Imaging 5HT7 Antagonist Effects in Bipolar Disorder

Bipolar Disorder Clinical Trial

Official title: Translational Validation of 5HT7 Antagonists as a Treatment for Cognitive Impairment in Bipolar Disorder: a Proof of Principle Neuroimaging Study

Status Recruiting

Clinical Trial Summary

The main aim of this research is to examine the potential of 5HT7 antagonists for the treatment of cognitive impairment in bipolar disorder by determining the effect of the 5HT7 antagonist JNJ-18038683 on cognitive and emotional processing related brain activity in cognitively impaired people with bipolar disorder and healthy participants using functional MRI (fMRI). This study is designed to contribute to the rational validation of 5HT7 antagonists as a treatment for cognitive impairment in bipolar disorder and to support the development of clinical trials and further drug development in this area. The study will also examine the effect of 5HT7 antagonism on brain function in healthy participants as this has never been investigated before, and to use as a comparator to determine whether 5HT7 antagonism effects disease specific impairments in task related brain activity and cerebral blood flow.

Clinical Trial Description

OBJECTIVE

Primary:

To determine the effect of 5HT7 antagonism on cognition related brain activations and cognitive performance in people with bipolar disorder.

Secondary:

To examine the effect of 5HT7 antagonism on emotional processing related brain activations in people with bipolar disorder.

To examine the effect of 5HT7 antagonism on behavioral measures of mood.

Exploratory:

To determine whether early behavioural 5HT7 antagonist drug effects can be detected which may be linked to altered brain activations.

To explore whether factors, such as baseline measures of cognitive impairment and polygenic risk score, predict the extent of JNJ-18038683 related treatment effects on brain activity.

STUDY DESIGN The study will use a randomized, double-blind, placebo controlled, cross-over, pharmacological functional MRI (fMRI) design to examine the neural and behavioural effects of one week's treatment with the 5HT7 antagonist, JNJ-18038683, and placebo. Participants will attend four study visits: a screening visit, a baseline visit and two neuroimaging visits. Each neuroimaging visit will be identical and comprise structural imaging, perfusion imaging with arterial spin labelling, resting state and task-based functional MRI. FMRI tasks will be working memory (N-back), emotional processing (faces), and paired associate visuospatial learning (PAL). On the neuroimaging visits, a neuropsychological battery will also be performed, subjective and behavioural effects will be assessed with standard questionnaires and adverse events will be recorded.

NUMBER OF SUBJECTS 34 cognitively impaired participants with bipolar disorder and 34 healthy participants will complete the study. Replacements are allowed in case of drop-out.

TARGET POPULATION Male and female patients with a current diagnosis of Bipolar Disorder and healthy volunteers. All participants will be right-handed. Patients will be primarily recruited through South London and Maudsley NHS Foundation Trust clinical services, with other trusts potentially contributing to recruitment. Participants will also be recruited by public advertising, online and social media and through NIHR Mental Health CRN. Healthy volunteers will be recruited through advertisement within King's College London, in the local press, online and through contacting participants from previous studies who have expressed an interest in further research participation.

STUDY DRUG (DOSE/ROUTE/REGIMEN) Name of product: JNJ-18038683, an investigational drug, a 5HT7 antagonist Dose: 20mg once daily Administration: Oral Duration of dosing: One week

JNJ-18038683 and matching placebos will be provided by Janssen Research and Development, LLC, the manufacturer of JNJ-18038683.

ASSESSMENTS:

Screening visit (Visit 1):

Participant's cognitive; mood and physical health suitability will be assessed during this visit. Participants will complete the RAVLT to screen for cognitive impairment. Bipolar disorder DSM-5 diagnosis will be confirmed using the M.I.N.I. 6.0. Mood and anxiety symptoms will be assessed using the HAM-D, YMRS, QIDS-CR, C-SSRS, Altman Self-Rating Mania scale and HAM-A mood rating scales. Substance use will be assessed using the cannabis experiences, Fagerstrom smoking and AUDIT alcohol questionnaires. All participants will undergo a physical examination, ECG, urine drug screen, breath alcohol test, pregnancy test for females, urinalysis and blood will be taken to assess hepatic, renal and haematological function and to determine bipolar disorder polygenic risk scores.

