Trial document




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  DRKS00000320

Trial Description

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Title

Randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with Major Depressive Disorder- the EMC trial.

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Trial Acronym

The Early Medication Change (EMC) Trial

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URL of the Trial

http://www.the-emc-trial.de

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Brief Summary in Lay Language

Common clinical view is that antidepressant response usually appears with a delay of several weeks (3-8 weeks). The recommended treatment duration until insufficient outcome can be assumed and treatment should be optimised between 3-8 weeks.
Challenging the idea of a delayed onset of antidepressants action, there is a substantial body of evidence strongly suggesting that a true drug response can be observed within the first 14 days of treatment. Moreover, the occurrence of improvement of depressive symptoms in the early course of treatment has been identified as being highly predictive for final treatment outcome.
Consequently, the vast majority of patients showing a favourable later outcome experience the respective onset within the first 2 weeks of treatment. Inversely, non-improvement after 2 weeks of treatment seems to indicate that a selected Antidepressant did not trigger the resilience-like component and has strongly limited chances to do so, even if continued in the course of treatment.
The EMC trial investigates for the first time prospectively whether Major depressive Disorder (MDD) patients with non-improvement after 14 days of Antidepressant treatment with EMC are more likely to become remitters compared to patients treated according to current guidelines, i.e., with a medication change after 4 weeks of treatment in case of non-response.

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Brief Summary in Scientific Language

MDD is a highly prevalent, often chronic or episodic lifelong disorder. Many studies showed that nearly all patients with MDD suffer from mild to very severe impairment in several domains of life like physical activities, social activities, or occupational responsibilities. The use of ADs for the treatment of MDD is well established. However, effect sizes of currently available ADs are rather small than medium more efficient ADs are not expected in the next years. Hence, it is sensible to develop new strategies to increase remission rates in acutely depressed patients by means of the ADs we currently have.
Current national and international clinical guidelines usually do not contain recommendations for adapting an individuals treatment during the early course of therapy, but schedule a treatment duration between 4-8 weeks until insufficient outcome is diagnosed and treatment change is recommended.
Challenging the idea of a delayed onset of ADs action, there is a substantial body of evidence from many retrospective studies with virtually all groups of ADs strongly suggesting that a true drug response can be observed within the first 14 days of treatment.
Early Improvement, defined by a decrease of >= 20% on the 17-item Hamilton Depression Rating Scale (HAMD17) is observed in 65-70% of patients with MDD.
Moreover, the occurrence of improvement of depressive symptoms in the early course of treatment has been identified as being highly predictive for final treatment outcome.
Consequently, the vast majority of patients showing a favourable later outcome experience the respective onset within the first 2 weeks of treatment. Inversely, there is substantial evidence showing that non-improvement in the first 2 weeks of AD treatment is highly predictive for poor final outcome.
So it can be reasonable to optimise their treatment in case of non-improvement after 2 weeks because of clear evidence that non-improvers with an early treatment optimisation would be more likely to become remitters compared to those patients with continued medication.
The EMC trial investigates for the first time prospectively whether MDD patients with non-improvement after 14 days of AD treatment with EMC are more likely to become remitters compared to patients treated according to current guidelines, i.e., with a medication change after 28 days of treatment in case of non-response.

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Do you plan to share individual participant data with other researchers?

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00000320
  •   2010/01/25
  •   2009/09/09
  •   yes
  •   Approved
  •   837.211.09(6717), Ethik-Kommission bei der Landesärztekammer Rheinland-Pfalz
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Secondary IDs

  •   U1111-1113-4716 
  •   2008-008280-96 
  •   NCT00974155  (www.clinicalTrials.gov)
  •   4035480 
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Health Condition or Problem studied

  •   F32.1 -  Moderate depressive episode
  •   F32.2 -  Severe depressive episode without psychotic symptoms
  •   F33.1 -  Recurrent depressive disorder, current episode moderate
  •   F33.2 -  Recurrent depressive disorder, current episode severe without psychotic symptoms
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Interventions/Observational Groups

