A Trial to Evaluate the Efficacy, Safety & Tolerability of Brexpiprazole in the Maintenance Treatment of Adults With Major Depressive Disorder

• ClinicalTrials.gov Identifier: NCT03538691
• Recruitment Status: Recruiting
• First Posted: May 29, 2018
• Last Update Posted: November 22, 2019
• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Information provided by (Responsible Party): Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Description

Brief Summary:

Major depressive disorder (MDD) is a serious medical illness associated with significant suicidal risk and marked disability. Despite the availability of numerous treatments, achievement of consistent and favorable long-term outcomes remains challenging.

This study will assess the safety, efficacy and tolerability of brexpiprazole as adjunctive therapy to protocol-specific open-label antidepressant therapy.

Condition or disease	Intervention/treatment	Phase
Major Depressive Disorder	Drug: Brexpiprazole; Drug: Placebo; Drug: Citalopram Hydrobromide; Drug: Escitalopram; Drug: Fluoxetine; Drug: Paroxetine; Drug: Sertraline; Drug: Duloxetine; Drug: Venlafaxine Extended Release Oral Capsule	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1450 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Brexpiprazole as Adjunctive Therapy in the Maintenance Treatment of Adults With Major Depressive Disorder
• Actual Study Start Date: July 13, 2018
• Estimated Primary Completion Date: September 2022
• Estimated Study Completion Date: September 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Brexpiprazole & Citalopram Hydrobromide; Brexpiprazole: oral tablet; 2 to 3 mg/day Citalopram hydrobromide: oral tablet; 20 or 40 mg/day	Drug: Brexpiprazole; Tablet; Other Name: OPC-34712; Drug: Citalopram Hydrobromide; Tablet; Other Name: Celexa
Placebo Comparator: Placebo & Citalopram Hydrobromide; Placebo: daily oral tablet Citalopram hydrobromide: oral tablet; 20 or 40 mg/day	Drug: Placebo; Tablet; Drug: Citalopram Hydrobromide; Tablet; Other Name: Celexa
Experimental: Brexpiprazole & Escitalopram; Brexpiprazole: oral tablet; 2 to 3 mg/day Escitalopram: oral tablet; 10 or 20 mg/day	Drug: Brexpiprazole; Tablet; Other Name: OPC-34712; Drug: Escitalopram; Tablet; Other Name: Lexapro
Placebo Comparator: Placebo & Escitalopram; Placebo: daily oral tablet Escitalopram: oral tablet; 10 or 20 mg/day	Drug: Placebo; Tablet; Drug: Escitalopram; Tablet; Other Name: Lexapro
Experimental: Brexpiprazole & Fluoxetine; Brexpiprazole: oral tablet; 2 to 3 mg/day Fluoxetine: oral capsule; 20 or 40 mg/day	Drug: Brexpiprazole; Tablet; Other Name: OPC-34712; Drug: Fluoxetine; Capsules; Other Name: Prozac
Placebo Comparator: Placebo & Fluoxetine; Placebo: daily oral tablet Fluoxetine: oral capsule; 20 or 40 mg/day	Drug: Placebo; Tablet; Drug: Fluoxetine; Capsules; Other Name: Prozac
Experimental: Brexpiprazole & Paroxetine; Brexpiprazole: oral tablet; 2 to 3 mg/day Paroxetine: oral controlled-release tablet; 37.5 or 50 mg/day	Drug: Brexpiprazole; Tablet; Other Name: OPC-34712; Drug: Paroxetine; Controlled-release tablets; Other Name: Paxil CR
Placebo Comparator: Placebo & Paroxetine; Placebo: daily oral tablet Paroxetine: oral controlled-release tablet; 37.5 or 50 mg/day	Drug: Placebo; Tablet; Drug: Paroxetine; Controlled-release tablets; Other Name: Paxil CR
Experimental: Brexpiprazole & Sertraline; Brexpiprazole: oral tablet; 2 to 3 mg/day Sertraline: oral tablet; 100, 150 or 200 mg/day	Drug: Brexpiprazole; Tablet; Other Name: OPC-34712; Drug: Sertraline; Tablet; Other Name: Zoloft
Placebo Comparator: Placebo & Sertraline; Placebo: daily oral tablet Sertraline: oral tablet; 100, 150 or 200 mg/day	Drug: Placebo; Tablet; Drug: Sertraline; Tablet; Other Name: Zoloft
Experimental: Brexpiprazole & Duloxetine; Brexpiprazole: oral tablet; 2 to 3 mg/day Duloxetine: oral delayed-release capsule; 40 or 60 mg/day	Drug: Brexpiprazole; Tablet; Other Name: OPC-34712; Drug: Duloxetine; Delayed-release capsule; Other Name: Cymbalta
Placebo Comparator: Placebo & Duloxetine; Placebo: daily oral tablet Duloxetine: oral delayed-release capsule; 40 or 60 mg/day	Drug: Placebo; Tablet; Drug: Duloxetine; Delayed-release capsule; Other Name: Cymbalta
Experimental: Brexpiprazole & Venlafaxine extended-release (XR); Brexpiprazole: oral tablet; 2 to 3 mg/day Venlafaxine XR: daily extended-release capsule; 75, 150, or 225 mg/day	Drug: Brexpiprazole; Tablet; Other Name: OPC-34712; Drug: Venlafaxine Extended Release Oral Capsule; Extended-release capsule; Other Name: Effexor XR
Placebo Comparator: Placebo & Venlafaxine extended-release (XR); Placebo: daily oral tablet Venlafaxine XR: daily extended-release capsule; 75, 150, or 225 mg/day	Drug: Placebo; Tablet; Drug: Venlafaxine Extended Release Oral Capsule; Extended-release capsule; Other Name: Effexor XR

