Depressive Disorder, Major
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy at 1 day post initial oral dose of zelquistinel (AGN-241751) compared with placebo in participants with Major Depressive Disorder (MDD).
Interventions
DRUGAGN-241751
AGN-241751 administered orally as a single tablet
DRUGPlacebo
Placebo administered orally as a single tablet
Sponsors
Syndeio Biosciences, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent from the participant has been obtained prior to any study -related procedures (as described in Appendix 3). * Male or female participants must be 18 to 65 years of age, inclusive, at the time of signing the informed consent. * Meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for MDD (based on confirmation from the modified Structured Clinical Interview for DSM disorders \[SCID\]), with a current major depressive episode of at least 8 weeks and not exceeding 18 months in duration at Visit 1. * Have a minimum score of 26 on the rater-administered Montgomery-Asberg depression rating scale (MADRS) and a minimum score of 24 on the computer-administered MADRS at both Visit 1 (Screening) and Visit 2 (Baseline). * Have a difference of no greater than 7 points between the rater-administered MADRS and computer-administered MADRS at both Visit 1 (Screening) and Visit 2 (Baseline). * Have a clinical global impression-severity (CGI-S) score ≥ 4 at both Visit 1 (Screening) and Visit 2 (Baseline). * Have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test if a woman of childbearing potential (WOCBP). * Female participants willing to minimize the risk of becoming pregnancy for the duration of the clinical study and follow-up period. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * not a WOCBP OR * A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 of protocol during the treatment period and for at least 5 terminal half-lives after the last dose of study treatment. * Male participants willing to minimize the risk of inducing pregnancy for the duration of the clinical study and follow-up period. A male participant must agree to use contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 5 terminal half-lives after the last dose of study treatment and refrain from donating sperm during this period. * Able, as assessed by the investigator, and willing to follow study instructions and likely to complete all required study visits. * Normal physical-examination findings, clinical-laboratory test results, and electrocardiogram (ECG) results from Visit 1 (Screening) or abnormal results that are determined to be not clinically significant by the investigator. * Body mass index (BMI) within the range 18 and 40 kg/m\^2 (inclusive). * Eligibility confirmed through a formal adjudication process (see Section 9 Diagnostic Assessments).
Exclusion criteria
Psychiatric and Treatment-Related Criteria * DSM-5-based diagnosis of any disorder other than MDD that was the primary focus of treatment within 6 months before Visit 1. Comorbid generalized anxiety disorder, social anxiety disorder, or specific phobias are acceptable provided they play a secondary role in the balance of symptoms and are not the primary driver of treatment decisions. * Lifetime history of meeting DSM-5 criteria for: * Schizophrenia spectrum or other psychotic disorder * Bipolar or related disorder * Major neurocognitive disorder * Neurodevelopmental disorder of greater than mild severity or of a severity that impacts the participant's ability to consent, follow study directions, or otherwise safely participate in the study * Dissociative disorder * Posttraumatic stress disorder * MDD with psychotic features * History of meeting DSM-5 criteria for alcohol or substance use disorder (other than nicotine or caffeine) within the 6 months before Visit 1. * DSM-5-based diagnosis of any personality disorder of sufficient severity to interfere with participation in this study in the opinion of the investigator. * History (based on participant report and/or medical records, and investigator judgment) of: * Inadequate response to electroconvulsive therapy (ECT), a monoamine oxidase inhibitor, ketamine, or adjunctive treatment with an antipsychotic * Treatment with clozapine or any depot antipsychotic * ECT, vagus nerve stimulation, transcranial magnetic stimulation, or any experimental central nervous system treatment during the current episode or in the 6 months before Visit 1 (whichever is longer) * Tardive dyskinesia, serotonin syndrome, or neuroleptic malignant syndrome * Having received: * Anticonvulsant/mood stabilizer, within 1 year prior to Visit 1 * Antipsychotic in the current episode, with the exception of quetiapine given for insomnia ≤ 50 mg/day provided it can be safely discontinued prior to Visit 2 * Combination therapy of 2 or more antidepressant therapies (ADTs) in the current episode if given for depression at adequate dose and duration * ADT augmentation agent in the current episode * Lifetime history of nonresponse to ≥ 2 antidepressants after adequate trials (adequate treatment is defined as at least 6 weeks at an adequate dose(s) based on approved