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
|Condition or disease||Intervention/treatment||Phase|
|Major Depressive Disorder Depression||Drug: ezogabine||Phase 2|
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:
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.
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 :||Interventional (Clinical Trial)|
|Actual Enrollment :||18 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Proof-Of-Concept Clinical Trial of a Novel KCNQ Potentiator in Major Depressive Disorder|
|Study Start Date :||August 2014|
|Actual Primary Completion Date :||December 2016|
|Actual Study Completion Date :||December 2016|
Ezogabine dosage plan to 900mg and then tapered down
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
- 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.
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02149836
|United States, New York|
|Icahn School of Medicine at Mount Sinai|
|New York, New York, United States, 10029|
|Principal Investigator:||James Murrough, MD||Icahn School of Medicine at Mount Sinai|