Trial Outcomes & Findings for Clinical Trial of Iclepertin Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-2) (NCT NCT04846881)

Last Updated: 2025-12-12

Results Overview

The change from baseline in MCCB (MATRICS Consensus Cognitive Battery) overall composite T-score at Week 26 is reported. This was analyzed using a mixed-effects model for repeated measurements (MMRM) comparing the change from baseline in MCCB overall composite T-score at Week 26 between iclepertin 10 mg daily and placebo. The MCCB comprises 10 tests to measure cognitive performance in 7 cognitive domains: speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. The composite T-score is derived from the 7 cognitive domain T-scores. The T-score is standardized to the normative population with a mean of 50 and standard deviation of 10. A higher MCCB overall composite T-score indicates better cognition.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

611 participants

Primary outcome timeframe

The MMRM model is a longitudinal analysis which incorporated values at screening, baseline and at Week 12 and Week 26. The data presented here represent the Least Squares Mean at Week 26.

Results posted on

2025-12-12

Participant Flow

This was a randomised, placebo-controlled, double-blind, multi-centre, multi-national, 26-week, parallel group trial, with a 4-week safety follow-up period. Participants had to complete the treatment and follow-up periods before they could enter the open label extension study.

All participants were screened for eligibility prior to participation in the trial. Participants attended a specialist site which ensured that they (the participants) strictly met all inclusion and none of the exclusion criteria. Participants were not to be allocated to a treatment sequence if any of the entry criteria were violated.

Participant milestones

Participant milestones
Measure	Iclepertin 10 mg This arm comprised participants who received 10 mg tablet of iclepertin orally once daily, with doses administered at least 24 hours (hrs) apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.	Placebo This arm comprised participants who received 10 mg tablet of iclepertin-matched Placebo orally once daily, with doses administered at least 24 hrs apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.
Overall Study STARTED	306	305
Overall Study Randomised to treatment	306	305
Overall Study Treated	305	305
Overall Study COMPLETED	267	267
Overall Study NOT COMPLETED	39	38

Reasons for withdrawal

Reasons for withdrawal
Measure	Iclepertin 10 mg This arm comprised participants who received 10 mg tablet of iclepertin orally once daily, with doses administered at least 24 hours (hrs) apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.	Placebo This arm comprised participants who received 10 mg tablet of iclepertin-matched Placebo orally once daily, with doses administered at least 24 hrs apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.
Overall Study Adverse Event	14	15
Overall Study Burden of study procedures	7	3
Overall Study Protocol deviation	6	4
Overall Study Perceived lack of efficacy	5	2
Overall Study Change of residence	2	0
Overall Study Technical problems	0	1
Overall Study Other than listed	3	10
Overall Study No reason available	1	3
Overall Study Patient randomised in error	1	0

Baseline Characteristics

Clinical Trial of Iclepertin Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-2)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Iclepertin 10 mg n=305 Participants This arm comprised participants who received 10 mg tablet of iclepertin orally once daily, with doses administered at least 24 hours (hrs) apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.	Placebo n=305 Participants This arm comprised participants who received 10 mg tablet of iclepertin-matched Placebo orally once daily, with doses administered at least 24 hrs apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.	Total n=610 Participants Total of all reporting groups
Age, Continuous	36.6 Years STANDARD_DEVIATION 8.5 • n=26 Participants	35.5 Years STANDARD_DEVIATION 8.5 • n=24 Participants	36.1 Years STANDARD_DEVIATION 8.5 • n=50 Participants
Sex: Female, Male Female	101 Participants n=26 Participants	93 Participants n=24 Participants	194 Participants n=50 Participants
Sex: Female, Male Male	204 Participants n=26 Participants	212 Participants n=24 Participants	416 Participants n=50 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	89 Participants n=26 Participants	78 Participants n=24 Participants	167 Participants n=50 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	199 Participants n=26 Participants	213 Participants n=24 Participants	412 Participants n=50 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	17 Participants n=26 Participants	14 Participants n=24 Participants	31 Participants n=50 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=26 Participants	1 Participants n=24 Participants	2 Participants n=50 Participants
Race (NIH/OMB) Asian	76 Participants n=26 Participants	69 Participants n=24 Participants	145 Participants n=50 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	3 Participants n=26 Participants	1 Participants n=24 Participants	4 Participants n=50 Participants
Race (NIH/OMB) Black or African American	41 Participants n=26 Participants	44 Participants n=24 Participants	85 Participants n=50 Participants
Race (NIH/OMB) White	166 Participants n=26 Participants	172 Participants n=24 Participants	338 Participants n=50 Participants
Race (NIH/OMB) More than one race	1 Participants n=26 Participants	4 Participants n=24 Participants	5 Participants n=50 Participants
Race (NIH/OMB) Unknown or Not Reported	17 Participants n=26 Participants	14 Participants n=24 Participants	31 Participants n=50 Participants

PRIMARY outcome

Timeframe: The MMRM model is a longitudinal analysis which incorporated values at screening, baseline and at Week 12 and Week 26. The data presented here represent the Least Squares Mean at Week 26.

