CONNEX-3: A Study to Test Whether Iclepertin Improves Learning and Memory in People With Schizophrenia

A Phase III Randomized, Double-blind, Placebo-controlled Parallel Group Trial to Examine the Efficacy and Safety of Iclepertin Once Daily Over 26 Week Treatment Period in Patients With Schizophrenia (CONNEX-3)

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 and visit the study site about 14 times. During this time, doctors regularly check participants' health and take note of any unwanted effects.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Iclepertin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 609
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Banfield, Argentina, B1828CKR
    • Clinica Privada Banfield
  • CABA, Argentina, C1405BOA
    • Fundación FunDaMos para la asistencia e investigación en psiquiatría
  • CABA, Argentina, C1133AAH
    • Fundación para el Estudio y Tratamiento de las Enfermedades Mentales (FETEM)
  • Córdoba, Argentina, X5000FAL
    • Instituto Modelo de Neurología Lennox
  • Córdoba, Argentina, 5004
    • CEN (Centro Especializado Neurociencias)
  • Córdoba, Argentina, X5003DCE
    • Instituto Médico DAMIC S.R.L.
  • La Plata, Argentina, 1900
    • Instituto de Neurociencias San Agustín
  • Rosario, Argentina, 2000
    • Instituto Medico de la Fundacion Estudios Clinicos
  • San Vicente, Argentina, X5006CBI
    • Centro Médico Luquez
• Austria
  • Vienna, Austria, 1090
    • AKH - Medical University of Vienna
• Belgium
  • Bertix, Belgium, 6880
    • CUP Vivalia -La Clairière
  • Bierbeek, Belgium, 3360
    • Sint-Kamillus
  • Duffel, Belgium, 2570
    • Universitair Psychiatrisch Centrum Duffel (UPC Duffel)
  • Mechelen, Belgium, 2800
    • Meclinas
• Brazil
  • Rio de Janeiro, Brazil, 22270-060
    • Ruschel Medicina e Pesquisa Clinica
  • São Paulo, Brazil, 04020-060
    • Clinica Viver - Centro de Desospitalizacao Humana
• Bulgaria
  • Plovdiv, Bulgaria, 4000
    • Medical Center "Spectar"
  • Plovdiv, Bulgaria, 4000
    • Filipopolis Ambulatory for Group Practice for Specialized Care in Psychiatry
  • Sofia, Bulgaria, 1510
    • Medical Center Hera EOOD
• China
  • Beijing, China, 100088
    • Beijing Anding Hospital
  • Changsha, China, 410011
    • The Second Xiangya Hospital of Central South University
  • Guangzhou, China, 510630
    • The Third Affiliated Hospital of Sun Yat-sen University
  • Huzhou, China, 313000
    • Huzhou Third Municipal Hospital
  • Nanjing, China, 210029
    • Nanjing Brain Hospital
  • Shenzhen, China, 518003
    • Shenzhen Kangning Hospital
  • Shijiazhuang, China, 050030
    • The first Hospital of Hebei Medical University
  • Tianjin, China, 300222
    • Tianjin Anding Hospital
  • Xi'an, China, 710061
    • First Affiliated Hospital of Xi'an JiaoTong University
  • Xi'an, China, 710101
    • Xi'an Mental Health Center
  • Zhumadian, China, 463000
    • Zhumadian Psychiatric Hospital
• Czechia
  • Klecany, Czechia, 25067
    • National Institute of Mental Health
  • Ostrava, Czechia, 708 00
    • MP Meditrine s.r.o.
  • Pilsen, Czechia, 30100
    • A-SHINE s.r.o
  • Prague, Czechia, 18600
    • INEP Medical s.r.o.
  • Prague, Czechia, 120 00
    • PRAGTIS s.r.o.
  • Říčany, Czechia, 251 01
    • Psychiatrie Ricany s.r.o.
• Denmark
  • Aalborg, Denmark, 9000
    • Aalborg Universitetsshospital
  • Aarhus, Denmark, 8200
    • Aarhus University Hospital
  • Glostrup Municipality, Denmark, 2600
    • Psykiatrisk Center Glostrup
• Finland
  • Espoo, Finland, 2740
    • HUS Jorvi Hospital
  • Helsinki, Finland, 00250
    • Aurora hospital
  • Turku, Finland, 20520
    • CRST - Clinical Research Services Turku
• Germany
  • Böblingen, Germany, 71034
    • Studienzentrum für Neurologie und Psychiatrie
  • Dortmund, Germany, 44287
    • LWL-Klinik Dortmund
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
  • München, Germany, 80336
    • Klinikum der Universität München - Campus Innenstadt
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen
• Lithuania
  • Kaunas, Lithuania, LT-44279
    • JSC Romuvos Clinic
  • Kaunas, Lithuania, LT-53137
    • LUHS KH Psichiatric Clinic Mariu Division
  • Vilnius, Lithuania, LT-10309
    • Vilnius City Mental Health Center
  • Šilutė, Lithuania, LT-99142
    • JSC Medical center "Puriena"
• Mexico
  • Chihuahua City, Mexico, 31203
    • Centro de Investigacion Integral MEDIVEST S.C
  • Culiacán, Mexico, 80230
    • Centro para el Desarrollo de la Medicina y de Asistencia Medica Especializada S.C.