  •   Level 1:
    After inclusion and appropriate washout of possible pre-medication with other antidepressants (ADs), patients will receive the selective serotonin reuptake inhibitor (SSRI) escitalopram for 14 days. The dose will be escalated to the participants highest tolerable dose (max. 20 mg/day). Non-improvers, defined by a decrease of < 20% on the 17-item Hamilton Depression Rating Scale (HAMD17) between day 0 and day 14 will be randomly assigned to EMC 1 or TAU 1, which both will last 42 days. Patients in the EMC 1 arm will be switched on day 15 to the dual acting (selective serotonergic and noradrenergic, SSNRI) AD venlafaxine. The dose will be escalated to the participants highest tolerable dose (max. 375 mg/day). After 14 days of venlafaxine treatment, non-improvers (HAMD17 decrease <20% from day 14-28) will have an augmentation therapy with lithium (plasma level range 0.6-0.8 mmol/l) for 28 days. For improvers under venlafaxine treatment (HAMD17 decrease >= 20% from day 14-28), venlafaxine will be continued for 28 days. Patients randomised to TAU 1 will be treated according to current guidelines, which recommend 28 days of unchanged therapy and use the response criterion (HAMD17 decrease >= 50%) to guide further strategy. Thus, escitalopram will not be changed on day 15, but continued to day 28. In case of response on day 28, escitalopram will be continued for further 28 days. In case of non-response on day 28 (HAMD17 decrease < 50%), escitalo-pram will be switched to venlafaxine (max. 375 mg/day), which will be administered for 28 days.
  •   Level 2:
    Improvers (HAMD17 decrease >= 20%) on day 14 will be treated according to current guidelines and will continue treatment with escitalopram at the highest tolerable dose. Non-responders (HAMD17 decrease of < 50% between d0 and d28) on d28 will be treated according to current guidelines and will be switched to venlafaxine. The dose of venlafaxine will be escalated to the participant?s highest tolerable dose (max. 375 mg/day). After 14 days of venlafaxine treatment (d29-d42), non-improvers 2 (HAMD17 decrease <20% between d28 and d42) will be randomly assigned to EMC 2 or TAU 2, which both will last 14 days. Patients in the EMC 2 arm will have an augmentation therapy with lithium (plasma level range 0.6-0.8 mmol/l) for 14 days. Patients randomised to TAU 2 will be treated according to current guidelines, which do not contain recommendations for an optimisation of treatment two weeks after medication switch. Therefore, these patients will continue venlafaxine treatment until day 56. For IML2 under venlafaxine treatment (HAMD17 decrease >= 20% between d28 and d42), venlafaxine will be continued for 14 days at the participants highest tolerable dose.
  •   Level 3:
    Responders (HAMD17 decrease of >= 50% between d0 and d28) on d28 will continue treatment with escitalopram at the highest tolerable dose. Remitters on d28 (HAMD17 sum score <=7) will be regarded as responders. After further 14 days of escitalopram treatment (d29-d42), non-improvers 3 (HAMD17 decrease <20% between d28 and d42) will be randomly assigned to EMC 3 or TAU 3, which both will last 14 days. Remitters on d42 (HAMD17 sum score <=7) will be regarded as improvers and will not be randomized. Patients in the EMC 3 arm will be switched to venlafaxine. The dose of venlafaxine will be escalated to the participant?s highest tolerable dose (max. 375 mg/day). Patients randomised to TAU 3 will be treated according to current guidelines, which do not contain recommendations for an optimisation of treatment in case of non-improvement after an initial response. For IML3 with continued escitalopram treatment (HAMD17 decrease >= 20% between d28 and d42), escitalopram will be continued for 14 days at the participants highest tolerable dose.
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Blinded
  •   assessor
  •   Active control
  •   Treatment
  •   Parallel
  •   IV
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Primary Outcome

Remission from MDD, defined as a HAMD17 sum score <=7 on day 56, is the primary endpoint and will be analyzed only for non-improvers on day 14 (level 1 of the EMC Trial).

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Secondary Outcome

- Response, defined as a HAMD17 sum score decrease >=50% on day 56
- Absolute change of HAMD17 sum score [day 56 -day 0]
- Remission and response, defined as a sum score <=11 on the 30-item Inventory of Depressive Symptomatology (IDS-C30) and 50% baseline score reduction, respectively, on day 56.
- Time to remission and time to response according to IDS and HAMD17
- Remission from MDD, defined as HAMD17 sum score <= 7 on day 56 (in subgroups of improvers on day 14 entering level 2 or level 3 of The EMC trial)
- Absolute change in SF-12 subscales "physical component score" and "mental component score" [day 56-day 0].
- Occurrence of Adverse Events, UKU ratings at all visits and relevant laboratory data (routine laboratory, therapeutic drug monitoring)

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

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Recruitment

  •   Actual
  •   2009/09/29
  •   889
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   65   Years
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Additional Inclusion Criteria

