A Pilot Dose-Response Biomarker Study of Brexpiprazole Treatment in PTSD

Sponsor
Duke University (Other)
Overall Status
Terminated
CT.gov ID
NCT02934932
Collaborator
Otsuka America Pharmaceutical (Industry)
15
1
3
12.2
1.2

Study Details

Study Description

Brief Summary

Determine if brexpiprazole treatment will be associated with a dose-dependent reduction in resting pupil diameter as a reflection of locus coeruleus (LC) norepinephrine (NE) neuron target engagement in a group of subjects with PTSD. All subjects will be evaluated by physical examination, ECG, standard blood chemistry, hematologic labs, toxicology testing, and urinalysis. Results of these studies must demonstrate a lack of clinically significant abnormalities prior to enrollment. Subjects will need to satisfy DSM-5 criteria for PTSD and receive a CAPS-5 score of 40 or greater on testing for study enrollment. Resting pupil diameter during pupillometric evaluation after two weeks on each treatment will serve as the primary outcome measure. This will be compared in the treatment groups using mixed effects repeated measures models to evaluate if there is a significant difference in pupil size among the treatments studied. As a secondary analysis this approach will be used to evaluate whether there is treatment effect on total CAPS-5 score. Lastly, the investigators will compute correlations between pupil size and CAPS-5 scores.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Primary Hypothesis: Brexpiprazole treatment will be associated with dose-dependent reduction in resting pupil diameter as a reflection of LC NE neuron target engagement in a group of subjects with PTSD. Secondary Hypothesis: Brexpiprazole therapy will be associated with a dosedependent decrease in CAPS-5 scores Tertiary Hypothesis: The pre-post treatment change in resting pupil diameter will be statistically significantly correlated with the pre-post change in CAPS-5 score.

Subjects will be screened and will undergo pupil measures with rating scales on Visit 1. Subject must be free of all psychotropic medications for one week before Day 1 assessment, except that prior FLX treatment will require 4 weeks of abstinence, and MAOIs will require 2 weeks of abstinence. They will be randomized to study drug an issued six weeks of study medication on Day 1 to take home. A phone call will then occur for safety assessment and medication adherence at every week. They will present back to the study site on Day 42 and undergo pupil measures with rating scales. They will then undergo a one week washout period. On Day 49 they will then be given another study drug to take home with rating scales and pupil measures obtained that day. A phone call will then occur for safety assessment and medication adherence at every week. They will present back to the study site on Day 91 and undergo pupil measures with rating scales. They will then undergo a one week washout period. On Day 98 they will then be given another study drug to take home with rating scales and pupil measures obtained that day. A phone call will then occur for safety assessment and medication adherence at every week. They will present back to the study site on Day 140 and undergo pupil measures with rating scales. No more study medication will be provide on Day 140 and a final visit will be scheduled for on Day 147, one week later, for and end of study interview with labs and physical exam. At each visit, other than the final visit, subjects will complete the CAPS-5, MADRS, Insomnia Severity Index, and Clinician Assessment for Adverse Effects.

Study Design

Study Type:
Interventional
Actual Enrollment :
15 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Pilot Dose-Response Biomarker Study of Brexpiprazole Treatment in PTSD
Actual Study Start Date :
Apr 25, 2017
Actual Primary Completion Date :
Apr 30, 2018
Actual Study Completion Date :
Apr 30, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Brexpiprazole 2mg

Subjects will be titrated to this dose of brexpiprazole for 6 weeks.

Drug: Brexpiprazole
Comparison of brexpiprazole 2mg to placebo Comparison of brexpiprazole 4mg to placebo
Other Names:
  • Rexulti
  • Experimental: Brexpiprazole 4mg

    Subjects will be titrated to this dose of brexpiprazole for 6 weeks.

    Drug: Brexpiprazole
    Comparison of brexpiprazole 2mg to placebo Comparison of brexpiprazole 4mg to placebo
    Other Names:
  • Rexulti
  • Placebo Comparator: Placebo

    Subjects will be titrated to this dose of placebo for 6 weeks.

    Drug: Brexpiprazole
    Comparison of brexpiprazole 2mg to placebo Comparison of brexpiprazole 4mg to placebo
    Other Names:
  • Rexulti
  • Outcome Measures

    Primary Outcome Measures

    1. Change in Resting Pupil Diameter [Baseline to 6 weeks for each treatment arm]

      Evaluate the effects of two doses of brexpiprazole on locus coeruleus (LC) norepinephrine (NE) neuron activity.

    Secondary Outcome Measures

    1. Change in CAPS-5 Ratings Score [Baseline to 6 weeks for each treatment arm]

      Determine the effect of brexpiprazole therapy on PTSD symptom severity

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Participants will be 18-65 years of age.

    • All subjects will be evaluated by physical examination, ECG, standard blood chemistry, hematologic labs, toxicology testing, and urinalysis at baseline and end of study. Results of these studies must demonstrate a lack of clinically significant abnormalities prior to enrollment. If results are outside of the normal reference range the study physician will be consulted to assess if clinically significant.

    • Subjects will need to satisfy DSM-5 criteria for PTSD and receive a CAPS-5 score of 40 or greater on testing for study enrollment.

    • Subjects will need to be free of psychotropic medications or treatments that could impact results of this study as deemed by the PI for at least 1 week.

    • If the subject's primary psychiatrist or treating primary care physician are providing the subject with psychotropic medications they will be notified and a discussion about tapering current psychotropic medications prior to study enrollment will occur.

    Exclusion Criteria:
    1. Subjects will be excluded if they have significant medical or neurologic conditions (other than mild to moderate TBI), specifically seizures, or movement disorders,

    2. have substance abuse within 12 months of study enrollment, substance dependence within past three months, per DSM-5 criteria (excluding caffeine and nicotine). The absence of substance use will be determined by self-report and confirmed by the results of urine toxicology at screening.

