AGN-241751 in the Treatment of Major Depressive Disorder
Condition: Depressive Disorder, Major
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Intervention: AGN-241751; Placebo
Intervention description: AGN-241751 administered orally as a single tablet; Placebo administered orally as a single tablet
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 251.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

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.