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Study to Treat Major Depressive Disorder (MDD) With a New Medication

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ClinicalTrials.gov Identifier: NCT02149836
Recruitment Status : Completed
First Posted : May 29, 2014
Results First Posted : April 16, 2019
Last Update Posted : April 16, 2019
Sponsor:
Information provided by (Responsible Party):
James Murrough, Icahn School of Medicine at Mount Sinai

Tracking Information
First Submitted Date  ICMJE May 22, 2014
First Posted Date  ICMJE May 29, 2014
Results First Submitted Date  ICMJE January 9, 2018
Results First Posted Date  ICMJE April 16, 2019
Last Update Posted Date April 16, 2019
Study Start Date  ICMJE August 2014
Actual Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 26, 2019)
Montgomery-Asberg Depression Rating Scale Comparison to Baseline [ Time Frame: baseline and after end of treatment (10 weeks) ]
The Montgomery-Asberg Depression Rating Scale (29) is a 10-item instrument used for the evaluation of depressive symptoms in adults and for the assessment of any changes to those symptoms. Each of the 10 items is rated on a scale of 0 to 6, with differing descriptors for each item. These individual item scores are added together to form a total score, which can range between 0 and 60 points. The MADRS is specifically designed to detect changes in depression severity in the context of a medication treatment trial.
Original Primary Outcome Measures  ICMJE
 (submitted: May 23, 2014)
Montgomery-Asberg Depression Rating Scale Comparison to Baseline [ Time Frame: baseline and end of treatment (8 weeks) ]
The Montgomery-Asberg Depression Rating Scale (29) is a 10-item instrument used for the evaluation of depressive symptoms in adults and for the assessment of any changes to those symptoms. Each of the 10 items is rated on a scale of 0 to 6, with differing descriptors for each item. These individual item scores are added together to form a total score, which can range between 0 and 60 points. The MADRS is specifically designed to detect changes in depression severity in the context of a medication treatment trial.
Change History Complete list of historical versions of study NCT02149836 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 26, 2019)
  • Patient Rated Inventory of Side Effects (PRISE) [ Time Frame: 8 weeks ]
    Number of symptom events as reported by the patient in a self-report measure. PRISE assesses the presence of treatment side effects in nine organ/function systems (gastrointestinal, nervous system, heart, eyes/ears, skin, genital/urinary, sleep, sexual functioning, and other)
  • Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: 8 weeks ]
    The Columbia-Suicide Severity Rating Scale (C-SSRS) is a comprehensive, semi-structured interview measure that uniquely measures the full spectrum of suicidality including passive and active suicidal ideation, suicidal intent as well as suicidal behaviors. Full range from 0 (low intensity suicidal ideation to 9 (high intensity suicidal ideation).
  • Changes in Reward System Activation After Treatment With Ezogabine [ Time Frame: baseline and post treatment (8 weeks) ]
    Functional MRI of reward processing: The primary neuroimaging endpoint is the degree of change observed in the reward system in the brain. Although it was an outcome measure, the data format is a set of 4-dimensional statistical maps and not reported in raw data. Mean changes in activation of the ventral tegmental area (VTA) or ventral striatum (VS) in response to reward cue to reward receipt, and VTA mean change in beta weight in response to reward cue at 8 weeks as compared to baseline. The Z-score indicates the number of standard deviations away from a reference population in the same age range. A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 23, 2014)
  • Patient Rated Inventory of Side Effects (PRISE) [ Time Frame: 8 weeks ]
    frequency of observed adverse events over the Ezogabine treatment period as captured by the PRISE; assesses the presence of treatment side effects in nine organ/function systems (gastrointestinal, nervous system, heart, eyes/ears, skin, genital/urinary, sleep, sexual functioning, and other)
  • Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: 8 weeks ]
    The Columbia-Suicide Severity Rating Scale (C-SSRS) (28) is a comprehensive, semi-structured interview measure that uniquely measures the full spectrum of suicidality including passive and active suicidal ideation, suicidal intent as well as suicidal behaviors.
  • Functional MRI comparison to baseline [ Time Frame: baseline and post treatment (8 weeks) ]
    Functional MRI of reward processing: The primary neuroimaging endpoint is the degree of change observed in VTA/midbrain and striatal brain activity during reward anticipation and receipt as a function of ezogabine treatment.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Treat Major Depressive Disorder (MDD) With a New Medication
Official Title  ICMJE A Proof-Of-Concept Clinical Trial of a Novel KCNQ Potentiator in Major Depressive Disorder
Brief Summary The purpose of this study is to test the antidepressant effects of Ezogabine in major depressive disorder (MDD). The investigators also aim to determine the safety and tolerability Ezogabine in patients with MDD. The investigators hypothesize that depressive symptoms will be significantly decreased following an 8-week treatment period of the medication compared to baseline.
Detailed Description

Study Introduction:

Major depressive disorder (MDD) is a global health disease associated with significant morbidity and costs. Many anti-depressants exist within the monoaminergic system yet novel therapeutics are still needed outside of this system. Ezogabine, currently approved by the FDA for adjunctive treatment of partial-onset seizures, may serve as a potential key agent for those with MDD. Ezogabine is known to bind to and activate KCNQ transmembrane K+ ion channels, specifically targeting KCNQ2 in the VTA. Such membrane activity has been show to play a role in previous studies involving a social defeat model of depression. Specifically, data has shown that KCNQ channels were upregulated only in resilient mice and moreover, ezogabine was able to potentiate KCNQ channel activity to result in a fast reversal of the depressed phenotype.

