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

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.

Study Overview

• Status: Terminated
• Conditions: Post Traumatic Stress Disorder
• Intervention / Treatment: Drug: Brexpiprazole

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 Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27712
      • Pamela Smith

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CAPS-5 Ratings Score	Determine the effect of brexpiprazole therapy on PTSD symptom severity	Baseline to 6 weeks for each treatment arm

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: Otsuka America Pharmaceutical
• Investigators: Principal Investigator: Steven T Szabo, MD, PhD, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2017
• Primary Completion (Actual): April 30, 2018
• Study Completion (Actual): April 30, 2018

Study Registration Dates

• First Submitted: October 14, 2016
• First Submitted That Met QC Criteria: October 14, 2016
• First Posted (Estimate): October 17, 2016

Study Record Updates

• Last Update Posted (Actual): March 5, 2019
• Last Update Submitted That Met QC Criteria: February 11, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Trauma and Stressor Related Disorders; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Serotonin Agents; Dopamine Agonists; Dopamine Agents; Brexpiprazole
• Other Study ID Numbers: Pro00071923

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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