Healthy
Conditions
Brief summary
The main objective of this trail is to investigate if and to what extent BI 409306, BI 425809 and lamotrigine attenuate ketamine induced cognitive deficits.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
3-treatment period design
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Healthy male subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests 2. Age of 18 to 55 years (inclusive) 3. BMI of 18.5 to 32 kg/m2 (inclusive) 4. Signed and dated written informed consent prior to admission to the study, in accordance with GCP and local legislation 5. Male subjects who meet any of the following criteria from at least 30 days before the first administration of trial medication until 30 days after trial completion: * Use of adequate contraception, e.g. use of condom (male subjects) plus any of the following methods (female partners): intrauterine device, hormonal contraception (e.g. implants, injectables, combined oral or vaginal contraceptives) that started at least 2 months prior to first drug administration, or barrier method (e.g. diaphragm with spermicide) * Sexually abstinent * Vasectomised (vasectomy at least 1 year prior to enrolment) * Surgically sterilised female partner (including hysterectomy, bilateral tubal occlusion or bilateral oophorectomy) * Postmenopausal female partner, defined as at least 1 year of spontaneous amenorrhea
Exclusion criteria
1. Any finding in the medical examination (including ECG) deviating from normal and assessed as clinically relevant by the investigator 2. Repeated measurement of systolic blood pressure outside the range of 100 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 bpm 3. Any laboratory value outside the reference range that the investigator considers to be of clinical relevance 4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator 5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders 6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair) 7. History of diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders 8. History of relevant orthostatic hypotension, fainting spells, or blackouts Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Paired Associate Learning (PAL) Total Errors Adjusted (PALTEA28) on Ketamine | At 4:20 and 5:06 hours:minutes after first drug administration in each treatment period. | Paired Associate Learning (PAL) assesses visual memory and new learning. Boxes are displayed on the screen and open in turn to reveal a number of patterns. Participants are instructed to try to remember the location in which each pattern was shown. After all the boxes have been opened, each pattern is then shown in the center of the screen in a randomised order, and the participant touches the box in which the pattern was located. If an error is made, all the patterns are re-presented to remind the participant of their locations. The PALTEA28 evaluates the number of errors committed by the subject plus an adjustment for the estimated number of errors they would have made on any stages that were not reached. Calculated across all assessed two, four, six and eight box trials. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Spatial Working Memory (SWM) Between Errors (BE468) on Ketamine | At 4:20 and 5:06 hours:minutes after first drug administration in each treatment period. | SWM assesses the ability of the participant to retain spatial information and manipulate it in working memory. A number of coloured boxes are presented on the screen, and the computer hides a token in these boxes one at a time. The participant is instructed to touch the boxes in turn to search for the token that has been hidden. The key task instruction is that the computer will never hide a token in the same coloured box twice in the same problem. The SWMBE468 evaluates the number of times the subject incorrectly revisits a box in which a token has previously been found. Calculated across all assessed four, six and eight token trials. |
| Rapid Visual Information Processing A' Prime (RVPA) on Ketamine | At 4:20 and 5:06 hours:minutes after first drug administration in each treatment period. | Rapid Visual Information Processing (RVP) is a sensitive measure of sustained attention, outputting measures of response accuracy, target sensitivity and reaction times. The RVPA is a quantitative measure for a subject's sensitivity to the target sequence regardless of response tendency. The RVPA ranges from 0.00 to 1.00. The higher the RVPA value, the better the sensitivity to the target sequence one has. |
Countries
United States
Participant flow
Recruitment details
The clinical trial was performed as a randomised, placebo-controlled, double-blind, doubledummy, three-way crossover trial in healthy male subjects to investigate if and to what extent BI 409306, BI 425809, and lamotrigine attenuated ketamine-induced cognitive deficits
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.
