CONNEX-3

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Trial Information

Short title:

1346-0013 Phase III BI 425809 Vs placebo in schizophrenia CONNEX-3

Long title:

A phase III randomized, double-blind, placebo-controlled parallel group trial to examine the efficacy and safety of BI 425809 once daily over 26 week treatment period in patients with schizophrenia (CONNEX-3)

Trial registries:

EudraCT  - 2020-003726-23

ClinicalTrials.gov – NCT04860830

Recruitment status

Recruitment Status: Green

Target - 4 

Actual - 0

Recruitment End Date - 01/09/2023

Contact Details

Study Location:

Glasgow Clinical Research Facility, Queen Elizabeth University Hospital

Principal Investigator:

Dr Nagore Penades

Email - nagore.penades@ggc.scot.nhs.uk

Mental Health CRF research nurse team:

CRF Mental Health Research Nurse team

Email – ggc.mentalhealthresearch@ggc.scot.nhs.uk

 

Study Overview

This is a Phase 3, randomised, double-blind placebo controlled trial assessing whether study drug, BI 425809 improves cognition in patients with schizophrenia compared to those randomised to placebo.

The primary objective of this trial is to assess the efficacy in improving cognitive impairment using MATRICS Consensus Cognitive Battery (MCCB) in patients with schizophrenia treated for 26 weeks with BI 425809 as compared with placebo. The key secondary objective is to assess the efficacy in daily functioning of 26-week treatment with BI 425809 as compared with placebo in terms of cognitive scales. The secondary objectives are to assess the efficacy in improving reasoning and problem solving and patients’ experience of cognitive impairment associated with their disease.

Eligibility Criteria

Inclusion:

  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 DSM-5 with the following clinical features:
  • Outpatient, clinically stable and in the residual (non-acute) phase of their illness.
  • No hospitalization1 or increase in level of psychiatric care2 due to worsening of schizophrenia within 12 weeks prior to randomization. –
  • PANSS score: items P1, P3-P6 ≤ 5 and item P2 and P7 ≤ 4 at Visit 1, and confirmed at Visit 2.
  1. 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.
  2. 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.
  • Doses should be within the recommended dose range listed in the approved product labelling of the country where the study is being conducted. –
  • Switch from 1-month to 3-monthinjectable formulation of same antipsychotic during the 12 weeks prior to randomization is allowed, but not with in last 35 days prior to randomization.
  • Note: If the total dose is stable, different dosage forms of the same antipsychotic treatment will be considered as one antipsychotic.
  1. 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 and hypnotic load up to 0.25 mg brotizolam-equivalent as needed (pro re nata, prn). Table of relevant medications and their equivalencies will be provided as a part of ISF
  • For any other psychoactive medications, doses should be within the recommended dose range listed in the approved product labelling of the country where the study is being conducted.
  1. 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 Protocol Section 4.2.2.3. 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.
  2. 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.
  1. Patients must, in the investigator’s opinion, exhibit reliability and physiologic capability (e.g. sufficient hearing, vision etc.), to comply with all protocol procedures, and have attained an educational achievement of minimum 8th grade.
  2. Patients and his/ her study partner must be fluent in the language of the batteries/questionnaires.

Exclusion:

