| Eligibility |
Inclusion Criteria:
1. The subject who are able to provide signed written informed consent.
2. Male and female outpatients 18 to 65 years of age, inclusive, at the time of signing
the informed consent.
3. Subjects with both a diagnosis of MDD, and in a current Major Depressive Episode,
according to the diagnostic criteria in DSM-IV-TR and confirmed by the Mini
International Neuropsychiatric Interview (MINI). The current Major Depressive Episode
must be = 8 weeks in duration.
4. Subjects must have reported a history for the current Major Depressive Episode of an
inadequate response to at least one and no more than three standard antidepressant
treatments (including any antidepressants being received during Screening period, if
the antidepressants treatment meets criteria of standard treatment). For the most
recent antidepressant treatment, the subject must not report = 50% improvement.
Standard treatment is defined as: an antidepressant treatment for at least 6 weeks in
duration (at least 3 weeks if combined treatment) at a minimum effective dose (or
higher) according to prescription drug labels. At least once of 1 to 3 standard
treatments is monotherapy for more than 6 weeks.
An inadequate response is defined as: < 50% reduction in depressive symptom severity,
as measured by the subject's self-report score on Visual Analogue Scale (VAS).
5. Subjects with a HAM-D17 Total Score = 18 at the Screening and Baseline visits.
Phase B (Double-blind Randomization Phase)
At the end of Phase A (Week 8 visit), the subjects entering Phase B should also meet all of
the following inclusion criteria (criteria for incomplete response):
1. HAM-D17 total score =14 at the end of phase A.
2. < 50% reduction in HAM-D17 total score at the end of phase A (end of Week 8) relative
to baseline.
3. A CGI-I score = 3 at Weeks 2, 4, 6, and 8.
Exclusion Criteria:
1. Females of childbearing potential and male subjects who are not willing to or cannot
practice contraceptive methods during the trial and for 30 days after the last dose.
2. Females who are breast-feeding or lactating and who have a positive pregnancy test
result (Urine or serum test) prior to screening or randomization (within 72 hours).
3. Subjects who report treatment with adjunctive antipsychotic medication with an
antidepressant during the current Major Depressive Episode.
4. Subjects who report allergies or an intolerability to all protocol-specified ADTs or
subjects with contraindication for protocol-specified ADTs described in their
prescription drug labels.
5. Subjects who have had an ECT treatment history at any time in the past or at present,
or who have had a vagus nerve stimulation or deep brain stimulation device implanted
for management of treatment-resistant depression.
6. Subjects with a current need for hospitalization or who have been hospitalized within
four weeks prior to screening for the current Major Depressive Episode.
7. Subjects with a current Axis I (DSM-IV-TR) diagnosis of:
- Delirium, dementia, amnestic or other cognitive disorder
- Schizophrenia, schizoaffective disorder, or other psychotic disorder
- Bipolar I or II disorder
- Eating disorder (including anorexia nervosa or bulimia)
- Obsessive compulsive disorder
- Panic disorder
- Post-traumatic stress disorder
8. Subjects with a current Axis II (DSM-IV-TR) diagnosis of borderline, antisocial,
paranoid, schizoid, schizotypal or histrionic personality disorder.
9. Subjects experiencing hallucinations, delusions or any psychotic symptomatology in the
current Major Depressive Episode.
10. Subjects who have met DSM-IV-TR criteria for substance abuse or dependence within the
past 180 days prior to screening; including alcohol and benzodiazepines, but excluding
caffeine and nicotine.
11. Subjects receiving new onset psychotherapy (individual, group, marriage, or family
therapy) within 6 weeks of screening or at any time during participation in the trial.
12. Subjects who present a serious risk of suicide.
- Subjects who answer "Yes" on the C-SSRS Suicidal Ideation Item 4 and whose most
recent episode meeting criteria for this C-SSRS Item 4 occurred within the last 6
months; OR
- Subjects who answer "Yes" on the C-SSRS Suicidal Ideation Item 5 and whose most
recent episode meeting criteria for this C-SSRS Item 5 occurred within the last 6
months; OR
- Subjects who answer "Yes" on any of the 5 C-SSRS Suicidal Behavior Items (actual
attempt, interrupted attempt, aborted attempt, preparatory acts or behaviors, or
suicidal behavior) and whose most recent episode meeting criteria for any of
these 5 C-SSRS Suicidal Behavior Items occurred within the last 2 years; OR
- Subjects who, in the opinion of the investigator, present a serious risk of
suicide.
