Clinical trial NCT03586427: AGN-241751 in the Treatment of Major Depressive Disorder
Official title: A Double-Blind, Placebo-Controlled, Fixed-Dose Study of AGN-241751 in Adult Participants With Major Depressive Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Depressive Disorder, Major
Lead sponsor: Gate Neurosciences, Inc
Sponsor class: INDUSTRY
First posted: 2018-07-13
Enrollment: 251
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy at 1 day post initial oral dose of AGN-241751 compared with placebo in participants with Major Depressive Disorder (MDD).


Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
timeFrame: Baseline to Day 1
Secondary outcomes:
measure: Change From Baseline in MADRS Total Score at Week 3
timeFrame: Baseline to Week 3
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Health Initiatives Research PLLC
state: Arkansas
city: Cerritos
country: United States
facility: Synexus US - Cerritos
state: California
city: Encino
country: United States
facility: Wake Research - Pharmacology Research Institute
state: California
city: Newport Beach
country: United States
facility: Wake Research - Pharmacology Research Institute
state: California
city: Oakland
country: United States
facility: Pacific Research Partners, LLC
state: California
city: Oceanside
country: United States
facility: North County Clinical Research, Inc.
state: California
city: Torrance
country: United States
facility: Collaborative Neuroscience Network
state: California
city: Wildomar
country: United States
facility: Elite Clinical Trials, Inc.
state: California
city: Atlanta
country: United States
facility: Synexus US - Atlanta
state: Georgia
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Lincolnwood
country: United States
facility: Pillar Clinical Research
state: Illinois
city: Boston
country: United States
facility: Boston Clinical Trials
state: Massachusetts
city: Berlin
country: United States
facility: Hassman Research Institute
state: New Jersey
city: Cherry Hill
country: United States
facility: Center for Emotional Fitness
state: New Jersey
city: Cedarhurst
country: United States
facility: Neurobehavioral Research, Inc
state: New York
city: Jamaica
country: United States
facility: Synexus US - Queens
state: New York
city: New York
country: United States
facility: Eastside Comprehensive Medical Center
state: New York
city: Rochester
country: United States
facility: Finger Lakes Clinical Research
state: New York
city: North Canton
country: United States
facility: Neuro-Behavioral Clinical Research, Inc
state: Ohio
city: Oklahoma City
country: United States
facility: IPS Research
state: Oklahoma
city: Memphis
country: United States
facility: Clinical Neuroscience Solutions, Inc - Memphis, TN
state: Tennessee
city: Memphis
country: United States
facility: Research Strategies of Memphis, LLC
state: Tennessee
city: Austin
country: United States
facility: Donald J. Garcia, Jr., MD, PA
state: Texas
city: Dallas
country: United States
facility: FutureSearch Trials of Dallas, LP
state: Texas
city: Bellevue
country: United States
facility: Northwest Clinical Research Center
state: Washington
Study officials:
affiliation: Gate Neurosciences, Inc
name: Ronald M Burch, MD PhD
role: STUDY_DIRECTOR
References: