Zelquistinel or Placebo for the Reduction of Symptoms of Major Depressive Disorder

This is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed dose clinical trial designed to evaluate the safety and efficacy of zelquistinel versus placebo in subjects with symptoms of major depressive disorder. Each subject will participate in this study up to 98 days: up to 28 days for screening, 42 days for double-blind treatment, and a 4-week follow-up period. Subjects will return to the clinic one time each week to have the severity of their depression assessed using the Hamilton depression rating scale-17. Adverse events that occurred since the last study visit will be recorded.

Inclusion criteria

Each subject must meet all of the following inclusion criteria to be eligible to participate in the study:

• Male or female subjects.
• Aged 18 to 64 years, inclusive.
• Subject has a diagnosis of major depressive disorder (MDD), single or recurrent episode, defined by the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); if single episode, the duration must be ≥8 weeks and ≤24 months. The diagnosis of MDD will be made by a site rater and supported by the Structured Clinical Interview for DSM-5 - Clinical Trials version (SCID-5-CT) and confirmed by remote, independent raters from the Massachusetts General Hospital Clinical Trials Network and Institute with a State versus trait, Assessability, Face validity, Ecological validity, and Rule of three Ps (pervasive, persistent, and pathological) (SAFER) interview:

• The current depressive episode is ≥8 weeks and ≤24 months in duration prior to the Screening Visit (V1);
• Have an appropriate severity of illness of at least moderately ill corresponding to a CGI-S score of ≥4 at the Screening and Baseline Visits (V1 and V2, respectively); and
• Importantly, have a sufficient history and/or independent report verifying that the current depressive episode is causing clinically significant distress or impairment in functioning.
• Subject has a Hamilton Depression Rating Scale-17 (HDRS-17) using the Structured Interview Guide for the Hamilton Rating Scale for Depression (SIGH-D) total score of ≥18 at the Screening Visit (V1) and Baseline Visit (V2) with no more than a 25% change from the Screening Visit (V1) to the Baseline Visit (V2).
• (Inclusion 5 removed in protocol amendment 4)
• (Inclusion 6 removed in protocol amendment 4)
• Female subjects must meet 1 of the following:

• Surgically sterile or at least 2 years menopausal (ie, postmenopausal is defined as a woman with the absence of menses for at least 12 consecutive months). Menopausal status is to be confirmed by assessing the follicle stimulating hormone level at Screening Visit (V1), or,
• If a woman of child bearing potential, subject must use an acceptable method of birth control from date of Screening to the last evaluation at Day 71. Must have a documented negative point of care urine pregnancy test within 24 hours prior to first dosing.
• Male subjects, including those who are surgically sterile, must use a medically acceptable form of contraception from the time of randomization until the last evaluation at Day 71. Male subjects are strongly advised to inform female partners of the need for them to use highly effective birth control during this time period.
• Subject must be medically stable by physical examination, medical history, vital signs, laboratory evaluations, and 12-lead electrocardiogram performed at the Screening Visit (V1) and Baseline (V2). If abnormalities are found, the subject may be included if the Investigator, contract research organization (CRO) and sponsor medical monitors judge the abnormalities to be not clinically significant.
• Ability to understand the nature and requirements of the study and is willing to comply with the study restrictions and agree to return for the required assessments.
• Provides written informed consent to participate in the trial.
• Is able to communicate with investigational site personnel, able to complete patient-reported outcome measures and in the opinion of the Investigator, can be reliably rated on assessment scales

Exclusion criteria

Any subject who meets any of the following criteria will be excluded from study participation:

• Evidence of treatment-resistant MDD, defined by having an inadequate response (≤25%) to 2 or more different medications approved for the treatment of MDD at an adequate dose (per locally approved label) for an adequate duration during the current episode using the Massachusetts General Hospital Antidepressant Treatment Rating Questionnaire (ATRQ).
• Current DSM-5 diagnosis of bipolar (or related disorders), antisocial personality disorder, obsessive compulsive disorder, borderline personality disorder, post-traumatic stress disorder, panic disorder, or attention-deficit/hyperactivity disorder. Subjects not meeting full DSM 5 criteria for borderline personality disorder but exhibiting recurrent suicidal gestures, threats, or self-mutilating behaviors should also be excluded.
• Subject has a current or prior DSM-5 diagnosis of a psychotic disorder, or MDD with psychotic features.
• Current concomitant treatment with Food and Drug Administration (FDA)-approved antidepressants, antipsychotics, mood stabilizers, sedatives, or stimulants. Current or past treatment with esketamine, ketamine, or psychedelics is prohibited. Subject must have current concomitant treatment discontinued at least 14 days prior to the Baseline Visit (V2). Subjects may continue anxiolytic agents, except for drugs that are also used to treat depression, or benzodiazepines, or sleep aids [see Section 5.5.1 for a nonexhaustive list] (except trazodone) so long as they have been on a stable dose for at least 3 months and do not intend to change dose during double-blind treatment period (Day 1, Week 1 through end of Week 6 [Day 43]). Subjects who use cannabis or cannabis-derived molecules, including tetrahydrocannabinol (THC), whether natural or chemically-synthesized, hemp seed oil, or cannabidiol (CBD) products (eg, gummies), must be discontinued for at least 14 days prior to the Baseline Visit (V2).
• Treatment with any experimental antidepressant agent or treatment with a psychedelic agent in an FDA-approved clinical study within the past 12 months.
• History of electroconvulsive therapy, vagus nerve stimulation, deep brain stimulation, or repetitive transcranial magnetic stimulation within the past 5 years or has had a failure of response to electroconvulsive therapy at any time.
• Subject has clinically significant renal dysfunction as assessed by the estimated glomerular filtration rate <70 mL/min using the Chronic Kidney Disease Epidemiology Collaboration - creatinine (CKD-EPI creatinine) methodology.
• Subject has liver protein and enzyme (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, total bilirubin, lactate dehydrogenase test result >1.5 times the upper limit of normal (subjects with a diagnosis of Gilbert's Syndrome may be eligible if no liver function or enzyme test results other than total bilirubin are >1.5 times upper limit of normal).
• Subject has resting pulse rate (supine) <50 or >100 bpm at the Screening Visit (V1) or predose Baseline (V2).
• Subject has resting diastolic blood pressure <50 mmHg at the Screening Visit (V1) or predose Baseline (V2).
• Subject has cardiac PR interval >250 msec at the Screening Visit (V1) or predose Baseline (V2), or QTcF or QTcB interval >450 msec in males or >470 msec in females, or QRS interval >120 msec.
• Evidence of alcohol abuse (>4 units of alcohol on most days; 1 unit=½ pint of beer, 1 glass of wine, or 1 ounce of hard liquor/spirits) or a positive saliva alcohol screen at Screening (V1) and predose at the Baseline Visit (V2). Alcohol consumption should be avoided for at least 24 hours prior to Baseline Visit (V2). Note: Subject may not be rescreened.
• Abuse of illicit substances, including psychedelic mushrooms by DSM-5 definition of substance use disorder within the 12 months prior to the Screening Visit (V1). Positive urine test for any drug of abuse is exclusionary.
• Positive urine test for any drug of abuse (except cannabis or cannabis-derived molecules such as THC whether natural or chemically-synthesized [see exclusion criterion 4]). Prescribed barbiturates may be continued so long as subjects have been on a stable dose for at least 3 months and may not change dose during the double-blind treatment period. Subjects may not be rescreened after failing a drug screen for a drug of abuse.
• HIV infection, COVID-19 infection, or active hepatitis B or C, syphilis, or other ongoing infectious disease at the Screening Visit (V1).
• Has laboratory evidence of hypothyroidism at Screening (V1) as measured by thyroid stimulating hormone (TSH) and reflex free thyroxine (T4). If TSH is abnormal and reflex T4 is normal, the subject may be included.
• Has current unstable diabetes or glycosylated hemoglobin (HbA1c) >7% at Screening (V1).
• Currently pregnant, planning to become pregnant during the course of the study, or nursing.
• Currently working a night shift or may be required to work night shift during the course of this study, from Screening through completion of final polysomnography.
• Malignancy in the last 5 years, with the exception of nonmetastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix.
• Subject has received new onset psychotherapy or had a change in the intensity of psychotherapy within 8-weeks prior to the Screening Visit (V1).
• Currently taking prohibited prescription or over-the-counter medications including herbal therapies (eg, echinacea, ginseng, ginko, elderberry, turmeric, ginger, valerian, chamomile, or St John's wort) and THC or cannabis-containing products [see exclusion criterion 4], which may interfere with the required study psychiatric assessments.
• History of allergy or sensitivity, or intolerance to zelquistinel, NMDAR ligands including ketamine, dextromethorphan, memantine, methadone, dextropropoxyphene, or ketobemidone.
• Treatment with any other investigational study drugs not used to treat depression within 90 days of screening in this study.
• Previously participated in this study or currently enrolled in any other clinical study.
• Body mass index of >35 kg/m2 at the Screening Visit (V1).
• Subject is an employee of Worldwide Clinical Trials (hereafter referred to as Worldwide), the Investigator or study site with direct involvement in the study or other studies under the direction of that Investigator or study site, as well as a family member of an employee or of the Investigator, or an employee of Gate Neurosciences, Inc., or a family member of an employee.
• In the opinion of the Investigator,

• The subject has a significant risk for suicidal behavior during the course of participation in the study, or
• At the Screening Visit (V1) (the subject scores "Yes" on Items 4 or 5 in the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale (C-SSRS) with reference to a 6-month period prior to Screening Visit (V1), or
• At Screening (V1) the subject has had 1 or more suicidal attempts with reference to a 2-year period prior to Screening Visit (V1), or
• The subject is considered to be an imminent danger to themself or others, or
• At the Baseline Visit (V2) (the subject scores "Yes" on Items 4 or 5 in the Suicidal Ideation section of the C-SSRS
• The subject is judged by the Investigator or CRO and Sponsor medical monitors to be inappropriate for the study for any reason.