A Study of Brexpiprazole Plus Ketamine in Treatment-Resistant Depression (TRD)

NCT03149991 | Completed Phase 4 Results FDA Drug

• 1 other identifier: KETBREX001
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 6

Brief Summary

This is a multi-site, double-blind, placebo-controlled study of the acute efficacy of brexpiprazole or placebo in combination with intranasal ketamine added to ongoing, stable, and adequate antidepressant therapy (ADT) in the treatment of adults with Major Depressive Disorder with Treatment Resistant Depression.

Conditions

Depression

Keywords

treatment resistant; inadequate response

Outcome Measures

Primary Outcomes (1)

• Change From Baseline on Symptoms of Depression Questionnaire (SDQ)

  Superiority will be demonstrated by a statistically significant greater decrease (p\<0.05, 2 sided) on the SDQ total score for participants receiving brexpiprazole versus placebo therapy. Symptoms of Depression Questionnaire (SDQ): This validated self-rating instrument has 44 items on a scale of 1-6, measuring multiple depressive symptom domains, with higher scores indicating worse depression symptoms. Participants reported on their experiences over the past three days.

  SDQ was assessed on Days 0, 1, 2, 5, 8, 11, 14, 17, 21, 23, 28

Secondary Outcomes (10)

• Long-term Sustained Response, as Measured by Achieving a 50% Reduction on the Montgomery-Asberg Depression Rating Scale (MADRS) on Day 28 (Number and Percentage of Participants Achieving Sustained Response Reported)

  MADRS was assessed on Days 0, 2, 3, 8, 11, 14, 17, 21, 23, 28; 50% reduction compared Day 28 to Baseline.

• Efficacy on Secondary Outcome Variables

  These secondary outcome variables were assessed on Days 0, 1 (except for MADRS this day), 2, 5, 8, 11, 14, 17, 21, 23, 28

• Safety and Tolerability Outcomes: Number of Participants With Abnormal Vital Signs (Elevated Blood Pressure)

  Blood pressure was measured during each administration of ketamine, occurring on days 0, 5, 8, 11, 14, and 21. This vital sign was measured 6 times following the intranasal administration of ketamine: 15 minutes post dose, 30 minutes post dose, 45 minutes

• Safety and Tolerability Outcomes: Number of Participants With Abnormal Vital Signs (Elevated Heart Rate)

  Heart rate was measured during each administration of ketamine, occurring on days 0, 5, 8, 11, 14, and 21.

• Safety and Tolerability Outcomes: 12-lead Electrocardiogram (ECG) - Total Number of Abnormal ECGs

  ECGs were conducted at baseline and 5, 8, 11, 14, and 21 days after baseline

Study Arms (2)

Ketamine/Brexpiprazole Arm

ACTIVE COMPARATOR

brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks

Drug: Brexpiprazole; Drug: Ketamine

Ketamine/Placebo Arm

PLACEBO COMPARATOR

placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks

Drug: Ketamine; Drug: Placebo

Interventions

Brexpiprazole DRUG

Administration of up to 3mg brexpiprazole

Also known as: rexulti

Ketamine/Brexpiprazole Arm

Ketamine DRUG

administration 6 times over two weeks of inhaled ketamine

Also known as: Inhaled ketamine

Ketamine/Brexpiprazole Arm; Ketamine/Placebo Arm

Placebo DRUG

Administration of placebo which matches brexpiprazole in size and number of tablets per dose

