| Eligibility |
Inclusion Criteria:
Participants are eligible to be included in the study only if they meet all the following
criteria:
1. Are adult men or women between 18 to 65 years of age (inclusive) at informed consent
2. Have a primary DSM-5 diagnosis of MDD, with prominent symptoms of anhedonia confirmed
by Structured Clinical Interview for DSM-5 Disorders, Clinical Trials Version
(SCID-5-CT)
1. The current episode must have started at least 3 weeks prior to screening visit
but no more than 12 months before the screening visit.
2. Have not failed 2 or more courses of antidepressant treatment in the current
episode
3. Have no more than a 3-point change in HAMD 17 between screening and baseline
4. Have sufficient history or an independent report to confirm that symptoms are
causing functional impairment or clinically significant distress
3. Meet the blinded rule list based on clinical scale criteria
4. Have body mass index (BMI) between 18-40 kg/m2 (inclusive)
5. Are medically stable (in the opinion of the investigator and Sponsor/Sponsors
delegate) based on medical history, vital signs, clinical laboratory tests, and
12-lead electrocardiogram (ECG) performed at screening and baseline
6. Agree to the following birth control:
1. Nonvasectomized men must agree to use a condom with spermicide, if sexually
active during the study, until 90 days after the last dose of study drug
administration. No restrictions are required for a vasectomized man, provided his
vasectomy was performed 4 months or more prior to the first dose of study drug. A
man who has been vasectomized less than 4 months prior to the first dose of study
drug must follow the same restrictions as a nonvasectomized man. Additionally,
men must refrain from sperm donation during study treatment and for at least 90
days following the last dose of study drug.
2. Women of child-bearing potential (women not surgically sterilized and between
menarche and 2 years postmenopausal) must have a negative serum pregnancy test at
screening and a negative urine pregnancy test at enrollment and agree to use
reliable birth control (eg, oral contraceptives or Norplant®; a reliable double
barrier method of birth control (diaphragms with contraceptive jelly; cervical
caps with contraceptive jelly; condoms with contraceptive foam); intrauterine
devices; partner with vasectomy; or abstinence) during the study and for 10 days
following the last dose of the study drug (BTRX-335140 or placebo). Women will be
considered surgically sterile, if they have had tubal ligation, bilateral
salpingo oophorectomy, or a hysterectomy.
Note: Abstinence will be allowed if, in the investigator's judgement, it is
determined that the participant is reliable, that abstinence is the preferred and
usual lifestyle of the participant, and that abstinence will be continued for the
duration of the study including the 10 days (women) or 90-day period (men)
following last dose of study drug as noted above.
3. Or engaged exclusively in a non-heterosexual relationship
7. Willing and able to give written informed consent to participate
8. Able to understand and comply with instructions in English
9. Are judged by the investigator to be reliable and agree to keep all appointments for
clinic visits, tests, and procedures, including venipuncture, and examinations
required by the protocol
Exclusion Criteria:
Participants will be excluded from the study if they meet any of the following criteria:
1. Have a history of any of the following DSM-5 disorders within the specified timeframe:
1. Currently or in the past year: diagnosis of personality disorder, attention
deficit disorder/attention deficit hyperactivity disorder, anorexia nervosa, or
bulimia nervosa. Participants with comorbid generalized anxiety disorder, social
anxiety disorder, or panic disorder for whom MDD is considered the primary
diagnosis are not excluded.
2. Lifetime: diagnosis of bipolar 1 or 2, schizophrenia, obsessive compulsive
disorder, or post-traumatic stress disorder
2. Have a history of substance or alcohol use disorder (AUD), per DSM-5 criteria, within
the past year
3. Are actively suicidal (eg, any suicide attempts within the past 12 months) or are at
serious suicidal risk as indicated by any current suicidal intent, including a plan,
as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) (score of "YES" on
suicidal ideations item 4 or 5 within 3 months prior to Visit 1 (Screening) and/or
based on clinical evaluation by the investigator; or are homicidal, in the opinion of
the investigator
4. Have a history or signs of Cushing's disease, Addison's Disease, primary amenorrhea or
other evidence of significant disorders of the hypothalamus-pituitary-adrenal axis
5. Have any other clinically significant medical or psychiatric condition or circumstance
prior to randomization that, in the opinion of the investigator, or Sponsor, could
affect participant safety, preclude evaluation of response, interfere with the ability
to comply with study procedures, or prohibit completion of the study, such as acute
stress disorder, adjustment disorder, impulse control disorder, uncontrolled diabetes
mellitus, renal or hepatic impairment, coronary artery disease, evidence of
significant active cardiac, respiratory, or hematologic disease, cancer with <5 year
remission (basal cell carcinoma is not excluded), chronic pain, fibromyalgia, gastric
bypass, lap band placement, or any other significant gastrointestinal condition
6. Have had prior seizures (other than remote history of childhood febrile seizure) or
other condition that would place the participant at increased risk of seizures or is
taking anticonvulsants for seizure control
7. Have a history of serious head injury (eg, skull fracture, cerebral contusion, or
trauma resulting in prolonged unconsciousness), intracranial neoplasm, or hemorrhage
8. Have ever had electroconvulsive treatment, vagal nerve stimulation, or treatment with
ketamine or esketamine for MDD
9. Have initiated transcranial magnetic stimulation, psychotherapy (such as Cognitive
Behavioral Therapy) or have had a change in psychotherapy, or other non-drug therapies
(such as acupuncture or hypnosis) within 4 weeks prior to Visit 1 (Screening) or at
any time during the acute phase of the study
10. Have a visual or physical motor impairment that could interfere with participant's
ability to perform study assessments, as assessed by the investigator
11. Have alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels =2 x
upper limit of normal (ULN) or a bilirubin level 1.5 x ULN unless due to a documented
history of Gilbert's syndrome
12. Have estimated glomerular filtration rate (eGFR) =60 mL/min/1.73m2 as calculated by
the Chronic Kidney Disease Epidemiology Collaboration [CKD EPI] 2009 creatinine
equation at Visit 1 (Screening)
13. Have positive hepatitis C virus (HCV) antibody (Ab), hepatitis B surface antigen (HBs
Ag), hepatitis A virus (HAV) IgM antibody (HAV-Ab [IgM]) or human immunodeficiency
virus (HIV) test at Visit 1 (Screening)
14. Have a thyroid-stimulating hormone (TSH) level of <0.9 x lower limit of normal (LLN)
or >1.2 x ULN on or off stable treatment for hyperthyroidism or hypothyroidism; if TSH
is abnormal, evaluate reflex Free T3 and Free T4. If reflex testing is normal, the
assessment of normal thyroid function will be determined based on the judgement of the
investigator, following discussion with the medical monitor.
15. Have any other clinically significant abnormalities (significant would include
laboratory deviations requiring acute medical intervention or further medical
evaluation) in laboratory results at screening, including clinical chemistries,
hematology, and urinalysis, and any clinical information that, in the judgment of the
investigator or Sponsor, should preclude a participant's participation at study entry
16. Have exclusionary ECG abnormalities obtained at Visit 1 (Screening) or Visit 2
(Baseline) that are QT interval corrected using Fridericia's formula (QTcF) >450 msec
in males or >470 msec in females, complete bundle branch block, evidence of myocardial
infarction or ischemia, and predominantly nonsinus conducted rhythms. Other
abnormalities can be exclusionary at the discretion of the principal investigator or
medical monitor. See Section 6.3.5 of protocol for guidance on ECG interpretations.
17. Have a positive urine drug screen for amphetamines, barbiturates, cocaine, methadone,
opioids, propoxyphene, tetrahydrocannabinol (THC), phencyclidine, or a positive blood
alcohol level assessed by breathalyzer at Visit 1 (Screening) and Visit 2 (Baseline).
For occasional (1 to 2 times per month maximum) cannabis users only, 1 retest is
allowed and participant must agree to abstain from use for the duration of the study;
a positive second test is exclusionary.
18. Have any use, by history, of Salvinorin A
19. Use of the following concomitant medications (contact the Sponsor-designated medical
monitor to determine eligibility when in doubt):
1. Psychoactive medication including stimulants, benzodiazepines and anxiolytics,
oral antipsychotics, mood stabilizers/anticonvulsants (carbamazepine,
lamotrigine, etc.), lithium, antidepressants, S adenosylmethionine, melatonin,
agomelatine, and hypnotics/sedatives within 5 half-lives or 14 days (whichever is
longer) of Visit 2 (Baseline)
2. Fluoxetine and irreversible monoamine oxidase inhibitors within 4 weeks of Visit
2 (Baseline) depot antipsychotics within 2 months of Visit 2 (Baseline)
3. Opioid agonists and antagonists
20. Are currently taking or have taken within 5 half-lives of Visit 2 (Baseline) any
medications or supplements that are moderate or strong inhibitors or inducers of
cytochrome P450 (CYP) 3A4 (non-comprehensive list in protocol), on a diet likely to
modulate CYP3A4 activity (eg, food/juice of grapefruit, Seville oranges), or are
taking substrates of P-glycoprotein (P gp) with narrow therapeutic windows (eg,
digoxin).
21. Are women who are either pregnant or breastfeeding
22. Have participated (received study treatment) in a clinical study or any other type of
medical research judged by the investigator or Sponsor to be scientifically or
medically incompatible with this study within 30 days prior to Visit 1 (Screening).
Contact the Sponsor-designated medical monitor to determine eligibility when in doubt.
23. Have participated in multiple interventional clinical studies, such that, in the
opinion of the investigator or Sponsor the participant is not a suitable candidate for
participation
24. Have previously completed or withdrawn from this study or any other study
investigating BTRX 335140
25. Are investigator site personnel directly affiliated with this study, and/or their
immediate families. Immediate family is defined as a spouse, parent, child, or
sibling, whether biological or legally adopted.
26. Are employees of the Sponsor or are employees of any third-party organizations (TPOs)
(eg, laboratory staff, study vendors and transportation providers) involved in the
study who require exclusion of their employees
27. Has any of the following:
1. useful vision in only 1 eye from a pre-existing ophthalmic disease or amblyopia;
2. a corneal transplant in either eye;
3. corneal dystrophy or family history of corneal dystrophy;
4. severe dry eye syndrome (keratitis sicca);
5. will not or cannot cooperate with ophthalmic examination requiring pupillary
dilation (includes history of severe adverse reaction to mydriatic agents or
untreated narrow angle glaucoma). Note: The following ocular disorders are
allowed: cataracts, prior cataract surgery, glaucoma (narrow angle glaucoma is
allowed if definitively treated with laser peripheral iridectomy), macular
degeneration, or ocular changes associated with diabetes mellitus or multiple
sclerosis.
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