  1. Participant with current DSM-5 diagnosis other than Schizophrenia, including but not limited to bipolar, schizoaffective, major depressive disorder etc. 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.
  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). Table of relevant medications and their equivalencies will be provided as a part of ISF
  1. Any suicidal behaviour in the past 1-year prior to screening and during the screening period.
  2. Suicidal ideation of type 5 in the 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.
  1. 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.
  2. Positive urine drug screen at Visit 1 based on central lab test. For a list of drugs assessed in the urine drug screen
  3. Patients who were treated with any of the following within 6 months prior to randomization:
  • Clozapine –
  • Stimulants (e.g. methylphenidate, dextroamphetamine, modafinil) –
  • Ketamine –
  • Electroconvulsive therapy (ECT) or Modified ECT –
  • Participation in any investigational psychoactive drug trial (both industry/ academic) in last 6 months, and 30 days or 5 half-lives for no-psychoactive drug trial, prior to randomization. –
  • Previous participation in any BI 425809 study. –
  • Patients who are treated with any of the following within the last 35 days prior to randomization: --
  • Strong or moderate CYP3A4 inhibitors including grapefruit juice –
  • Strong or moderate CYP3A4 inducers including St. John’s wort (Hypericum perforatum) –
  • Dietary supplements and herbal remedies that may impact cognition, in the investigator´s judgement –
  • Antiepileptics –
  • Tricyclic antidepressants –
  • Traditional Chinese medicine/ non-Western therapy –
  • Medical devices therapy (e.g. TMS, neurofeedback) –
  • Patients who plan to change their current life-style habits including but not limited to alcohol, nicotine or caffeine use, or diet, during the treatment period. –
  • Patients who have participated in a clinical trial with repeated assessments (i.e. a single assessment is not exclusionary) with the MCCB and/ or any other schizophrenia cognitive battery within 12 weeks prior to screening. –
  • Any formal Cognitive Remediation Therapy (CRT) within 12 weeks prior to screening. Initiation of CRT is not allowed during the study. –
  • Initiation or change in any type or frequency of psychotherapy (e.g. cognitive behavioral therapy, social skills training, vocational/occupational therapy) within 12 weeks prior to randomization. Patients with ongoing, stable psychotherapy for more than 12 weeks prior to randomization (and intend to maintain the same frequency during the study) may qualify as per clinical judgement of the investigator. –
  • Any of the following, in the judgment of the investigator: --
  • Clinically significant finding of the physical examination, vital signs (including blood pressure (BP) and pulse rate (PR)), ECG or laboratory value (as measured by the central laboratory) that would jeopardize the patient´s safety while participating in the trial or their capability to participate in the trial. –
  • Symptomatic/unstable/uncontrolled or clinically relevant concomitant disease or any other clinical condition that would jeopardize the patient´s safety while participating in the trial or capability to participate in the trial. -- Significant or unstable physical condition that may require change in medication or hospitalization that would impact cognitive function.
  • Planned major surgery requiring withdrawal from study medication for more than 2 weeks during the study period.
  • Haemoglobin (Hb) below lower limit of normal at Visit 1 assessed by the central lab.
  • Patients with known active infection with SARS-CoV-2 within the last 35 days prior to randomization.

Study Visits

Participants who meet the eligibility criteria will attend 14 study visits at the CRF and 4 of these visits will require the attendance (where possible) of the study partner. If the study partner is not able to attend the study visits they can speak to the study team via phone. Participants will be offered an opportunity to take part in the optional parts of the study, namely to provide a blood sample for DNA bio-banking (3 times). The maximum treatment duration in the study is 26 weeks and participants will be in the trial for about 8.5 months. A summary of the study visits is below:

Screening Visit(s) – 6.5 (this can be completed over 2 days)

Medical history, height/weight, vital signs, physical examination, ECG, cognitive testing, questionnaires, study partner questionnaires, blood and urine samples.

Visit 2 – 7.5 hours 

Height/weight, vital signs, physical examination, ECG, cognitive testing, questionnaires/assessments, study partner questionnaires, blood and urine samples. Randomised to receive either BI 425809 or placebo.

Visit 3 – 1.5 hour

Questionnaires/assessments, blood and urine samples.

Visit 4 – 1.5 hours

Questionnaires/assessments, blood and urine samples.

Visit 5 – 3 hours

Height/weight, vital signs, physical examination, ECG, questionnaires/assessments.

Visit 6 – 5 hours

Cognitive testing, questionnaires/assessments, study partner questionnaires, blood and urine samples,

Visit 7 – 1 hours

Questionnaires/assessments

Visit 8 – 0.5 hours

Height/weight, vital signs, physical examination, blood and urine samples, ECG,  questionnaires/assessments.

Visit 9 – 1 hour

Questionnaires/assessments, blood and urine samples.

Visit 10 – 2 hours

Questionnaires/assessments, blood and urine samples.

Visit 11 (End of Trial) – 8 hours

Height/weight, vital signs, physical examination, ECG, cognitive testing, questionnaires/assessments, study partner questionnaires, blood and urine samples

Follow up - 1 hour

Vital signs, questionnaires and assessment of adverse events

Follow up 2 - 2 hours

Physical examination, vital signs, weight, questionnaires/assessments, blood and urine samples and assessment of adverse events.

Patient Expenses

Reasonable travel expenses and meals will be reimbursed. Participants will receive the following payment dependent on the number of visits completed:

Completion of visits 1, 2, 5, 6, 8 and End of Trial: £50 per visit

If the participants downloads and use the medication adherence monitoring app on their own smartphone, they will be reimbursed £7 per month to cover the cost of data transmission.