A Study of Brexpiprazole Plus Ketamine in Treatment-Resistant Depression (TRD)
Condition: Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
Intervention: Brexpiprazole; Ketamine; Placebo
Intervention description: Administration of up to 3mg brexpiprazole; administration 6 times over two weeks of inhaled ketamine; Administration of placebo which matches brexpiprazole in size and number of tablets per dose
Intervention MeSH terms: Ketamine; Brexpiprazole
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 51.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: treatment resistant; inadequate response

Summary:

      This is a multi-site, double-blind, placebo-controlled study of the acute efficacy of
      brexpiprazole or placebo in combination with intranasal ketamine added to ongoing, stable,
      and adequate antidepressant therapy (ADT) in the treatment of adults with Major Depressive
      Disorder with Treatment Resistant Depression.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female, 18 to 65 years of age, inclusive, at screening.

          2. Able to read, understand, and provide written, dated informed consent prior to
             screening. Participants will be deemed likely to comply with study protocol and
             communicate with study personnel about adverse events and other clinically important
             information.

          3. Diagnosed with MDD, single or recurrent, and currently experiencing a major depressive
             episode (MDE) of at least eight weeks in duration, prior to screening, according to
             the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders,
             Fifth Edition (DSM-5). The diagnosis of MDD will be made by a site psychiatrist and
             supported by the SCID-5. The diagnosis will be confirmed by remote, independent raters
             from the MGH CTNI (Massachusetts General Hospital Clinical Trials Network and
             Institute) with a SAFER interview.

          4. Has a history of treatment resistant depression (TRD) during the current MDE, as
             assessed by the investigator and remote centralized rater using the MGH ATRQ. TRD is
             defined as failure to achieve a satisfactory response (e.g., less than 50% improvement
             of depression symptoms), as perceived by the participant, to at least 2 "treatment
             courses" during the current episode of a therapeutic dose of an antidepressant therapy
             (ADT) of at least 8 weeks duration (including the current ADT). The adequacy of dose
             and duration of the antidepressant therapy will be determined as per the MGH ATRQ
             criteria. The TRD status will be confirmed by remote, independent raters from the MGH
             CTNI who will administer the MGH ATRQ, via teleconference, between the screening visit
             and the baseline visit. Participants must currently be on a stable (for at least 4
             weeks) and adequate (according to the MGH ATRQ) dose of ongoing antidepressant therapy
             (any antidepressant therapy, with the exception of MAOIs), of which total duration
             must be at least 8 weeks.

          5. Meet the threshold on the total MADRS score of >20 at both the screen visit and the
             baseline visit (Day -7/-28 and Day 0), and as confirmed by the remote centralized MGH
             CTNI rater between the screen visit and the baseline visit.

          6. In good general health, as ascertained by medical history, physical examination (PE)
             (including measurement of supine and standing vital signs), clinical laboratory
             evaluations, and ECG.

          7. If female, a status of non-childbearing potential or use of an acceptable form of
             birth control per the following specific criteria:

               -  Non-childbearing potential (e.g., physiologically incapable of becoming pregnant,
                  i.e., permanently sterilized (status post hysterectomy, bilateral tubal
                  ligation), or is post-menopausal with her last menses at least one year prior to
                  screening); or

               -  Childbearing potential, and meets the following criteria:

                    -  Childbearing potential, including women using any form of hormonal birth
                       control, on hormone replacement therapy started prior to 12 months of
                       amenorrhea, using an intrauterine device (IUD), having a monogamous
                       relationship with a partner who has had a vasectomy, or is sexually
                       abstinent.

                    -  Negative urinary pregnancy test at screening, confirmed by a negative
                       urinary pregnancy test at randomization prior to receiving study treatment.

                    -  Willing and able to continuously use one of the following methods of birth
                       control during the course of the study, defined as those which result in a
                       low failure rate (i.e., less than 1% per year) when used consistently and
                       correctly: implants, injectable or patch hormonal contraception, oral
                       contraceptives, IUD, double-barrier contraception, sexual abstinence. The
                       form of birth control will be documented at screening and baseline.

          8. Body mass index between 18-35 kg/m2.

          9. Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive
             behavioral, insight-oriented, et al.) and frequency (e.g., weekly or monthly) of the
             therapy has been stable for at least three months prior to screening and if the type
             and frequency of the therapy is expected to remain stable during the course of the
             subject's participation in the study.

         10. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines
             or trazodone) will be allowed if the therapy has been stable for at least 4 weeks
             prior to screening and if it is expected to remain stable during the course of the
             subject's participation in the study. Patients can also continue treatment with
             benzodiazepines used for anxiety if therapy has been stable for at least 4 weeks prior
             to screening and if it is expected to remain stable during the course of the subject's
             participation in the study.

        Exclusion Criteria:

          1. Female of childbearing potential who is not willing to use one of the specified forms
             of birth control during the study.