Outcome Measures

Primary Outcome Measures :

1. Time-to-Relapse by any criteria as defined in blinded addendum [ Time Frame: Up to 26 weeks ]

Secondary Outcome Measures :

1. Change from randomization at week 20 in Sheehan Disability Scale (SDS) mean total score at Week 46 [ Time Frame: Up to 26 weeks ]
   Scores range from 0 to 10, with a score of 10 being worse than a score of 0. Measuring period will be from randomization visit at week 20 until final visit at week 46, totaling 26 weeks.
2. Time-to-functional relapse based on SDS criteria. [ Time Frame: Up to 26 weeks ]
   Scores range from 0 to 10, with a score of 10 being worse than a score of 0
3. Percentage of subjects who relapse [ Time Frame: Up to 26 weeks ]
4. Percentage of subjects maintaining remission [ Time Frame: Up to 26 weeks ]
5. Mean change from randomization at week 20 in Montgomery Asberg Depression Rating Scale (MADRS) total score at Week 46 [ Time Frame: Up to 26 weeks ]
   Scale ranges from 0 to 60 with a higher score indicating worsening symptoms of depression. Measuring period will be from randomization visit at week 20 until final visit at week 46, totaling 26 weeks
6. Mean change from randomization at week 20 in Clinical Global Impression - Severity of Illness (CGI-S) score at Week 46 [ Time Frame: Up to 26 weeks ]
   Score ranges from 1 to 7 with a score of 7 being a worse outcome than a score of 1. Measuring period will be from randomization visit at week 20 until final visit at week 46, totaling 26 weeks
7. Mean change from randomization at week 20 in each of the SDS individual item scores at Week 46 [ Time Frame: Up to 26 weeks ]
   Scores range from 0 to 10, with a score of 10 being worse than a score of 0. Measuring period will be from randomization visit at week 20 until final visit at week 46, totaling 26 weeks

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Subjects with both a diagnosis of recurrent major depressive disorder, and in a current major depressive episode of ≥ 8 weeks in duration, as defined by Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) and confirmed by both the Mini International Neuropsychiatric Interview (MINI) and an adequate clinical psychiatric evaluation.
• Subjects must have reported a history for the current major depressive episode of an inadequate response to 1 or 2 adequate antidepressant treatments, and subjects must currently be taking a protocol-mandated antidepressant treatment at an adequate dose and duration, and most not have reported ≥ 50% improvement. For subjects who are currently on an adequate dose of protocol-mandated antidepressant therapy (ADT), but for an inadequate duration, can use the screening period to achieve adequate duration. At Phase A baseline visit, all subjects must have either 2 or 3 documented inadequate responses to antidepressant treatment in total for the current episode as defined by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ)
• Subjects with a Hamilton Rating Scale for Depression (HAM-D17) total score ≥ 18 at the screening visit, and Phase A baseline visits.
• Subjects willing to discontinue all prohibited psychotropic medications to meet protocol-required washouts prior to and during the trial period.

Exclusion Criteria:

• Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving investigational medicinal product (IMP).
• Sexually active males or females of childbearing potential who do 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 IMP.
• Subjects who report treatment with adjunctive antipsychotic medication with an antidepressant for a minimum of 3 weeks during the current major depressive episode
• Subjects who report allergies or an intolerability (lifetime treatment history) to trial-provided ADTs that have not been prescribed to the subject during the current major depressive episode.
• Subjects who have received ECT for the current major depressive episode
• Subjects who have had an inadequate response to ECT at any time in the past or who have had a vagus nerve stimulation or deep brain stimulation device implanted at any time for the management of treatment-resistant depression. Subjects who have had transcranial magnetic stimulation during the current major depressive episode.
• Subjects with a current need for involuntary commitment or who have been hospitalized within 4 weeks of screening for the current major depressive episode.

