Clinical Trial of Iclepertin Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-1)

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-1)

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.

Inclusion criteria

1. Patients must be capable of providing signed and dated written informed consent by date of Visit 1 in accordance with ICH Harmonized Tripartite Guideline for Good Clinical Practice (ICH-GCP) and the local legislation prior to the admission to the trial.

2. Male or female patients who are 18-50 years (inclusive) of age at time of consent.

3. Diagnosis of schizophrenia utilizing Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) with the following clinical features:

   • Outpatient, clinically stable and in the residual (non-acute) phase of their illness.
   • No hospitalization or increase in level of psychiatric care due to worsening of schizophrenia within 12 weeks prior to randomization.
   • Positive and Negative Syndrome Scale (PANSS) score: items P1, P3-P6 ≤ 5 and item P2 and P7 ≤ 4 at Visit 1, and confirmed at Visit 2.

4. Patients should have functional impairment in day-to-day activities such as difficulties following conversation or expressing themselves, difficulties to stay focused, difficulties to remember instructions, what to say or how to get to places, per investigator judgement.

5. Patients maintained on current antipsychotic treatment (minimum 1 and maximum 2 antipsychotics, but clozapine is not allowed) for at least 12 weeks and on current dose for at least 35 days prior to randomization.

   -- For patients on two antipsychotics, at least one antipsychotic must be within the approved label dose range. The second antipsychotic must not exceed the maximum daily dose per local label.

   Note: If the total dose is stable, different dosage forms of the same antipsychotic treatment will be considered as one antipsychotic.

6. 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.

   • Maximum daily benzodiazepine load of up to 1 mg lorazepam-equivalent.
   • For any other psychoactive medications, doses cannot exceed the maximum daily dose per local label.

7. Women of childbearing potential (WOCBP) must be ready and able to use highly effective methods of birth control per Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (ICH M3 (R2)) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the protocol. Such methods should be used throughout the trial, and for a period of at least 35 days after last trial drug intake, and the patient must agree to periodic pregnancy testing during participation in the trial.

8. Have a study partner, defined as any person either private or professional who knows the patient well, has been capable of interacting with the patient on regular basis, and preferably consistent throughout the study.

   • The study partner must interact with the subject a minimum 1 hour per week and, preferably, at least 2 times a week. At least one interaction per week should be in person.
   • The study partner must have educational achievement of minimum 8th grade.
   • Professional study partners (e.g. study nurse, social worker etc.) are allowed if not involved in administration of any of the protocol assessments.

Further inclusion criteria apply.

Exclusion criteria

1. Participant with current DSM-5 diagnosis other than Schizophrenia, including but not limited to bipolar, schizoaffective, major depressive disorder etc. Mini International Neuropsychiatric Interview (M.I.N.I.) for Psychotic disorders should be used for guidance.

2. Cognitive impairment due to developmental, neurological (e.g., epilepsy, stroke) or other disorders including head trauma, or patients with dementia or epilepsy.

3. Severe movement disorders

   • Leading to cognitive impairment (e.g. Parkinson dementia), or
   • Interfering with the efficacy assessments, or
   • Due to antipsychotic treatment that cannot be controlled with low dose anticholinergic treatment (equal to maximum 1 mg benztropine twice daily).

4. Any suicidal behavior in the past 1-year prior to screening and during the screening period.

5. Suicidal ideation of type 5 in the Columbia Suicide Severity Rating Scale (C-SSRS) (i.e. active suicidal thought with plan and intent) in the past 3 months prior to screening and up to and including Visit 2.

   -- Patients with Suicidal Ideation type 4 in the C-SSRS (i.e. active suicidal thought with intent but without specific plan), within 3 months prior to screening and up to and including Visit 2, can be randomized in the study, if assessed and documented by a licensed mental health professional that there is no immediate risk of suicide.

6. History of moderate or severe substance use disorder (other than caffeine and nicotine), as defined in DSM-5 within the last 12 months prior to informed consent.

7. Positive urine drug screen at Visit 1 based on central lab test.

8. Patients who were treated with any of the following within 6 months prior to randomization:

   • Clozapine
   • Stimulants (e.g. methylphenidate, dextroamphetamine, modafinil)
   • Ketamine or esketamine
   • Electroconvulsive therapy (ECT) or Modified ECT Further exclusion criteria apply.