Population: Randomized Set (RS): included all patients who signed informed consent and were randomized into the trial, regardless of whether a patient was treated with trial medication. Patients randomized in error and discontinued from the study before the start of trial medication were excluded from the RS. Patients in the RS were analyzed under the randomized trial medication.

Outcome measures

Outcome measures
Measure	Iclepertin 10 mg n=305 Participants This arm comprised participants who received 10 mg tablet of iclepertin orally once daily, with doses administered at least 24 hours (hrs) apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.	Placebo n=305 Participants This arm comprised participants who received 10 mg tablet of iclepertin-matched Placebo orally once daily, with doses administered at least 24 hrs apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.
Change From Baseline in the Overall Composite T-score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) After 26 Weeks of Treatment	2.719 T-score Standard Error 0.3377	1.997 T-score Standard Error 0.3345

SECONDARY outcome

Timeframe: The MMRM model is a longitudinal analysis which incorporated values at screening, baseline and at Week 12 and Week 26. The data presented here represent the Least Squares Mean at Week 26.

SCoRS is a 20-item interview-based assessment of cognitive deficits and the degree to which they affect day-to-day functioning. Each item is rated on a 4-point scale, ranging from "No impairment" to "Severe Impairment", with higher ratings reflecting a greater degree of impairment. The SCoRS rater integrates information from separate patient and study partner interviews to generate a total score. SCoRS total score is between 20 and 80 where higher score values represent greater degree of impairment in day-to-day functions due to cognitive deficits. The total score was the sum of the 20 item scores. If six or more of the 20 items were missing, the total score was not derived and treated as missing for that participant at the visit, otherwise, missing items were imputed with the mean of the observed items for the purpose of total score calculation.

Outcome measures

Outcome measures
Measure	Iclepertin 10 mg n=305 Participants This arm comprised participants who received 10 mg tablet of iclepertin orally once daily, with doses administered at least 24 hours (hrs) apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.	Placebo n=305 Participants This arm comprised participants who received 10 mg tablet of iclepertin-matched Placebo orally once daily, with doses administered at least 24 hrs apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.
Change From Baseline in SCoRS (Schizophrenia Cognition Rating Scale) Interviewer Total Score at Week 26	-5.053 Scores on a scale Standard Error 0.4268	-5.767 Scores on a scale Standard Error 0.4261

SECONDARY outcome

Timeframe: The MMRM model is a longitudinal analysis which incorporated values at screening, baseline and at Week 12 and Week 26. The data presented here represent the Least Squares Mean at Week 26.

The VRFCAT is a virtual reality shopping trip performed on a tablet. The task has several linked and sequential scenarios, including matching a recipe to the content of kitchen cabinets, preparing a shopping list, taking the correct bus, shopping efficiently, and catching the correct return bus. These tasks are performed in a fixed sequence. The tool records the total amount of time taken to complete the sequence of tasks, adjusting for number of errors and forced progressions. A T-score is generated from this adjusted total time. The lower the adjusted total time T-score, the better is the patient's functional capacity. The T-score has a mean of 50 and a standard deviation of 10 in the normative population.

Outcome measures

Outcome measures
Measure	Iclepertin 10 mg n=305 Participants This arm comprised participants who received 10 mg tablet of iclepertin orally once daily, with doses administered at least 24 hours (hrs) apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.	Placebo n=305 Participants This arm comprised participants who received 10 mg tablet of iclepertin-matched Placebo orally once daily, with doses administered at least 24 hrs apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.
Change From Baseline in VRFCAT (Virtual Reality Functional Capacity Assessment Tool) Adjusted Total Time T-score at Week 26	3.898 T-score Standard Error 0.7531	3.565 T-score Standard Error 0.7481

SECONDARY outcome

Timeframe: The MMRM model is a longitudinal analysis which incorporated values at screening, and at Week 15 and Week 24. The data presented here represent the Least Squares Mean at Week 24.

The Patient Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS) score evaluates how cognitive difficulties impact the daily life of individuals with schizophrenia. It is composed of 28 items on a 5-category Likert scale (1=not at all/not at all hard, 5=very much/very hard), and the total score was derived by calculating the average score of the first 26 items, where higher scores indicate a worse patient experience. The questionnaire takes 5-15 minutes to complete and provides insights into cognitive impairment associated with schizophrenia (CIAS) impact.

