NCT04846881

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

Completed Phase 3 Results posted Last updated 12 December 2025

What this trial tests

Phase 3 trial testing Iclepertin in Schizophrenia in 611 participants. Completed in 17 November 2024.

Timeline

24 August 2021

Primary endpoint
18 October 2024

17 November 2024

Quick facts

Lead sponsor	Boehringer Ingelheim
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	611
Start date	24 August 2021
Primary completion	18 October 2024
Estimated completion	17 November 2024
Sites	127 locations across France, Japan, Netherlands, Slovakia, Malaysia, Ukraine, Serbia, Chile

Drugs / interventions tested

• Iclepertin — full drug profile →
• Placebo

Conditions studied

• Schizophrenia — all drugs for Schizophrenia →

Sponsor

Boehringer Ingelheim — full company profile →

Who can join

Adults 18 to 50, any sex, with Schizophrenia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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 Primary · 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 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 c

Group	Value	95% CI
Iclepertin 10 mg	2.719	± 0.3377
Placebo	1.997	± 0.3345

Change From Baseline in SCoRS (Schizophrenia Cognition Rating Scale) Interviewer Total Score at Week 26 Secondary · 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 sc

Group	Value	95% CI
Iclepertin 10 mg	-5.053	± 0.4268
Placebo	-5.767	± 0.4261

Change From Baseline in VRFCAT (Virtual Reality Functional Capacity Assessment Tool) Adjusted Total Time T-score at Week 26 Secondary · 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 pa

Group	Value	95% CI
Iclepertin 10 mg	3.898	± 0.7531
Placebo	3.565	± 0.7481

Change From Screening Visit 1a to Week 24 in Patient Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS) Total Score Secondary · 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.

Group	Value	95% CI
Iclepertin 10 mg	-0.333	± 0.0312
Placebo	-0.345	± 0.031

Change From Baseline in the T-score of the Number of Correct Responses on Tower of London (ToL) at Week 26 Secondary · 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

Group	Value	95% CI
Iclepertin 10 mg	0.148	± 0.6446
Placebo	1.283	± 0.6433

Adverse events — posted to ClinicalTrials.gov

Time frame: 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.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Iclepertin 10 mg

Serious: 11/305 (4%)

Deaths: 1/305

Placebo

Serious: 16/305 (5%)

Deaths: 0/305

Serious adverse events (27 terms)

Reaction	System	Iclepertin 10 mg	Placebo
Schizophrenia	Psychiatric disorders	—	—
Suicidal ideation	Psychiatric disorders	—	—
Craniofacial fracture	Injury, poisoning and procedural complications	—	—
Suicide attempt	Psychiatric disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Intestinal fistula	Gastrointestinal disorders	—	—
Pancreatitis	Gastrointestinal disorders	—	—
COVID-19 pneumonia	Infections and infestations	—	—
Enterobacter infection	Infections and infestations	—	—
Lymphadenitis bacterial	Infections and infestations	—	—
Pathogen resistance	Infections and infestations	—	—
Pneumonia	Infections and infestations	—	—
Craniocerebral injury	Injury, poisoning and procedural complications	—	—
Pneumocephalus	Injury, poisoning and procedural complications	—	—
Pulmonary contusion	Injury, poisoning and procedural complications	—	—
Road traffic accident	Injury, poisoning and procedural complications	—	—
Spinal column injury	Injury, poisoning and procedural complications	—	—
Subdural haemorrhage	Injury, poisoning and procedural complications	—	—
Upper limb fracture	Injury, poisoning and procedural complications	—	—
Systemic lupus erythematosus	Musculoskeletal and connective tissue disorders	—	—
Neurofibroma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Haemorrhage intracranial	Nervous system disorders	—	—
Subarachnoid haemorrhage	Nervous system disorders	—	—
Drug abuse	Psychiatric disorders	—	—
Renal failure	Renal and urinary disorders	—	—

Other adverse events (4 terms — click to expand)

Reaction	System	Iclepertin 10 mg	Placebo
Headache	Nervous system disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Schizophrenia	Psychiatric disorders	—	—
Somnolence	Nervous system disorders	—	—

Most-reported serious reactions: Schizophrenia, Suicidal ideation, Craniofacial fracture, Suicide attempt, Anaemia, Intestinal fistula, Pancreatitis, COVID-19 pneumonia.

Data from ClinicalTrials.gov NCT04846881 adverse events section.

Sponsor's own description

This study is open to adults with schizophrenia. Schizophrenia can affect the way a person thinks, their memory and their mental functioning. Examples include struggling to remember things, or to read a book or pay attention to a movie. Some people have difficulty calculating the right change or planning a trip so that they arrive on time. The purpose of this study is to find out whether a medicine called Iclepertin improves learning and memory in people with schizophrenia.

Participants are put into two groups randomly, which means by chance. One group takes Iclepertin tablets and the other group takes placebo tablets. Placebo tablets look like Iclepertin tablets but do not contain any medicine. Participants take a tablet once a day for 26 weeks. In addition, all participants take their normal medication for schizophrenia.

During this time, doctors regularly test learning and memory of the participants by use of questionnaires, interviews, and computer tests. The results of the mental ability tests are compared between the groups.

Participants are in the study for about 8 months. During this time, they visit the study site about 15 times and get about 3 phone calls from the study team. The doctors also regularly check participants' health and take note of any unwanted effects.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials, and of some current trends aiming to de-risk trial programmes of novel agents.
   Correll CU, Solmi M, Cortese S, Fava M, et al · · 2023 · cited 90× · PMID 36640403 · DOI 10.1002/wps.21056
2. New and emerging treatments for schizophrenia: a narrative review of their pharmacology, efficacy and side effect profile relative to established antipsychotics.
   Lobo MC, Whitehurst TS, Kaar SJ, Howes OD. · · 2022 · cited 74× · PMID 34838528 · DOI 10.1016/j.neubiorev.2021.11.032
3. Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia.
   Rosenbrock H, Desch M, Wunderlich G. · · 2023 · cited 56× · PMID 36971864 · DOI 10.1007/s00406-023-01576-z
4. New Developments in the Treatment of Schizophrenia: An Expert Roundtable.
   Kantrowitz JT, Correll CU, Jain R, Cutler AJ. · · 2023 · cited 23× · PMID 36932673 · DOI 10.1093/ijnp/pyad011
5. Novel Compounds in the Treatment of Schizophrenia-A Selective Review.
   Tsapakis EM, Diakaki K, Miliaras A, Fountoulakis KN. · · 2023 · cited 21× · PMID 37626549 · DOI 10.3390/brainsci13081193
6. Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia.
   Veselinović T, Neuner I. · · 2022 · cited 18× · PMID 35831706 · DOI 10.1007/s40263-022-00935-z
7. Pharmacological Treatment of Cognitive Impairment Associated With Schizophrenia: State of the Art and Future Perspectives.
   Vita A, Nibbio G, Barlati S. · · 2024 · cited 13× · PMID 39144119 · DOI 10.1093/schizbullopen/sgae013
8. Finding the Right Dose: NMDA Receptor-Modulating Treatments for Cognitive and Plasticity Deficits in Schizophrenia and the Role of Pharmacodynamic Target Engagement.
   Sehatpour P, Kantrowitz JT. · · 2025 · cited 12× · PMID 39218136 · DOI 10.1016/j.biopsych.2024.08.019