package insert recommendations) or a non-response to an antidepressant after adequate treatment for the current major depressive episode. * Positive result at Visit 1 from the urine drug screen (UDS) test for any prohibited medication. Exception: participants with a positive UDS at Visit 1 for opiates, cannabinoids, or episodic use of benzodiazepines may be allowed in the study provided: * The drug was used for a legitimate medical purpose; * The drug can be discontinued prior to participation in the study (except for episodic use of benzodiazepines which may be continued); and * A repeat UDS is negative for these substances prior to enrollment (except for episodic use of benzodiazepines which may be continued) * Suicide risk, as determined by meeting any of the following criteria: * A suicide attempt within the past year * Significant risk, as judged by the investigator, based on the psychiatric interview or information collected in the C-SSRS at Visit 1 (Screening) or Visit 2 (Baseline) * MADRS Item 10 score ≥ 5 at Visit 1 (Screening) or Visit 2 (Baseline) on the MADRS * At imminent risk of injuring self or others or causing significant damage to property, as judged by the investigator. * Requiring concomitant treatment with any of the prohibited medications, supplements, or herbal products listed in Appendix 6 of protocol, including any psychotropic drug or any drug with psychotropic activity, except as described in Section 7.7.2. of protocol. * Prior participation in any investigational study of AGN-241751. * Initiation or termination of psychotherapy for depression within the 3 months preceding Visit 1, or plans to initiate, terminate, or change such therapy during the course of the study. (Support meetings or counselling \[eg, marital counselling\] are allowed provided they are no more frequent than weekly and do not have treatment of depression as their objective). * Ongoing treatment with phototherapy, or termination of phototherapy within 1 month of Visit 1. * Known allergy or sensitivity to the study medication or its components. Other Medical Criteria * BMI \< 18 kg/m\^2 or \> 40 kg/m\^2 at screening. * Females who are pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study. * WOCBP and male partners of WOCBP, not using a reliable means of contraception (Appendix 5 of protocol). * Participant has a condition or is in a situation which, in the investigator's opinion, may put the participant at significant risk, may confound the study results, or may interfere significantly with the participant's participation in the study. * Any cardiovascular disease that is clinically significant, unstable, or decompensated. * Heart rate (supine) of ≤ 45 beats per minute (bpm) or ≥ 120 bpm, or any heart rate that is clinically symptomatic at Visit 1 or Visit 2 based upon vital signs. * Any systolic and/or diastolic blood pressure (BP) that is symptomatic or clinically significant in the opinion of the investigator. * History of congenital QTc prolongation or QTc prolongation (screening ECG with QTcF ≥ 450 msec for men and QTcF ≥ 470 msec for women). * Hypothyroidism or hyperthyroidism, unless stabilized on appropriate pharmacotherapy with no change in dosage for at least 1 month before Visit 1. * History of seizure disorder, stroke, significant head injury, tumor of the central nervous system, or any other condition that predisposes to seizure. * Known human immunodeficiency virus (HIV) infection. * Positive hepatitis C antibody on screening, with the exception of participants for whom the reflex hepatitis C virus ribonucleic acid (HCV RNA) test is negative. * Positive test for hepatitis B surface antigen and/or hepatitis B core antibody immunoglobulin M. * Screening liver enzyme test (aspartate aminotransferase \[AST\] and/or alanine aminotransferase \[ALT\]) results \> 2 times the upper limit of normal (ULN). Other Criteria * Current enrollment in an investigational drug or device study or participation in such a study within 6 months of entry into this study. * Employee, or immediate relative of an employee, of the sponsor, any of its affiliates or partners, or the study center. * Inability to speak, read, and understand the English language sufficiently to understand the nature of the study, to provide written informed consent, or to allow the completion of all study assessments.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Baseline to Day 1 | The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change score indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in MADRS Total Score at Week 3 | Baseline to Week 3 | The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change score indicates improvement. |
Countries
United States
Participant flow
Pre-assignment details
After providing written consent, participants entered a single-blind placebo lead-in screening period of up to 7 days. Participants received single-blind placebo during the screening period. Participants meeting the eligibility criteria at the end of the screening period were randomized into one of the 5 treatment groups and entered the double-blind treatment period.
