Major Depressive Disorder (MDD)Phase 4NCT01483053
Cardiovascular Effects of Agomelatine and Escitalopram in Patients With Major Depressive Disorder (MDD)
A Phase 4 study testing Agomelatine and Escitalopram in people with Major Depressive Disorder (MDD), run by Baker Heart and Diabetes Institute at 3 sites in Australia.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Major Depressive Disorder (MDD)
- What is being tested?
- Agomelatine and Escitalopram
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 3 sitesAustralia
- Study dates
- Jan 2014to Feb 2015
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
3 sites in 1 country.
Australia3 sites
Monash Medical Centre - Monash Health
Clayton, Victoria, 3168
David Barton
Arup Dhar
Alfred and Baker Medical Unit - Alfred Hospital
Melbourne, Victoria, 3004
Gavin Lambert
Arup Dhar
Baker IDI Heart & Diabetes Institute
Melbourne, Victoria, 3004
Gavin Lambert
Arup Dhar
About this study
Official title: A Randomised Trial Investigating the Cardiovascular Effects of Agomelatine and Escitalopram in Patients With Major Depressive Disorder.
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.
Read more
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.
- Conditions
- Major Depressive Disorder (MDD)
- Being tested
- Agomelatine, Escitalopram
- Keywords
- Major depressive disorder, Sympathetic nervous system activation, Cardiovascular risk factors, Agomelatine, Escitalopram
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AgomelatineDrug
Also called Valdoxan
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.
EscitalopramDrug
Also called Lexapro, Various generics, for example:, Esitalo, Esipram
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.
| Study group | Role | What they receive |
|---|---|---|
| Agomelatine | Active comparator | 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. Receives: Drug: Agomelatine |
| Escitalopram | Active comparator | 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. Receives: Drug: Escitalopram |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change from baseline in markers of sympathetic nervous system activity.
The investigators will measure sympathetic nervous system activity via whole body noradrenaline spillover and microneurography. Data will be used to examine the relationship between the degree of sympathetic nervous system activity and early signs of cardiac structure and function abnormalities, insulin resistance, and morning surge in blood pressure. This may help in identifying MDD patients who are at an increased risk.
Measured: Baseline and following 12 weeks of antidepressant treatment.
Secondary outcomes (4)
Change from baseline in the magnitude of morning surge in blood pressure.
The investigators will explore the association between sympathetic nervous system activity and stress reactivity to the morning surge in blood pressure in patients with MDD. Blood pressure data will be used to test the hypothesis that MDD patients with high sympathetic activity have greater morning surges in blood pressure than patients with normal sympathetic activity.
Measured: Baseline and following 12 weeks of antidepressant treatment.
To determine the association between sympathetic nervous system activity and left ventricular hypertrophy.
The investigators will measure the relationship between sympathetic nervous system activity and left ventricular mass in patients with MDD. ECG, ECHO and blood pressure data will be used to test the hypothesis that MDD patients with elevated sympathetic activity display early signs of LVH and diastolic dysfunction.
Measured: Baseline
Change from baseline in insulin resistance.
The investigators will explore the association between sympathetic nervous system activity and stress reactivity to signs of insulin resistance in patients with MDD. Oral glucose tolerance data will be used to test the hypothesis that MDD patients with elevated sympathetic activity display early signs of insulin resistance.
Measured: Baseline and following 12 weeks of antidepressant treatment.
Change from baseline on markers of cardiac risk.
The investigators will explore the association between agomelatine/escitalopram treatment and markers of cardiac risk. They will test the hypothesis that agomelatine/escitalopram treatment has a favourable effect on blood pressure variability and morning surge in blood pressure, sympathetic stress reactivity and markers of insulin resistance.
Measured: Baseline and following 12 weeks of antidepressant treatment.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Dec 2011 (estimated)
- Study startJan 2014
- Primary completionFeb 2015 (estimated)
- Study completionFeb 2015 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Major Depressive Disorder (MDD)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Baker Heart and Diabetes Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Servier Laboratories (Australia) Pty Ltd, The Alfred, Monash Medical Centre
- Responsible party
- Sponsor
- Investigators
- Gavin Lambert, Study director, Baker IDI Heart & Diabetes InstituteDavid Barton, Principal investigator, Monash Medical Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01483053
- Sponsor's protocol ID
- 498/11
- Status last verified
- Dec 2013
- First submitted
- 27 Nov 2011
- Last updated
- 18 Dec 2013
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Dec 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised Trial Investigating the Cardiovascular Effects of Agomelatine and Escitalopram in Patients With Major Depressive Disorder.
- ClinicalTrials.gov ID
- NCT01483053
- Acronym / sponsor ID
- 498/11
- Conditions
- Major Depressive Disorder (MDD)
- Keywords
- Major depressive disorder, Sympathetic nervous system activation, Cardiovascular risk factors, Agomelatine, Escitalopram
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Baker Heart and Diabetes InstituteUniversity, hospital or other
- Collaborators
- Servier Laboratories (Australia) Pty Ltd, The Alfred, Monash Medical Centre
- Study start
- Jan 2014
- Primary completion
- Feb 2015 (estimated)
- Study completion
- Feb 2015 (estimated)
- First posted
- 1 Dec 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Agomelatine | Active comparator | Drug: AgomelatineParticipants 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. |
| Escitalopram | Active comparator | Drug: EscitalopramParticipants 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (22 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AgomelatineAlso: ValdoxanParticipants 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. | Drug | Agomelatine |
| EscitalopramAlso: Lexapro, Various generics, for example:, Esitalo, EsipramParticipants 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. | Drug | Escitalopram |
Primary outcome
Change from baseline in markers of sympathetic nervous system activity.
Time frame: Baseline and following 12 weeks of antidepressant treatment.
The investigators will measure sympathetic nervous system activity via whole body noradrenaline spillover and microneurography. Data will be used to examine the relationship between the degree of sympathetic nervous system activity and early signs of cardiac structure and function abnormalities, insulin resistance, and morning surge in blood pressure. This may help in identifying MDD patients who are at an increased risk.
4 secondary outcomes
Change from baseline in the magnitude of morning surge in blood pressure.
Time frame: Baseline and following 12 weeks of antidepressant treatment.
To determine the association between sympathetic nervous system activity and left ventricular hypertrophy.
Time frame: Baseline
Change from baseline in insulin resistance.
Time frame: Baseline and following 12 weeks of antidepressant treatment.
Change from baseline on markers of cardiac risk.
Time frame: Baseline and following 12 weeks of antidepressant treatment.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Dec 2013.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gavin Lambert study director
Baker IDI Heart & Diabetes Institute
David Barton principal investigator
Monash Medical Centre
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Agomelatine and Escitalopram in people with Major Depressive Disorder (MDD), run by Baker Heart and Diabetes Institute at 3 sites in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 18 Dec 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Sarah Tremethick (+61 3 8532 1145, sarah.tremethick@bakeridi.edu.au), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change from baseline in markers of sympathetic nervous system activity. (time frame: Baseline and following 12 weeks of antidepressant treatment.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Dec 2013.