Safety and Efficacy Study Comparing ETS6103 With Amitriptyline in the Treatment of Major Depressive Disorder (MDD)

Study Overview
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Brief Summary
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To demonstrate that the antidepressant activity of ETS6103 is not inferior to amitriptyline in subjects who have an unsatisfactory response to / are resistant to treatment with SSRIs.

Official Title
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Double Blind, Non-inferiority Study to Evaluate the Antidepressant Activity of ETS6103 Compared to Amitriptyline in Treating Major Depressive Disorder in Patients With Unsatisfactory Response to Selective Serotonin Re-uptake Inhibitors.

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: ETS6103 (low dose)
* Drug: ETS6103 (high dose)
* Drug: Amitriptyline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Male or female Age 18-65 years inclusive Subjects with a current episode of moderate to severe Major Depressive Disorder meeting the criteria of Diagnostic and Statistical Manual of Mental Disorders (DSM) IV -TR and documented using the brief structured interview Mini International Neuropsychiatric Interview (MINI) version 5.0 and with a minimum duration of two weeks and a maximum of twelve months Minimum Hamilton Depression Scale (HAM-D) 17 items total score of 18 at screening and ≥12 at the end of the lead-in phase prior to randomization. Female subjects of childbearing potential must have a negative pregnancy test at the Screening Visit and must use an acceptable method of contraception throughout the study and for 30 days after. Male subjects with female partners of child-bearing potential must use an acceptable method of contraception throughout the study and for 30 days after. Able to understand and comply with the requirements of the study as judged by the investigator Exclusion Criteria: Considered by the investigator to be at significant risk of suicide or scoring 5 or more on the Montgomery Asberg Depression Rating Scale (c) question 10 Significant other psychiatric illness which would interfere with trial assessments co-morbid generalized anxiety disorder (GAD) and panic disorder will be permitted where MDD is considered the primary diagnosis Significant physical illness which would interfere with trial assessments Recent (within 1 week of screening) antidepressants (except for fluoxetine [within 4 weeks of screening] and St John's Wort or Monoamine oxidase inhibitors (MAOI) [within 14 days of screening]), Benzodiazepine or any other psychotropic medication including lithium or other mood stabilizers within 1 week of screening Oral anticoagulant therapy within one month of screening Formal psychotherapy or alternative treatments for one week prior to screening or during the study Reduced hepatic function defined as liver enzyme levels ≥2.5 times upper limit of normal Renal insufficiency defined as creatinine clearance <30 mL/min Epilepsy Uncontrolled hypothyroidism Uncontrolled hypertension Acute porphyria Urinary retention, prostatic hypertrophy, narrow angle glaucoma or increased intraocular pressure or any other clinically relevant contraindication stated in the Summary of Product Characteristics (SmPC) for citalopram, tramadol or amitriptyline History of significant cardiac dysrhythmia or history of myocardial infarction within 1 year prior to screening Significant history of alcohol or substance abuse Regular alcohol intake above the recommended United Kingdom (UK) guideline of 4 units per day for males or 3 units per day for females Pregnant or lactating women Known hepatitis B or C or human immunodeficiency virus (HIV) or syphilis seropositivity. A corrected QT interval of >470ms for female subjects of >450ms for male subjects, calculated using the QTcB (Bazett Correction Formula) , or second degree or higher heart block on an electrocardiography (ECG) recording, at screening. Allergy to the study drugs or excipients Treatment with another investigational medicinal product within the 30 days prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ETS6103 (low dose)<br>ETS6103 (low dose) extended release tablets (encapsulated) taken once daily orally for the duration of randomised phase of the study (8 weeks). | Drug: ETS6103 (low dose)<br> <br> |
| Experimental: ETS6103 (high dose)<br>ETS6103 (high dose) extended release tablets (encapsulated) taken once daily orally for the duration of randomised phase of the study (8 weeks). | Drug: ETS6103 (high dose)<br> <br> |
| Active Comparator: Amitriptyline<br>Amitriptyline tablets (encapsulated) Standard dosing regime | Drug: Amitriptyline<br> <br> |
| No Intervention: Lead-in phase<br>Citalopram tablets: Standard dosing regime | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Baseline-adjusted (Montgomery-Asberg Depression Scale) MADRS Score at the End of Treatment. | The mean difference in baseline-adjusted MADRS score at the end of treatment in the per protocol population using the last observation carried forward (LOCF) method. MADRS is used to assess the range of symptoms that are most frequently observed in patients with major depression. The MADRS test includes 10 items and uses a 0 to 6 severity scale, with higher scores indicating increasing depressive symptoms. The total MADRS score is derived by adding all the scores from the 10 items, meaning the lowest possible score is 0 and the highest possible is 60. | Baseline (start of randomized treatment) and 8 weeks post start of treatment |