General Investigational Plan:

Objectives:

A. Primary Efficacy Objective: To test the antidepressant effects of Ezogabine in MDD.

B. Primary Safety Objective: To characterize the safety and tolerability of Ezogabine in patients with MDD.

C. Secondary Objectives: To measure the effects of Ezogabine on ventral tegmental area (VTA)-striatal reward circuitry in MDD using reward task-based functional MRI. Rationale: Ezogabine is hypothesized to modulate the firing rate of VTA dopamine (DA) neurons and thereby influence the functioning of the mesolimbic reward system.

Hypotheses

A. Efficacy Hypothesis:

Hypothesis 1a: Depressive symptoms will be significantly decreased following an 8-week treatment period compared to baseline, as measured by change in Montgomery-Åsberg Depression Rating Scale (MADRS).

Hypothesis 1b: The antidepressant response rate at study end (defined as 50% in depressive symptoms compared to baseline) will exceed 50%, consistent with known response rates of current antidepressant agents.

B. Safety Hypothesis: Ezogabine will be safe and adverse event rates will be similar to rates observed in other adult populations. Specific safety items to be monitored include frequency and intensity of adverse events as measured by the Patient Rated Inventory of Side Effects (PRISE) and treatment-emergent suicidal ideation or behavior as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Major Depressive Disorder
  • Depression
Intervention  ICMJE Drug: ezogabine

Treatment Week 1: 100mg of Ezogabine by mouth three times per day (total daily dose = 300mg) Treatment Week 2: dose will be increased to 150 mg Ezogabine by mouth three times per day (total daily dose = 450mg).

Treatment Week 3: dose will be increased to 200mg of Ezogabine by mouth three times per day (total daily dose = 600mg).

Treatment Week 4: dose will be increased to 250mg of Ezogabine by mouth three times per day (total daily dose = 750mg).

Treatment Week 5: dose will be increased to 300mg of Ezogabine by mouth three times per (total daily dose = 900mg).

Participants will continue to take 900mg of Ezogabine per day and return weekly to the clinic for the remainder of the study.

Following this primary outcome visit, participants will be instructed to taper the study medication over the following 3 weeks based on FDA recommended guidelines as follows:

250 mg po TID daily x 1 week, then 200 mg po daily x 1 week, then 100 mg po daily x 1 week, then discontinue

Other Names:
  • Potiga
  • Retigabine
Study Arms  ICMJE Experimental: ezogabine
Ezogabine dosage plan to 900mg and then tapered down
Intervention: Drug: ezogabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 20, 2016)
18
Original Estimated Enrollment  ICMJE
 (submitted: May 23, 2014)
20
Actual Study Completion Date  ICMJE December 2016
Actual Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female participants, 18-65 years of age;
  • Current diagnosis of major depressive disorder according as determined by a psychiatrist and confirmed with The Mini-International Neuropsychiatric Interview (MINI);
  • At least moderate depression severity as defined by a score of >= 21 on the Montgomery-Asberg Depression Rating Scale (MADRS);
  • At least a moderate level of anhedonia based on a Snaith-Hamilton Pleasure Scale (SHAPS) score ≥ 20;
  • If female of childbearing potential, must agree to use of a medically accepted form of contraception, or else agree to abstinent;
  • Participants must have a level of understanding of the English language sufficient to agree to all tests and examinations required by the study and must be able to participate fully in the informed consent process.

Exclusion Criteria:

  • Lifetime diagnosis of schizophrenia or any psychotic disorder, bipolar disorder, obsessive compulsive disorder or pervasive developmental disorders or mental retardation;
  • Diagnosis of a substance use disorder within the past 6 months (excluding substance use disorder in sustained remission)
  • Female participants who are pregnant, nursing, for may become pregnant;
  • Any unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease); endocrinologic, neurologic (including history of severe head injury), immunologic, or hematologic disease;
  • Clinically significant abnormalities of laboratories, physical examination, or ECG;
  • Prolonged QT Interval at screening, operationalized as a QTc of > 480 ms at baseline;
  • Hypokalemia (potassium value less than 3.5mEq/L) or hypomagnesemia (magnesium value less than 1.6mEq/L) at baseline;
  • A history of retinal abnormalities (ie, pigment changes, retinal dystrophy) or findings of retinal pathology on ophthalmological exam at baseline
  • Antidepressant medication within 2 weeks of start of treatment (4 weeks for fluoxetine)*
  • Other psychotropic medication, including antipsychotics and mood stabilizers within 2 weeks of start of treatment; subjects will be allowed to remain on a stable dose of zolpidem 10 mg nightly for sleep or a benzodiazepine as needed for sleep or anxiety (dosage equivalent to lorazepam 1 mg daily or less)
  • No current or recent significantly elevated risk of self-harm or violence as determined by the PI.
  • For subjects who may participate in the MRI portion of the study, claustrophobia, any trauma or surgery which may have left magnetic material in the body, magnetic implants or pacemakers, and inability to lie still for 1 hour or more.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02149836
Other Study ID Numbers  ICMJE GCO 14-0597
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party James Murrough, Icahn School of Medicine at Mount Sinai
Study Sponsor  ICMJE Icahn School of Medicine at Mount Sinai
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: James Murrough, MD Icahn School of Medicine at Mount Sinai
PRS Account Icahn School of Medicine at Mount Sinai
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP