EMBARC: Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01407094
• Collaborator: (none)
• Enrollment: 296
• Locations: 4
• Arms: 3
• Actual Duration (Months): 56.1
• Patients Per Site: 74
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This study will examine multiple carefully selected clinical and biological markers, using both existing state-of-the-art technologies as well as pioneering, innovative approaches. The study is designed to identify moderators and mediators of treatment response for depression in order to specify a biosignature of treatment response for depression. Evaluation of the usefulness of these markers in a carefully conducted clinical trial comparing an antidepressant to placebo will assist in developing a Depression Treatment Response Index (DTRI) to help clinicians match treatments to patients with MDD, resulting in timely selection of treatments best suited for individual patients and thus approaching personalized treatment. The resulting index provides a truly novel means of synthesizing the contribution of key clinical and biological parameters in an easy to use tool for clinical care.

Condition or Disease	Intervention/Treatment	Phase
Depression	Drug: Sertraline; Drug: Placebo; Drug: BupropionXL	Phase 2

Detailed Description

The current study is designed to identify biomarkers for the prediction of differential treatment outcomes between the SSRI antidepressant sertraline (SERT) and placebo (PBO) in a randomized trial for patients with MDD. In addition, a second stage will collect data to explore moderators and mediators of treatment outcomes between pharmacologically distinct active treatment arms: sertraline (SERT), a serotonergic antidepressant or bupropion (BUP), a nonserotonergic antidepressant. To reduce biologic heterogeneity, we will only enroll patients with early onset of DSM IV MDD (before age 30) because these criteria in probands have been shown to be associated with increased familial loading in families. Patients will also have recurrent MDD with 2 or more recurrences (including current episode). Additionally, patients will be required to have a current symptom severity score of 14 or more on the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR), both at study screening and at the randomization (baseline) visit. In the first stage, patients will receive an 8-week course of treatment in one of the two study arms. As part of the Sequential Multiple Assignment Randomized Trial (SMART) design patients that have not achieved a response at the end of 8 weeks to their stage one treatment, defined by < 50% improvement on the Clinical Global Improvement scale (CGI), will be switched to Stage 2 treatment (8 weeks). Patients who have achieved satisfactory response (>= 50% improvement on the CGI) will be continued on treatment for an additional 8 weeks.

Specific Aims

Moderator Aims (Aim 1): To identify baseline clinical, neuroimaging, neurophysiological, and behavioral moderators of differential treatment outcome (mean symptom change and tolerability) for sertraline (SERT, a serotonergic antidepressant) versus placebo (PBO) for the treatment of MDD. Symptom change will be measured using the mean change from baseline in the 17-item Hamilton Rating Scale for Depression (HRSD17). Tolerability will be measured using the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) and the Treatment Emergent Symptom Scale (TESS).

Mediator Aims (Aim 2): To identify early phase (week 1) changes in neuroimaging, neurophysiological, and behavioral tasks as mediators of differential treatment outcomes (symptom change, tolerability) to SERT and PBO.

Main Treatment Effects Aim (Aim 3): To compare the 8-week outcomes of SERT vs. PBO using mixed model regression analysis to maximize power to discriminate treatment efficacy differences.

Primary Outcomes:

• 17-item Hamilton Rating Scale for Depression (HRSD17)

Secondary Outcomes:

• the Frequency, Intensity, and Burden Side Effects Rating (FIBSER)

Study Design

• Study Type: Interventional
• Actual Enrollment: 296 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Patients were entered into Stage 1, treated with sertraline (Treatment A) or placebo (Treatment B), and used for the primary analysis which included the identification of potential mediators and moderators of response for these two treatments. In stage two, responders to Treatment A remained on sertraline, and non-responders were switched to bupropion (Treatment C). Responders to Treatment B remained on placebo, and non-responders were switched to sertraline (Treatment D).Patients were entered into Stage 1, treated with sertraline (Treatment A) or placebo (Treatment B), and used for the primary analysis which included the identification of potential mediators and moderators of response for these two treatments. In stage two, responders to Treatment A remained on sertraline, and non-responders were switched to bupropion (Treatment C). Responders to Treatment B remained on placebo, and non-responders were switched to sertraline (Treatment D).
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) for Depression
• Actual Study Start Date: Jul 29, 2011
• Actual Primary Completion Date: Apr 1, 2016
• Actual Study Completion Date: Apr 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Sertraline SSRI monotherapy	Drug: Sertraline; 50-200mg/day; Other Names: Zoloft
Placebo Comparator: Placebo Placebo control	Drug: Placebo; 1-4 pills per day
Active Comparator: Bupropion BupropionXL	Drug: BupropionXL; 150-450 mg/day; Other Names: WelbutrinXL