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Discontinuation of trial treatment | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Other than listed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total |
|---|---|
| Age, Continuous | 36.9 Years STANDARD_DEVIATION 8.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 37 | 0 / 24 | 0 / 25 | 0 / 26 |
| other Total, other adverse events | 10 / 37 | 5 / 24 | 5 / 25 | 2 / 26 |
| serious Total, serious adverse events | 0 / 37 | 0 / 24 | 0 / 25 | 0 / 26 |
Outcome results
Primary
Paired Associate Learning (PAL) Total Errors Adjusted (PALTEA28) on Ketamine
Paired Associate Learning (PAL) assesses visual memory and new learning. Boxes are displayed on the screen and open in turn to reveal a number of patterns. Participants are instructed to try to remember the location in which each pattern was shown. After all the boxes have been opened, each pattern is then shown in the center of the screen in a randomised order, and the participant touches the box in which the pattern was located. If an error is made, all the patterns are re-presented to remind the participant of their locations. The PALTEA28 evaluates the number of errors committed by the subject plus an adjustment for the estimated number of errors they would have made on any stages that were not reached. Calculated across all assessed two, four, six and eight box trials.
Time frame: At 4:20 and 5:06 hours:minutes after first drug administration in each treatment period.
Population: Pharmacodynamic (PD) set (PDS): PD analyses were based on the PDS which was defined as all randomised subjects who performed the post ketamine tests in at least one period. Number of participants differs due to incomplete crossover design.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (R) | Paired Associate Learning (PAL) Total Errors Adjusted (PALTEA28) on Ketamine | 24.169 Errors | Standard Error 2.5972 |
| 25 mg BI 425809 (T3) | Paired Associate Learning (PAL) Total Errors Adjusted (PALTEA28) on Ketamine | 23.829 Errors | Standard Error 3.2275 |
| 50 mg BI 409306 (T2) | Paired Associate Learning (PAL) Total Errors Adjusted (PALTEA28) on Ketamine | 28.170 Errors | Standard Error 3.2334 |
| 300 mg Lamotrigine (T1) | Paired Associate Learning (PAL) Total Errors Adjusted (PALTEA28) on Ketamine | 22.911 Errors | Standard Error 3.085 |
Comparison: A linear mixed effects model, i.e. analyses of covariance (ANCOVA) was used for analysis of the primary endpoint. This model included effects for sequence, subject within sequence, period, baseline values (pre-ketamine baseline and on-ketamine baseline) and treatment. The effect 'subject within sequence' were considered as random, whereas the other effects were considered as fixed.p-value: 0.929695% CI: [-7.975, 7.297]ANCOVA
Comparison: A linear mixed effects model, i.e. analyses of covariance (ANCOVA) was used for analysis of the primary endpoint. This model included effects for sequence, subject within sequence, period, baseline values (pre-ketamine baseline and on-ketamine baseline) and treatment. The effect 'subject within sequence' were considered as random, whereas the other effects were considered as fixed.p-value: 0.29995% CI: [-3.631, 11.634]ANCOVA
Comparison: A linear mixed effects model, i.e. analyses of covariance (ANCOVA) was used for analysis of the primary endpoint. This model included effects for sequence, subject within sequence, period, baseline values (pre-ketamine baseline and on-ketamine baseline) and treatment. The effect 'subject within sequence' were considered as random, whereas the other effects were considered as fixed.p-value: 0.732295% CI: [-8.565, 6.05]ANCOVA
Secondary
Rapid Visual Information Processing A' Prime (RVPA) on Ketamine
Rapid Visual Information Processing (RVP) is a sensitive measure of sustained attention, outputting measures of response accuracy, target sensitivity and reaction times. The RVPA is a quantitative measure for a subject's sensitivity to the target sequence regardless of response tendency. The RVPA ranges from 0.00 to 1.00. The higher the RVPA value, the better the sensitivity to the target sequence one has.
Time frame: At 4:20 and 5:06 hours:minutes after first drug administration in each treatment period.
Population: Pharmacodynamic (PD) set (PDS): PD analyses were based on the PDS which was defined as all randomised subjects who performed the post ketamine tests in at least one period. Number of participants differs due to incomplete crossover design.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (R) | Rapid Visual Information Processing A' Prime (RVPA) on Ketamine | 0.8743 Score on a scale | Standard Error 0.00702 |
| 25 mg BI 425809 (T3) | Rapid Visual Information Processing A' Prime (RVPA) on Ketamine | 0.8796 Score on a scale | Standard Error 0.00807 |
| 50 mg BI 409306 (T2) | Rapid Visual Information Processing A' Prime (RVPA) on Ketamine | 0.8800 Score on a scale | Standard Error 0.0081 |
| 300 mg Lamotrigine (T1) | Rapid Visual Information Processing A' Prime (RVPA) on Ketamine | 0.9075 Score on a scale | Standard Error 0.00782 |
Comparison: A linear mixed effects model, i.e. analyses of covariance (ANCOVA) was used for analysis of the secondary endpoint. This model included effects for sequence, subject within sequence, period, baseline values (pre-ketamine baseline and on-ketamine baseline) and treatment. The effect 'subject within sequence' were considered as random, whereas the other effects were considered as fixed.p-value: 0.508195% CI: [-0.0106, 0.0213]ANCOVA
Comparison: A linear mixed effects model, i.e. analyses of covariance (ANCOVA) was used for analysis of the secondary endpoint. This model included effects for sequence, subject within sequence, period, baseline values (pre-ketamine baseline and on-ketamine baseline) and treatment. The effect 'subject within sequence' were considered as random, whereas the other effects were considered as fixed.p-value: 0.472395% CI: [-0.0102, 0.0217]ANCOVA
Comparison: A linear mixed effects model, i.e. analyses of covariance (ANCOVA) was used for analysis of the secondary endpoint. This model included effects for sequence, subject within sequence, period, baseline values (pre-ketamine baseline and on-ketamine baseline) and treatment. The effect 'subject within sequence' were considered as random, whereas the other effects were considered as fixed.p-value: <0.000195% CI: [0.018, 0.0486]ANCOVA
Secondary
Spatial Working Memory (SWM) Between Errors (BE468) on Ketamine
SWM assesses the ability of the participant to retain spatial information and manipulate it in working memory. A number of coloured boxes are presented on the screen, and the computer hides a token in these boxes one at a time. The participant is instructed to touch the boxes in turn to search for the token that has been hidden. The key task instruction is that the computer will never hide a token in the same coloured box twice in the same problem. The SWMBE468 evaluates the number of times the subject incorrectly revisits a box in which a token has previously been found. Calculated across all assessed four, six and eight token trials.
Time frame: At 4:20 and 5:06 hours:minutes after first drug administration in each treatment period.
Population: Pharmacodynamic (PD) set (PDS): PD analyses were based on the PDS which was defined as all randomised subjects who performed the post ketamine tests in at least one period. Number of participants differs due to incomplete crossover design.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (R) | Spatial Working Memory (SWM) Between Errors (BE468) on Ketamine | 15.684 Errors | Standard Error 1.3412 |
| 25 mg BI 425809 (T3) | Spatial Working Memory (SWM) Between Errors (BE468) on Ketamine | 16.032 Errors | Standard Error 1.5427 |
| 50 mg BI 409306 (T2) | Spatial Working Memory (SWM) Between Errors (BE468) on Ketamine | 14.600 Errors | Standard Error 1.5704 |
| 300 mg Lamotrigine (T1) | Spatial Working Memory (SWM) Between Errors (BE468) on Ketamine | 12.826 Errors | Standard Error 1.5005 |
Comparison: A linear mixed effects model, i.e. analyses of covariance (ANCOVA) was used for analysis of the secondary endpoint. This model included effects for sequence, subject within sequence, period, baseline values (pre-ketamine baseline and on-ketamine baseline) and treatment. The effect 'subject within sequence' were considered as random, whereas the other effects were considered as fixed.p-value: 0.824995% CI: [-2.776, 3.471]ANCOVA
Comparison: A linear mixed effects model, i.e. analyses of covariance (ANCOVA) was used for analysis of the secondary endpoint. This model included effects for sequence, subject within sequence, period, baseline values (pre-ketamine baseline and on-ketamine baseline) and treatment. The effect 'subject within sequence' were considered as random, whereas the other effects were considered as fixed.p-value: 0.497395% CI: [-4.26, 2.091]ANCOVA
Comparison: A linear mixed effects model, i.e. analyses of covariance (ANCOVA) was used for analysis of the secondary endpoint. This model included effects for sequence, subject within sequence, period, baseline values (pre-ketamine baseline and on-ketamine baseline) and treatment. The effect 'subject within sequence' were considered as random, whereas the other effects were considered as fixed.p-value: 0.065895% CI: [-5.909, 0.192]ANCOVA