Phase 1 Study to Assess the Safety/Tolerability of Brexpiprazole as Adjunctive Therapy in Elderly Subjects With Major Depressive Disorder

This study has been completed.
Sponsor:
Collaborator:
H. Lundbeck A/S
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier:
NCT01670279
First received: August 7, 2012
Last updated: January 5, 2016
Last verified: January 2016
  Purpose
The purpose of this study is to assess the safety and tolerability of ascending multiple oral doses of brexpiprazole as adjunctive therapy in the treatment of elderly subjects with MDD.

Condition Intervention Phase
Major Depressive Disorder
Drug: Brexpiprazole
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 1, Multicenter, Randomized, Double-blind, Sequential Cohort, Placebo-controlled Trial to Assess the Safety and Tolerability of Ascending Multiple Oral Doses of Brexpiprazole as Adjunctive Therapy in the Treatment of Elderly Subjects With Major Depressive Disorder

Resource links provided by NLM:


Further study details as provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Primary Outcome Measures:
  • Number of Participants Who Tolerated Brexpiprazole [ Time Frame: 45 Days ] [ Designated as safety issue: Yes ]
    Safety and tolerability of brexpiprazole was noted to be primary outcome measure. Brexpiprazole was judged to be tolerated if at least 6 out of 8 (75%) of the participants in a test cohort tolerated the dose after 14 days of QD dosing at the end of the fixed dose phase based on the blinded data. Dose toleration was defined as follows: during the course of the trial, the participants did not experience any moderate or severe adverse events (AEs) or potentially clinically relevant changes from Baseline in laboratory values, vital signs, electrocardiogram (ECG) tracings, Columbia-Suicide Severity Rating Scale (C-SSRS), or extrapyramidal symptom (EPS) ratings, which were assessed as possibly related to the study drug, and would have warranted a dose decrease or discontinuation of the study drug. The safety and tolerability of brexpiprazole was defined by parameters: AEs, laboratory values, vital signs, ECG, C-SSRS, or EPS ratings, the results of each of the parameters reported separately.

  • Number of AEs Reported. [ Time Frame: Throughout the study, up to 119 days ] [ Designated as safety issue: Yes ]
    The AEs were one of the primary parameters to measure the safety and tolerability of individual participants. The AEs were captured for all participants from the time the ICF was signed until the end of the trial. AEs were measured throughout the 14-day titration and 28-day fixed dose phase until follow-up (30 [±2] days after last dose of study medication).

  • Incidence of Laboratory Values of Potential Clinical Significance [ Time Frame: Titration Day 7, Fixed dose Day 14 and 28 and Last Visit ] [ Designated as safety issue: Yes ]
    The laboratory values were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal values in serum chemistry, hematology, urinalyses and prolactin tests that were identified based on pre-defined criteria.

  • Incidence of Vital Signs of Potential Clinical Significance [ Time Frame: Baseline, Titration Day 1, 2, 7, 8, Fixed Days 1, 2, 14, 15, 28, 29, Early Termination and Last Visit. ] [ Designated as safety issue: Yes ]
    The vital signs were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance included abnormal values in heart rate, systolic and diastolic blood pressure, respiratory rate and weight that were identified based on pre-defined criteria.

  • Incidence of ECG Evaluations of Potential Clinical Significance [ Time Frame: Titratrion Day 1 and 7, Fixed dose Day 1, 14, 28, Early Termination ] [ Designated as safety issue: Yes ]
    The measurement of ECG was one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal changes in heart rate and ECG intervals of PR, QRS, QT, QTcB, and QTcF that were identified based on pre-defined criteria.

  • Incidence of Physical Examination Evaluation of Potential Clinical Significance [ Time Frame: Physical examination was performed at Screening, check-in, and discharge ] [ Designated as safety issue: Yes ]
    The physical examination evaluation was one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal changes in the following body systems: head, ears, eyes, nose, and throat; thorax; abdomen; urogenital; extremities; neurological; and skin and mucosae.

  • Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score [ Time Frame: End of Titration, Day 15, Day 29, Early Termination and Last visit ] [ Designated as safety issue: Yes ]
    EPS was one of the primary parameters to measure the safety and tolerability of individual participants. The SAS is a rating scale used to measure EPS. The SAS scale consists of a list of 10 symptoms of parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia), with each item rated from 0 to 4, with 0 being normal and 4 being the worst. The SAS Total score is sum of ratings for all 10 items, with possible Total scores from 0 to 40.

  • Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score [ Time Frame: End of Titration, Day 15, Day 29, Early Termination and Last visit ] [ Designated as safety issue: Yes ]
    EPS was one of the primary parameters to measure the safety and tolerability of individual participants. The Barnes Akathisia Rating Scale was an EPS rating scale. The Barnes Akathisia Rating Scale was used to assess the presence and severity of akathisia. This scale consists of 4 items. Only the 4th item, the Global Clinical Assessment of Akathisia, was evaluated in this trial. This item is rated on a 6 point scale, with 0 being best (absent) and 5 being worst (severe akathisia).

  • Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. [ Time Frame: End of Titration, Day 15, Day 29, Early Termination and Last visit ] [ Designated as safety issue: Yes ]
    EPS was one of the primary parameters to measure the safety and tolerability of individual participants. The AIMS Scale was an EPS rating scale. The AIMS is a 12 item scale. The first 10 items are rated from 0 to 4 (0=best, 4=worst). Items 11 and 12, related to dental status, have dichotomous responses, 0=no and 1=yes. The AIMS Total Score is the sum of the ratings for the first seven items. The possible total scores are from 0 to 28.

  • Change From Baseline to Study Completion in C-SSRS Score. [ Time Frame: Baseline, End of Titration, Fixed dose Day 14 and 28, Day 15 and 29, Early Termination, Last Visit ] [ Designated as safety issue: Yes ]
    The C-SSRS was one of the primary parameters to measure the safety and tolerability of individual participants. Suicidality was monitored during the trial using the C-SSRS. This scale consists of a baseline evaluation that assesses the lifetime experience of the participant with suicide events and suicidal ideation and a post-baseline evaluation that focuses on suicidality since the last trial visit.


Enrollment: 18
Study Start Date: July 2012
Study Completion Date: May 2013
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
14 day titration phase and two fixed dose phases. The first fixed dose phase is 14 days with a daily dose of 2mg brexpiprazole/placebo. The second fixed dose phase is 14 days with a daily dose of 3 mg brexpiprazole/placebo.
Drug: Brexpiprazole
up to 3mg oral dose once daily
Experimental: Cohort 2
14 day titration phase and a 14 day fixed dose phase a daily dose of 3mg brexpiprazole/placebo.
Drug: Brexpiprazole
up to 3mg oral dose once daily
Experimental: Cohort 3
21 day titration phase and a 14 day fixed dose phase a daily dose of 3mg brexpiprazole/placebo.
Drug: Brexpiprazole
up to 3mg oral dose once daily
Placebo Comparator: Placebo
Placebo
Drug: Placebo

Detailed Description:
This is a phase 1, multicenter, randomized, double-blind, placebo-controlled, multiple ascending dose trial in 3 sequential cohorts of elderly subjects (age 70 to 85 years old) with MDD. Brexpiprazole will be administered as an adjunct treatment to the current antidepressant therapy that the subject is receiving. Total individual subject duration is expected to be no more than 119 days (a 30-day screening period, a 14-day washout period, up to 45-day in-clinic treatment period, and a 30-day follow-up after the last dose of trial medication).
  Eligibility

Ages Eligible for Study:   70 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects who are able to provide written informed consent
  • Ability to understand the nature of the trial and follow protocol requirements
  • Male and female patients 70 to 85 years of age
  • Subjects with normal or clinically stable findings on physical examination, medical history, clinical laboratory determinations, ECGs in relation to age
  • BMI of 18 to 35 kg/m2.
  • Stable subjects with a principal psychiatric diagnosis of MDD
  • Subjects willing to discontinue all prohibited psychotropic and other prohibited medication

Exclusion Criteria:

  • Sexually active males who are not practicing 2 different methods of birth control during the trial and for 30 days after the last dose of trial medication or who will not remain abstinent during the trial and for 30 days after the last dose
  • Subjects who have had a vagus nerve stimulation device implanted or who have received ECT within 6 months of Screening
  • Subjects with a current Axis I (DSM-IV-TR) diagnosis of:

    • Delirium, dementia, amnestic, or other cognitive disorder
    • Eating disorder (including anorexia nervosa or bulimia)
    • Obsessive-compulsive disorder
    • Panic disorder
    • Posttraumatic stress disorder or current or prior Axis I (DSM-IV-TR) diagnosis of Schizophrenia, schizoaffective disorder, or other psychotic disorder, Bipolar I or II disorder or bipolar disorder not otherwise specified
  • Subjects with a clinically significant current Axis II (DSM-IV-TR) diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder
  • Subjects experiencing hallucinations, delusions, or any psychotic symptomatology
  • Subjects who have Active Suicidal Ideation with Some Intent to Act and whose most recent episode occurred within the last 6 months
  • Subjects who have met DSM-IV-TR criteria for substance abuse or dependence within the past 180 days
  • Subjects with hypothyroidism or hyperthyroidism and/or an abnormal result for free T4 at Screening
  • Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders
  • Subjects with IDDM
  • Subjects with uncontrolled hypertension (DBP > 95 mmHg) or symptomatic hypotension
  • Subjects with epilepsy, a history of epilepsy, or a history of seizure
  • Subjects with a positive drug screen for cocaine or other drugs of abuse
  • The following laboratory test and ECG results are exclusionary:

    1. Platelets ≤ 75,000/mm3
    2. Hemoglobin ≤ 9 g/dL
    3. Neutrophils, absolute ≤ 1000/mm3
    4. AST > 3 × upper limit of normal
    5. ALT > 3 × upper limit of normal
    6. Creatinine ≥ 2 mg/dL
    7. HbA1c ≥ 7%
    8. QTcF ≥ 450 msec
  • Treatment with a MAOI within the 2 weeks prior to the first dose of trial medication
  • Use of benzodiazepines and/or hypnotics within 1 week prior the first dose of trial medication
  • Use of oral neuroleptics within 30 days prior to or long-acting approved neuroleptics ≤ 1 full cycle plus 14 days prior to the first dose of trial medication on Day 1
  • Prohibited concomitant medications used prior to randomization or anticipated need for such medications during the trial
  • Subjects who would be likely to require prohibited concomitant therapy during the trial
  • Subjects who received brexpiprazole in any prior clinical trial
  • Subjects with a history of neuroleptic malignant syndrome
  • Subjects with a history of true allergic response to more than 1 class of medications
  • Prisoners or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness
  • Subjects who participated in a clinical trial within the last 180 days or who participated in more than 2 clinical trials within the past year.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01670279

Locations
United States, Florida
Accurate Clinical Trials
Kissimmee, Florida, United States
Miami Jewish Health System
Miami, Florida, United States
United States, Missouri
St. Louis Clinical Trials
St. Louis, Missouri, United States
United States, Pennsylvania
CRI Lifetree- Philadelphia Research Center
Philadelphia, Pennsylvania, United States
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
H. Lundbeck A/S
Investigators
Study Director: James M. Youakim, MD Otsuka Pharmaceutical Development & Commercialization, Inc.
  More Information

No publications provided

Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT01670279     History of Changes
Other Study ID Numbers: 331-12-291 
Study First Received: August 7, 2012
Results First Received: August 4, 2015
Last Updated: January 5, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
Major Depressive Disorder (MDD)

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Major
Behavioral Symptoms
Mental Disorders
Mood Disorders

ClinicalTrials.gov processed this record on February 11, 2016