          2. Female that is pregnant or breastfeeding.

          3. Female with a positive pregnancy test at screening or baseline.

          4. History during the current MDE of failure to achieve satisfactory response (e.g., less
             than 50% improvement of depression symptoms) to >7 treatment courses of a therapeutic
             dose of an antidepressant therapy of at least 8 weeks duration, according to the MGH
             ATRQ, as confirmed by the remote, independent MGH CTNI rater.

          5. Total MADRS score of <20 at the screen visit or the baseline visit, or as assessed by
             the remote, independent MGH CTNI rater and reported to the site.

          6. Current diagnosis of a substance use disorder (abuse or dependence, as defined by
             DSM-IV-TR™), with the exception of nicotine dependence, at screening or within 6
             months prior to screening.

          7. Current Axis I disorder, diagnosed at screening with the use of the Structured
             Clinical Interview for DSM-5 AXIS I Disorders (SCID-5), that is the principal focus of
             treatment and MDD the secondary focus of treatment for the past 6 months or more.

          8. History of bipolar disorder, schizophrenia or schizoaffective disorders, or any
             history of psychotic symptoms in the current or previous depressive episodes.

          9. History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise
             specified, within 5 years of screening.

         10. Any Axis I or Axis II Disorder, which at screening is clinically predominant to their
             MDD or has been predominant to their MDD at any time within 6 months prior to
             screening.

         11. In the judgment of the investigator, the subject is considered at significant risk for
             suicidal behavior during the course of his/her participation in the study.

         12. Has failed to respond to ECT during the current depressive episode.

         13. Has received VNS at any time prior to screening.

         14. Has dementia, delirium, amnestic, or any other cognitive disorder.

         15. Has a clinically significant abnormality on the screening physical examination that
             might affect safety, study participation, or confound interpretation of study results
             according to the study clinician.

         16. Participation in any clinical trial with an investigational drug or device within the
             past month or concurrent to study participation.

         17. Current episode of:

               -  Hypertension, Stage 1 as defined by a systolic blood pressure ≥160 mmHg or
                  diastolic blood pressure ≥100 mHg at the Baseline Visit (Visit 1) within 1.5
                  hours prior to randomization on two of three measurements (standing and supine)
                  at least 15 minutes apart.

               -  Recent myocardial infarction (within one year) or a history of myocardial
                  infarction.

               -  Syncopal event within the past year.

               -  Congestive heart failure (CHF) New York Heart Association Criteria >Stage 2

               -  Angina pectoris.

               -  Heart rate <45 or >110 beats per minute at screening or randomization (Baseline
                  Visit).

               -  QTcF (Fridericia-corrected) ≥450 msec at screening or randomization (Baseline
                  Visit).

         18. Chronic lung disease excluding asthma.

         19. Lifetime history of surgical procedures involving the brain or meninges, encephalitis,
             meningitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's or
             Parkinson's Disease), epilepsy, mental retardation, or any other
             disease/procedure/accident/intervention which, according to the screening clinician,
             is deemed associated with significant injury to or malfunction of the CNS, or history
             of significant head trauma within the past 2 years.

         20. Presents with any of the following lab abnormalities:

               -  Thyroid stimulating hormone (TSH) outside of the normal limits and clinically
                  significant as determined by the investigator. Free thyroxine (T4) levels may be
                  measured if TSH level is high. Subject will be excluded if T4 level is clinically
                  significant.

               -  Patients with diabetes mellitus fulfilling any of the following criteria:

                    -  Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.5%
                       at screening.

                    -  Admitted to hospital for treatment of diabetes mellitus or diabetes
                       mellitus-related illness in the past 12 weeks.

                    -  Not under physician care for diabetes mellitus.

                    -  Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for
                       the 4 weeks prior to screening. For thiazolidinediones (glitazones) this
                       period should not be less than 8 weeks.

               -  Any other clinically significant abnormal laboratory result (determined as such
                  by the investigator and MGH CTNI medical monitor) at the time of the screening.

         21. History of hypothyroidism and has been on a stable dosage of thyroid replacement
             medication for less than 2 months prior to screening. (Subjects on a stable dosage of
             thyroid replacement medication for at least 2 months or more prior to screening are
             eligible for enrollment.)

         22. History of hyperthyroidism which was treated (medically or surgically) less than 6
             months prior to screening.

         23. History of positive screening urine test for drugs of abuse at screening: cannabinoids
             (if the patient has a legitimate medical prescription for cannabis, patient must agree
             to abstain during the entirety of the study and to have a negative test at baseline),
             cocaine, amphetamines, barbiturates, opiates (unless use is in accordance with
             guidance provided in table of allowed and excluded medications).

         24. Patients with exclusionary laboratory values (see Table 1), or requiring treatment
             with exclusionary concomitant medications (see Appendix 1).

         25. Patients on exclusionary concomitant psychotropic medications, the half-life of which
             would not allow sufficient time for patients to have been free of the medication
             post-taper for five half-lives within the maximum screening period (28 days).

         26. Patients with a history of narrow angle glaucoma.

         27. Liver or renal Function tests which meet the exclusion criteria in Table 1, or a
             history of hepatic or renal dysfunction.