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

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Primary Purpose

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Lu AF35700

About this trial

This is an interventional treatment trial for Schizophrenia

Eligibility Criteria

18 Years - 60 Years (Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

US802

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Lu AF35700 (Group D1)

Lu AF35700 (Group D2)

Lu AF35700 (Group 5-HT6)

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT02333487

First Posted

January 6, 2015

Last Updated

May 11, 2020

Sponsor

H. Lundbeck A/S

1. Study Identification

Unique Protocol Identification Number

NCT02333487

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2020

Overall Recruitment Status

Completed

Study Start Date

December 30, 2014 (Actual)

Primary Completion Date

February 11, 2016 (Actual)

Study Completion Date

February 11, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

H. Lundbeck A/S

4. Oversight

Data Monitoring Committee

No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Schizophrenia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

22 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Lu AF35700 (Group D1)

Arm Type

Experimental

Arm Description

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

Arm Title

Lu AF35700 (Group D2)

Arm Type

Experimental

Arm Description

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

Arm Title

Lu AF35700 (Group 5-HT6)

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Lu AF35700

Intervention Description

5 mg tablets for oral administration

Primary Outcome Measure Information:

Title

Emax D1 Dopamine

Description

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