ETS6103-003: Safety and Efficacy Study Comparing ETS6103 With Amitriptyline in the Treatment of Major Depressive Disorder (MDD)

• Sponsor: e-Therapeutics PLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02014363
• Collaborator: (none)
• Enrollment: 164
• Location: 1
• Arms: 4
• Duration (Months): 24
• Patients Per Site Per Month: 6.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: ETS6103 (low dose); Drug: ETS6103 (high dose); Drug: Amitriptyline	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 164 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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.
• Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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).	Drug: ETS6103 (low dose)
Experimental: 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).	Drug: ETS6103 (high dose)
Active Comparator: Amitriptyline Amitriptyline tablets (encapsulated) Standard dosing regime	Drug: Amitriptyline
No Intervention: Lead-in phase Citalopram tablets: Standard dosing regime

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CPS Research	Glasgow	Scotland	United Kingdom	G20 OXA

Sponsors and Collaborators

• e-Therapeutics PLC

Investigators

• Principal Investigator: Alan G Wade, MBChb, CPS Research

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: e-Therapeutics PLC
• ClinicalTrials.gov Identifier: NCT02014363
• Other Study ID Numbers: ETS6103-003; 2013-000719-26
• First Posted: Dec 18, 2013
• Last Update Posted: Jan 11, 2017
• Last Verified: Nov 1, 2016

• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Amitriptyline

Study Results

Participant Flow

Arm/Group Title	ETS6103 (Low Dose)	ETS6103 (High Dose)	Amitriptyline
Arm/Group Description	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)	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)	Amitriptyline tablets (encapsulated) Standard dosing regime Amitriptyline
Period Title: Overall Study
STARTED	55	54	55
COMPLETED	38	35	31
NOT COMPLETED	17	19	24

Baseline Characteristics

Arm/Group Title	ETS6103 (Low Dose)	ETS6103 (High Dose)	Amitriptyline	Total
Arm/Group Description	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)	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)	Amitriptyline tablets (encapsulated) Standard dosing regime Amitriptyline	Total of all reporting groups
Overall Participants	55	54	55	164
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	55 100%	54 100%	55 100%	164 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.8 (11.85)	41.1 (12.74)	35.6 (11.95)	38.8 (12.18)
Gender (Count of Participants)
Female	16 29.1%	14 25.9%	19 34.5%	49 29.9%
Male	39 70.9%	40 74.1%	36 65.5%	115 70.1%
Region of Enrollment (Count of Participants)
United Kingdom	55 100%	54 100%	55 100%	164 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Baseline-adjusted (Montgomery-Asberg Depression Scale) MADRS Score at the End of Treatment.
Description	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

Outcome Measure Data

Analysis Population Description

Per protocol population (all subjects of the full analysis set for whom no relevant protocol deviations were documented).

Arm/Group Title	ETS6103 (Low Dose)	ETS6103 (High Dose)	Amitriptyline
Arm/Group Description	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)	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)	Amitriptyline tablets (encapsulated) Standard dosing regime Amitriptyline
Measure Participants	44	43	39
Least Squares Mean (Standard Error) [Scores on a scale]	-6.1396 (1.64423)	-6.0076 (1.65174)	-11.3762 (1.7344)

Adverse Events

Arm/Group Title	ETS6103 (Low Dose)		ETS6103 (High Dose)		Amitriptyline
Arm/Group Description	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)		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)		Amitriptyline tablets (encapsulated) Standard dosing regime Amitriptyline
All Cause Mortality
	ETS6103 (Low Dose)		ETS6103 (High Dose)		Amitriptyline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	ETS6103 (Low Dose)		ETS6103 (High Dose)		Amitriptyline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/55 (1.8%)		1/54 (1.9%)		1/55 (1.8%)
Cardiac disorders
Myocardial infarction	0/55 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0
Hepatobiliary disorders
Cholecystitis	1/55 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0
Psychiatric disorders
Alcohol abuse	0/55 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1
Other (Not Including Serious) Adverse Events
	ETS6103 (Low Dose)		ETS6103 (High Dose)		Amitriptyline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/55 (78.2%)		50/54 (92.6%)		47/55 (85.5%)
Cardiac disorders
Palpitations	2/55 (3.6%)	2	0/54 (0%)	0	3/55 (5.5%)	3
Gastrointestinal disorders
Dry mouth	3/55 (5.5%)	3	7/54 (13%)	7	26/55 (47.3%)	26
Vomiting	3/55 (5.5%)	4	6/54 (11.1%)	8	6/55 (10.9%)	6
Nausea	6/55 (10.9%)	6	5/54 (9.3%)	7	0/55 (0%)	0
Diarrhoea	1/55 (1.8%)	1	3/54 (5.6%)	3	4/55 (7.3%)	4
Dyspepsia	0/55 (0%)	0	2/54 (3.7%)	2	4/55 (7.3%)	4
Constipation	0/55 (0%)	0	0/54 (0%)	0	5/55 (9.1%)	5
Gastro-oesophageal reflux disease	2/55 (3.6%)	2	1/54 (1.9%)	1	1/55 (1.8%)	1
General disorders
Fatigue	3/55 (5.5%)	3	7/54 (13%)	7	4/55 (7.3%)	4
Infections and infestations
Upper respiratory tract infection	4/55 (7.3%)	4	5/54 (9.3%)	5	0/55 (0%)	0
Investigations
Electrocardiogram QT prolonged	3/55 (5.5%)	3	1/54 (1.9%)	1	2/55 (3.6%)	2
Blood pressure increased	0/55 (0%)	0	1/54 (1.9%)	1	3/55 (5.5%)	3
Mean cell volume	1/55 (1.8%)	1	2/54 (3.7%)	2	1/55 (1.8%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/55 (1.8%)	1	2/54 (3.7%)	2	1/55 (1.8%)	1
Nervous system disorders
Headache	6/55 (10.9%)	6	5/54 (9.3%)	5	3/55 (5.5%)	3
Dizziness	2/55 (3.6%)	2	5/54 (9.3%)	5	4/55 (7.3%)	4
Tremor	0/55 (0%)	0	0/54 (0%)	0	8/55 (14.5%)	8
Somnolence	0/55 (0%)	0	1/54 (1.9%)	1	5/55 (9.1%)	5
Psychiatric disorders
Abnormal dreams	7/55 (12.7%)	7	8/54 (14.8%)	8	3/55 (5.5%)	3
Anxiety	1/55 (1.8%)	1	1/54 (1.9%)	1	5/55 (9.1%)	5
Nightmare	2/55 (3.6%)	2	4/54 (7.4%)	4	1/55 (1.8%)	1
Irritability	1/55 (1.8%)	1	2/54 (3.7%)	2	1/55 (1.8%)	1
Renal and urinary disorders
Proteinuria	1/55 (1.8%)	1	1/54 (1.9%)	1	2/55 (3.6%)	2
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	3/55 (5.5%)	3	3/54 (5.6%)	3	2/55 (3.6%)	2
Cough	4/55 (7.3%)	4	1/54 (1.9%)	1	1/55 (1.8%)	1
Skin and subcutaneous tissue disorders
Pruritus	3/55 (5.5%)	3	7/54 (13%)	8	0/55 (0%)	0
Hyperhidrosis	4/55 (7.3%)	4	1/54 (1.9%)	1	2/55 (3.6%)	2
Rash	1/55 (1.8%)	1	5/54 (9.3%)	6	0/55 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is an agreement between the Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.