Participants by arm
| Arm | Count |
|---|---|
| AGN-241751 Dose 1 AGN-241751 0.25 mg administered as 1 tablet taken orally one time each week for 3 weeks
Placebo administered as 1 tablet taken orally every day except days AGN-214751 was taken | 48 |
| AGN-241751 Dose 2 AGN-241751 1 mg administered as 1 tablet taken orally one time each week for 3 weeks
Placebo administered as 1 tablet taken orally every day except days AGN-214751 was taken | 50 |
| AGN-241751 Dose 3 AGN-241751 3 mg administered as 1 tablet taken orally one time each week for 3 weeks
Placebo administered as 1 tablet taken orally every day except days AGN-214751 was taken | 52 |
| AGN-241751 Dose 4 AGN-241751 10 mg administered as 1 tablet taken orally one time each week for 3 weeks
Placebo administered as 1 tablet taken orally every day except days AGN-214751 was taken | 50 |
| Placebo Placebo administered as 1 tablet taken orally every day | 51 |
| Total | 251 |
Baseline characteristics
| Characteristic | AGN-241751 Dose 1 | AGN-241751 Dose 2 | AGN-241751 Dose 3 | AGN-241751 Dose 4 | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 41.8 years STANDARD_DEVIATION 14.02 | 41.8 years STANDARD_DEVIATION 13.53 | 42.2 years STANDARD_DEVIATION 14.23 | 42.9 years STANDARD_DEVIATION 13.48 | 40.0 years STANDARD_DEVIATION 14.49 | 41.7 years STANDARD_DEVIATION 13.88 |
| Current antidepressant usage | 7 Participants | 13 Participants | 13 Participants | 13 Participants | 11 Participants | 57 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants | 24 Participants | 22 Participants | 15 Participants | 20 Participants | 99 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 24 Participants | 24 Participants | 28 Participants | 32 Participants | 27 Participants | 135 Participants |
| Region of Enrollment United States | 48 participants | 50 participants | 52 participants | 50 participants | 51 participants | 251 participants |
| Sex: Female, Male Female | 33 Participants | 15 Participants | 16 Participants | 20 Participants | 30 Participants | 114 Participants |
| Sex: Female, Male Male | 15 Participants | 35 Participants | 36 Participants | 30 Participants | 21 Participants | 137 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 50 | 0 / 52 | 0 / 50 | 0 / 51 |
| other Total, other adverse events | 17 / 48 | 18 / 50 | 12 / 52 | 19 / 50 | 16 / 51 |
| serious Total, serious adverse events | 0 / 48 | 0 / 50 | 0 / 52 | 0 / 50 | 0 / 51 |
Outcome results
Primary
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change score indicates improvement.
Time frame: Baseline to Day 1
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AGN-241751 Dose 1 | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -8.6 score on a scale | Standard Error 1.21 |
| AGN-241751 Dose 2 | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -8.0 score on a scale | Standard Error 1.19 |
| AGN-241751 Dose 3 | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -9.5 score on a scale | Standard Error 1.18 |
| AGN-241751 Dose 4 | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -10.6 score on a scale | Standard Error 1.18 |
| Placebo | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -7.7 score on a scale | Standard Error 1.18 |
Comparison: Each dose group was compared to placebop-value: >0.05Mixed Models Analysis
Secondary
Change From Baseline in MADRS Total Score at Week 3
The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change score indicates improvement.
Time frame: Baseline to Week 3
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AGN-241751 Dose 1 | Change From Baseline in MADRS Total Score at Week 3 | -11.5 score on a scale | Standard Error 1.56 |
| AGN-241751 Dose 2 | Change From Baseline in MADRS Total Score at Week 3 | -12.5 score on a scale | Standard Error 1.54 |
| AGN-241751 Dose 3 | Change From Baseline in MADRS Total Score at Week 3 | -14.1 score on a scale | Standard Error 1.55 |
| AGN-241751 Dose 4 | Change From Baseline in MADRS Total Score at Week 3 | -13.5 score on a scale | Standard Error 1.54 |
| Placebo | Change From Baseline in MADRS Total Score at Week 3 | -13.6 score on a scale | Standard Error 1.54 |