  • León, Mexico, 37000
    • Hospital Aranda de La Parra
  • Mexico City, Mexico, 07369
    • Centro de Investigación Clinica Acelerada, S.C.
  • Monterrey, Mexico, 64460
    • Hospital Universitario Dr Jose Eleuterio Gonzalez
  • Monterrey, Mexico, 64310
    • Iecsi S.C.
  • San Luis Potosí City, Mexico, 78213
    • Bind Investigaciones S.C.
• Portugal
  • Leiria, Portugal, 2410-197
    • ULS da Região de Leiria, E.P.E.
  • Lisbon, Portugal, 1649-035
    • ULS de Santa Maria, E.P.E
  • Loures, Portugal, 2674-514
    • ULS de Loures-Odivelas, E.P.E
• Serbia
  • Belgrade, Serbia, 11000
    • General Hospital Euromedik
  • Belgrade, Serbia, 11000
    • Clinical Hospital Center Dr. Dragisa Misovic
  • Gornja Toponica, Serbia, 18202
    • Special Hospital for Psychiatric Diseases Gornja Toponica
• South Korea
  • Busan, South Korea, 47392
    • Inje University Busan Paik Hospital
  • Daegu, South Korea, 705-717
    • Yeungnam University Medical Center
  • Gwangju, South Korea, 61453
    • Chonnam National University Hospital
  • Seongnam, South Korea, 13620
    • Seoul National University Bundang Hospital
  • Seongnam-si, South Korea, 13496
    • CHA Bundang Medical Center
  • Yangsan, South Korea, 50612
    • Pusan National University Yangsan Hospital
• Taiwan
  • Kaohsiung City, Taiwan, 802
    • Kai-Syuan Psychiatric Hospital
  • Keelung, Taiwan, 204
    • Chang Gung Memorial Hospital-Keelung
  • Taichung, Taiwan, 40201
    • Chung Shan Medical University Hospital
  • Tainan, Taiwan, 704
    • NCKUH
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
  • Taoyuan, Taiwan, 333
    • Chang Gung Memorial Hospital, Linkou
  • Taoyuan District, Taiwan, 33058
    • Taoyuan Psychiatric Center
• United Kingdom
  • Bodmin, United Kingdom, PL31 2QT
    • Bodmin Community Hospital
  • Cheltenham, United Kingdom, GL53 9DZ
    • The Fritchie Centre
  • Chester, United Kingdom, CH2 1BQ
    • Redesmere
  • Edinburgh, United Kingdom, EH4 2XU
    • Western General Hospital
  • Glasgow, United Kingdom, G51 4TF
    • Queen Elizabeth University Hospital
  • London, United Kingdom, SE5 8AZ
    • Maudsley Hospital
  • Oxford, United Kingdom, OX3 7JX
    • Warneford Hospital
  • Southampton, United Kingdom, SO30 3JB
    • Moorgreen Hospital
• United States
  • California
    • Anaheim, California, United States, 92805
      • Advanced Research Center, Inc.
    • Culver City, California, United States, 90230
      • ProScience Research Group
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Pico Rivera, California, United States, 90660
      • CNRI - Los Angeles
    • Stanford, California, United States, 94304
      • Stanford University Medical Center
    • Walnut Creek, California, United States, 94596
      • Sunwise Clinical Research-Walnut Creek-70166
  • Florida
    • Hollywood, Florida, United States, 33021
      • Advanced Medical Research Group Inc
    • Maitland, Florida, United States, 32751
      • Accel Research Sites Network
    • Miami, Florida, United States, 33136
      • University of Miami
    • Miami, Florida, United States, 33155
      • Ivetmar Medical Group, LLC
    • Orlando, Florida, United States, 32803
      • Nova Psychiatry Inc.
  • Georgia
    • Atlanta, Georgia, United States, 30328
      • Synexus Clinical Research-Atlanta-67262
    • Augusta, Georgia, United States, 30912
      • Augusta University
  • Maryland
    • Gaithersburg, Maryland, United States, 20877
      • Center for Behavioral Health, LLC
  • Missouri
    • St Louis, Missouri, United States, 63141
      • Arch Clinical Trials, LLC
  • Nebraska
    • Omaha, Nebraska, United States, 68144
      • Omaha Insomnia and Psychiatric Services
  • New Jersey
    • Berlin, New Jersey, United States, 08009
      • Hassman Research Institute-Berlin-60540
  • North Carolina
    • Raleigh, North Carolina, United States, 27608
      • UNC Center for Excellence in Community Mental Health, North Carolina Psychiatric Research Center
  • Ohio
    • Dayton, Ohio, United States, 45417
      • Midwest Clinical Research
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73116
      • Cutting Edge Research Group
    • Oklahoma City, Oklahoma, United States, 73112
      • Rivus Wellness and Research Institute
  • Pennsylvania
    • State College, Pennsylvania, United States, 16801
      • Oasis Life Care
  • Texas
    • Houston, Texas, United States, 77030
      • Ben Taub General Hospital
    • Richmond, Texas, United States, 77407
      • LinQ Research, LLC-Richmond-70076