13. Medical history or clinical evidence (abnormal clinical significant laboratory test,
vital signs, or ECG findings, judged by investigator) shows the health condition of
the subject may cause an undue adverse event or interfere with assessments of
safety/efficacy during the course of the trial.
14. Subjects with a history of ischemic heart disease or myocardial infarction, congestive
heart failure (whether controlled or uncontrolled), angioplasty, stenting, or coronary
artery bypass surgery.
15. Subjects with insulin-dependent diabetes mellitus (IDDM, i.e., any subjects using
insulin) and uncontrolled non-IDDM are excluded. Subjects with non-IDDM may be
eligible for the trial if their condition is stable as determined by satisfying ALL of
the following criteria:
- Glycosylated hemoglobin (HbA1c) < 7.0%, AND
- Screening glucose must be = 125 mg/dL or = 6.94 mmol/L (fasting) or <200 mg/dL or
<11.1 mmol/L (non-fasting). If the non-fasting screening glucose is = 200 mg/dL
or = 11.1 mmol/L, subjects must be retested in a fasted state and the retest
value must be = 125 mg/dL or = 6.94 mmol/L, AND
- Subject has been maintained on a stable regimen of oral anti-diabetic
medication(s) for at least 28 days prior to screening or diabetes has been
well-controlled by diet for at least 28 days prior to screening, AND
- Subject has not had any hospitalizations within the 12 months prior to screening
due to diabetes or complications related to diabetes, AND
- Subject's diabetes is not newly diagnosed during screening for the trial.
16. 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. Eligibility of subjects excluded based on an abnormal free T4 result can
be discussed with the medical monitor if, in the investigator's judgment, the subject
is a suitable candidate for the trial.
17. Subjects with a history of neuroleptic malignant syndrome (NMS) or 5-HT syndrome.
18. Subjects with a history of true allergic response (i.e., not intolerance) to more than
one class of medications.
19. Subjects with epilepsy or a history of seizures, except for a single seizure episode,
for instance childhood febrile seizure, post traumatic, or alcohol withdrawal.
20. Subjects with uncontrolled hypertension (diastolic blood pressure [DBP] > 95 mmHg in
any position) or symptomatic hypotension, or orthostatic hypotension which is defined
as a decrease of = 30 mmHg in systolic blood pressure (SBP) and/or a decrease of = 20
mmHg in DBP after at least 3 minutes standing compared to the previous supine blood
pressure, OR development of symptoms.
21. The following laboratory test and ECG results are exclusionary:
- QTc = 450 msec (for males) or = 470 msec (for females) in ECG
- Platelets =75×109/L (7,5000/mm3)
- Hemoglobin =90 g/L (9 g/dL)
- Neutrophils =1×109/L (1,000/ mm3)
- AST or ALT > 2 ×upper limit of normal (ULN)
- Creatinine = 2 mg/dL
- Creatine phosphokinase (CPK) > 3 × ULN
- HbA1c = 7.0%
22. Treatment with MAOI (e.g., Nardil® [phenelzine]) within the 2 weeks prior to the start
of Phase A.
23. Use of benzodiazepines and/or hypnotics (including non-benzodiazepine sleep aids)
within 1 week prior to the start of Phase A, but excluding short-acting
non-benzodiazepine sleep aids (ie, zolpidem, zaleplon, zopiclone, and eszopiclone
only).
24. Subjects who participated in a clinical trial within the past 90 days or who
participated in more than two clinical trials within the past year.
25. Any subject who, in the opinion of the investigator, should not participate in the
trial. Such as, any subject who is impossible to compliance with the protocol, or who
would be likely to require prohibited concomitant medication/therapy during the trial.
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