Baseline visit (Visit 2) If the screening assessments indicate suitability, participants will then attend a baseline visit. They will complete a brief physical health examination including recording vital signs, ECG, urine drug screen, breath alcohol test and a pregnancy test for females. Mood and anxiety symptoms will be assessed using the HAM-D, YMRS, QIDS-CR, C-SSRS, Altman Self-Rating Mania scale and HAM-A mood rating scales. Sleep will be assessed using the PSQI. Cognition will be assessed using the ISBD-BANC cognitive battery and subjective cognitive impairment will be assessed using the PDQ and FAST questionnaires. Participants will be provided with the week 1 study medication pack, determined by randomization code, and a study diary to record taking each day's medication and any adverse events experienced.

Imaging visits (Visit's 3 and 4):

Participants will undergo a brief medical examination, ECG and urine drug screen. Cognition, mood, psychosocial functioning and sleep will be assessed at each neuroimaging visit using the ISBD-BANC, PDQ, QIDS-CR, C-SSRS, YMRS, FAST and PSQI. A blood sample will be taken at each visit to monitor hepatic, renal and haematological functions and so that plasma can be stored to potentially measure JNJ-18038683 levels. During each imaging session, participants will complete the n-back working memory, paired associate visuospatial learning (PAL), and emotional faces recognition fMRI tasks, an arterial spin labelling (ASL) scan to assess cerebral blood flow, a resting state scan, and a T1 and T2 structural scan.

PROCEDURES

Randomisation:

Participants will be randomized into the study provided they have satisfied all selection criteria. Each participant will be assigned to a sequence of treatment administrations by means of a computer-generated, pseudo random code based on stacks of William's Squares, to ensure each treatment is equally distributed across each study period. A blinded randomization list will be provided by the pharmacist or delegate to the investigator and, in accordance with the randomization list, if a participant is withdrawn from the study, the replacement participant will be allocated to the same treatment sequence as the subject they are replacing. Replacement numbers will be discussed and agreed between the investigator and the pharmacist.

Analytical Plan:

A brief plan for data analysis is provided in the main body of the protocol. A detailed Statistical Analytical Plan will be produced before the end of the data collection phase of the study. A brief description of the main endpoints is provided here:

Primary endpoints:

1. Change in cognitive task related right superior frontal gyrus and dorsolateral prefrontal cortex brain activations associated with JNJ-18038683 treatment.

2. Change in cognitive performance, as measured by change in International Society for Bipolar Disorders Battery for the Assessment of Cognition (ISBD-BANC) test battery composite score, associated with JNJ-18038683 treatment (Co-primary).

Secondary endpoints:

1. Change in emotional processing related amygdala brain activations associated with JNJ-18038683 treatment.

2. Change in cognitive and emotional network connectivity associated with JNJ-18038683 treatment.

3. Change in other behavioural measures of cognition (ISBD-BANC test battery individual task scores) and mood scores (Quick Inventory of Depressive Symptomatology, Young Mania Rating Scale) associated with JNJ-18038683 treatment.

Safety:

Listings, summary tables and graphs will be produced for safety and tolerability assessments. ;

Related Conditions & MeSH terms

• Bipolar Disorder
• Disease

• NCT number: NCT03633357
• Study type: Interventional
• Source: King's College London
• Contact: Natalie Gottlieb, PhD
• Phone: +447725 179208
• Email: natalie.n.gottlieb@kcl.ac.uk
• Status: Recruiting
• Phase: N/A
• Start date: August 16, 2018
• Completion date: June 2022