A Trial to Evaluate the Efficacy, Safety & Tolerability of Brexpiprazole in the Maintenance Treatment of Adults With Major Depressive Disorder
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Intervention: Brexpiprazole; Antidepressant therapy
Intervention description: Administered as tablets.; Protocol-specified oral ADTs included:
citalopram hydrobromide (Celexa®) tablets, escitalopram (Lexapro®) tablets, fluoxetine (Prozac®) capsules, paroxetine (Paxil CR®) controlled-release tablets, sertraline (Zoloft®) tablets, duloxetine (Cymbalta®) delayed-release capsules, venlafaxine XR (Effexor XR®) extended-release (XR) capsules.
Intervention MeSH terms: Antidepressive Agents; Brexpiprazole
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 1149.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Brexpiprazole; MDD

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants 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.

          -  Participants must have reported a history for the current major depressive episode of
             an inadequate response to 1 or 2 adequate antidepressant treatments, and participants
             must currently be taking a protocol-mandated antidepressant treatment at an adequate
             dose and duration, and most not have reported ≥ 50% improvement. For participants 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 participants 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).

          -  Participants with a Hamilton Rating Scale for Depression (HAM-D17) total score ≥ 18 at
             the screening visit, and Phase A baseline visits.

          -  Participants 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.

          -  Participants who report treatment with adjunctive antipsychotic medication with an
             antidepressant for a minimum of 3 weeks during the current major depressive episode.

          -  Participants who report allergies or an intolerability (lifetime treatment history) to
             trial-provided ADTs that have not been prescribed to the participant during the
             current major depressive episode.

          -  Participants who have received electroconvulsive therapy (ECT) for the current major
             depressive episode.

          -  Participants 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. Participants who have had
             transcranial magnetic stimulation during the current major depressive episode.

          -  Participants with a current need for involuntary commitment or who have been
             hospitalized within 4 weeks of screening for the current major depressive episode.

          -  Participants 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

          -  Participants with a current DSM-5 diagnosis of borderline, antisocial, paranoid,
             schizoid, schizotypal, or histrionic personality disorder or intellectual disability.

          -  Participants experiencing hallucinations, delusions, or any psychotic symptomatology
             in the current major depressive episode.

          -  Participants receiving new onset psychotherapy (individual, group, marriage or family
             therapy) within 42 days of screening or at any time during participation in the trial.

          -  Participants 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.

          -  Participants 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.

          -  Participants 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.

          -  Participants with diabetes mellitus (IDDM and non-IDDM) are ineligible for the trial
             unless their condition is stable and well-controlled.

          -  Participants with uncontrolled hypertension (DBP > 95 millimetres of mercury [mmHg])
             or symptomatic hypotension, or orthostatic hypotension which is defined as a decrease
             of ≥ 30 mmHg in systolic blood pressure (SBP) and/or decrease of ≥ 20 mmHg in
             diastolic blood pressure (DBP) after at least 3 minutes standing compared to the
             previous supine blood pressure OR development of symptoms.

          -  Participants with known ischemic heart disease or history of myocardial infarction-or
             congestive heart failure (whether controlled or uncontrolled).

          -  Participants with epilepsy or a history of seizures, except for a single seizure
             episode.

          -  Participants 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 participant
             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
             participant or interpretation of the trial results, and participation is agreed to by
             the medical monitor prior to treatment.

          -  Treatment with a monoamine oxidase inhibitor (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.

          -  Participants who would be likely to require prohibited concomitant therapy during the
             trial.

          -  Participants who have been exposed to brexpiprazole in any prior clinical trial or has
             received commercial brexpiprazole (Rexulti).

          -  Participants with a history of neuroleptic malignant syndrome or serotonin syndrome.

          -  Participants with a history of true allergic response to more than one class of
             medications.

          -  Prisoners or participants who are compulsorily detained for treatment of either a
             psychiatric or physical illness.

          -  Participants who participated in any clinical trial within the last 60 days or who
             participated in more than 2 clinical trials within the past year.