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FASTMAS (Fast-Fail Trials in Mood and Anxiety Spectrum Disorders) Kappa Opioid Receptor Phase 1 Study (KOR1)

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ClinicalTrials.gov Identifier: NCT02218775
Recruitment Status : Withdrawn (Funding for the study ended with one subject consented, but not randomized)
First Posted : August 18, 2014
Last Update Posted : May 28, 2015
Sponsor:
Collaborator:
Yale University
Information provided by (Responsible Party):
Andrew Krystal, Duke University

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.

Condition or disease Intervention/treatment Phase
Anxiety Disorders Drug: LY2456302 Phase 1

Detailed Description:
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 they will undergo interval history and safety assessments, take their medication at 11 am, and then have MRI imaging at 1:30 pm. A blood sample to determine LY2456302 level will be obtained immediately before and after the MRI imaging session so that we can determine the relationship between ventral striatal activation during the task and serum level of LY2456302. They will then return to the research unit the following day where they will take their last dose of study medication at 11 am and at 1:30 pm will undergo a [11C]-Carfentanil PET mu opioid receptor occupancy study. A blood sample to determine LY2456302 level will be obtained immediately before and after the PET imaging session so that we can determine the relationship between receptor occupancy and serum level of study drug. The following day subjects will have an arterial line placed and undergo LY2879788 PET Kappa Occupancy Study at 9:30 am with a single blood sample taken prior to 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. A blood sample to determine LY2456302 level will also be obtained immediately before and after the PET imaging session so that we can compute the relationship between serum level and receptor occupancy. Subjects will then return 6 days later for a safety assessment after which their participation in the study will end.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Health Services Research
Official Title: A Phase 1 Study of Kappa and Mu Opioid Receptor Occupancy Associated With Repeated Dosing of LY24516302
Study Start Date : October 2014
Actual Primary Completion Date : April 2015
Actual Study Completion Date : April 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anxiety

Arm Intervention/treatment
Experimental: LY2456302
LY2456302 dosed orally at 10 mg daily for 2 weeks in healthy volunteers
Drug: LY2456302
Mood and Anxiety Disorders




Primary Outcome Measures :
  1. 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

  2. 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.

  3. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 21 through 65 years of age
  • Body mass index 19 through 30 lbs/in2
  • Reliable and willing to be available for the duration of the study
  • Willing and able to give written informed consent to participate
  • Able to understand and comply with instructions
  • If female of childbearing potential, must agree to use dual methods of contraception and be willing and able to continue contraception for 6 weeks after the last dose of study drug. Females using oral contraception must have started using it at least 2 months prior to the Baseline Visit
  • If male of childbearing potential, must have undergone surgical sterilization (such as a vasectomy) or agree to use a condom used with a spermicide during participation in the study and for 1 month afterward

Exclusion Criteria:

  • Any clinically significant abnormality of any of the hematology, clinical, chemistry, or urine drug tests
  • Magnetic resonance imaging contraindications at 3 Tesla (e.g., ferromagnetic implants or shrapnel or other incompatibilities)
  • Any clinically significant abnormality of the 12-lead ECG; QTc (corrected QT) interval recorded on screening or predose greater than 450 msec
  • Any clinically significant history of neurologic disease, cancer, or cardiac, respiratory, metabolic, hepatic, renal, gastrointestinal (except appendectomy), dermatological, venereal, hematological disorder or disease
  • Any clinically significant history of Axis I psychiatric disorder, or history of attempted suicide
  • History of seeking advice from a physician or counselor for abuse or misuse of alcohol, non-medical drugs, medicinal drugs or other substance abuse, for example, solvents
  • Any current or previous recreational use of Class A drugs such as opiates, cocaine, ecstasy, LSD (Lysergic acid diethylamide), and amphetamines (Class B)
  • Positive drugs-of-abuse test result at initial exam or at any time during the study
  • An alcoholic intake greater than 7 units per week or unwillingness to stop alcohol consumption for the duration of the study {1 unit = 8 g ethanol (250 mL of beer, 1 glass wine [100 mL], 1 measure spirits [30 mL])}
  • Use of prescribed medication within 30 days of the first study day, or nonprescription medication including herbal remedies except standard dose vitamin supplements and acetaminophen (up to 4 g/day) within 15 days of the first study drug administration, or any medication that would need to be continued during the study
  • Use of any investigational medication within 3 months prior to the start of this study or scheduled to receive an investigational drug other than LY2456302 during the course of this study
  • Any smoking of cigarettes or use of any nicotine containing products within the last month or at any time during the study
  • History of blood donation in the last 3 months
  • History of severe allergies or multiple adverse drug reactions
  • Known hypersensitivity to LY2456302
  • Any history of a clinically significant gastrointestinal condition
  • Any other condition that in the opinion of the investigator would preclude participation in the study
  • Pregnant or lactating
  • History of peptic ulcer disease or gastritis or positive urea breath test

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02218775


Locations
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United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06510
Sponsors and Collaborators
Andrew Krystal
Yale University
Investigators
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Principal Investigator: Andrew D Krystal, MD, MS Duke University

Publications:
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Responsible Party: Andrew Krystal, Professor, Department of Psychiatry and Behavorial Sciences, Duke University
ClinicalTrials.gov Identifier: NCT02218775     History of Changes
Other Study ID Numbers: Pro00052483
HHSN271201200006I ( Other Identifier: NIMH/NIH )
First Posted: August 18, 2014    Key Record Dates
Last Update Posted: May 28, 2015
Last Verified: May 2015

Keywords provided by Andrew Krystal, Duke University:
Kappa opioid receptor
Mu opioid receptor
LY2456302
Anhedonia
Mood and Anxiety Spectrum Disorders

Additional relevant MeSH terms:
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Anxiety Disorders
Mental Disorders
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents