Positron Emission Tomography (PET) Study Investigating Dopamine and Serotonin Receptor Occupancy After Multiple Oral Dosing of Lu AF35700

Study Overview
=================
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.

Official Title
-----------------
Interventional, Open-label, Positron Emission Tomography (PET) Study Investigating D1 Dopamine, D2 Dopamine, and 5-HT6 Serotonin Receptor Occupancy After Multiple Oral Dosing of Lu AF35700 in Male Patients With Schizophrenia

Conditions
-----------------
Schizophrenia

Intervention / Treatment
-----------------
* Drug: Lu AF35700


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The patient is a man aged between ≤18 and ≥60 years BMI of ≥19 kg/m2 to ≤ 37 kg/m2 The patient has a primary diagnosis of schizophrenia according to DSM-5™ (code 295.90) The patient has a Clinical Global Impression - Severity of Illness (CGI-S) score ≤ 4 (moderately ill) at screening and safety baseline The patient is currently under oral therapy with one or more of the antipsychotic medications listed in Appendix II. The patient has a Positive and Negative Syndrome Scale (PANSS) total score ≤ 80 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: The patient experienced an acute exacerbation requiring hospitalization within the last 3 months. The patient experienced an acute exacerbation requiring change in antipsychotic medication (with reference to drug or dose) within the last 4 weeks. The patient has a diagnosis or history of substance use disorder (except nicotine) according to DSM-5-TR® criteria ≤3 months prior to screening 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. 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. The patient has had past episodes of extrapyramidal symptoms (EPS) under current medication within the last 3 month The patient takes other medication than those listed as allowed concomitant medication in Appendix III The patient is occupationally exposed to significant levels of ionizing radiation. Other protocol-defined inclusion and exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lu AF35700 (Group D1)<br>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 | Drug: Lu AF35700<br>* 5 mg tablets for oral administration<br>|
| Experimental: Lu AF35700 (Group D2)<br>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 | Drug: Lu AF35700<br>* 5 mg tablets for oral administration<br>|
| Experimental: Lu AF35700 (Group 5-HT6)<br>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 | Drug: Lu AF35700<br>* 5 mg tablets for oral administration<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | 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. | 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 |