    3. Women who are pregnant, breast-feeding, or planning to become pregnant while enrolled in this study will also be excluded.

    4. Subjects with a history of severe drug allergy or hypersensitivity, or known hypersensitivity to the Brexpiprazole or its ingredients.

    5. The subject has a history of tardive dyskinesia.

    6. The subject has clinically significant extrapyramidal symptoms (EPS) including akathisia.

    7. The subject has epilepsy or a history of seizures, except for a single seizure episode (e.g., childhood febrile seizure, post traumatic, or alcohol withdrawal).

    8. The subject has chronic, uncontrolled, or unstable clinically relevant medical conditions Including:

    • Uncontrolled hypertension defined as blood pressure greater than 180/90

    • Hypotension defined as a blood pressure less than 90/60

    • Moderate to severe hepatic impairment (Child-Pugh score ≥7)

    • Moderate, Severe or End-Stage Renal Impairment (CrCL <60ml/min)

    • Known CYP2DG Poor Metabolizers

    • Heart failure NYHA Class III or IV

    • Diabetes mellitus or HbA1c greater than 5.7% (which defines pre-diabetes)

    • Hypertriglyceridemia defined as triglycerides greater than 200mg/dL

    • Low white blood cell count (below lower range of normal)

    • History of leukopenia or neutropenia

    • Arrhythmia with heart rate greater than 100bpm

    • Myocardial infarction in the past 6 months

    • Cerebrovascular accident in the past 6 months

    • Recurrent syncope

    • Seizure disorder

    • Currently receiving treatment for malignancy

    • QTc interval of greater than 450ms on electrocardiogram

    1. The subject has a neurodegenerative disorder (Alzheimer disease, Parkinson's disease, multiple sclerosis, Huntington disease, etc.).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Pamela Smith Durham North Carolina United States 27712

    Sponsors and Collaborators

    • Duke University
    • Otsuka America Pharmaceutical

    Investigators

    • Principal Investigator: Steven T Szabo, MD, PhD, Duke University

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Duke University
    ClinicalTrials.gov Identifier:
    NCT02934932
    Other Study ID Numbers:
    • Pro00071923
    First Posted:
    Oct 17, 2016
    Last Update Posted:
    Mar 5, 2019
    Last Verified:
    Feb 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 15 participants signed consent; 6 screen failed. All subjects received all three treatments with treatment order randomized within each subject.
    Arm/Group Title All Participants
    Arm/Group Description All participants who began the study.
    Period Title: Overall Study
    STARTED 9
    COMPLETED 6
    NOT COMPLETED 3

    Baseline Characteristics

    Arm/Group Title All Participants
    Arm/Group Description All participants who signed consent.
    Overall Participants 15
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    44.4
    (12.49)
    Sex: Female, Male (Count of Participants)
    Female
    9
    60%
    Male
    6
    40%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    Not Hispanic or Latino
    15
    100%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    1
    6.7%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    3
    20%
    White
    11
    73.3%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    15
    100%

    Outcome Measures

    1. Primary Outcome
    Title Change in Resting Pupil Diameter
    Description Evaluate the effects of two doses of brexpiprazole on locus coeruleus (LC) norepinephrine (NE) neuron activity.
    Time Frame Baseline to 6 weeks for each treatment arm

    Outcome Measure Data

    Analysis Population Description
    Data not collected.
    Arm/Group Title Brexpiprazole 2mg Brexpiprazole 4mg Placebo
    Arm/Group Description Subjects will be titrated to this dose of brexpiprazole for 6 weeks. Brexpiprazole: Comparison of brexpiprazole to placebo Subjects will be titrated to this dose of brexpiprazole for 6 weeks. Brexpiprazole: Comparison of brexpiprazole to placebo Subjects will be titrated to this dose of placebo for 6 weeks. Brexpiprazole: Comparison of brexpiprazole to placebo
    Measure Participants 0 0 0
    2. Secondary Outcome
    Title Change in CAPS-5 Ratings Score
    Description Determine the effect of brexpiprazole therapy on PTSD symptom severity
    Time Frame Baseline to 6 weeks for each treatment arm

    Outcome Measure Data

    Analysis Population Description
    Data not collected.
    Arm/Group Title Brexpiprazole 2mg Brexpiprazole 4mg Placebo
    Arm/Group Description Subjects will be titrated to this dose of brexpiprazole for 6 weeks. Brexpiprazole: Comparison of brexpiprazole to placebo Subjects will be titrated to this dose of brexpiprazole for 6 weeks. Brexpiprazole: Comparison of brexpiprazole to placebo Subjects will be titrated to this dose of placebo for 6 weeks. Brexpiprazole: Comparison of brexpiprazole to placebo
    Measure Participants 0 0 0

    Adverse Events

    Time Frame 6 weeks
    Adverse Event Reporting Description
    Arm/Group Title All Participants
    Arm/Group Description All participants who began the study.
    All Cause Mortality
    All Participants
    Affected / at Risk (%) # Events
    Total 0/9 (0%)
    Serious Adverse Events
    All Participants
    Affected / at Risk (%) # Events
    Total 0/9 (0%)
    Other (Not Including Serious) Adverse Events
    All Participants
    Affected / at Risk (%) # Events
    Total 0/9 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Steven Szabo
    Organization Duke University
    Phone 919-681-8742
    Email steven.szabo@duke.edu
    Responsible Party:
    Duke University
    ClinicalTrials.gov Identifier:
    NCT02934932
    Other Study ID Numbers:
    • Pro00071923
    First Posted:
    Oct 17, 2016
    Last Update Posted:
    Mar 5, 2019
    Last Verified:
    Feb 1, 2019