• Subjects with a primary DSM-5 diagnosis of:

  1. Schizophrenia Spectrum and Other Psychotic Disorders
  2. Bipolar and Related Disorders
  3. Obsessive Compulsive Disorders
  4. Feeding and Eating Disorders
  5. Neurocognitive Disorders
  6. Panic Disorder
  7. Post-Traumatic Stress Disorder
• Subjects with a current DSM-5 diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder or intellectual disability.
• Subjects experiencing hallucinations, delusions, or any psychotic symptomatology in the current major depressive episode
• Subjects receiving new onset psychotherapy (individual, group, marriage or family therapy) within 42 days of screening or at any time during participation in the trial
• Subjects who have met DSM-5 criteria for substance use disorder (moderate or severe) within the past 60 days; including alcohol and benzodiazepines, but excluding nicotine
• Subjects with hypothyroidism or hyperthyroidism (unless condition has been stabilized with medications for at least the past 90 days) 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 such as any history of myocardial infarction, congestive heart failure, HIV seropositive status/acquired immunodeficiency syndrome, chronic hepatitis B or C.
• Subjects with diabetes mellitus (IDDM and non-IDDM) are ineligible for the trial unless their condition is stable and well-controlled.
• Subjects with uncontrolled hypertension (DBP > 95 mmHg) or symptomatic hypotension, or orthostatic hypotension which is defined as a decrease of ≥ 30 mmHg in SBP and/or decrease of ≥ 20 mmHg in DBP after at least 3 minutes standing compared to the previous supine blood pressure OR development of symptoms.
• Subjects with known ischemic heart disease or history of myocardial infarction-or congestive heart failure (whether controlled or uncontrolled)
• Subjects with epilepsy or a history of seizures, except for a single seizure episode
• Subjects with a positive drug screen for cocaine or other drugs of abuse (excluding known prescription stimulants and other medications and marijuana). Detectable levels of alcohol, marijuana, barbiturates, or opiates in the drug screen are not exclusionary if, in the investigator's documented opinion, the subject does not meet DSM-5 criteria for moderate to severe substance use disorder and the positive test does not signal a clinical condition that would impact the safety of the subject or interpretation of the trial results, and participation is agreed to by the medical monitor prior to treatment.
• Treatment with an MAOI within 14 day prior to the first dose of IMP in Phase A.
• Use of benzodiazepines and/or hypnotics (including non-benzodiazepine sleep aids) within 7 days prior to first dose of IMP in Phase A.
• Use of varenicline within 5 days prior to the first dose of IMP in Phase A.
• Use of oral (or immediate release intramuscular) neuroleptics within 7 days prior or long-acting approved neuroleptics ≤ 1 full cycle plus 1/2 cycle prior to the first dose of IMP in Phase A.
• Subjects who would be likely to require prohibited concomitant therapy during the trial.
• Subjects who have been exposed to brexpiprazole in any prior clinical trial or has received commercial brexpiprazole (Rexulti).
• Subjects with a history of neuroleptic malignant syndrome or serotonin syndrome.
• Subjects with a history of true allergic response to more than one class of medications
• Prisoners or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.
• Subjects who participated in any clinical trial within the last 60 days or who participated in more than 2 clinical trials within the past year

Contacts and Locations

Contacts

Contact: Otsuka Call Center; 844-687-8522; OtsukaRMReconciliation@rmpdc.org

Locations

United States, California

For additional information regarding sites, contact 844-687-8522; Recruiting

Los Angeles, California, United States, 90024

Sponsors and Collaborators

Otsuka Pharmaceutical Development & Commercialization, Inc.

More Information

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT03538691
• Other Study ID Numbers: 331-201-00079
• First Posted: May 29, 2018
• Last Update Posted: November 22, 2019
• Last Verified: November 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Brexpiprazole; MDD

Additional relevant MeSH terms:

Depressive Disorder; Depression; Depressive Disorder, Major; Mood Disorders; Mental Disorders; Behavioral Symptoms; Duloxetine Hydrochloride; Dexetimide; Citalopram; Fluoxetine; Paroxetine; Venlafaxine Hydrochloride; Sertraline; Brexpiprazole; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Serotonin Agents; Physiological Effects of Drugs; Antidepressive Agents, Second-Generation; Antidepressive Agents; Psychotropic Drugs; Antiparkinson Agents; Anti-Dyskinesia Agents; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists