Major Depressive Disorder
Conditions
Brief summary
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.
Interventions
DRUGETS6103 (low dose)
DRUGETS6103 (high dose)
DRUGAmitriptyline
Sponsors
e-Therapeutics PLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Baseline-adjusted (Montgomery-Asberg Depression Scale) MADRS Score at the End of Treatment. | Baseline (start of randomized treatment) and 8 weeks post start 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. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ETS6103 (Low Dose) ETS6103 (low dose) extended release tablets (encapsulated) taken once daily orally for the duration of randomised phase of the study (8 weeks).
ETS6103 (low dose) | 55 |
| ETS6103 (High Dose) ETS6103 (high dose) extended release tablets (encapsulated) taken once daily orally for the duration of randomised phase of the study (8 weeks).
ETS6103 (high dose) | 54 |
| Amitriptyline Amitriptyline tablets (encapsulated) Standard dosing regime
Amitriptyline | 55 |
| Total | 164 |
Baseline characteristics
| Characteristic | ETS6103 (High Dose) | Amitriptyline | ETS6103 (Low Dose) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 54 Participants | 55 Participants | 55 Participants | 164 Participants |
| Age, Continuous | 41.1 years STANDARD_DEVIATION 12.74 | 35.6 years STANDARD_DEVIATION 11.95 | 39.8 years STANDARD_DEVIATION 11.85 | 38.8 years STANDARD_DEVIATION 12.18 |
| Gender Female | 14 Participants | 19 Participants | 16 Participants | 49 Participants |
| Gender Male | 40 Participants | 36 Participants | 39 Participants | 115 Participants |
| Region of Enrollment United Kingdom | 54 Participants | 55 Participants | 55 Participants | 164 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 43 / 55 | 50 / 54 | 47 / 55 |
| serious Total, serious adverse events | 1 / 55 | 1 / 54 | 1 / 55 |
Outcome results
Primary
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.
Time frame: Baseline (start of randomized treatment) and 8 weeks post start of treatment
Population: Per protocol population (all subjects of the full analysis set for whom no relevant protocol deviations were documented).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ETS6103 (Low Dose) | Change From Baseline in Baseline-adjusted (Montgomery-Asberg Depression Scale) MADRS Score at the End of Treatment. | -6.1396 Scores on a scale | Standard Error 1.64423 |
| ETS6103 (High Dose) | Change From Baseline in Baseline-adjusted (Montgomery-Asberg Depression Scale) MADRS Score at the End of Treatment. | -6.0076 Scores on a scale | Standard Error 1.65174 |
| Amitriptyline | Change From Baseline in Baseline-adjusted (Montgomery-Asberg Depression Scale) MADRS Score at the End of Treatment. | -11.3762 Scores on a scale | Standard Error 1.7344 |