Study in Major Depressive Disorder With BTRX-335140 (NMRA-335140) vs Placebo

Study Overview
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Brief Summary
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A proof of concept (POC) study evaluating the impact of BTRX-335140 (NMRA-335140) relative to placebo on symptoms of major depressive disorder (MDD) in adult participants with MDD and symptoms of anhedonia and anxiety following 8 weeks of double-blind treatment as assessed by the HAMD-17 Scale.

Official Title
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A Phase 2a, Randomized, Double-blind, Placebo-controlled Proof of Concept Study to Evaluate the Effects of Oral BTRX-335140 (NMRA-335140) Versus Placebo in Subjects With Major Depressive Disorder

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: BTRX-335140
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants are eligible to be included in the study only if they meet all the following criteria: Are adult men or women between 18 to 65 years of age (inclusive) at informed consent 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) The current episode must have started at least 3 weeks prior to screening visit but no more than 12 months before the screening visit. Have not failed 2 or more courses of antidepressant treatment in the current episode Have no more than a 3-point change in HAMD 17 between screening and baseline Have sufficient history or an independent report to confirm that symptoms are causing functional impairment or clinically significant distress Meet the blinded rule list based on clinical scale criteria Have body mass index (BMI) between 18-40 kg/m2 (inclusive) 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 Agree to the following birth control: 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. 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. Or engaged exclusively in a non-heterosexual relationship Willing and able to give written informed consent to participate Able to understand and comply with instructions in English 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: Have a history of any of the following DSM-5 disorders within the specified timeframe: 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. Lifetime: diagnosis of bipolar 1 or 2, schizophrenia, obsessive compulsive disorder, or post-traumatic stress disorder Have a history of substance or alcohol use disorder (AUD), per DSM-5 criteria, within the past year 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 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 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 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 Have a history of serious head injury (eg, skull fracture, cerebral contusion, or trauma resulting in prolonged unconsciousness), intracranial neoplasm, or hemorrhage Have ever had electroconvulsive treatment, vagal nerve stimulation, or treatment with ketamine or esketamine for MDD 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 Have a visual or physical motor impairment that could interfere with participant's ability to perform study assessments, as assessed by the investigator 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 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) 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) 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. 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 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. 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. Have any use, by history, of Salvinorin A Use of the following concomitant medications (contact the Sponsor-designated medical monitor to determine eligibility when in doubt): 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) Fluoxetine and irreversible monoamine oxidase inhibitors within 4 weeks of Visit 2 (Baseline) depot antipsychotics within 2 months of Visit 2 (Baseline) Opioid agonists and antagonists 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). Are women who are either pregnant or breastfeeding 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. 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 Have previously completed or withdrawn from this study or any other study investigating BTRX 335140 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. 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 Has any of the following: useful vision in only 1 eye from a pre-existing ophthalmic disease or amblyopia; a corneal transplant in either eye; corneal dystrophy or family history of corneal dystrophy; severe dry eye syndrome (keratitis sicca); 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BTRX-335140<br>BTRX-335140 | Drug: BTRX-335140<br>* Active Drug<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Depression Rating Scale (HAMD-17) | Change from baseline to Week 8 in the HAMD-17 score; Minimum 0, Maximum 52; Higher scores mean a worse outcome | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression of Improvement (CGI-I) score | The CGI-I is a clinician rating of how much the participant's illness has improved or worsened relative to a baseline state, a 7-point scale is used from 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. | 8 weeks | 
| Change from baseline in Snaith-Hamilton Pleasure Scale (SHAPS) score | The SHAPS is a self-report 14-item, instrument, developed for the assessment of hedonic capacity. Participants score whether they experience pleasure in performing a list of activities or experiences. Participants can rate the answers as definitely/strongly agree, agree, disagree or strongly disagree. Definitely agree will be rated 1, Agree will be rated 2, Disagree will be rated 3, and Definitely disagree will be rated 4. The participant's item responses are summed to provide a total score ranging from 14 to 56. A higher total SHAPS score indicates higher levels of current anhedonia. | 8 weeks | 
| Change from baseline in Hospital Anxiety and Depression Scale (HADS) subscales (ie, anxiety subscale [HADS-A] and depression subscale [HADS-D]) scores | The Hospital Anxiety and Depression Scale (HADS) is a 14-item self-report questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and depression with higher scores indicating more severe symptoms. | 8 weeks | 
| Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) score | The HAM-A is a 14-item scale to measure severity of different anxiety-related symptoms in participants. Each of the 14 items is rated by the clinician on a 5-point scale ranging from 0 (not present) to 4 (maximum degree) with a total score range of 0 to 52 where higher score indicates greater symptom severity. | 8 weeks | 
| Change from baseline in Sheehan Disability Scale (SDS) score | The Sheehan Disability Scale (SDS) is a 3-item self-report questionnaire used to assess the effect of the participant's symptoms on their work (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. | 8 weeks | 
| Change from baseline to end of study in Clinical Global Impression Scale - Severity (CGI-S) scores | The CGI-S is a clinician rating of the severity of the participant's illness. The CGI-S is scored on a 7-point scale where a score of 1 indicates that the participant is normal, not at all ill, a score of 4 indicates that the participant is moderately ill, and a score of 7 indicates that the participant is among the most extremely ill participants. | 8 weeks | 
| Percentage of participants with a HAMD-17 response | HAMD-17 response rate, where response is defined as ≥ 50% decrease in HAMD-17 total score from Baseline to Week 4 and Week 8. HAMD-17 is a 17-item questionnaire to capture symptom severity with a total score ranging from 0 to 52 with higher scores indicating more depressive symptoms. | 8 weeks | 
| Assessment of safety through the occurrence of TEAEs, SAEs, and adverse events of special interest (AESIs) | Change from baseline in vital signs measurements, body weights, body mass index (BMI), clinical laboratory test results, C SSRS scores, Clinical Opiate Withdrawal Scale (COWS) scores; physical examination findings, ECG results, and ophthalmologic examination findings. | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NMRA-335140, Neumora, NMRA-140