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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lu AF35700 (Group D1) | Experimental | Up to 3 PET scans, besides baseline scan, using [11C]-NNC 112 tracer to detect D1 dopamine receptor occupancy before and after multiple oral dosing of Lu AF35700 |
|
| Lu AF35700 (Group D2) | Experimental | Up to 3 PET scans, besides baseline scan, using [11C]-Raclopride to detect D2 dopamine receptor occupancy before and after multiple oral dosing of Lu AF35700 |
|
| Lu AF35700 (Group 5-HT6) | Experimental | Up to 3 PET scans, besides baseline scan, using [11C]- Lu AE60157 tracer to detect 5-HT6 (5-hydroxytryptamine-6) receptor occupancy before and after multiple oral dosing of Lu AF35700 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lu AF35700 | Drug | 5 mg tablets for oral administration |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Change from baseline to 344 hours post last dose |
| 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. | Change from baseline to 344 hours post last dose |
| 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. | Change from baseline to 344 hours post last dose |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
Other protocol-defined inclusion and exclusion criteria may apply
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| Name | Affiliation | Role |
|---|---|---|
| Email contact via H. Lundbeck | LundbeckClinicalTrials@lundbeck.com | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| US802 | Rockville | Maryland | 20850 | United States |
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
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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, Cohort C4: Dosing with 5 mg for 4 days (Days 1, 3, 5, and 7). 5-HT6 receptor occupancy measured using [11C]-Lu AE60157. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Lu AF35700 (Group D2) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Number | 95% Confidence Interval | percentage | Change from baseline to 344 hours post last dose |
|
Up to week 12.
Adverse Events were monitored irrespective of Lu AF35700 dosing cohort, i.e., unable to know what Lu AF35700 dose event occurred at.
It was pre-specified in the study to report Adverse Events by tracer group only.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 using [11C]-NNC 112 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Chest pain | Blood and lymphatic system disorders | MedDRA (18.1) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anxiety | Psychiatric disorders | MedDRA (18.1) | Non-systematic Assessment |
An estimate of the confidence interval for the parameter Emax in the dopamine D2 receptor occupancy model was not calculable.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Email contact via | H. LUndbeck A/S | +4536301311 | LundbeckClinicalTrials@Lundbeck.com |
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| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C000726227 | Lu AF35700 |
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| Change from baseline to 344 hours post last dose |
| 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. | Change from baseline to 344 hours post last dose |
| 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. | Change from baseline to 344 hours post last dose |
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. |
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| 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. | Posted | Number | 95% Confidence Interval | ng/mL | Change from baseline to 344 hours post last dose |
|
|
|
| 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. | Posted | Number | percentage | Change from baseline to 344 hours post last dose |
|
|
|
| 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. | Posted | Number | 95% Confidence Interval | ng/mL | Change from baseline to 344 hours post last dose |
|
|
|
| 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. | Posted | Number | 95% Confidence Interval | percentage | Change from baseline to 344 hours post last dose |
|
|
|
| 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. | Posted | Number | 95% Confidence Interval | ng/mL | Change from baseline to 344 hours post last dose |
|
|
|
| 0 |
| 6 |
| 1 |
| 6 |
| 5 |
| 6 |
| EG001 | 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 using [11C]-raclopride | 0 | 8 | 1 | 8 | 6 | 8 |
| EG002 | 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 (5-hydroxytryptamine-6) receptor occupancy using [11C]-Lu AE60157 | 0 | 8 | 1 | 8 | 7 | 8 |
| Worsening of schizophrenia | Psychiatric disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Psychotic Disorder | Psychiatric disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Tympanic Membrane Disorder | Ear and labyrinth disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Ear Pain | Ear and labyrinth disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Otorrhoea | Ear and labyrinth disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA (18.1) | Non-systematic Assessment |
|
| Abdominal Discomfort | Gastrointestinal disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Blood Urine Present | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Weight Increased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Musculoskeletal Pain | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Neck Pain | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Chest Pain | General disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Schizophrenia | Psychiatric disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Tootache | Gastrointestinal disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Aspartate aminotarnsferase increased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Blood lactate dehydrogenase increased | Investigations | MedDRA (18.1) | Non-systematic Assessment |
|
| Eczema | Skin and subcutaneous tissue disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Gamma-glutamyl transferase increased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Oral herpes | Infections and infestations | MedDRA (18.1) | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA (18.1) | Non-systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA (18.1) | Non-systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Pollakiuria | Renal and urinary disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Axillary mass | Musculoskeletal and connective tissue disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Eye irritation | Eye disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Penis disorder | Reproductive system and breast disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Rhinitis | Infections and infestations | MedDRA 18.1 | Non-systematic Assessment |
|
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