Schizophrenia
Conditions
Brief summary
The primary objective of the current study is to investigate the safety and tolerability of BI 409306 in schizophrenic patients following oral administration of multiple low, medium, and high doses over 14 days. A secondary objective is the exploration of the pharmacokinetics and pharmacodynamics of BI 409306 in schizophrenic patients.
Interventions
DRUGPlacebo
matching placebo
DRUGBI 409306
BI 409306
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Patients with established diagnoses of schizophrenia (per Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)) with the following clinical features: 1. Clinically stable and are in the residual (non-acute) phase of their illness for at least 8 weeks. 2. Maintained on current antipsychotic medications and current dose for at least 8 weeks. 3. Have no more than a moderate severity rating on hallucinations and delusions (e.g. Brief Psychiatric Rating Scale (BPRS) Hallucinatory Behavior or Unusual Thought Content item score \< or =4). 4. Have no more than a moderate severity rating on positive formal thought disorder (e.g. BPRS Conceptual Disorganization item score \< or =4). 5. Have no more than a moderate severity rating on negative symptoms (Positive and Negative Syndrome Scale negative syndrome total score \<15). 6. Have a minimal level of extrapyramidal symptoms (e.g. Simpson-Angus Scale total score \< 6) and depressive symptoms (e.g. Calgary Depression Scale total score \< 10). 2. Male or female patients age \> or = 18 and \< or =55 years. 3. Patients must exhibit reliability and physiologic capability to comply with all protocol procedures. 4. Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation. If the patient needs a legal representative, then this legal representative must give written consent as well.
Exclusion criteria
1. Patient treated with more than one antipsychotic or not stabilized on antipsychotic treatment, or having had electroconvulsive therapy within the last 30 days 2. Patient's cognitive impairment severity compromises the validity of the cognitive outcome measures, in the clinical judgment of the investigator. 3. Any suicidal behavior in the past 2 years (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior). 4. Any suicidal ideation of type 4 or 5 in the Columbia Suicidal Severity Rating Scale (C-SSRS) in the past 3 months (i.e. active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent). 5. Any finding of the medical examination (including BP, PR and ECG) or laboratory value deviating from normal and of clinical relevance in the judgment of the investigator. 6. Any evidence of a clinically relevant concomitant disease. 7. History or diagnosis of symptomatic and unstable/uncontrolled gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, haematological or hormonal disorders. 8. Female patients that are of child-bearing potential or currently breastfeeding. 9. Known history, or new diagnosis per screening labs, of HIV infection. 10. History of neurologic (e.g. stroke, seizure without a clear and resolved etiology, concussion accompanying loss of consciousness) or psychiatric condition that the investigator deems may interfere with interpretability of data 11. History of malignancy within the last 5 years, except for basal cell carcinoma. 12. Planned elective surgery requiring general anaesthesia, or hospitalisation for more than 1 day during the study period. 13. Any other clinical condition that, in the opinion of the investigator, would jeopardize a patient's safety while participating in this clinical trial. 14. Significant history of drug dependence or abuse (including alcohol, as defined in Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) or in the opinion of the investigator) within the last two years prior to informed consent, or a positive urine drug screen for cocaine, opioid, phencyclidine (PCP), amphetamine or marijuana at screening. 15. Participation in another trial with an investigational drug or procedure within 30 days prior to screening or previous participation in any BI 409306 study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Drug-related Adverse Events | From first drug administration until 30 days after last drug administration, up to 44 days. | Number of participants with drug-related adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Cmax,ss) | 2 hours (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h, 24h, 48h and 72h after drug administration on day 14. | Maximum measured concentration of BI 409306 in plasma at steady-state (Cmax,ss) is presented. |
| Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma After Single Dose (Tmax) | 2 hours (h) before first drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h and 14h after first drug administration. | Time from dosing to maximum measured concentration of BI 409306 in plasma after single dose (tmax) is presented. |
| Maximum Measured Concentration of BI 409306 in Plasma After Single Dose (Cmax) | 2 hours (h) before first drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h and 14h after first drug administration | Maximum measured concentration of BI 409306 in plasma after single dose (Cmax) is presented. |
| Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 Extrapolated to Infinity After a Single Dose (AUC0-infinity) | 2 hours (h) before first drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h and 14h after first drug administration. | Area under the concentration-time curve of BI 409306 in plasma over the time interval from 0 extrapolated to infinity after a single dose (AUC0-infinity) is presented. |
| Area Under the Concentration-time Curve of BI 409306 in Plasma at Steady State Over a Uniform Dosing Interval Tau (AUCtau,ss) | 2 hours (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h, 24h, 48h and 72h after drug administration on day 14. | Area under the concentration-time curve of BI 409306 in plasma at steady state over a uniform dosing interval tau (AUCtau,ss) is presented. |
| Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Tmax,ss) | 2 hours (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h, 24h, 48h and 72h after drug administration on day 14. | Time from dosing to maximum measured concentration of BI 409306 in plasma at steady-state (tmax,ss) is presented. |
Countries
United States
Participant flow
Recruitment details
This was a randomized, double-blind, parallel-group, placebo-controlled trial in patients with mild-to-moderate schizophrenia. Patients were enrolled in the study once informed consent had been obtained. Patients who subsequently met all eligibility criteria at screening were randomized in a 1:1:1:1 ratio to one of four treatment groups.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| BI 409306 25mg Patients received BI 409306 25mg (low dose), administered orally, once daily for 14 days | 10 |
| BI 409306 50mg Patients received BI 409306 50mg (medium dose), administered orally, once daily for 14 days | 10 |
| BI 409306 100mg Patients received BI 409306 100mg (high dose), administered orally, once daily for 14 days | 10 |
| Placebo Patients received placebo, administered orally, once daily for 14 days | 10 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | BI 409306 25mg | BI 409306 50mg | BI 409306 100mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 37.9 Years STANDARD_DEVIATION 9.5 | 42.5 Years STANDARD_DEVIATION 9 | 42.5 Years STANDARD_DEVIATION 8.4 | 37.8 Years STANDARD_DEVIATION 9.5 | 40.2 Years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 2 Participants | 2 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 6 Participants | 8 Participants | 8 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 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 |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 4 Participants | 7 Participants | 5 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 6 Participants | 3 Participants | 5 Participants | 19 Participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 10 Participants | 7 Participants | 10 Participants | 8 Participants | 35 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 10 | 9 / 10 | 6 / 10 | 4 / 10 | 23 / 40 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 40 |
Outcome results
Primary
Number of Participants With Drug-related Adverse Events
Number of participants with drug-related adverse events.
Time frame: From first drug administration until 30 days after last drug administration, up to 44 days.
Population: Treated set which included all randomized patients who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 409306 25mg | Number of Participants With Drug-related Adverse Events | 1 Participants |
| BI 409306 50mg | Number of Participants With Drug-related Adverse Events | 3 Participants |
| BI 409306 100mg | Number of Participants With Drug-related Adverse Events | 2 Participants |
| Placebo | Number of Participants With Drug-related Adverse Events | 3 Participants |
Secondary
Area Under the Concentration-time Curve of BI 409306 in Plasma at Steady State Over a Uniform Dosing Interval Tau (AUCtau,ss)
Area under the concentration-time curve of BI 409306 in plasma at steady state over a uniform dosing interval tau (AUCtau,ss) is presented.
Time frame: 2 hours (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h, 24h, 48h and 72h after drug administration on day 14.
Population: Pharmacokinetic (PK) set which included all participants who received at least one dose of BI 409306 and had no important protocol violations relevant to the evaluation of PK and provided at least one evaluable observation for a PK endpoint. Two patients were discontinued from treatment after 6 days (25 mg group) or 5 days (50 mg group) after withdrawing consent.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 409306 25mg | Area Under the Concentration-time Curve of BI 409306 in Plasma at Steady State Over a Uniform Dosing Interval Tau (AUCtau,ss) | 147 nanomole*hour/Litre (nmol*h/L) | Geometric Coefficient of Variation 112 |
| BI 409306 50mg | Area Under the Concentration-time Curve of BI 409306 in Plasma at Steady State Over a Uniform Dosing Interval Tau (AUCtau,ss) | 969 nanomole*hour/Litre (nmol*h/L) | Geometric Coefficient of Variation 104 |
| BI 409306 100mg | Area Under the Concentration-time Curve of BI 409306 in Plasma at Steady State Over a Uniform Dosing Interval Tau (AUCtau,ss) | 2280 nanomole*hour/Litre (nmol*h/L) | Geometric Coefficient of Variation 86.8 |
Secondary
Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 Extrapolated to Infinity After a Single Dose (AUC0-infinity)
Area under the concentration-time curve of BI 409306 in plasma over the time interval from 0 extrapolated to infinity after a single dose (AUC0-infinity) is presented.
Time frame: 2 hours (h) before first drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h and 14h after first drug administration.
Population: Pharmacokinetic (PK) set which included all participants who received at least one dose of BI 409306 and had no important protocol violations relevant to the evaluation of PK and provided at least one evaluable observation for a PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 409306 25mg | Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 Extrapolated to Infinity After a Single Dose (AUC0-infinity) | 217 nanomole*hour/Litre (nmol*h/L) | Geometric Coefficient of Variation 107 |
| BI 409306 50mg | Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 Extrapolated to Infinity After a Single Dose (AUC0-infinity) | 770 nanomole*hour/Litre (nmol*h/L) | Geometric Coefficient of Variation 98.4 |
| BI 409306 100mg | Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 Extrapolated to Infinity After a Single Dose (AUC0-infinity) | 2020 nanomole*hour/Litre (nmol*h/L) | Geometric Coefficient of Variation 108 |
Secondary
Maximum Measured Concentration of BI 409306 in Plasma After Single Dose (Cmax)
Maximum measured concentration of BI 409306 in plasma after single dose (Cmax) is presented.
Time frame: 2 hours (h) before first drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h and 14h after first drug administration
Population: Pharmacokinetic (PK) set which included all participants who received at least one dose of BI 409306 and had no important protocol violations relevant to the evaluation of PK and provided at least one evaluable observation for a PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 409306 25mg | Maximum Measured Concentration of BI 409306 in Plasma After Single Dose (Cmax) | 138 nanomole/Litre (nmol/L) | Geometric Coefficient of Variation 91.9 |
| BI 409306 50mg | Maximum Measured Concentration of BI 409306 in Plasma After Single Dose (Cmax) | 431 nanomole/Litre (nmol/L) | Geometric Coefficient of Variation 73.3 |
| BI 409306 100mg | Maximum Measured Concentration of BI 409306 in Plasma After Single Dose (Cmax) | 998 nanomole/Litre (nmol/L) | Geometric Coefficient of Variation 106 |
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 presented.
Time frame: 2 hours (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h, 24h, 48h and 72h after drug administration on day 14.
Population: Pharmacokinetic (PK) set which included all participants who received at least one dose of BI 409306 and had no important protocol violations relevant to the evaluation of PK and provided at least one evaluable observation for a PK endpoint. Two patients were discontinued from treatment after 6 days (25 mg group) or 5 days (50 mg group) after withdrawing consent.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 409306 25mg | Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Cmax,ss) | 99.2 nanomole/Litre (nmol/L) | Geometric Coefficient of Variation 86.8 |
| BI 409306 50mg | Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Cmax,ss) | 631 nanomole/Litre (nmol/L) | Geometric Coefficient of Variation 90.9 |
| BI 409306 100mg | Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Cmax,ss) | 1290 nanomole/Litre (nmol/L) | Geometric Coefficient of Variation 74.4 |
Secondary
Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma After Single Dose (Tmax)
Time from dosing to maximum measured concentration of BI 409306 in plasma after single dose (tmax) is presented.
Time frame: 2 hours (h) before first drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h and 14h after first drug administration.
Population: Pharmacokinetic (PK) set which included all participants who received at least one dose of BI 409306 and had no important protocol violations relevant to the evaluation of PK and provided at least one evaluable observation for a PK endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 409306 25mg | Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma After Single Dose (Tmax) | 0.625 Hours |
| BI 409306 50mg | Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma After Single Dose (Tmax) | 0.625 Hours |
| BI 409306 100mg | Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma After Single Dose (Tmax) | 0.750 Hours |
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 presented.
Time frame: 2 hours (h) before drug administration and 10minutes (min), 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h, 24h, 48h and 72h after drug administration on day 14.
Population: Pharmacokinetic (PK) set which included all participants who received at least one dose of BI 409306 and had no important protocol violations relevant to the evaluation of PK and provided at least one evaluable observation for a PK endpoint. Two patients were discontinued from treatment after 6 days (25 mg group) or 5 days (50 mg group) after withdrawing consent.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 409306 25mg | Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Tmax,ss) | 0.750 Hours |
| BI 409306 50mg | Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Tmax,ss) | 0.333 Hours |
| BI 409306 100mg | Time From Dosing to Maximum Measured Concentration of BI 409306 in Plasma at Steady-state (Tmax,ss) | 0.625 Hours |