Study to Evaluate the Efficacy, Safety and Tolerability of an Oral Aripiprazole/Escitalopram Combination Therapy in Participants With Major Depressive Disorder (MDD)

A Multicenter, Randomized, Double-blind Study to Evaluate the Efficacy, Safety and Tolerability of an Oral Aripiprazole/Escitalopram Combination Therapy in Patients With Major Depressive Disorder

This will be a multicenter, randomized, double-blind study designed to assess the efficacy, safety and tolerability of an oral Aripiprazole/Escitalopram combination therapy in participants with MDD who have demonstrated an incomplete response to a prospective trial of Escitalopram, and report a treatment history for the current MDD episode of an inadequate response to at least one and no more than three adequate trials of an approved antidepressant other than Escitalopram. An inadequate response is defined as less than a 50% reduction in depressive symptom severity as assessed by the participant's self-report on the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ) and evaluated by the investigator as part of the participant's medical and psychiatric history. An adequate trial is defined as an antidepressant treatment for at least 6 weeks duration (or at least 3 weeks for combination treatments) at an approved dose as specified in the ATRQ.

Study Overview

• Status: Terminated
• Conditions: Major Depressive Disorder (MDD)
• Intervention / Treatment: Drug: Escitalopram; Drug: Blinded capsule; Drug: Aripiprazole

Detailed Description

The study will be organized as follows:

• Screening Phase
• Single-blind Prospective Treatment Phase
• Single-blind Continuation Phase (Responder) or Double-blind Randomization Phase (non-Responder)
• 30 day Post Treatment Follow-up

Assigned Interventions:

• Escitalopram monotherapy
• Aripiprazole/Escitalopram combination therapy
• Aripiprazole monotherapy

• Study Type: Interventional
• Enrollment (Actual): 211
• Phase: Phase 3

Contacts and Locations

Study Locations

• Estonia
  • Jamejala, Estonia, 71024
  • Tallinn, Estonia, 10617
  • Tartu, Estonia, 50406
  • Tartu, Estonia, 50407
• Finland
  • Helsinki, Finland, 00250
  • Helsinki, Finland, 00260
  • Kuopio, Finland, 70100
  • Oulu, Finland, 90100
• Germany
  • Berlin, Germany, 10117
  • Berlin, Germany, 10969
  • Hamburg, Germany, 20246
  • Munich, Germany, 80336
  • Ostfildern, Germany, 73760
• India
  • Gujarat
    • Ahmedabad, Gujarat, India, 380006
      • Study Site 1
    • Ahmedabad, Gujarat, India, 380006
      • Study Site 2
  • Karnataka
    • Mangalore, Karnataka, India, 575001
  • Maharashtra
    • Mumbai, Maharashtra, India, 400026
    • Pune, Maharashtra, India, 411030
  • Uttar Pradesh
    • Varanasi, Uttar Pradesh, India, 221005
• Italy
  • Catania, Italy, 95123
  • Siena, Italy, 53100
• Korea, Republic of
  • Gwangju, Korea, Republic of, 501-75
  • Seoul, Korea, Republic of, 150-713
  • Seoul, Korea, Republic of, 138-736
  • Seoul, Korea, Republic of, 139-872
  • Seoul, Korea, Republic of, 156-755
• Mexico
  • Durango, Mexico, 34000
  • San Luis Potosi, Mexico, 78218
  • DF
    • Mexico, DF, Mexico, 06700
  • Estado Do Mexico
    • Tlalnepantla de Baz, Estado Do Mexico, Mexico, 54050
  • Jalisco
    • Zapopan, Jalisco, Mexico, 45200
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64040
  • Sinaloa
    • Culiacan, Sinaloa, Mexico, 80020
  • Tabasco
    • Villahermosa, Tabasco, Mexico, 86035
• Taiwan
  • Changhua, Taiwan, 500
  • Kaohsiung, Taiwan, 802
  • Keelung, Taiwan, 204
  • Taoyuan, Taiwan, 333
• United States
  • California
    • Cerritos, California, United States, 90703
    • Costa Mesa, California, United States, 92626
    • Irvine, California, United States, 92618
    • San Diego, California, United States, 92102
    • Santa Ana, California, United States, 92705
  • Colorado
    • Denver, Colorado, United States, 80204
  • Connecticut
    • Cromwell, Connecticut, United States, 06416
    • Hartford, Connecticut, United States, 06106
  • Florida
    • Fort Walton Beach, Florida, United States, 32547
    • Gainesville, Florida, United States, 32607
  • Illinois
    • Chicago, Illinois, United States, 60612
    • Libertyville, Illinois, United States, 60048
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
    • Fall River, Massachusetts, United States, 02721
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
  • New York
    • Bronx, New York, United States, 10467
    • Fresh Meadows, New York, United States, 11366
    • Staten Island, New York, United States, 10305
  • North Carolina
    • Cary, North Carolina, United States, 27518
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
  • Tennessee
    • Memphis, Tennessee, United States, 38119
  • Texas
    • DeSoto, Texas, United States, 75115
  • Virginia
    • Richmond, Virginia, United States, 23230
  • Wisconsin
    • Brown Deer, Wisconsin, United States, 53223

