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A Trial to Assess Brexpiprazole Versus Placebo for the Treatment of Acute Manic Episodes Associated With Bipolar I Disorder

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ClinicalTrials.gov Identifier: NCT03259555
Recruitment Status : Completed
First Posted : August 23, 2017
Results First Posted : February 10, 2020
Last Update Posted : February 10, 2020
Sponsor:
Collaborator:
H. Lundbeck A/S
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Tracking Information
First Submitted Date  ICMJE August 4, 2017
First Posted Date  ICMJE August 23, 2017
Results First Submitted Date  ICMJE December 13, 2019
Results First Posted Date  ICMJE February 10, 2020
Last Update Posted Date February 10, 2020
Actual Study Start Date  ICMJE September 14, 2017
Actual Primary Completion Date January 2, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 3, 2020)
Change From Baseline In Young-Mania Rating Scale (YMRS) Score At Week 3 [ Time Frame: Baseline, Week 3 ]
The YMRS was utilized to assess a participant's level of manic symptoms. It consists of 11 items: 1) elevated mood, 2) increased motor activity-energy, 3) sexual interest, 4) sleep, 5) irritability, 6) speech (rate and amount), 7) language-thought disorder, 8) content, 9) disruptive-aggressive behavior, 10) appearance, and 11) insight. Seven items are rated on a 0- to 4-scale, while four items (Items 5, 6, 8, and 9) are rated on a 0- to 8-scale with 0, 2, 4, 6, and 8 being the possible scores (twice the weight of the other items). For all items, 0 is the "best" rating and the highest score (4 or 8) is the 'worst' rating. The YMRS total score is the sum of ratings for all 11 items; therefore, possible total scores range from 0 to 60, with higher scores signifying more severe manic symptoms. Comparison between treatment groups was carried out using mixed-effect model repeated measure (MMRM).
Original Primary Outcome Measures  ICMJE
 (submitted: August 22, 2017)
Change from baseline in Young-Mania Rating Scale (YMRS) Score [ Time Frame: Up to 21 days or early termination ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 3, 2020)
Change From Baseline In Clinical Global Impression-Bipolar (CGI-BP) Severity Score In Mania At Week 3 [ Time Frame: Baseline, Week 3 ]
The CGI-BP scale refers to the global impression of the participant with respect to bipolar disorder. The scale rates the participant's severity of illness (CGI-BP severity of illness: mania, depression, and overall bipolar illness) based on a 7-point scale: 1 = normal, not at all ill, 2 = minimally ill, 3 = mildly ill, 4 = moderately ill, 5 = markedly ill, 6 = severely ill, 7 = very severely ill.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 22, 2017)
  • Change from baseline in Clinical Global Impression-Bipolar (CGI-BP) severity of illness score in mania [ Time Frame: Up to 21 days or early termination ]
  • Change from baseline in YMRS score for each trial visit [ Time Frame: Up to 14 days or early termination ]
  • Change from baseline in CGI-BP severity of illness score in mania for each trial visit [ Time Frame: Up to 14 days or early termination ]
  • Change from preceding phase score in mania for CGI-BP at each trial visit [ Time Frame: Up to 21 days or early termination ]
  • YMRS response rate for each trial visit [ Time Frame: Up to 21 days or early termination ]
    Response is defined as ≥ 50% reduction in YMRS total score from baseline or total score ≤ 12
  • YMRS remission rate for each trial visit [ Time Frame: Up to 21 days or early termination ]
    Remission is defined as YMRS score ≤ 12%
  • CGI-BP change from preceding phase response rate in mania for each trial visit [ Time Frame: Up to 21 days or early termination ]
    Response is defined as a CGI-BP change from preceding phase score in mania of 1 or 2 from baseline
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: August 22, 2017)
  • Change from baseline in Montgomery Asberg Depression Score (MADRS) [ Time Frame: Up to 7 days ]
  • Global Assessment of Functioning (GAF) score [ Time Frame: Up to 21 days or early termination ]
    Will assess change from baseline in score
  • Adverse Events (AEs) [Safety] [ Time Frame: Up to 21 days or early termination with a 21 day follow-up period ]
    Occurrence of AEs will be reviewed for notable observations or trends
  • Clinical Laboratory Tests [Safety] [ Time Frame: Up to 21 days or early termination ]
    Hematology, serum chemistry (including prolactin & glycosylated hemoglobin) coagulation parameters, & urinalysis. Lab results will be assessed for notable observations or changes
  • Physical examination (including weight & waist circumference) [Safety] [ Time Frame: Up to 21 days or early termination ]
    Subject will be examined for any notable observations or changes
  • Vital Signs [Safety] [ Time Frame: Up to 21 days or early termination ]
    Vital signs will be assessed for any notable measurements or changes
  • ECGs [Safety] [ Time Frame: Up to 21 days or early termination ]
    ECGs will be assessed for any notable measurements or changes
  • Simpson-Angus Scale (SAS) total score [Safety] [ Time Frame: Up to 21 days or early termination ]
    Used in the assessment of extrapyramidal symptoms (EPS)
  • Abnormal Involuntary Movement Scale (AIMS) Movement Rating Score [Safety] [ Time Frame: Up to 21 days or early termination ]
    Used in the assessment of extrapyramidal symptoms (EPS)
  • Barnes Akathisia Rating Scale (BARS) Global Score [ Time Frame: Up to 21 days or early termination ]
    Used in the assessment of extrapyramidal symptoms (EPS)
  • Suicidality via Columbia-Suicide Severity Rating Scale (C-SSRS) [Safety] [ Time Frame: Up to 21 days or early termination ]
 
Descriptive Information
Brief Title  ICMJE A Trial to Assess Brexpiprazole Versus Placebo for the Treatment of Acute Manic Episodes Associated With Bipolar I Disorder
Official Title  ICMJE A Multicenter, Randomized, Double-blind Trial of Brexpiprazole Versus Placebo for the Acute Treatment of Manic Episodes, With or Without Mixed Features, Associated With Bipolar I Disorder
Brief Summary To demonstrate the efficacy of brexpiprazole for the acute treatment of manic episodes, with or without mixed features, in participants with a diagnosis of bipolar I disorder.
Detailed Description A multicenter, randomized, double-blind trial of brexpiprazole versus placebo for the acute treatment of manic episodes, with or without mixed features, associated with bipolar I disorder. This study also demonstrated the safety and tolerability of brexpiprazole in the study population of males and females aged 18 to 65 years (inclusive, at time of consent).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Participants received a dose of brexpiprazole or placebo for a maximum of 21 days and were evaluated throughout the duration of the study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Bipolar I Disorder
  • Manic Episode
Intervention  ICMJE
  • Drug: Brexpiprazole
    Brexpiprazole was administered orally with flexible dosing from 2 to 4 mg/day; titrated to a maximum of 4 mg/day for 3 weeks.
  • Drug: Placebo
    Administered orally daily for 3 weeks.
Study Arms  ICMJE
  • Experimental: Brexpiprazole
    Participants received a starting dose of 2 milligrams (mg)/day brexpiprazole from Days 1 to 3, followed by titration to 3 mg/day on Day 4. Participants may have been titrated (or re-titrated) to a higher dose of brexpiprazole, up to a maximum of 4 mg/day, based on treatment response and at the investigator's discretion anytime at Day 7 or thereafter. Participants who were unable to tolerate their current dose could have been titrated down to a minimum of 2 mg/day any time after Day 4.
    Intervention: Drug: Brexpiprazole
  • Placebo Comparator: Placebo
    Matching placebo was administered in the same way as brexpiprazole to maintain the blind.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 14, 2019)
322
Original Estimated Enrollment  ICMJE
 (submitted: August 22, 2017)
320
Actual Study Completion Date  ICMJE January 2, 2019
Actual Primary Completion Date January 2, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female participants, ages 18 to 65 years, inclusive, at the time of informed consent.
  • Participants willing to discontinue all prohibited medications to meet protocol-required washouts prior to and during the trial period.
  • Participants with a Diagnostic & Statistical Manual on Mental Disorders, 5th Edition (DSM-5) diagnosis of bipolar I disorder displaying an acute manic episode with or without mixed features requiring hospitalization. Diagnosis confirmed by the MINI International Neuropsychiatric Interview and a history of at least 1 previous manic episode with or without mixed features with manic symptoms of sufficient severity to require one of the following interventions: hospitalization or treatment with a mood stabilizer, or treatment with an antipsychotic agent. "Require" was defined as an intervention that occurred rather than one that was recommended.
  • Young-mania rating scale (YMRS) score of ≥24 at screening and baseline.

Exclusion Criteria:

  • Sexually active male or women of childbearing potential who did not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of investigational medicinal product.
  • Females who were breastfeeding and/or who had a positive pregnancy test result prior to receiving trial medication.
  • Participants considered unresponsive to clozapine or who were only responsive to clozapine.
  • Participants with a history of DSM-5 diagnosis other than bipolar I disorder, including schizophrenia, schizoaffective disorder, major depressive disorder, attention-deficit/hyperactivity disorder, delirium, dementia, amnestic, or other cognitive disorders. Also, participants with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder. All other current diagnoses must have been discussed with the medical monitor.
  • Participants whose current manic episode had lasted for more than 4 weeks overall, or who had required hospitalization >21 days for the current acute episode at the time of the screening visit, excluding hospitalization for psychosocial reasons.
  • Participant with manic symptoms better accounted for by another general medical condition or direct physiological effect of substance (for example, medication).
  • Participants who have had electroconvulsive treatment within the past 2 months.
  • Participants with a positive drug screen for cocaine or other illicit drugs.
  • Abnormal laboratory test results, vital signs or electrocardiogram findings, unless based on investigator's judgment the findings are not medically significant or would not impact the safety of the participant or the interpretation of the trial results.
  • Rapid cyclers with more than 6 episodes in the previous year.
  • Participants with hypothyroidism or hyperthyroidism (unless condition has been stabilized with medications for at least the past 90 days) or an abnormal result for free thyroxine at screening.
  • Participants with uncontrolled hypertension or symptomatic hypotension or orthostatic hypotension.
  • Participant with epilepsy or history of seizures.
  • Participants who participated in a clinical trial within the last 60 days or who participated in more than 2 clinical trials within the past year.
  • Use of psychotropic medications (other than benzodiazepines) within 7 days of the baseline YMRS.
  • Participants who currently had clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders.
  • Participants who received brexpiprazole in any prior clinical trial or currently taking commercially available brexpiprazole (Rexulti).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Bulgaria,   Poland,   Serbia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03259555
Other Study ID Numbers  ICMJE 331-201-00080
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
Access Criteria: Otsuka will share data on an Otsuka-owned remotely accessible data sharing platform with Python and R analytical software. Research requests should be directed to clinicaltransparency@Otsuka-us.com
Responsible Party Otsuka Pharmaceutical Development & Commercialization, Inc.
Study Sponsor  ICMJE Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators  ICMJE H. Lundbeck A/S
Investigators  ICMJE
Study Director: Matthew Leoni, M.D. Otsuka Pharmaceutical Development & Commercialization, Inc.
PRS Account Otsuka Pharmaceutical Development & Commercialization, Inc.
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP