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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01483053




Registration number
NCT01483053
Ethics application status
Date submitted
27/11/2011
Date registered
1/12/2011
Date last updated
18/12/2013

Titles & IDs
Public title
Cardiovascular Effects of Agomelatine and Escitalopram in Patients With Major Depressive Disorder (MDD)
Scientific title
A Randomised Trial Investigating the Cardiovascular Effects of Agomelatine and Escitalopram in Patients With Major Depressive Disorder.
Secondary ID [1] 0 0
498/11
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Major Depressive Disorder (MDD) 0 0
Condition category
Condition code
Mental Health 0 0 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Agomelatine
Treatment: Drugs - Escitalopram

Active comparator: Agomelatine - Participants who are randomly assigned to the agomelatine group will be treated with agomelatine oral tablets for twelve weeks. Participants will begin their agomelatine treatment at 25mg/day dosage, increasing to 50mg/day as clinically indicated.

Active comparator: Escitalopram - Participants who are randomly assigned to the escitalopram group will be treated with escitalopram oral tablets for twelve weeks. Participants will begin their escitalopram treatment at 10mg/day dosage, increasing to 20mg/day as clinically indicated.


Treatment: Drugs: Agomelatine
Participants who are randomly assigned to the agomelatine group will be treated with agomelatine oral tablets for twelve weeks. Participants will begin their agomelatine treatment at 25mg/day dosage, increasing to 50mg/day as clinically indicated.

Treatment: Drugs: Escitalopram
Participants who are randomly assigned to the escitalopram group will be treated with escitalopram oral tablets for twelve weeks. Participants will begin their escitalopram treatment at 10mg/day dosage, increasing to 20mg/day as clinically indicated.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change from baseline in markers of sympathetic nervous system activity.
Timepoint [1] 0 0
Baseline and following 12 weeks of antidepressant treatment.
Secondary outcome [1] 0 0
Change from baseline in the magnitude of morning surge in blood pressure.
Timepoint [1] 0 0
Baseline and following 12 weeks of antidepressant treatment.
Secondary outcome [2] 0 0
To determine the association between sympathetic nervous system activity and left ventricular hypertrophy.
Timepoint [2] 0 0
Baseline
Secondary outcome [3] 0 0
Change from baseline in insulin resistance.
Timepoint [3] 0 0
Baseline and following 12 weeks of antidepressant treatment.
Secondary outcome [4] 0 0
Change from baseline on markers of cardiac risk.
Timepoint [4] 0 0
Baseline and following 12 weeks of antidepressant treatment.

Eligibility
Key inclusion criteria
* Aged 18-65 years.
* Capable of understanding and willing to provide signed and dated written, voluntary informed consent in advance of any protocol-specific procedures.
* MDD or MDD with melancholia according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Patients with comorbid panic or anxiety disorders will be included if MDD is the primary diagnosis.
* Hamilton Depression (HAM D) > 18.
* Beck Depression Inventory (BDI-II) >18.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Aged < 18 or > 65 years.
* Current antidepressant treatment.
* Previous failed response to SSRI treatment at the maximum tolerated dose for at least 4 weeks.
* Known or suspected hypersensitivity to either escitalopram or agomelatine or any of their ingredients.
* Current high suicide risk.
* Comorbid panic or anxiety disorders as the primary diagnosis.
* Pre-existing and/or current diagnosed heart disease.
* Comorbid medical conditions including type 1 diabetes, hepatic impairment (cirrhosis or active liver disease), medicated hypertension, epilepsy, bleeding disorders, alcohol/drug dependence, infectious blood diseases, psychotic disorders, personality disorders, eating disorders, mental retardation, dementia (ie, Mini Mental State Examination [MMSE] < 23), or gastrointestinal illness or previous bariatric (weight loss) surgery that may impair antidepressant absorption.
* Participants on betablockers (for example, metoprolol).
* Participants currently taking the following contraindicated medications for agomelatine and/or escitalopram:

* Cytochrome (CYP) P450 1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin)
* Monoamine Oxidase Inhibitors;

* Irreversible non-selective monoamine oxidase inhibitors (MAOIs)
* Reversible, selective MAO-A inhibitor (e.g. moclobemide)
* Reversible, non-selective MAOI (e.g. linezolid)
* Pimozide

Participants who are eligible to take part in the study are prohibited to take the contraindicated medications listed above for the entire duration of the study.

* Clinically significant abnormalities on examination or laboratory testing and clinically significant medical conditions not listed above that are serious and/or unstable.
* Pregnant or breastfeeding women.
* Women of childbearing potential (WOCP) who are not using medically accepted contraception (ie, intrauterine devices [IUDs], hormonal contraceptives [oral, depot, patch or injectable], and double barrier methods such as condoms or diaphragms with spermicidal gel or foam). Women who are postmenopausal (ie, amenorrhea for at least 12 consecutive months) or surgically sterile are not considered to be WOCP.
* Sexually active men with WOCP partners who are not using medically accepted contraception.

Medically accepted contraception for women and sexually active men with WOCP partners will be continued throughout the study and for 30 days after the last antidepressant dose.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
UNKNOWN
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/01/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/02/2015
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Monash Medical Centre - Monash Health - Clayton
Recruitment hospital [2] 0 0
Alfred and Baker Medical Unit - Alfred Hospital - Melbourne
Recruitment hospital [3] 0 0
Baker IDI Heart & Diabetes Institute - Melbourne
Recruitment postcode(s) [1] 0 0
3168 - Clayton
Recruitment postcode(s) [2] 0 0
3004 - Melbourne

Funding & Sponsors
Primary sponsor type
Other
Name
Baker Heart and Diabetes Institute
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Servier Laboratories (Australia) Pty Ltd
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
The Alfred
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Monash Medical Centre
Address [3] 0 0
Country [3] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
There is strong evidence that patients with major depressive disorder (MDD) are at increased risk of developing coronary heart disease (CHD). This elevated risk is independent of classical risk factors such as smoking, obesity, hypercholesterolemia, diabetes and hypertension. The risk of CHD is increased 1½-2 fold in those with minor depression and 3-4½ fold in subjects with MDD. Put simply, the relative risk of developing CHD is proportional to the severity of the depression. While the mechanism of increased cardiac risk attributable to MDD is not known disturbances in autonomic function most likely do play a part.

In untreated patients with MDD (with no underlying CHD) the investigators have identified that a marked sympathetic nervous activation and diminished heart rate variability (HRV) occurs in a proportion (approximately one third) of patients. Diminished HRV has been linked to increased incidence rates of acute cardiac events in conditions such as hypertension, diabetes and myocardial infarction. Importantly, whether treating depression actually improves the risk of: (1) CHD development or (2) recurrence of cardiac events in patients with existing CHD remains unknown.

The investigators, and others, have provided a growing body of evidence linking elevated sympathetic activity and exaggerated sympathetic responses to stress to early stages of end organ dysfunction and markers of disease development. Of particular note, in addition to possible effects on HRV is the association of chronic sympathetic nervous activation to: (a) abnormal blood pressure regulation and (b) the development of insulin resistance.

The investigators therefore plan to examine the cardiovascular effects of two different antidepressant medications, agomelatine and escitalopram, in patients with MDD. In addition, the investigators plan to investigate the effects these two medications have on sympathetic nervous system activity, blood pressure, HRV, endothelial function, metabolic and psychological effects.

Findings from this study will assist us to identify of biological correlates of sympathetic nervous activation which will enable us to: (1) identify those at potentially increased cardiac risk, and (2) potentially implement additional therapeutic strategies in order to reduce cardiac risk. Indeed, it is not known whether antidepressant treatment alone would be sufficient to reverse any adverse effects of sympathetic nervous activation. This study aims to answer this important clinical question.
Trial website
https://clinicaltrials.gov/study/NCT01483053
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Gavin Lambert
Address 0 0
Baker IDI Heart & Diabetes Institute
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Sarah Tremethick
Address 0 0
Country 0 0
Phone 0 0
+61 3 8532 1145
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01483053