Study of Systemic and Ocular Safety and Pharmacokinetics of BI 409306 in Patients With Schizophrenia, Alzheimer's Disease, and Healthy Volunteers

Randomised, Parallel-group, Double-blind Study of Systemic and Ocular Safety and Pharmacokinetics of BI 409306 in Patients With Schizophrenia, Alzheimer's Disease, and Age-comparable Healthy Volunteers

Single site, parallel-group, double-blind trial of low or high dose of BI 409306 to evaluate the ocular and systemic safety and pharmacokinetics during 14 day treatment period in patients with schizophrenia, Alzheimer's disease, or age comparable healthy volunteers.

Inclusion criteria:

• Schizophrenia group:

  • Patients with established diagnoses of schizophrenia (per Diagnostic and Statistic Manual of Mental Disorder, version V) with the all of the following clinical features:

    • Clinically stable and are in the residual (non-acute) phase of their illness for at least 8 weeks prior to randomisation

    • Current antipsychotic and concomitant psychotropic medications must meet the criteria below:

      • Maintained on current atypical (second generation) antipsychotic medications (in any approved dosage form) other than Clozapine and on current dose for at least 8 weeks prior to randomisation, and/or
      • Maintained on current typical (first generation) antipsychotic medications and on current dose for at least 6 months, optionally combined with anticholinergics if treated with a stable dose for at least 6 months prior to randomisation, and/or
      • Maintained on current concomitant psychotropic medications other than anticholinergics, antiepileptics and lithium, and on current dose for at least 8 weeks prior to randomisation. Antiepileptics and lithium are allowed if initiated at least 6 months prior to randomisation.

    • Have no more than a moderate severity rating on hallucinations and delusions (Positive and Negative Syndrome Scale (PANSS), positive syndrome Hallucinatory Behavior item score <= 4 and Delusions item score <= 4)

    • Have no more than a moderate severity rating on positive formal thought disorder (PANSS, positive syndrome Conceptual Disorganization item score <= 4)

    • Have a minimal level of extrapyramidal symptoms (Simpson-Angus Scale total score < 6) and depressive symptoms (PANSS, general psychopathology syndrome Depression item score <= 4)

  • Male or female patients age 18 to 55 years.

• Alzheimer's Disease group:

  • Patients with diagnosis of mild Alzheimer's Dementia based on DSM-V and in accordance with the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.
  • Mini-Mental State Examination (MMSE) score of 18-26.
  • Male or female patients age 55 to 85 years, who have not been taking acetyl cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and/or memantine for at least 3 months or on stable dose of acetyl cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and/or memantine at least 3 months before randomization.Patients older than 85 years may be included based on an acceptable general health status, (e.g. concomitant diseases, physical capability to follow the required study procedures [visits etc.]) per investigators judgement.
  • Availability of a pre-existing cranial computer tomography (CCT) or magnetic resonance imaging (MRI) scan of the brain (initiation of radiological imaging is not required) not older than one year prior to screening; if not available, a CCT must be performed at screening. Results of radiological brain imaging must be compatible with Diagnosis of Alzheimer's Disease and exclusion of relevant signs indicative of potential vascular dementia (see also exclusion criteria).
  • If needed, a caregiver may be present during site activities.

• Age-comparable male or female healthy volunteers age 18 to 85 years. Healthy volunteers older than 85 years may be included based on an acceptable general health status, (e.g. concomitant diseases, physical capability to follow the required study procedures [visits etc.]) per investigators judgement:

  • After 10 patients with schizophrenia (as described above) are entered into the study, the median age of the group will be computed. Five healthy volunteers at or below the median age but greater than 18 years old and five healthy volunteers above the median but less than 55 will be entered into the study.
  • Similarly, after 10 patients with AD are entered, the median age will be computed. Five healthy volunteers at or below the median age but greater than 55 years old and five healthy volunteers above the median but less than 85 will be entered into the study.

• Subjects must exhibit reliability and physiologic capability to comply with all protocol procedures.

• Signed and dated written informed consent by date of Visit 1 in accordance with Good Clinical Practice and the local legislation. If the patient needs a legal representative, then this legal representative must give written informed consent as well.

Exclusion criteria:

• Presence of active ocular conditions with or without visual impairment due to any causes (e.g. cataract, chorioretinal macular lesion, amblyopia, active diabetic retinopathy, uncontrolled glaucoma, active inflammation or infection, etc.) in one eye or both eyes at the screening phase.

• Planned ocular treatment (e.g. intravitreal antivascular growth factor, corticosteroids) or surgery during the study period.

• Current or planned use of ocular or systemic corticosteroids.

• Current or planned use of medications known to be toxic to the retina, lens, optic nerve

• Subjects treated with more than two antipsychotic medications (including more than two dosage forms).

• Dementia in Alzheimers Disease patients, secondary to other disorders (based on clinical data and/or current laboratory findings and/or on a pre-existing cranial MRI or CCT).

• Neurological disease (other than Dementia of Alzheimer Type such as: Lewy body dementia - primary diagnosis, Huntington's disease, Parkinson's Disease encephalitis, epilepsy, vascular or multi-infarct dementia, stroke, congenital mental deficiency, or multiple sclerosis), or mental retardation.

• Subjects needing to take long-acting hypnotics or anxiolytic (i.e. Diazepam).

• For AD patients, the following drugs are prohibited for 3 months prior to randomization and for the duration of the trial:

  • tricyclic antidepressants,
  • antidepressants that are monoamine oxidase inhibitors,
  • neuroleptics with moderate or greater anticholinergic potency (e.g., chlorpromazine, fluphenazine, loxapine, perphenazine, thioridazine),
  • anticholinergic medications.
  • Intake of St. John's wort, Carbamazepine and extracts from Ginko as they are relevant CYP2C19 inducers.

• Substantial concomitant cerebrovascular disease (defined by a history of a stroke/intracranial haemorrhagia temporally related to the onset of worsening of cognitive impairment).

• Any suicidal ideation of type 4 or 5 in the Columbia Suicidal Severity Rating Scale (C-SSRS) in the past 3 months.

• Any suicidal behavior in the past 2 years (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior).

• History or diagnosis of symptomatic and unstable/uncontrolled gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, haematological or hormonal disorders.

• For female subjects:

  --Pre-menopausal women (last menstruation <=1 year prior to informed consent) who:

  • are nursing or pregnant or
  • are of child-bearing potential and are not practicing an acceptable method of birth control

• For male subjects: Men who are able to father a child, unwilling to be abstinent or use adequate contraception.

• Known history, or new diagnosis of HIV infection.

• Significant renal disease (CLCR < 30 mL/min).

• Bodyweight < 50 kg.

• Indication of liver disease.

• History of neurologic (e.g. stroke, seizure without a clear and resolved etiology, concussion accompanying loss of consciousness) or psychiatric condition.

• History of malignancy within the last 5 years, except for basal cell carcinoma.

• Planned elective surgery requiring general anaesthesia, or hospitalisation during the study period.

• Significant history of drug dependence

• Clinically significant uncompensated hearing loss. Use of hearing aids is not allowed.

• Further exclusion criteria apply.