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

• Signed and dated written informed consent.
• Male or female patients who are 18-50 years (inclusive) of age at time of consent.

• Diagnosis of schizophrenia utilizing Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5).

  -- Patients must be clinically stable and in the residual (non-acute) phase of their illness with no hospitalization or increase level of care due to worsening of schizophrenia in the past 12 weeks or no uncontrolled positive symptoms.

• Patients should have functional impairment in day-to-day activities per investigator judgement.
• Patients maintained on current antipsychotic treatment for at least 12 weeks and on current dose for at least 35 days prior to randomization.
• Patients with any other concomitant psychoactive medications (except for anticholinergics) need to be maintained on same drug for at least 12 weeks and on current dose/ regimen for at least 35 days prior to randomization.
• Women of childbearing potential must use highly effective methods of birth control.
• Have a study partner who interacts with the patient on a regular basis. Further inclusion criteria apply.

Exclusion criteria

• Patient with current DSM-5 diagnosis other than Schizophrenia.
• Cognitive impairment due to other causes, or patients with dementia or epilepsy.
• Severe movement disorders.
• Any suicidal behavior in past year or suicidal ideation in the past 3 months.
• History of moderate or severe substance use disorder within the last 12 months prior to informed consent.
• Positive urine drug screen.
• Patients who were treated with Clozapine, stimulants, ketamine or electroconvulsive therapy within 6 months prior to randomization.
• Current participation in any investigational drug trial.
• Cognitive Remediation Therapy within 12 weeks prior to screening.
• Initiation or change in any type or frequency of psychotherapy within 12 weeks prior to randomization.
• Any clinically significant finding or condition that would jeopardize the patient´s safety while participating in the trial or their capability to participate in the trial.
• Haemoglobin (Hb) below lower limit of normal .
• History of haemolytic anaemia, red blood cell (RBC) membrane diseases, known Glucose-6-phosphate dehydrogenase deficiency, anaemia of any cause or patients planning to donate blood.
• Severe renal impairment.
• Indication of liver disease.
• Any documented active or suspected malignancy or history of malignancy within 5 years.
• Women who are pregnant, nursing, or who plan to become pregnant while in the trial.