Outcome measures

Outcome measures
Measure	Iclepertin 10 mg n=305 Participants This arm comprised participants who received 10 mg tablet of iclepertin orally once daily, with doses administered at least 24 hours (hrs) apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.	Placebo n=305 Participants This arm comprised participants who received 10 mg tablet of iclepertin-matched Placebo orally once daily, with doses administered at least 24 hrs apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.
Change From Screening Visit 1a to Week 24 in Patient Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS) Total Score	-0.333 Scores on a scale Standard Error 0.0312	-0.345 Scores on a scale Standard Error 0.031

SECONDARY outcome

Timeframe: Baseline and at Week 26

Change from baseline in the T-score of the number of correct responses on Tower of London at Week 26, using an analysis of covariance (ANCOVA) model, is reported. The Tower of London evaluates executive functions such as reasoning and problem-solving ability. It measures the number of correct responses in solving an exercise that involves moving colored balls to match a target configuration. The higher the ToL T-score, the better is the patient's cognitive function. A mean T-score of 50 and a standard deviation of 10 reflects the T-score in the normative population. The administration time was about 7 minutes.

Outcome measures

Outcome measures
Measure	Iclepertin 10 mg n=305 Participants This arm comprised participants who received 10 mg tablet of iclepertin orally once daily, with doses administered at least 24 hours (hrs) apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.	Placebo n=305 Participants This arm comprised participants who received 10 mg tablet of iclepertin-matched Placebo orally once daily, with doses administered at least 24 hrs apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.
Change From Baseline in the T-score of the Number of Correct Responses on Tower of London (ToL) at Week 26	0.148 T-Score Standard Error 0.6446	1.283 T-Score Standard Error 0.6433

Adverse Events

Iclepertin 10 mg

Serious events: 11 serious events

Other events: 73 other events

Deaths: 1 deaths

Placebo

Serious events: 16 serious events

Other events: 59 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Iclepertin 10 mg n=305 participants at risk This arm comprised participants who received 10 mg tablet of iclepertin orally once daily, with doses administered at least 24 hours (hrs) apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.	Placebo n=305 participants at risk This arm comprised participants who received 10 mg tablet of iclepertin-matched Placebo orally once daily, with doses administered at least 24 hrs apart, taken with water. Participants were treated for 26 weeks, followed by 4 weeks follow-up after trial drug termination.
Infections and infestations Nasopharyngitis	7.2% 22/305 • Serious AEs and other AEs: From first dose of study drug to last dose over a 26-week treatment period, plus a 12-day residual effect period. All-cause mortality: From first drug administration till end of study over a 30-week observation period. The Treated Set (TS) included all patients who signed informed consent and were treated with at least one dose of the trial medication. Patients in the TS were analyzed under the actual trial medication received at randomization.	5.6% 17/305 • Serious AEs and other AEs: From first dose of study drug to last dose over a 26-week treatment period, plus a 12-day residual effect period. All-cause mortality: From first drug administration till end of study over a 30-week observation period. The Treated Set (TS) included all patients who signed informed consent and were treated with at least one dose of the trial medication. Patients in the TS were analyzed under the actual trial medication received at randomization.
Nervous system disorders Headache	9.8% 30/305 • Serious AEs and other AEs: From first dose of study drug to last dose over a 26-week treatment period, plus a 12-day residual effect period. All-cause mortality: From first drug administration till end of study over a 30-week observation period. The Treated Set (TS) included all patients who signed informed consent and were treated with at least one dose of the trial medication. Patients in the TS were analyzed under the actual trial medication received at randomization.	8.2% 25/305 • Serious AEs and other AEs: From first dose of study drug to last dose over a 26-week treatment period, plus a 12-day residual effect period. All-cause mortality: From first drug administration till end of study over a 30-week observation period. The Treated Set (TS) included all patients who signed informed consent and were treated with at least one dose of the trial medication. Patients in the TS were analyzed under the actual trial medication received at randomization.
Nervous system disorders Somnolence	5.9% 18/305 • Serious AEs and other AEs: From first dose of study drug to last dose over a 26-week treatment period, plus a 12-day residual effect period. All-cause mortality: From first drug administration till end of study over a 30-week observation period. The Treated Set (TS) included all patients who signed informed consent and were treated with at least one dose of the trial medication. Patients in the TS were analyzed under the actual trial medication received at randomization.	4.9% 15/305 • Serious AEs and other AEs: From first dose of study drug to last dose over a 26-week treatment period, plus a 12-day residual effect period. All-cause mortality: From first drug administration till end of study over a 30-week observation period. The Treated Set (TS) included all patients who signed informed consent and were treated with at least one dose of the trial medication. Patients in the TS were analyzed under the actual trial medication received at randomization.
Psychiatric disorders Schizophrenia	6.6% 20/305 • Serious AEs and other AEs: From first dose of study drug to last dose over a 26-week treatment period, plus a 12-day residual effect period. All-cause mortality: From first drug administration till end of study over a 30-week observation period. The Treated Set (TS) included all patients who signed informed consent and were treated with at least one dose of the trial medication. Patients in the TS were analyzed under the actual trial medication received at randomization.	4.9% 15/305 • Serious AEs and other AEs: From first dose of study drug to last dose over a 26-week treatment period, plus a 12-day residual effect period. All-cause mortality: From first drug administration till end of study over a 30-week observation period. The Treated Set (TS) included all patients who signed informed consent and were treated with at least one dose of the trial medication. Patients in the TS were analyzed under the actual trial medication received at randomization.

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
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