- Major Depressive Disorder (MDD), first episode or recurrent, according to DSM-IV
- A HAMD17 score of >=18 pts. (Rationale: Although there exist different cut-offs for mild to moderate depression varying between 13/14-17/18 pts., the cut-off of >=18 pts. is the most often used in clinical trials and assures the inclusion of at least moderately depressed patients).
- Age between 18 and 65 years and age <= 60 years at the time of the first depressive episode. (Rationale: This age range assures the inclusion of patients with early-onset depression in contrast to late-onset depression, for which different pathophysiological mechanisms have been suggested. In addition, the vast majority of studies on the predictive value of early improvement included patients aged <= 65 years).
- Ability of subject to understand character and individual consequences of clinical trial.
- Signed and dated informed consent of the subject must be available before start of any specific trial procedures.

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Exclusion Criteria

- Acute risk of suicide needing an intervention not comprised by protocol treatment (e.g. electroconvulsive therapy)
- Patients with a lifetime DSM-IV diagnosis of dementia, schizophrenia, schizoaffective disorder, bipolar disorder
- Patients with a DSM-IV diagnosis of posttraumatic stress disorder, obsessive-compulsive disorder, anxiety disorder, or eating disorder and the requirement of a treatment not comprised by protocol treatment.
- Patients with DSM-IV substance dependency requiring acute detoxification.
- Depression due to organic brain disorder including Multiple Sclerosis and Parkinsons Disease
- Women who are pregnant, breastfeeding or planning to become pregnant during the trial
- Women who are not sterile by surgery or for more than two years postmenopausal or women with childbearing potential who not practicing a medically accepted contraception during trial (reliable contraception are systemic contraceptives (oral, implant, injection), diaphragm or condoms with spermicide, sexual abstinence).
- A clear history of non-response to an adequate treatment trial in the current major depressive episode to any protocol antidepressant. A clear history of non-response has to be assumed, when to following criteria are fulfilled:
­ -ad Escitalopram: Treatment with a mDDD 15 mg/d for 4 weeks or CPL 15-80 ng/ml for four weeks without response, i.e. a symptom reduction >= 50% between start and end of treatment.
­ -ad Venlafaxine: Treatment with a mDDD 300 mg/d for weeks 4 weeks or CPL 195-400 ng/ml for four weeks without response
­ -ad Lithium: Treatment with CPL 0.6-0.8 mmol Li+ for four weeks without response
- History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
- Clinically significant or unstable medical or surgical condition that may preclude safe and complete study participation. Such conditions may include gastrointestinal, cardiovascular, vascular disease, pulmonary/respiratory, hepatic impairment, renal, metabolic diseases, endocrinological, neurological, immune-deficiency, hematopoietic disease, or malignancies as determined by medical history, physical examination, or laboratory tests.
- Participation in other clinical trials during the present clinical trial or within the last 6 months.
- Medical or psychological condition that would not permit signing of informed consent.

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Addresses

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    • Universitätsmedizin der Johannes Gutenberg Universität Mainz
    • Mr.  Prof. Dr.  Ulrich  Förstermann 
    • Obere Zahlbacher Strasse 63
    • 55131  Mainz
    • Germany
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    • Klinik für Psychiatrie und Psychotherapie der Universitätsmedizin Mainz
    • Mr.  Priv.-Doz. Dr. med. habil.  Andre  Tadic 
    • Untere Zahlbacher Strasse 8
    • 55131  Mainz
    • Germany
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    • Klinik für Psychiatrie und Psychotherapie, Universitätsmedizin Mainz
    • Mr.  Priv.-Doz. Dr. med. habil.  Andre  Tadic 
    • Untere Zahlbacher Str. 8
    • 55131  Mainz
    • Germany
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Sources of Monetary or Material Support

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    • Bundesministerium für Bildung und Forschung Federal Ministry of Education and Research
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Status

  •   Recruiting complete, follow-up complete
  •   2014/04/30
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Trial Publications, Results and other Documents

  •   Rationale and design of the randomised clinical
    trial comparing early medication change (EMC)
    strategy with treatment as usual (TAU) in patients
    with Major Depressive Disorder - the EMC trial
    André Tadić1*, Stanislav Gorbulev2, Norbert Dahmen1,3, Christoph Hiemke1, Dieter F Braus4, Joachim Röschke5,6,
    Dietrich van Calker7, Daniel Wachtlin2, Kai Kronfeld2, Thorsten Gorbauch2, Monika Seibert-Grafe2, Klaus Lieb1,
    the EMC Study Group, Trials 2010, 11:21
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* This entry means the parameter is not applicable or has not been set.