Further exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Iclepertin 10 mg; Patients with schizophrenia took one tablet of 10 milligram (mg) iclepertin orally once daily for 26 weeks. Patients were permitted to remain on other antipsychotic and psychotropic medications, as specified in the eligibility criteria.	Drug: Iclepertin; One tablet of 10 mg once daily for 26 weeks.; Other Names: BI 425809
Placebo Comparator: Placebo; Patients with schizophrenia took one tablet of placebo matching iclepertin orally once daily for 26 weeks. Patients were permitted to remain on other antipsychotic and psychotropic medications, as specified in the eligibility criteria.	Drug: Placebo; One tablet once daily for 26 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 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	The MCCB assesses 7 cognitive domains, including speed of processing, attention vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. T-scores in the general population have a mean of 50 and standard deviation of 10, and a higher score indicates better cognition. The primary analysis was a restricted maximum likelihood (REML) based approach using a mixed-effects model for repeated measurements (MMRM), which included the fixed categorical effects of treatment at each visit, fixed categorical effect of the stratification factor using the screening MCCB overall composite T-score, and a fixed effect for the continuous covariate of baseline at each visit. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-subject dependencies. Intercurrent events were addressed using different pre-defined strategies.	The MMRM model incorporates values from baseline (Week 0), Week 12 and Week 26. The data represent the Least Squares Means at Week 26.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Schizophrenia Cognition Rating Scale (SCoRS) Interviewer Total Score After 26 Weeks of Treatment	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. Higher ratings reflect a greater degree of impairment. The interviewer integrates information from separate patient and study partner interviews to generate a total score, which ranges from 20 to 80. The analysis was a REML-based approach using a MMRM model, which included the discrete fixed effects of treatment at each visit, fixed categorical covariate of the stratification factor using the screening MCCB overall composite T-score, a fixed effect for the continuous covariate of baseline at each visit. Visit was treated as the repeated measure with an unstructured covariance structure to model the within-subject measurements. Subjects were considered as a random effect. Intercurrent events were addressed using different pre-defined strategies.	The MMRM model incorporates values from baseline (Week 0), Week 12 and Week 26. The data represent the Least Squares Means at Week 26.
Change From Baseline to Week 26 in the Adjusted Total Time T-score in Virtual Reality Functional Capacity Assessment Tool (VRFCAT)	The VRFCAT is a virtual reality shopping trip performed on a tablet, and was used as an electronic Functional Capacity measure by measuring the total time adjusting for the number of errors. T-scores in the general population have a mean of 50 and standard deviation of 10, and a higher score indicates a better functional outcome. The analysis was a REML-based approach using a MMRM model, which included the discrete fixed effects of treatment at each visit, fixed categorical covariate of the stratification factor using the screening MCCB overall composite T-score, a fixed effect for the continuous covariate of baseline at each visit. Visit was treated as the repeated measure with an unstructured covariance structure to model the within-subject measurements. Subjects were considered as a random effect. Intercurrent events were addressed using different pre-defined strategies.	The MMRM model incorporates values from baseline (Week 0), Week 12 and Week 26. The data represent the Least Squares Means at Week 26.
Change From Baseline to Week 26 in the T-score of the Number of Correct Responses on Tower of London	This is an Executive Functions/Reasoning and Problem Solving test where patients were shown two images on opposite sides of a tablet screen. Each image showed a different configuration of 3 colored balls arranged on 3 pegs. Patients were required to accurately determine the total number of times the balls in one picture would have to be moved in order to make the arrangement of balls identical to that of the other opposing picture, while employing the standard rules employed in tower tests. T-scores in the general population have a mean of 50 and standard deviation of 10, and a higher score indicates a better outcome. The analysis was performed with an analysis of covariance (ANCOVA) model, which included treatment, stratification factor of screening MCCB overall composite T-score (< 30, ≥ 30), and baseline number of correct responses on Tower of London T-score.	At baseline (Week 0) and at Week 26.