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants with a current diagnosis of a major depressive episode. The current depressive episode must be ≥8 weeks in duration
• Participants willing to discontinue all prohibited psychotropic medication starting from the time of signing the informed consent and during the study period
• Participants with a Hamilton Depression Rating Scale (HAM-D17) Total Score ≥18 at the Baseline Visit for the Prospective Treatment Phase

Exclusion Criteria:

• Lack of prior treatment with an antidepressant during the current depressive episode
• Participants who report treatment with adjunctive or monotherapy antipsychotic treatment during the current depressive episode
• Participants experiencing hallucinations, delusions or any psychotic symptomatology in the current depressive episode
• Participants with epilepsy or significant history of seizure disorders
• Participants with a clinically significant current diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal or histrionic personality disorder
• Participants who have received electroconvulsive therapy (ECT) in the last 10 years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase B: Single-blind Prospective Treatment Phase; Participants received initial dose of escitalopram 10 milligram (mg) blinded capsule (over-encapsulated tablet), orally, once daily, increased to 20 mg/day at the end of Week 1 based upon tolerability profile, for up to maximum of Week 8. No dose reductions were allowed after Week 4 and no dose increments were allowed after Week 3. Participants with incomplete response at the end of the Phase B (Week 8) entered Phase C and the rest of the participants continued to Phase B+.	Drug: Escitalopram; Escitalopram capsule administered orally, once daily without regard to meals.; Drug: Blinded capsule; Blinded capsule administered orally, once daily.
Experimental: Phase B+: Single-blind Phase B Responders; Participants with response (≥50% reduction in depressive symptom severity in Hamilton Depression Rating Scale {HAM-D17} Total Score; or a HAM-D17 Total Score of <14 at Week 8 or a Clinical Global Impression of Improvement {CGI-I} Score of <3 at the Week 6 or 8) at the end of the Phase B (Week 8) continued treatment with the single-blind escitalopram monotherapy at the dose (10 or 20 mg/day blinded capsules) taken during the final week of Phase B, for up to maximum of Week 14, in Phase B+.	Drug: Escitalopram; Escitalopram capsule administered orally, once daily without regard to meals.; Drug: Blinded capsule; Blinded capsule administered orally, once daily.
Experimental: Phase C: Aripiprazole/Escitalopram Combination; Participants with incomplete response (less than 50% reduction in depressive symptom severity between Baseline and Week 8 measured by the HAM-D17 Total Score and HAM-D17 Total Score of ≥14 at Week 8 and CGI-I Score of ≥3 at Week 6 and 8) at Week 8 received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily at Week 9. Participants were up titrated to aripiprazole target dose of 12 mg/day at Week 10 (if initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on initial 6 mg/day dose), and thereafter received same dose up to maximum of Week 14. No dose increases were allowed for aripiprazole after end of Week 12, however, doses might be decreased at any visit based upon tolerability. In combination with aripiprazole, participants received escitalopram (10 or 20 mg/day blinded capsules) taken during final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments allowed for escitalopram during Phase C.	Drug: Escitalopram; Escitalopram capsule administered orally, once daily without regard to meals.; Drug: Blinded capsule; Blinded capsule administered orally, once daily.; Drug: Aripiprazole; Aripiprazole capsule administered orally, once daily without regard to meals.
