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

Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
Overall Status
Terminated
CT.gov ID
NCT01111552
Collaborator
(none)
237
60
5
14
4
0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

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 Design

Study Type:
Interventional
Actual Enrollment :
237 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Jul 29, 2010
Actual Primary Completion Date :
Sep 27, 2011
Actual Study Completion Date :
Sep 27, 2011

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Phase B: Single-blind Prospective Treatment Phase

Escitalopram 10 mg capsule, orally, once daily increased to 20 mg/day at the end of Week 1 based upon tolerability profile, plus one matching placebo capsule, for 8 weeks. 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 oral capsules.

Drug: Placebo
Study drug matching placebo capsule.

Active Comparator: Phase B+: Single-blind Phase B Responders

Participants with response 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) taken during the final week of Phase B plus one matching placebo capsule, for an additional 6 weeks, in Phase B+.

Drug: Escitalopram
Escitalopram oral capsules.

Drug: Placebo
Study drug matching placebo capsule.

Active Comparator: Phase C: Escitalopram Monotherapy

Participants with incomplete response at Week 8 who were randomized to this arm group received escitalopram monotherapy 10 or 20 mg capsule, orally, once daily, whichever dose was taken during the final week of Phase B plus one matching placebo capsule for 6 weeks, in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C.

Drug: Escitalopram
Escitalopram oral capsules.

Drug: Placebo
Study drug matching placebo capsule.

Active Comparator: Phase C: Aripiprazole Monotherapy

Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily plus one matching placebo capsule for 6 weeks, in Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated. No dose increments were allowed after Week 12; however, doses may have been decreased at any week, based upon tolerability.

Drug: Aripiprazole
Aripiprazole oral capsules.
Other Names:
  • OPC-14597
  • Drug: Placebo
    Study drug matching placebo capsule.

    Active Comparator: Phase C: Aripiprazole/Escitalopram Combination Therapy

    Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily in combination with the escitalopram 10 or 20 mg orally, once daily plus one matching placebo capsule for 6 weeks, in Phase C. No dose adjustments were allowed for escitalopram during Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated.

    Drug: Escitalopram
    Escitalopram oral capsules.

    Drug: Aripiprazole
    Aripiprazole oral capsules.
    Other Names:
  • OPC-14597
  • Drug: Placebo
    Study drug matching placebo capsule.

    Outcome Measures

    Primary Outcome Measures

    1. 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) [Week 8 to 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. Last observation carried forward (LOCF) method was used for analyses.

    Secondary Outcome Measures

    1. Phase C: Clinical Global Impression - Improvement Scale (CGI-I) Score at The End of Phase C (Week 14) [Week 14]

      The CGI-I is a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. Last observation carried forward (LOCF) method was used for analyses.

    2. 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) [Week 8 to Week 14]

      The 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. All items are rated on an 11-point continuum (0= no impairment to 10= most severe) with the total SDS score ranging from 0 (no impairment) to 30 (most severe). A negative change from Week 8 indicates improvement. Last observation carried forward (LOCF) method was used for analyses.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 17-item 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Birmingham Alabama United States 35216
    2 Little Rock Arkansas United States 72223
    3 Carson California United States 90746
    4 Garden Grove California United States 95231
    5 Imperial California United States 92251
    6 Mission Viejo California United States 92691
    7 Redlands California United States 92374
    8 San Diego California United States 92128
    9 Atlanta Georgia United States 30308
    10 Atlanta Georgia United States 30328
    11 Hoffman Estates Illinois United States 60169
    12 Terre Haute Indiana United States 47802
    13 Overland Park Kansas United States 66211
    14 Prairie Village Kansas United States 66206
    15 Wichita Kansas United States 67207
    16 Baltimore Maryland United States 21204
    17 New York New York United States 10021
    18 Toledo Ohio United States 43623
    19 Bartlett Tennessee United States 38134
    20 Wichita Falls Texas United States 76309
    21 Brisbane Queensland Australia 4000
    22 Everton Park Queensland Australia 4053
    23 Malvern Victoria Australia 3144
    24 Melbourne Victoria Australia 3004
    25 Fremantle Western Australia Australia 6959
    26 Bourgas Bulgaria 8000
    27 Lovech Bulgaria 5500
    28 Novi Iskar Bulgaria 1282
    29 Pleven Bulgaria 5800
    30 Plovdiv Bulgaria 4000
    31 Rousse Bulgaria 7003
    32 Sofia Bulgaria 1113
    33 Sofia Bulgaria 1431
    34 Sofia Bulgaria 1606
    35 Tsarev Brod Bulgaria 9747
    36 Tserova Koria Bulgaria 5047
    37 Varna Bulgaria 9000
    38 Tirupati Andhra Pradesh India 517507
    39 Vijayawada Andhra Pradesh India 500072
    40 Manipala Karnataka India 576104
    41 Pune Maharashtra India 411004
    42 Ludhiana Punjab India 141001
    43 Chennai Tamil Nadu India 600003
    44 Kanpur Uttar Pradesh India 208005
    45 Quezon City NCR Philippines 1101
    46 Quezon City NCR Philippines 1102
    47 Bucuresti Romania 010825
    48 Bucuresti Romania 030455
    49 Study Site 1 Bucuresti Romania 041914
    50 Study Site 2 Bucuresti Romania 041914
    51 Craiova Romania 200620
    52 Craiova Romania 540139
    53 Iasi Romania 700282
    54 Targoviste Romania 130081
    55 Targu Mures Romania 540139
    56 Michalovce Slovakia 07101
    57 Rimavska Sobota Slovakia 97901
    58 Svidnik Slovakia 8901
    59 Trencin Slovakia 91101
    60 Zlate Moravce Slovakia 95301

    Sponsors and Collaborators

    • Otsuka Pharmaceutical Development & Commercialization, Inc.

