatment. 1207 (66%) of 1836 patients were male and 629 (34%) patients were female. Most patients were either White (903 [49%]) or Asian (558 [30%]), and the majority were not of Hispanic or Latino ethnicity (1238 [67%]). The mean age was 34·7 years (SD 8·8). At week 26, there was no significant difference between treatment groups in the primary endpoint. The adjusted mean difference for iclepertin versus placebo for MCCB overall composite T-score was 0·127 [95% CI -0·396 to 0·650]; p=0·63). On-treatment adverse events were reported in 604 (66%) of 918 and 633 (69%) of 917 patients in the iclepertin and placebo groups, respectively. One patient receiving placebo died during the treatment period; the death was deemed unrelated to the trial treatment. INTERPRETATION: Iclepertin was not associated with significant improvements in cognition in adults with schizophrenia, but it was well tolerated by patients. Findings from CONNEX provide insights into the challenges associated with studying new pharmacotherapies for CIAS. FUNDING: Boehringer Ingelheim.

Duke Scholars

Author Richard S.E. Keefe Psychiatry & Behavioral Sciences, Behavioral Medicine & Neur ...