Schizophrenia
Conditions
Brief summary
The purpose of this PET study is to verify the binding of Lu AF35700 after multiple oral dosing at the dopamine and the serotonin receptors in male patients with schizophrenia.
Detailed description
There were 3 to 4 cohorts of 2 patients per receptor group. Lu AF35700 was administered as multiple oral doses for up to 21 days before the PET scans were performed. The doses in all groups were selected with the aim of characterising the exposure response (occupancy) curve. The doses for all groups, with the exception of A1, B1, and C1, were subject to change within the dose range already investigated and found tolerable. The next dose for the groups was established at a dosing conference based on an evaluation of the occupancy obtained, and safety, tolerability, and pharmacokinetic data from all previous cohorts.
Interventions
DRUGLu AF35700
5 mg tablets for oral administration
Sponsors
H. Lundbeck A/S
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. The patient is a man aged between ≤18 and ≥60 years 2. BMI of ≥19 kg/m2 to ≤ 37 kg/m2 3. The patient has a primary diagnosis of schizophrenia according to DSM-5™ (code 295.90) 4. The patient has a Clinical Global Impression - Severity of Illness (CGI-S) score ≤ 4 (moderately ill) at screening and safety baseline 5. The patient is currently under oral therapy with one or more of the antipsychotic medications listed in Appendix II. 6. The patient has a Positive and Negative Syndrome Scale (PANSS) total score ≤ 80 7. The patient has a score of ≤ 4 (moderate) on the following PANSS items at screening and at safety baseline: P7 (hostility), G8 (uncooperativeness)
Exclusion criteria
1. The patient experienced an acute exacerbation requiring hospitalization within the last 3 months. 2. The patient experienced an acute exacerbation requiring change in antipsychotic medication (with reference to drug or dose) within the last 4 weeks. 3. The patient has a diagnosis or history of substance use disorder (except nicotine) according to DSM-5-TR® criteria ≤3 months prior to screening 4. The patient is at significant risk of harming himself or others according to the investigator's judgment or as indicated by an answer of yes to the question 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) at the Screening Visit within the last six months on the lifetime version of C-SSRS. 5. Based on investigators judgment the patient has a medical or neurological disorder or treatment for such disorder that could interfere with the study treatment or impair treatment compliance. 6. The patient has had past episodes of extrapyramidal symptoms (EPS) under current medication within the last 3 month 7. The patient takes other medication than those listed as allowed concomitant medication in Appendix III 8. The patient is occupationally exposed to significant levels of ionizing radiation. Other protocol-defined inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Emax D1 Dopamine | Change from baseline to 344 hours post last dose | Maximal target occupancy (Emax) on the D1 dopamine receptor using PET with \[11C\]-NNC 112 tracer compound. The relationship between systemic exposure of Lu AF35700 and D1 dopamine occupancy was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and plasma concentration which gives 50% of Emax (EC50). Both Emax and EC50 were estimated using one model for all post-baseline scans combined. No statistical testing was performed. |
| EC50 D1 Dopamine | Change from baseline to 344 hours post last dose | Plasma concentration which gives 50% of Emax (EC50) The relationship between systemic exposure of Lu AF35700 and D1 dopamine occupancy was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and plasma concentration which gives 50% of Emax (EC50). Both Emax and EC50 were estimated using one model for all post-baseline scans combined. No statistical testing was performed. |
| Emax D2 Dopamine | Change from baseline to 344 hours post last dose | Maximal target occupancy (Emax) on the D2 dopamine receptor using PET with \[11C\]-Raclopride tracer compound. The relationship between systemic exposure of Lu AF35700 and D2 dopamine occupancy was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and plasma concentration which gives 50% of Emax (EC50). Emax was estimated using one model for all post-baseline scans combined. No statistical testing was performed. |
| EC50 D2 Dopamine | Change from baseline to 344 hours post last dose | Plasma concentration which gives 50% of Emax (EC50) The relationship between systemic exposure of Lu AF35700+Lu AF36152 and D2 dopamine occupancy was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and plasma concentration which gives 50% of Emax (EC50). Both Emax and EC50 were estimated using one model for all post-baseline scans combined. No statistical testing was performed. |
| Emax 5-HT6 Serotonin | Change from baseline to 344 hours post last dose | Maximal target occupancy (Emax) on the 5-HT6 receptor using PET with \[11C\]-Lu AE60157 as tracer compound. The relationship between systemic exposure of Lu AF35700+Lu AF36152 and 5-HT6 occupancy was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and plasma concentration which gives 50% of Emax (EC50). Emax was estimated using one model for all post-baseline scans combined. No statistical testing was performed. |
| EC50 5-HT6 Serotonin | Change from baseline to 344 hours post last dose | Plasma concentration which gives 50% of Emax (EC50) The relationship between systemic exposure of Lu AF35700+Lu AF36152 and 5\_HT6 serotonin occupancy was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and plasma concentration which gives 50% of Emax (EC50). Both Emax and EC50 were estimated using one model for all post-baseline scans combined. No statistical testing was performed. |
Countries
United States
Participant flow
Pre-assignment details
The study consisted of 6 to 8 patients assigned to one of 3 groups (D1, D2, or 5-HT6). Each group characterising the Lu AF35700 plasma concentration/receptor occupance (RO) relationship of 1 of 3 receptors using 1 of 3 ligands: Group D1 using \[11C\]-NNC 112, Group D2 using \[11C\]-raclopride, and Group 5-HT6 using \[11C\]-Lu AE60157
Participants by arm
| Arm | Count |
|---|---|
| Lu AF35700 (Group D1) Lu AF35700: Daily dosing for up to 21 days (10 mg for 21 days for Cohort A1, 10 mg for 3 days and 15 mg for 18 days for Cohort A2, and 10 mg for 3 days and 20 mg for 17 days for Cohort A3).