Change From Screening Visit 1a to Week 24 in Patient Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS) Total Score	PRECIS consists of 26 items covering 6 domains (memory, communication, self-control, executive function, attention, and sharp thinking), and 2 additional items assessing the overall degree of bother associated with all domains. Questions are answered via a 5-category Likert scale, with higher scores indicating a worse patient experience. The total score, ranging from 26 to 130, is the average score of the first 26 items. The analysis was a REML-based approach using a MMRM model, which included the discrete fixed effects of treatment at each visit, fixed categorical covariate of the stratification factor using the screening MCCB overall composite T-score, and continuous fixed effects for the corresponding baseline endpoint value at each visit. Visit was treated as the repeated measure with an unstructured covariance structure to model the within-subject measurements. Subjects were considered as a random effect. Intercurrent events were addressed using different pre-defined strategies.	The MMRM model incorporates values from baseline (screening), Week 15 and Week 24. The data represent the Least Squares Means at Week 24.
Ocular Safety Sub-study: Change From Baseline in Humphrey Visual Field 24-2 Swedish Interactive Thresholding Algorithm (SITA) Standard at Week 24	The Humphrey visual field is a diagnostic test to measure visual fields, or perimetry. The Humphrey visual field test measures the entire area of peripheral vision that can be seen while the eye is focused on a central point. During this test, lights of varying intensities appear in different parts of the visual field while the patient's eye is focused on a central spot. The perception of these lights is charted and then compared to results of a healthy eye at the same age of the patient to determine if any damage has occurred. Visual field Index goes from 100%= perfect to 0= no vision.	Measurements were performed at baseline (screening) and at Week 24.
Ocular Safety Sub-study: Change From Baseline in Spectral Domain Ocular Coherence Tomography (OCT)	The central retinal thickness measurements were recorded for each eye via high definition optical coherence tomography (spectral domain OCT) to evaluate the retinal and sub-retinal structures.	Measurements were performed at baseline (screening) and at Week 24.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Keefe RSE, Harvey PD, Correll CU, Falkai P, Hashimoto N, Klein H, Krystal JH, Marder S, Medalia A, Sumiyoshi T, Wang G, Zhang H, Blahova Z, Bichard-Sall I, English BA, Fu E, Gruenenfelder F, Groeschl M, Kimura K, Tang W, von der Goltz C, Fowler C. Efficacy and safety of iclepertin for cognitive impairment associated with schizophrenia (CONNEX programme): results from three phase 3 randomised controlled trials. Lancet Psychiatry. 2025 Dec;12(12):906-920. doi: 10.1016/S2215-0366(25)00296-2.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 2021
• Primary Completion (Actual): October 28, 2024
• Study Completion (Actual): November 20, 2024

Study Registration Dates

• First Submitted: April 26, 2021
• First Submitted That Met QC Criteria: April 26, 2021
• First Posted (Actual): April 27, 2021

Study Record Updates

• Last Update Posted (Actual): February 6, 2026
• Last Update Submitted That Met QC Criteria: January 28, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia; Nootropic Agents; BI 425809
• Other Study ID Numbers: 1346-0013; 2020-003726-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Once the criteria in section "Time Frame" are fulfilled, researchers can use the following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement".

Furthermore, researchers can request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website.

• IPD Sharing Time Frame: One year after the approval has been granted by major Regulatory Authorities and after the primary manuscript has been accepted for publication, or after termination of the development program.
• IPD Sharing Access Criteria: For study documents - upon signing of a 'Document Sharing Agreement'. For study data - 1. after the submission and approval of the research proposal (checks will be performed by the sponsor and/or the independent review panel, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a legal agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No