Alzheimer Disease, Schizophrenia
Conditions
Brief summary
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.
Interventions
DRUGPlacebo matching BI 409306 25 mg
Film-coated tablet
DRUGPlacebo matching BI 409306 50 mg
Film-coated tablet
DRUGBI 409306 25 mg
Film-coated tablet
DRUGBI 409306 50 mg
Film-coated tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | From the first dose of trial medication until 7 days after last in-take of trial medication, 21 days. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants With Drug-related AEs as Determined by the Investigator at EOT | From the first dose of trial medication until 7 days after last in-take of trial medication, 21 days. | 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. |
| Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Cmax,ss) | 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. | Maximum measured concentration of BI 409306 in plasma at steady-state (Cmax,ss) is reported. |
| Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Tmax,ss) | 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) is reported. |
Countries
United States
Participant flow
Recruitment details
The 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
Pre-assignment details
All participants were screened for eligibility to participate in the trial. Participants attended a specialist sites which ensured that they met all strictly implemented inclusion/exclusion criteria. Participants were not to be entered to trial treatment if any one of the specific entry criteria was violated.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 10 |
| 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. | 11 |
| 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. | 10 |
| 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. | 10 |
| 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. | 9 |
| 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. | 11 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | BI 409306 25 Milligram (mg) - Alzheimer Patients | BI 409306 100 mg - Alzheimer Patients | BI 409306 25 mg - Schizophrenia Patients | BI 409306 100 mg - Schizophrenia Patients | BI 409306 25 mg - Healthy Volunteers | BI 409306 100 mg - Healthy Volunteers | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 74.5 Years STANDARD_DEVIATION 9.2 | 77.8 Years STANDARD_DEVIATION 8.6 | 40.5 Years STANDARD_DEVIATION 9.1 | 35.1 Years STANDARD_DEVIATION 7.8 | 55.9 Years STANDARD_DEVIATION 22.4 | 60.2 Years STANDARD_DEVIATION 21.6 | 57.7 Years STANDARD_DEVIATION 21.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants | 2 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 9 Participants | 9 Participants | 9 Participants | 5 Participants | 9 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 6 Participants | 5 Participants | 2 Participants | 2 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 11 Participants | 3 Participants | 5 Participants | 7 Participants | 9 Participants | 44 Participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 2 Participants | 2 Participants | 4 Participants | 5 Participants | 27 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 8 Participants | 8 Participants | 5 Participants | 6 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 11 | 0 / 10 | 0 / 10 | 0 / 9 | 0 / 11 |
| other Total, other adverse events | 6 / 10 | 6 / 11 | 6 / 10 | 4 / 10 | 5 / 9 | 11 / 11 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 | 0 / 10 | 0 / 10 | 0 / 9 | 0 / 11 |
Outcome results
Primary
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.
Time frame: From the first dose of trial medication until 7 days after last in-take of trial medication, 21 days.
Population: The treated set (TS) included all participants who were documented to have been administered at least 1 dose of investigational treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 409306 25 Milligram (mg) - Alzheimer Patients | 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 | 40.0 Percentage of participants |
| BI 409306 100 mg - Alzheimer Patients | 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 | 27.3 Percentage of participants |
| BI 409306 25 mg - Schizophrenia Patients | 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 | 0.0 Percentage of participants |
| BI 409306 100 mg - Schizophrenia Patients | 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 | 20.0 Percentage of participants |
| BI 409306 25 mg - Healthy Volunteers | 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 | 22.2 Percentage of participants |
| BI 409306 100 mg - Healthy Volunteers | 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 | 72.7 Percentage of participants |
Secondary
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.
Time frame: 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.
Population: The Pharmacokinetic (PK) set (PKS) included all participants in the TS who provided at least 1 evaluable observation for at least 1 PK endpoint without important protocol violations relevant to the evaluation of PK. Only participants with evaluable results for this PK parameter are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 409306 25 Milligram (mg) - Alzheimer Patients | Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Cmax,ss) | 696 nanomoles per litre (nmol/L) | Geometric Coefficient of Variation 86.6 |
| BI 409306 100 mg - Alzheimer Patients | Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Cmax,ss) | 2290 nanomoles per litre (nmol/L) | Geometric Coefficient of Variation 115 |
| BI 409306 25 mg - Schizophrenia Patients | Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Cmax,ss) | 202 nanomoles per litre (nmol/L) | Geometric Coefficient of Variation 72.1 |
| BI 409306 100 mg - Schizophrenia Patients | Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Cmax,ss) | 1050 nanomoles per litre (nmol/L) | Geometric Coefficient of Variation 60.4 |
| BI 409306 25 mg - Healthy Volunteers | Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Cmax,ss) | 466 nanomoles per litre (nmol/L) | Geometric Coefficient of Variation 37.5 |
| BI 409306 100 mg - Healthy Volunteers | Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Cmax,ss) | 1550 nanomoles per litre (nmol/L) | Geometric Coefficient of Variation 153 |
Secondary
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.
Time frame: From the first dose of trial medication until 7 days after last in-take of trial medication, 21 days.
Population: The treated set (TS) included all participants who were documented to have been administered at least 1 dose of investigational treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 409306 25 Milligram (mg) - Alzheimer Patients | The Percentage of Participants With Drug-related AEs as Determined by the Investigator at EOT | 30.0 Percentage of participants |
| BI 409306 100 mg - Alzheimer Patients | The Percentage of Participants With Drug-related AEs as Determined by the Investigator at EOT | 36.4 Percentage of participants |
| BI 409306 25 mg - Schizophrenia Patients | The Percentage of Participants With Drug-related AEs as Determined by the Investigator at EOT | 0.0 Percentage of participants |
| BI 409306 100 mg - Schizophrenia Patients | The Percentage of Participants With Drug-related AEs as Determined by the Investigator at EOT | 20.0 Percentage of participants |
| BI 409306 25 mg - Healthy Volunteers | The Percentage of Participants With Drug-related AEs as Determined by the Investigator at EOT | 33.3 Percentage of participants |
| BI 409306 100 mg - Healthy Volunteers | The Percentage of Participants With Drug-related AEs as Determined by the Investigator at EOT | 81.8 Percentage of participants |
Secondary
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.
Time frame: 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.
Population: The Pharmacokinetic (PK) set (PKS) included all participants in the TS who provided at least 1 evaluable observation for at least 1 PK endpoint without important protocol violations relevant to the evaluation of PK. Only participants with evaluable results for this PK parameter are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 409306 25 Milligram (mg) - Alzheimer Patients | Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Tmax,ss) | 0.750 Hours |
| BI 409306 100 mg - Alzheimer Patients | Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Tmax,ss) | 1.000 Hours |
| BI 409306 25 mg - Schizophrenia Patients | Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Tmax,ss) | 0.500 Hours |
| BI 409306 100 mg - Schizophrenia Patients | Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Tmax,ss) | 0.525 Hours |
| BI 409306 25 mg - Healthy Volunteers | Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Tmax,ss) | 0.500 Hours |
| BI 409306 100 mg - Healthy Volunteers | Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Tmax,ss) | 0.917 Hours |