D1 receptor occupancy measured using \[11C\]-NNC 112. | 6 |
| Lu AF35700 (Group D2) Lu AF35700: Daily dosing for 21 days (10 mg for 3 days and 20 mg for 18 days).
D2 receptor occupancy measured using \[11C\]-raclopride. | 8 |
| Lu AF35700 (Group 5-HT6) Lu AF35700: Cohort C1: Daily dosing with 10 mg for 21 days, Cohort C2: Daily dosing with 5 mg for 21 days, Cohort C3: Daily dosing with 5 mg for 7 days, and Cohort C4: Dosing with 5 mg for 4 days (Days 1, 3, 5, and 7).
5-HT6 receptor occupancy measured using \[11C\]-Lu AE60157. | 8 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Lu AF35700 (Group D1) | Lu AF35700 (Group D2) | Lu AF35700 (Group 5-HT6) | Total |
|---|---|---|---|---|
| Age, Continuous | 41 years | 39 years | 43 years | 41 years |
| Region of Enrollment United States | 6 participants | 8 participants | 8 participants | 22 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 8 Participants | 8 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 5 / 6 | 6 / 8 | 7 / 8 |
| serious Total, serious adverse events | 1 / 6 | 1 / 8 | 1 / 8 |
Outcome results
Primary
EC50 5-HT6 Serotonin
Plasma concentration which gives 50% of Emax (EC50) The relationship between systemic exposure of Lu AF35700+Lu AF36152 and 5\_HT6 serotonin occupancy was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and plasma concentration which gives 50% of Emax (EC50). Both Emax and EC50 were estimated using one model for all post-baseline scans combined. No statistical testing was performed.
Time frame: Change from baseline to 344 hours post last dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lu AF35700 (Group D1) | EC50 5-HT6 Serotonin | 0.4 ng/mL |
Primary
EC50 D1 Dopamine
Plasma concentration which gives 50% of Emax (EC50) The relationship between systemic exposure of Lu AF35700 and D1 dopamine occupancy was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and plasma concentration which gives 50% of Emax (EC50). Both Emax and EC50 were estimated using one model for all post-baseline scans combined. No statistical testing was performed.
Time frame: Change from baseline to 344 hours post last dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lu AF35700 (Group D1) | EC50 D1 Dopamine | 1.4 ng/mL |
Primary
EC50 D2 Dopamine
Plasma concentration which gives 50% of Emax (EC50) The relationship between systemic exposure of Lu AF35700+Lu AF36152 and D2 dopamine occupancy was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and plasma concentration which gives 50% of Emax (EC50). Both Emax and EC50 were estimated using one model for all post-baseline scans combined. No statistical testing was performed.
Time frame: Change from baseline to 344 hours post last dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lu AF35700 (Group D1) | EC50 D2 Dopamine | 29.1 ng/mL |
Primary
Emax 5-HT6 Serotonin
Maximal target occupancy (Emax) on the 5-HT6 receptor using PET with \[11C\]-Lu AE60157 as tracer compound. The relationship between systemic exposure of Lu AF35700+Lu AF36152 and 5-HT6 occupancy was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and plasma concentration which gives 50% of Emax (EC50). Emax was estimated using one model for all post-baseline scans combined. No statistical testing was performed.
Time frame: Change from baseline to 344 hours post last dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lu AF35700 (Group D1) | Emax 5-HT6 Serotonin | 88.1 percentage |
Primary
Emax D1 Dopamine
Maximal target occupancy (Emax) on the D1 dopamine receptor using PET with \[11C\]-NNC 112 tracer compound. The relationship between systemic exposure of Lu AF35700 and D1 dopamine occupancy was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and plasma concentration which gives 50% of Emax (EC50). Both Emax and EC50 were estimated using one model for all post-baseline scans combined. No statistical testing was performed.
Time frame: Change from baseline to 344 hours post last dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lu AF35700 (Group D1) | Emax D1 Dopamine | 81.9 percentage |
Primary
Emax D2 Dopamine
Maximal target occupancy (Emax) on the D2 dopamine receptor using PET with \[11C\]-Raclopride tracer compound. The relationship between systemic exposure of Lu AF35700 and D2 dopamine occupancy was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and plasma concentration which gives 50% of Emax (EC50). Emax was estimated using one model for all post-baseline scans combined. No statistical testing was performed.
Time frame: Change from baseline to 344 hours post last dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lu AF35700 (Group D1) | Emax D2 Dopamine | 102 percentage |