Outcome Measures

Primary Outcome Measures

1. Hamilton Rating Scale for Depression [Week 8]

   The Hamilton Rating Scale for depression is a measure of depressive severity (HAM-D17; HDRS) Scores range from 0-52 Lower scores indicate less depressive symptomatology, and so are the more desirable.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Adults, age 18-65

• Written informed consent obtained

• Outpatients with a current primary diagnosis of nonpsychotic recurrent or chronic MDD per the SCID-I

• QIDS-SR score of ≥ 14 at Screening Visit and Randomization (Baseline) Visit

• No failed antidepressant trials of adequate dose and duration, as defined by the MGH-ATRQ, in the current episode

• Agrees to, and is eligible for, all biomarkers procedures (EEG/psychological testing, MRI, and blood draws)

Exclusion Criteria:

• History of inadequate response (to trials at adequate dose for adequate duration) or poor tolerability to sertraline (SERT) or bupropion (BUP)

• Pregnant or breastfeeding

• Plan to become pregnant over the ensuing 12 months following study entry or are sexually active and not using adequate contraception

• History (lifetime) of psychotic depression, schizophrenia, bipolar (I, II, or NOS) disorder, schizoaffective disorder, or other Axis I psychotic disorder

• Current primary anxiety disorder diagnosis

• Meeting DSM-IV criteria for substance abuse in the last 2 months or substance dependence in the last 6 months (except for nicotine)

• Require immediate hospitalization for psychiatric disorder

• Have an unstable general medical condition (GMC) that will likely require hospitalization or to be deemed terminal (life expectancy < 6 months after study entry)

• Require medications for their GMCs that contraindicate any study medication

• Have epilepsy or other conditions requiring an anticonvulsant

• Receiving or have received during the index episode vagus nerve stimulation, ECT, or rTMS, or other somatic antidepressant treatments

• Currently taking any of the following exclusionary medications: antipsychotic medications, anticonvulsant medications, mood stabilizers, central nervous system stimulants, daily use of benzodiazepines or hypnotics, or antidepressant medication used for the treatment of depression or other purposes such as smoking cessation, since these agents may interfere with the testing of the major hypotheses under study. Nonexcluded concomitant medications are acceptable as long as their clinician determines that antidepressant treatment is safe and appropriate.

• Significant liver disease that would contraindicate any study medication

• Taking thyroid medication for hypothyroidism may be included only if they have been stable on the thyroid medication for 3 months

• Using agents that are potential augmenting agents (e.g., T3 in the absence of thyroid disease, SAMe, St. John's Wort, lithium, buspirone, Omega 3 fatty acids)

• Therapy that is depression specific, such as CBT or Interpersonal Psychotherapy of Depression (IPT) is not allowed during participation (participants can participate if they are receiving psychotherapy that is not targeting the symptoms of depression, such as supportive therapy, marital therapy).

• Subjects must be fluent in English and have the capacity to understand the nature of the study and sign the written informed consent since non-English speaking personnel are not available for this study, and the research instruments are not yet translated and validated in other languages.

• Currently actively suicidal or considered a high suicide risk

• Are currently enrolled in another study, and participation in that study contraindicates participation in the EMBARC study.

• Any reason not listed herein yet, determined by the site PI, medical personnel, or designee that constitutes good clinical practice and that would in the opinion of the site PI, medical personnel, or designee make participation in the study hazardous.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital Boston	Boston	Massachusetts	United States	02114
2	University of Michigan Ann Arbor	Ann Arbor	Michigan	United States	48104
3	Columbia Univerisity New York City	New York	New York	United States	10032
4	UT Southwestern Medical Center Dallas	Dallas	Texas	United States	75309

Sponsors and Collaborators

• University of Texas Southwestern Medical Center

Investigators

• Principal Investigator: Madhukar H Trivedi, M.D., UT Southwestern Medical Center
• Principal Investigator: Patrick J McGrath, M.D., Columbia University
• Principal Investigator: Myrna Weissman, Ph.D., Columbia University
• Principal Investigator: Ramin Parsey, M.D., Columbia University
• Principal Investigator: Maurizio Fava, M.D., Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• EMBARC Study Website

Publications

• Chase HW, Fournier JC, Greenberg T, Almeida JR, Stiffler R, Zevallos CR, Aslam H, Cooper C, Deckersbach T, Weyandt S, Adams P, Toups M, Carmody T, Oquendo MA, Peltier S, Fava M, McGrath PJ, Weissman M, Parsey R, McInnis MG, Kurian B, Trivedi MH, Phillips ML. Accounting for Dynamic Fluctuations across Time when Examining fMRI Test-Retest Reliability: Analysis of a Reward Paradigm in the EMBARC Study. PLoS One. 2015 May 11;10(5):e0126326. doi: 10.1371/journal.pone.0126326. eCollection 2015.
• Fournier JC, Chase HW, Greenberg T, Etkin A, Almeida JR, Stiffler R, Deckersbach T, Weyandt S, Cooper C, Toups M, Carmody T, Kurian B, Peltier S, Adams P, McInnis MG, Oquendo MA, McGrath PJ, Fava M, Weissman M, Parsey R, Trivedi MH, Phillips ML. Neuroticism and Individual Differences in Neural Function in Unmedicated Major Depression: Findings from the EMBARC Study. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Mar;2(2):138-148. doi: 10.1016/j.bpsc.2016.11.008. Epub 2016 Dec 6.
• Greenberg T, Chase HW, Almeida JR, Stiffler R, Zevallos CR, Aslam HA, Deckersbach T, Weyandt S, Cooper C, Toups M, Carmody T, Kurian B, Peltier S, Adams P, McInnis MG, Oquendo MA, McGrath PJ, Fava M, Weissman M, Parsey R, Trivedi MH, Phillips ML. Moderation of the Relationship Between Reward Expectancy and Prediction Error-Related Ventral Striatal Reactivity by Anhedonia in Unmedicated Major Depressive Disorder: Findings From the EMBARC Study. Am J Psychiatry. 2015 Sep 1;172(9):881-91. doi: 10.1176/appi.ajp.2015.14050594. Epub 2015 Jul 17.
• Petkova E, Ogden RT, Tarpey T, Ciarleglio A, Jiang B, Su Z, Carmody T, Adams P, Kraemer HC, Grannemann BD, Oquendo MA, Parsey R, Weissman M, McGrath PJ, Fava M, Trivedi MH. Statistical Analysis Plan for Stage 1 EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care) Study. Contemp Clin Trials Commun. 2017 Jun;6:22-30. doi: 10.1016/j.conctc.2017.02.007. Epub 2017 Feb 24.
• Pizzagalli DA, Webb CA, Dillon DG, Tenke CE, Kayser J, Goer F, Fava M, McGrath P, Weissman M, Parsey R, Adams P, Trombello J, Cooper C, Deldin P, Oquendo MA, McInnis MG, Carmody T, Bruder G, Trivedi MH. Pretreatment Rostral Anterior Cingulate Cortex Theta Activity in Relation to Symptom Improvement in Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Jun 1;75(6):547-554. doi: 10.1001/jamapsychiatry.2018.0252.
• Trivedi MH, McGrath PJ, Fava M, Parsey RV, Kurian BT, Phillips ML, Oquendo MA, Bruder G, Pizzagalli D, Toups M, Cooper C, Adams P, Weyandt S, Morris DW, Grannemann BD, Ogden RT, Buckner R, McInnis M, Kraemer HC, Petkova E, Carmody TJ, Weissman MM. Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC): Rationale and design. J Psychiatr Res. 2016 Jul;78:11-23. doi: 10.1016/j.jpsychires.2016.03.001. Epub 2016 Mar 15.
• Trivedi MH, South C, Jha MK, Rush AJ, Cao J, Kurian B, Phillips M, Pizzagalli DA, Trombello JM, Oquendo MA, Cooper C, Dillon DG, Webb C, Grannemann BD, Bruder G, McGrath PJ, Parsey R, Weissman M, Fava M. A Novel Strategy to Identify Placebo Responders: Prediction Index of Clinical and Biological Markers in the EMBARC Trial. Psychother Psychosom. 2018;87(5):285-295. doi: 10.1159/000491093. Epub 2018 Aug 15.
• Trombello JM, Pizzagalli DA, Weissman MM, Grannemann BD, Cooper CM, Greer TL, Malchow AL, Jha MK, Carmody TJ, Kurian BT, Webb CA, Dillon DG, McGrath PJ, Bruder G, Fava M, Parsey RV, McInnis MG, Adams P, Trivedi MH. Characterizing anxiety subtypes and the relationship to behavioral phenotyping in major depression: Results from the EMBARC study. J Psychiatr Res. 2018 Jul;102:207-215. doi: 10.1016/j.jpsychires.2018.04.003. Epub 2018 Apr 6.
• Ulke C, Tenke CE, Kayser J, Sander C, Böttger D, Wong LYX, Alvarenga JE, Fava M, McGrath PJ, Deldin PJ, Mcinnis MG, Trivedi MH, Weissman MM, Pizzagalli DA, Hegerl U, Bruder GE. Resting EEG Measures of Brain Arousal in a Multisite Study of Major Depression. Clin EEG Neurosci. 2019 Jan;50(1):3-12. doi: 10.1177/1550059418795578. Epub 2018 Sep 5.
• Webb CA, Trivedi MH, Cohen ZD, Dillon DG, Fournier JC, Goer F, Fava M, McGrath PJ, Weissman M, Parsey R, Adams P, Trombello JM, Cooper C, Deldin P, Oquendo MA, McInnis MG, Huys Q, Bruder G, Kurian BT, Jha M, DeRubeis RJ, Pizzagalli DA. Personalized prediction of antidepressant v. placebo response: evidence from the EMBARC study. Psychol Med. 2019 May;49(7):1118-1127. doi: 10.1017/S0033291718001708. Epub 2018 Jul 2.

• Responsible Party: Madhukar H. Trivedi, Principal Investigator, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT01407094
• Other Study ID Numbers: STU 092010-151
• First Posted: Aug 1, 2011
• Last Update Posted: Dec 26, 2018
• Last Verified: Dec 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Madhukar H. Trivedi, Principal Investigator, University of Texas Southwestern Medical Center: Depression, Major Depressive Disorder, Mood Disorder
• Additional relevant MeSH terms: Depression; Depressive Disorder; Sertraline

Study Results

Participant Flow

Pre-assignment Detail	Final enrollment Stage 1: 296 (146 SERT, 150 PBO). Individuals who responded to their Stage 1 treatment remained on that treatment in Stage 2. Individuals who did not respond to their Stage 1 treatment were switched to a different treatment in Stage 2.

Arm/Group Title	Sertraline	Placebo	BupropionXL
Arm/Group Description	SSRI monotherapy Sertraline: 50-200mg/day	Placebo control Placebo: 1-4 pills per day	BupropionXL 150-450 mg/day Other names: WelbutrinXL
Period Title: Stage 1
STARTED	146	150	0
COMPLETED	112	123	0
NOT COMPLETED	34	27	0
Period Title: Stage 1
STARTED	134	46	53
COMPLETED	113	35	38
NOT COMPLETED	21	11	15

Baseline Characteristics

Arm/Group Title	Sertraline	Placebo	BupropionXL	Total
Arm/Group Description	SSRI monotherapy Sertraline: 50-200mg/day	Placebo control Placebo: 1-4 pills per day	BupropionXL 150-450mg/day	Total of all reporting groups
Overall Participants	146	150	0	296
Age (Count of Participants)
<=18 years	6 4.1%	4 2.7%	10 Infinity
Between 18 and 65 years	139 95.2%	145 96.7%	284 Infinity
>=65 years	1 0.7%	1 0.7%	2 Infinity
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.2 (13.8)	36.9 (12.8)	37.05 (13.3)
Sex: Female, Male (Count of Participants)
Female	102 69.9%	92 61.3%	194 Infinity
Male	44 30.1%	58 38.7%	102 Infinity
Region of Enrollment (participants) [Number]
United States	146 100%	150 100%	296 Infinity

Outcome Measures

1. Primary Outcome

Title	Hamilton Rating Scale for Depression
Description	The Hamilton Rating Scale for depression is a measure of depressive severity (HAM-D17; HDRS) Scores range from 0-52 Lower scores indicate less depressive symptomatology, and so are the more desirable.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Note subjects in the efficacy trial were those that completed 8 weeks of treatment, 115 in the sertraline group, and 123 in the placebo group. SERT had 34 wash-outs, PBO had 27.

Arm/Group Title	Sertraline	Placebo	BupropionXL
Arm/Group Description	SSRI monotherapy Sertraline: 50-200mg/day	Placebo control Placebo: 1-4 pills per day	BupropionXL 150-450mg/day
Measure Participants	146	150	0
Mean (Standard Deviation) [units on a scale]	11.06 (6.71)	12.52 (7.68)

Adverse Events

Time Frame	8 weeks for each Stage (1 and 2)
Adverse Event Reporting Description	For both Serious and Other adverse events: SERT total is the sum of Stages 1 or 2, Treatment A plus Treatment D (210+73); PBO total is the sum of Stages 1 or 2, Treatment B (150+46). BUP was only used during Stage 2 (Treatment C).
Arm/Group Title	Sertraline		Placebo		BupropionXL
Arm/Group Description	SSRI monotherapy Sertraline: 50-200mg/day		Placebo control Placebo: 1-4 pills per day		BupropionXL 150-450 mg/day
All Cause Mortality
	Sertraline		Placebo		BupropionXL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Sertraline		Placebo		BupropionXL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/283 (3.5%)		7/196 (3.6%)		1/53 (1.9%)
Cardiac disorders
ER Visit	1/283 (0.4%)	1	0/196 (0%)	0	0/53 (0%)	0
Endocrine disorders
ER Visit	0/283 (0%)	0	1/196 (0.5%)	1	0/53 (0%)	0
Gastrointestinal disorders
ER Visit	1/283 (0.4%)	1	0/196 (0%)	0	0/53 (0%)	0
General disorders
ER Visit	1/283 (0.4%)	1	0/196 (0%)	0	0/53 (0%)	0
ER Visit	1/283 (0.4%)	1	0/196 (0%)	0	0/53 (0%)	0
Nervous system disorders
Seizure	0/283 (0%)	0	0/196 (0%)	0	1/53 (1.9%)	1
Psychiatric disorders
Suicidality	1/283 (0.4%)	1	0/196 (0%)	0	0/53 (0%)	0
Suicidality	0/283 (0%)	0	1/196 (0.5%)	1	0/53 (0%)	0
Suicidality	0/283 (0%)	0	1/196 (0.5%)	1	0/53 (0%)	0
Panic attack	1/283 (0.4%)	1	0/196 (0%)	0	0/53 (0%)	0
Panic attack	0/283 (0%)	0	1/196 (0.5%)	1	0/53 (0%)	0
ER Visit	1/283 (0.4%)	1	0/196 (0%)	0	0/53 (0%)	0
Suicidality	0/283 (0%)	0	1/196 (0.5%)	1	0/53 (0%)	0
Hospitalization	1/283 (0.4%)	1	0/196 (0%)	0	0/53 (0%)	0
Reproductive system and breast disorders
Pregnancy	0/283 (0%)	0	2/196 (1%)	2	0/53 (0%)	0
Pregnancy	1/283 (0.4%)	1	0/196 (0%)	0	0/53 (0%)	0
Other (Not Including Serious) Adverse Events
	Sertraline		Placebo		BupropionXL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	233/283 (82.3%)		89/196 (45.4%)		27/53 (50.9%)
Cardiac disorders
Palpitations	13/283 (4.6%)	13	3/196 (1.5%)	3	3/53 (5.7%)	3
Gastrointestinal disorders
Diarrhea	34/283 (12%)	34	11/196 (5.6%)	11	2/53 (3.8%)	2
General disorders
Dizziness	12/283 (4.2%)	12	6/196 (3.1%)	6	6/53 (11.3%)	6
Fatigue	13/283 (4.6%)	13	2/196 (1%)	2	1/53 (1.9%)	1
Dry Mouth	33/283 (11.7%)	33	8/196 (4.1%)	8	0/53 (0%)	0
Headaches	41/283 (14.5%)	41	46/196 (23.5%)	46	9/53 (17%)	9
Insomnia	30/283 (10.6%)	30	3/196 (1.5%)	3	1/53 (1.9%)	1
Nausea	57/283 (20.1%)	57	10/196 (5.1%)	10	5/53 (9.4%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between 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.