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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Alzheimer Disease
• Intervention / Treatment: Drug: Placebo matching BI 409306 50 mg; Drug: BI 409306 25 mg; Drug: Placebo matching BI 409306 25 mg; Drug: BI 409306 50 mg

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92037
      • University of California San Diego
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
      • Memory Enhancement Center of America, Inc.
  • Texas
    • Austin, Texas, United States, 78754
      • Community Clinical Research, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI 409306 25 milligram (mg) - Alzheimer patients; Alzheimer patients received once daily (QD) orally one tablet of 25 mg of BI 409306 and two 50 mg matching placebo tablets for 14 days.	Drug: Placebo matching BI 409306 50 mg; Film-coated tablet; Drug: BI 409306 25 mg; Film-coated tablet
Experimental: BI 409306 100 mg - Alzheimer patients; Alzheimer patients received once daily (QD) orally 100 mg of BI 409306 (two 50 mg active tablets) and one 25 mg matching placebo tablet for 14 days.	Drug: Placebo matching BI 409306 25 mg; Film-coated tablet; Drug: BI 409306 50 mg; Film-coated tablet
Experimental: BI 409306 25 mg - Schizophrenia patients; Schizophrenia patients (cognitive impairment associated with schizophrenia) received once daily (QD) orally one tablet of 25 mg of BI 409306 and two 50 mg matching placebo tablets for 14 days.	Drug: Placebo matching BI 409306 50 mg; Film-coated tablet; Drug: BI 409306 25 mg; Film-coated tablet
Experimental: BI 409306 100 mg - Schizophrenia patients; Schizophrenia patients (cognitive impairment associated with schizophrenia) received once daily (QD) orally 100 mg of BI 409306 (two 50 mg active tablets) and one 25 mg matching placebo tablet for 14 days.	Drug: Placebo matching BI 409306 25 mg; Film-coated tablet; Drug: BI 409306 50 mg; Film-coated tablet
Active Comparator: BI 409306 25 mg - Healthy volunteers; Age-comparable healthy volunteers received once daily (QD) orally one tablet of 25 mg of BI 409306 and two 50 mg matching placebo tablets for 14 days.	Drug: Placebo matching BI 409306 50 mg; Film-coated tablet; Drug: BI 409306 25 mg; Film-coated tablet
Active Comparator: BI 409306 100 mg - Healthy volunteers; Age-comparable healthy volunteers received once daily (QD) 100 mg of BI 409306 (two 50 mg active tablets) and one 25 mg matching placebo tablet orally for 14 days.	Drug: Placebo matching BI 409306 25 mg; Film-coated tablet; Drug: BI 409306 50 mg; Film-coated tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percentage of Participants With Adverse Events (AEs), Coded to the Medical Dictionary for Regulatory Activities - System Organ Class Eye Disorders, as Determined by the Investigator at the End of Trial	The percentage of participants with Adverse Events (AEs), coded to the Medical Dictionary for Regulatory Activities (MedDRA) - System Organ Class (SOC) 'Eye disorders', as determined by the investigator at the End of Trial (EOT) is reported. Percentages were rounded to one decimal place.	From the first dose of trial medication until 7 days after last in-take of trial medication, 21 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percentage of Participants With Drug-related AEs as Determined by the Investigator at EOT	The percentage of participants with drug-related adverse events (AEs) as determined by the investigator at end of trial (EOT) is reported. Percentages were rounded to one decimal place.	From the first dose of trial medication until 7 days after last in-take of trial medication, 21 days.
Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Cmax,ss)	Maximum measured concentration of BI 409306 in plasma at steady-state (Cmax,ss) is reported.	Pharmacokinetic blood samples were taken at 2:00 (hours: minutes) before and 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 4:00, 6:00 (hours: minutes) after drug administration on day 14.
Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Tmax,ss)	Time from dosing to maximum measured concentration of BI 409306 in plasma at steady-state (tmax,ss) is reported.	Pharmacokinetic blood samples were taken at 2:00 (hours: minutes) before and 0:20, 0:30, 0:45, 1:00, 1:30, 2:00, 4:00, 6:00 (hours: minutes) after drug administration on day 14.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Investigators: Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2015
• Primary Completion (Actual): August 3, 2017
• Study Completion (Actual): August 10, 2017

Study Registration Dates

• First Submitted: March 17, 2015
• First Submitted That Met QC Criteria: March 17, 2015
• First Posted (Estimated): March 19, 2015

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 11, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Schizophrenia; Alzheimer Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Phosphodiesterase Inhibitors; BI 409306
• Other Study ID Numbers: 1289.27

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