| Eligibility |
Inclusion Criteria:
1. Provide signed informed consent which includes pharmacogenomic (PGx) testing.
2. Have a diagnosis of MDD without psychotic features, according to the Diagnostic and
Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria, based on
clinical assessment and confirmed by the Mini International Neuropsychiatric Interview
(MINI).
3. Have a history of TRD within the past 5 years as documented by the Massachusetts
General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ) (5-year
version). That is, within the past 5 years study participants must have had a
clinically meaningful inadequate response (estimated < 50% improvement per
Investigator/patient consensus and documented by the Investigator) to at least two
treatment courses with antidepressant regimens. These must involve at least two
different pharmacologic treatment classes* and have been given at accepted therapeutic
doses for an adequate duration (at least 6 weeks). One of these treatment failures
must have occurred within the current episode.
*Note: Non-pharmacological treatment (eg, cognitive behavioral therapy,
electroconvulsive therapy, repetitive transcranial magnetic stimulation, vagus nerve
stimulation, acupuncture) are not counted as treatment regimen.
4. To be eligible, patients must have DGM4 genotype results obtained from the designated
Clinical Laboratory Improvement Amendments (CLIA) lab, and all eligible DGM4-positive
patients and about 20% DGM4-negative patients will be randomly included by an IRT
system in order to achieve the appropriate randomization ratio of DGM4-positive vs
negative patients.
5. Pregnancy conception limitations
- Female patients must be postmenopausal or surgically sterile or, if of
childbearing potential and the partner is not vasectomized (6 months minimum),
must agree to use a medically acceptable form of contraception from the time of
signing the informed consent form (ICF) through at least 60 days following the
last administration of study drug. If only the barrier method is used, a double
barrier must be employed. Postmenopausal women must have had = 24 months of
spontaneous amenorrhea. Surgically sterile women are defined as those who have
had a hysterectomy, bilateral ovariectomy, or bilateral tubal ligation. All women
of childbearing potential must have a negative pregnancy test result before
administration of study drug.
- Male patients must be biologically incapable of having children (eg,
vasectomized) or must agree to use the above forms of birth control for
themselves and their partner from the time of signing the informed consent form
through at least 120 days following the last administration of study drug.
6. Be fluent in the local language.
7. Male or female aged 18 to 70, inclusive, at time of enrollment.
8. Have a HAMD-17 total score = 21 at screening.
9. Be willing to discontinue the use of antidepressant drugs (including over-the-counter
medications to treat depression [eg, St John's Wort]) at least 5 half-lives (or at
least 1 week for herbal or other over-the-counter medications for depression) prior to
baseline (Day -1). For fluoxetine, a washout period of at least 3 weeks for = 20
mg/day and at least 4 weeks for > 20 mg/day is required.
Exclusion Criteria:
1. Prior participation in a study with liafensine
2. Used any investigational drug product, device, or biologic within 6 months or five
half-lives (whichever is longer) prior to baseline (Day -1).
3. A positive pregnancy test result or currently breastfeeding.
4. Clinically significant illness (including chronic, persistent, or acute infection),
medical/surgical procedure, or trauma within 30 days prior to screening or between
screening and baseline (Day 1) as determined by the investigator.
5. A history or presence of a clinically significant hepatic, renal, gastrointestinal,
cardiovascular, endocrine, respiratory, immunologic, hematologic, dermatologic, or
neurologic abnormality, or any other condition, that in the investigator's opinion,
represent potential risk to the patient's safety, full participation in the study, or
affect the absorption, distribution, metabolism, or excretion of liafensine.
6. Presence of autoimmune hepatitis, primary sclerosing cholangitis, untreated hepatitis
C, active hepatitis B, or any other uncontrolled or unstable liver disease according
to local guidance.
7. Uncontrolled human immunodeficiency virus (HIV) infection according to local guidance.
8. Uncontrolled abnormal thyroid function according to local guidance.
9. One or more clinical laboratory evaluations are outside the reference range, at
screening, that are in the investigator's opinion, of potential risk to the patient's
safety.
10. Has at the Screening Visit:
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 1.5x
the upper limit of normal (ULN) at screening.
- Total bilirubin (TBL) > 2 mg/dL (34.2 µmol/L) at screening, unless there is an
explained indirect hyperbilirubinemia, eg, Gilbert's syndrome.