Ketamine/Placebo Arm

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, 18 to 65 years of age, inclusive, at screening.
• Able to read, understand, and provide written, dated informed consent prior to screening. Participants will be deemed likely to comply with study protocol and communicate with study personnel about adverse events and other clinically important information.
• Diagnosed with MDD, single or recurrent, and currently experiencing a major depressive episode (MDE) of at least eight weeks in duration, prior to screening, according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The diagnosis of MDD will be made by a site psychiatrist and supported by the SCID-5. The diagnosis will be confirmed by remote, independent raters from the MGH CTNI (Massachusetts General Hospital Clinical Trials Network and Institute) with a SAFER interview.
• Has a history of treatment resistant depression (TRD) during the current MDE, as assessed by the investigator and remote centralized rater using the MGH ATRQ. TRD is defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms), as perceived by the participant, to at least 2 "treatment courses" during the current episode of a therapeutic dose of an antidepressant therapy (ADT) of at least 8 weeks duration (including the current ADT). The adequacy of dose and duration of the antidepressant therapy will be determined as per the MGH ATRQ criteria. The TRD status will be confirmed by remote, independent raters from the MGH CTNI who will administer the MGH ATRQ, via teleconference, between the screening visit and the baseline visit. Participants must currently be on a stable (for at least 4 weeks) and adequate (according to the MGH ATRQ) dose of ongoing antidepressant therapy (any antidepressant therapy, with the exception of MAOIs), of which total duration must be at least 8 weeks.
• Meet the threshold on the total MADRS score of \>20 at both the screen visit and the baseline visit (Day -7/-28 and Day 0), and as confirmed by the remote centralized MGH CTNI rater between the screen visit and the baseline visit.
• In good general health, as ascertained by medical history, physical examination (PE) (including measurement of supine and standing vital signs), clinical laboratory evaluations, and ECG.
• If female, a status of non-childbearing potential or use of an acceptable form of birth control per the following specific criteria:
• Non-childbearing potential (e.g., physiologically incapable of becoming pregnant, i.e., permanently sterilized (status post hysterectomy, bilateral tubal ligation), or is post-menopausal with her last menses at least one year prior to screening); or
• Childbearing potential, and meets the following criteria:
• Childbearing potential, including women using any form of hormonal birth control, on hormone replacement therapy started prior to 12 months of amenorrhea, using an intrauterine device (IUD), having a monogamous relationship with a partner who has had a vasectomy, or is sexually abstinent.
• Negative urinary pregnancy test at screening, confirmed by a negative urinary pregnancy test at randomization prior to receiving study treatment.
• Willing and able to continuously use one of the following methods of birth control during the course of the study, defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly: implants, injectable or patch hormonal contraception, oral contraceptives, IUD, double-barrier contraception, sexual abstinence. The form of birth control will be documented at screening and baseline.
• Body mass index between 18-35 kg/m2.
• Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive behavioral, insight-oriented, et al.) and frequency (e.g., weekly or monthly) of the therapy has been stable for at least three months prior to screening and if the type and frequency of the therapy is expected to remain stable during the course of the subject's participation in the study.
• Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines or trazodone) will be allowed if the therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study. Patients can also continue treatment with benzodiazepines used for anxiety if therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study.

You may not qualify if:

• Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study.
• Female that is pregnant or breastfeeding.
• Female with a positive pregnancy test at screening or baseline.
• History during the current MDE of failure to achieve satisfactory response (e.g., less than 50% improvement of depression symptoms) to \>7 treatment courses of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration, according to the MGH ATRQ, as confirmed by the remote, independent MGH CTNI rater.
• Total MADRS score of \<20 at the screen visit or the baseline visit, or as assessed by the remote, independent MGH CTNI rater and reported to the site.
• Current diagnosis of a substance use disorder (abuse or dependence, as defined by DSM-IV-TR™), with the exception of nicotine dependence, at screening or within 6 months prior to screening.
• Current Axis I disorder, diagnosed at screening with the use of the Structured Clinical Interview for DSM-5 AXIS I Disorders (SCID-5), that is the principal focus of treatment and MDD the secondary focus of treatment for the past 6 months or more.
• History of bipolar disorder, schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes.
• History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified, within 5 years of screening.
• Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant to their MDD at any time within 6 months prior to screening.
• In the judgment of the investigator, the subject is considered at significant risk for suicidal behavior during the course of his/her participation in the study.
• Has failed to respond to ECT during the current depressive episode.
• Has received VNS at any time prior to screening.
• Has dementia, delirium, amnestic, or any other cognitive disorder.
• Has a clinically significant abnormality on the screening physical examination that might affect safety, study participation, or confound interpretation of study results according to the study clinician.

Sponsors & Collaborators

• Massachusetts General Hospital: lead

Study Sites (6)

Collaborative Neuroscience Network, LLC.

Garden Grove, California, 92845, United States

Location

Pacific Research Partners, LLC

Oakland, California, 94607, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Massachusetts General Hospital, Depression Clinical and Research Program

Boston, Massachusetts, 02114, United States

Location

Nathan Kline Institute for Psychiatric Research

Orangeburg, New York, 10562, United States

Location

Montefiore Medical Center

The Bronx, New York, 10467, United States

Location

MeSH Terms

Conditions

Depression

Interventions

brexpiprazole; Ketamine

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Results Point of Contact

• Title: Dr. Rebecca Hock
• Organization: Massachusetts General Hospital

rhock@mgh.harvard.edu

617-872-3711

Study Officials

• Maurizio Fava, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Vice Chair, Psychiatry

Study Record Dates

• First Submitted: February 24, 2017
• First Posted: May 11, 2017
• Study Start: September 14, 2017
• Primary Completion: March 31, 2019
• Study Completion: June 15, 2019
• Last Updated: July 24, 2020
• Results First Posted: July 24, 2020

Record last verified: 2020-07

Locations

US (6)