Clinical Trial: FASTMAS (Fast-Fail Trials in Mood and Anxiety Spectrum Disorders) Kappa Opioid Receptor Phase 1 Study

Study Status: Withdrawn
Recruit Status: Withdrawn
Study Type: Interventional

Official Title: A Phase 1 Study of Kappa and Mu Opioid Receptor Occupancy Associated With Repeated Dosing of LY24516302

Brief Summary: The available treatments for patients with mood and anxiety spectrum disorders have significant limitations. This study will contribute significantly to public health by taking steps to address these limitations by aiding in the interpretation of a study that: 1) tests a promising new treatment for mood and anxiety spectrum disorders; 2) evaluates a potential target in the brain which could serve as the basis for development of additional new candidate compounds for the treatment of patients with mood and anxiety spectrum disorders; 3) establishes more expeditious methods for evaluating potential new therapies for patients with mood and anxiety spectrum disorders; and 4) specifically establishes methods for the development of new therapies targeting anhedonia, an important RDoC (Research Domain Criteria) endpoint.

Detailed Summary: This study is an open-label study of two weeks of daily dosing of LY2456302 carried out in 10 healthy volunteers. Subjects will have an initial screening visit where they will have the opportunity to sign informed consent. Those who choose to do so will undergo a series of screening tests to determine whether they meet inclusion/exclusion criteria for this study. Those who qualify will return in 1-7 days for a baseline set of assessments which will include: having MRI imaging carried out on the first day (structural MRI, fMRI during the Monetary Incentive Delay Task, and Resting State Connectivity fMRI), and on the second day having an arterial line placed; undergoing a [11C]-Carfentanil (a synthetic, highly specific mu opioid receptor (mu-OR) agonist) PET mu opioid receptor occupancy study; undergoing a LY2879788 ( radioactive biochemical substance (in particular, a ligand) that is used for diagnosis or for research-oriented study of the receptor systems of the body) PET Kappa Occupancy Study with a single blood sample taken prior to the scan, a sample during the scan, and samples taken at 15, 30, 45, 60, 75, 90, and 120 minutes after the scan to determine whole blood radioactivity, plasma radioactivity, and un-metabolized tracer fraction over time which are needed to determine the input function to the kinetic model for analysis of parameter estimation needed to compute receptor occupancy from the PET scan data; completing a SHAPS; and undergoing a PRT. Note that arterial line placement and serial blood samples are only needed for the LY2879788 scans because, unlike for [11C]-Carfentanil, there is no accepted reference region in the brains of humans for this ligand which necessitates the development of a kinetic model for scan parameter estimation. The next day subjects will begin taking LY2456302 10 mg daily at 11 am and return to the research unit 6 days later for a safety assessment visit. Subjects will then return to the research unit 7 days later during which
Sponsor: Andrew Krystal

Current Primary Outcome:

• Primary: Kappa opioid receptor occupancy determined with LY2879788 PET imaging; Mu opioid receptor occupancy determined with [11C]-Carfentanil PET imaging [ Time Frame: Both on Day 1 ]
  Baseline readings prior to drug dosing
• Primary: Kappa opioid receptor occupancy determined with LY2879788 PET imaging; Mu opioid receptor occupancy determined with [11C]-Carfentanil PET imaging [ Time Frame: Day 16: Trough LY2879788 PET Kappa Occupancy Study (22.5 hours after dosing) ]
  KOR occupancy using LY2879788 imaging at time of peak blood level of LY2456302 achieved with 2 weeks of daily dosing of 10 mg. LY2456302.
• Peak PET Mu Occupancy [ Time Frame: Day 15 ]
  Mu occupancy using [11C]-Carfentanil PET imaging at time of peal blood level of LY2456302 achieved with 2 weeks of daily dosing of 10 mg LY2456302

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Reward Circuit Engagement Outcome [ Time Frame: Day 0 ]
  Task related fMRI ventral striatal activation occurring with reward and loss anticipation during the Monetary Incentive Delay Task
• Reward Circuit Engagement Outcome [ Time Frame: Day 14 (time of peak drug level) ]
  Task related fMRI ventral striatal activation occurring with reward and loss anticipation during the Monetary Incentive Delay Task
• Clinical Anhedonia Outcome Utilizing the Snaith-Hamilton Pleasure Scale (SHAPS) [ Time Frame: Screening (Day -7 to Day -1) ]
  The SHAPS is a well validated 14 item questionnaire used to assess anhedonia (the inability to experience pleasure from activities usually found to be enjoyable). Scores on the SHAPS can range from 14 to 56 with higher scores corresponding to higher levels of anhedonia. The SHAPS is the only anhedonia measure to has been found to significantly improve with the administration of a treatment.
• Clinical Anhedonia Outcome Utilizing the Snaith-Hamilton Pleasure Scale (SHAPS) [ Time Frame: Day 1 ]
  The SHAPS is a well validated 14 item questionnaire used to assess anhedonia (the inability to experience pleasure from activities usually found to be enjoyable). Scores on the SHAPS can range from 14 to 56 with higher scores corresponding to higher levels of anhedonia. The SHAPS is the only anhedonia measure to has been found to significantly improve with the administration of a treatment.
• Anhedonia Outcome Utilizing the Snaith-Hamilton Pleasure Scale (SHAPS) [ Time Frame: Day 15 ]
  The SHAPS is a well validated 14 item questionnaire used to assess anhedonia (the inability to experience pleasure from activities usually found to be enjoyable). Scores on the SHAPS can range from 14 to 56 with higher scores corresponding to higher levels of anhedonia. The SHAPS is the only anhedonia measure to has been found to significantly improve with the administration of a treatment.
• Behavioral Anhedonia Outcome as measured by the Probabilistic Reward Task (PRT) [ Time Frame: Day 1 ]
  This outcome measure was designed to objectively assess participants' propensity to modulate behavior as a function of reinforcement history. This task has been validated in multiple independent samples
• Behavioral Anhedonia Outcome as measured by the Probabilistic Reward Task (PRT) [ Time Frame: Day 15 ]
  Results will be assessed at this time point as compared to Day 1

Original Secondary Outcome: Same as current

Information By: Duke University

Dates:
Date Received: August 15, 2014
Date Started: October 2014
Date Completion:
Last Updated: May 26, 2015
Last Verified: May 2015