Experimental: Phase C: Escitalopram Monotherapy; Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received escitalopram dose (10 or 20 mg/day blinded capsules) taken during the final week of Phase B for up to maximum Week 14, in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.	Drug: Escitalopram; Escitalopram capsule administered orally, once daily without regard to meals.; Drug: Blinded capsule; Blinded capsule administered orally, once daily.
Experimental: Phase C: Aripiprazole Monotherapy; Participants with incomplete response (less than a 50% reduction in depressive symptom severity between the Baseline and Week 8 as measured by the HAM-D17 Total Score and a HAM-D17 Total Score of ≥14 at Week 8 and a CGI-I Score of ≥3 at Week 6 and 8) at Week 8, received initial dose of aripiprazole 6 mg blinded capsule, orally, once daily for Week 9. Participants were up titrated to the aripiprazole target dose of 12 mg/day at Week 10 (if the initial 6 mg/day dose was tolerated) or down titrated to 3 mg/day (if significant tolerability issues arise on the initial 6 mg/day dose), and thereafter received the same dose for up to maximum of Week 14. No dose increases were allowed for aripiprazole after the end of Week 12, however, doses might be decreased at any visit based upon tolerability.	Drug: Blinded capsule; Blinded capsule administered orally, once daily.; Drug: Aripiprazole; Aripiprazole capsule administered orally, once daily without regard to meals.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase C: Mean Change From End of Phase B (Week 8) in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score to End of Phase C (Week 14)	The MADRS assessed severity of depressive symptoms. It ranges from a minimum of 0 to a maximum of 60 (higher scores indicating a greater severity of depressive symptoms). Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and a lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). A negative change from Week 8 indicates improvement.	Week 8 to Week 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase C: Mean Clinical Global Impression - Improvement (CGI-I) Scale Score at the End of Phase C (Week 14)	CGI-I is a 7-point clinician-rated scale ranging from 1 to 7, rated as 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. A higher score indicates greater impairment.	Week 14
Phase C: Mean Change From End of Phase B (Week 8) in the Sheehan Disability Scale (SDS) Mean Score to End of Phase C (Week 14)	SDS is a 3-item clinician-rated questionnaire used to evaluate impairments in the domains of work, social life/leisure, and family life/home responsibility. The participant is asked to rate the degree to which their functioning is impaired on an 11-point scale, ranging from 0 (not at all) to 10 (extremely). The scores for the 3 domains are summed into a total score that ranges from 0 (unimpaired) to 30 (highly impaired). A higher score indicates greater impairment. A negative change from Week 8 indicates improvement.	Week 8 to Week 14

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2010
• Primary Completion (Actual): September 20, 2011
• Study Completion (Actual): September 20, 2011

Study Registration Dates

• First Submitted: April 22, 2010
• First Submitted That Met QC Criteria: April 26, 2010
• First Posted (Estimate): April 27, 2010

Study Record Updates

• Last Update Posted (Actual): October 20, 2021
• Last Update Submitted That Met QC Criteria: September 28, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Depression; MDD; Major Depressive Disorder
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Pathologic Processes; Mood Disorders; Depression; Depressive Disorder; Disease; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Dopamine Agonists; Dopamine Agents; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Antagonists; Antidepressive Agents, Second-Generation; Aripiprazole; Citalopram
• Other Study ID Numbers: 31-08-255; 2010-018796-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
• IPD Sharing Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
• IPD Sharing Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No