- Alkaline phosphatase (ALP) > 1.5x the ULN at screening. Note: Laboratory tests
can be repeated to see if values return to normal range, but any such laboratory
abnormality must be resolved by the Baseline Visit (Day -1).
11. Clinically significant vital sign abnormality at screening. This includes, but is not
limited to, the following, in the supine (after at least 5 min rest) and standing
(after 1 min and 3 min standing): systolic blood pressure = 140 mmHg; diastolic blood
pressure = 90 mmHg; or heart rate < 50 or > 90 beats per minute. If the initial blood
pressure is = 140/90 mmHg, the lowest value from up to 3 additional attempts, which
also must not be = 140/90 mmHg, should be used. Patients with symptomatic orthostatic
hypotension, at the discretion of investigator, will be excluded.
12. Corrected QT interval measurement according to the Fridericia rule (QTcF) > 450 msec
for men and > 470 msec for women during controlled rest at screening, or history of
long-QT syndrome.
13. ECGs containing any of the following readings:
- Left bundle branch block
- Right bundle branch block with QRS duration > 140 ms
- Intraventricular conduction defect with QRS duration > 140 ms
- Long QT syndrome
14. History of seizure, other than childhood febrile seizures.
15. History of clinically significant head trauma, including closed head injury with loss
of consciousness, that is, in the opinion of the investigator, likely to affect
central nervous system function.
16. History of clinically significant symptomatic orthostatic hypotension (ie, postural
syncope).
17. History of narrow angle glaucoma.
18. History of cancer within 2 years prior to screening or between screening and baseline
(Day -1), except for non-metastatic basal and/or squamous cell carcinoma of the skin.
19. Use of prescription or nonprescription medications for attention-deficit hyperactivity
disorder (ADHD), narcolepsy, or cognitive enhancement (eg, methylphenidate,
atomoxetine, modafinil, ginkgo biloba, and huperzine A) within 30 days prior to
screening or between screening and baseline (Day -1).
20. Regular consumption of (eg, more days than not) excessive quantities of
xanthine-containing beverages (eg, more than five cups of coffee or the equivalent per
day) within 30 days prior to screening or between screening and baseline (Day -1).
21. Urine drug screen (UDS) positive for a drug of abuse, with the exception of cannabis
in countries where it is legally available (see Table 3 for list of drugs of abuse).
Where legal, prior use of cannabis is permitted provided the patient agrees to abstain
from smoking or ingesting cannabis or cannabis products during the study.
22. Use of potent inducers of CYP3A4 (eg, rifampin, rifabutin, phenytoin, carbamazepine,
or phenobarbital) within 2 weeks prior to baseline (Day-1).
23. Current diagnosis or history of a psychotic disorder, MDD with psychotic features,
manic or hypomanic episode of bipolar or related disorders.
24. Current diagnosis of anxiety disorder (if primary), post-traumatic stress disorder,
obsessive compulsive disorder (if primary), intellectual disability (DSM-5 diagnostic
code 319), borderline personality disorder, antisocial personality disorder,
histrionic personality disorder, or narcissistic personality disorder according to the
DSM-5 criteria, or any other psychiatric or neurologic disorder or symptom due to a
general medical condition, that, in the judgement of the investigator, could pose
undue risk to the patient or compromise the study.
25. Hospitalized or discharged from psychiatric ward within 8 weeks prior to the screening
visit and planned hospitalization for any condition(s) during the study.
26. Moderate or severe alcohol use disorder or other substance use disorder (except
nicotine or caffeine), within 6 months prior to screening, according to the DSM-5
criteria.
27. Significant risk of suicide determined by:
1. Acute suicidality as evidenced by answering "yes" to Question 5 ("In the Past
Year") on the C-SSRS, indicating active suicidal ideation with specific plan and
intent for suicide, at screening, or baseline (Day -1); or
2. History of suicidal behavior as indicated by a "yes" response on the Suicidal
Behavior section of the C-SSRS ("In the past year") or
3. A score = 5 on Item 10 (suicidal thoughts) of the MADRS at screening or baseline
(Day -1); or
4. Has attempted suicide within 6 months prior to the initial screening visit.
28. Previous allogenic bone marrow transplant.
29. Received non-leukocyte-depleted whole blood transfusion within 4 months prior to PGx
testing at Screening.
30. Currently employed by the sponsor or by a clinical trial site participating in this
study, or a first-degree relative of an employee of the sponsor or of an employee at a
participating clinical trial site.
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