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    ClinicalTrials.gov Identifier:
    NCT01111552
    Other Study ID Numbers:
    • 31-08-256
    • 2010-018858-12
    First Posted:
    Apr 27, 2010
    Last Update Posted:
    Oct 26, 2021
    Last Verified:
    Sep 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 69 investigative sites in Australia, Bulgaria, India, Philippines, Romania, Russia, Slovakia, and the United States from 29 July 2010 to 27 September 2011.
    Pre-assignment Detail A total of 237 major depressive disorder(MDD)participants were enrolled in Phase B(Single-blind Prospective Treatment Phase)to receive escitalopram monotherapy(10 or 20mg/day),of which 54 responders continued to Phase B+(Single-blind Phase B Responders),received escitalopram monotherapy(10 or 20mg/day).66 non-responders were randomized in 1:1:1 ratio to Phase C(Double-blind Randomization Phase),received escitalopram or aripiprazole monotherapy or aripiprazole/escitalopram combination therapy.
    Arm/Group Title Phase B: Single-blind Prospective Treatment Phase Phase B+: Single-blind Phase B Responders Phase C: Escitalopram Monotherapy Phase C: Aripiprazole Monotherapy Phase C: Aripiprazole/Escitalopram Combination Therapy
    Arm/Group Description Escitalopram 10 mg capsule, orally, once daily increased to 20 mg/day at the end of Week 1 based upon tolerability profile, plus one matching placebo capsule, for 8 weeks. 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+. Participants with response 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) taken during the final week of Phase B plus one matching placebo capsule, for an additional 6 weeks, in Phase B+. Participants with incomplete response at Week 8 who were randomized to this arm group received escitalopram monotherapy 10 or 20 mg capsule, orally, once daily, whichever dose was taken during the final week of Phase B plus one matching placebo capsule for 6 weeks, in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C. Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily plus one matching placebo capsule for 6 weeks, in Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated. No dose increments were allowed after Week 12; however, doses may have been decreased at any week, based upon tolerability. Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily in combination with the escitalopram 10 or 20 mg orally, once daily plus one matching placebo capsule for 6 weeks, in Phase C. No dose adjustments were allowed for escitalopram during Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated.
    Period Title: Phase B (Day 1 to Week 8)
    STARTED 237 0 0 0 0
    COMPLETED 120 0 0 0 0
    NOT COMPLETED 117 0 0 0 0
    Period Title: Phase B (Day 1 to Week 8)
    STARTED 0 54 22 21 23
    COMPLETED 0 45 17 17 18
    NOT COMPLETED 0 9 5 4 5

    Baseline Characteristics

    Arm/Group Title Phase B: Single-blind Prospective Treatment Phase
    Arm/Group Description Escitalopram 10 mg capsule, orally, once daily increased to 20 mg/day at the end of Week 1 based upon tolerability profile, plus one matching placebo capsule, for 8 weeks. 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+.
    Overall Participants 237
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    45.2
    (11.3)
    Sex: Female, Male (Count of Participants)
    Female
    156
    65.8%
    Male
    81
    34.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    18
    7.6%
    Not Hispanic or Latino
    218
    92%
    Unknown or Not Reported
    1
    0.4%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    2
    0.8%
    Asian
    15
    6.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    30
    12.7%
    White
    186
    78.5%
    More than one race
    0
    0%
    Unknown or Not Reported
    4
    1.7%

    Outcome Measures

    1. Primary Outcome
    Title 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)
    Description 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. Last observation carried forward (LOCF) method was used for analyses.
    Time Frame Week 8 to Week 14

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) Sample included all participants in the Randomized Sample who received at least one dose of double-blind trial medication and had at least one post-randomization efficacy evaluation in Phase C.
    Arm/Group Title Phase C: Escitalopram Monotherapy Phase C: Aripiprazole Monotherapy Phase C: Aripiprazole/Escitalopram Combination Therapy
    Arm/Group Description Participants with incomplete response at Week 8 who were randomized to this arm group received escitalopram monotherapy 10 or 20 mg capsule, orally, once daily, whichever dose was taken during the final week of Phase B plus one matching placebo capsule for 6 weeks, in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C. Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily plus one matching placebo capsule for 6 weeks, in Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated. No dose increments were allowed after Week 12; however, doses may have been decreased at any week, based upon tolerability. Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily in combination with the escitalopram 10 or 20 mg orally, once daily plus one matching placebo capsule for 6 weeks, in Phase C. No dose adjustments were allowed for escitalopram during Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated.
    Measure Participants 22 21 23
    Least Squares Mean (Standard Error) [score on a scale]
    -8.0
    (1.7)
    -9.6
    (1.7)
    -9.2
    (1.6)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase C: Escitalopram Monotherapy, Phase C: Aripiprazole/Escitalopram Combination Therapy
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.595
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.3
    Confidence Interval (2-Sided) 95%
    -5.9 to 3.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase C: Aripiprazole Monotherapy, Phase C: Aripiprazole/Escitalopram Combination Therapy
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.869
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value 0.4
    Confidence Interval (2-Sided) 95%
    -4.4 to 5.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Phase C: Clinical Global Impression - Improvement Scale (CGI-I) Score at The End of Phase C (Week 14)
    Description The CGI-I is a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. Last observation carried forward (LOCF) method was used for analyses.
    Time Frame Week 14

    Outcome Measure Data

    Analysis Population Description
    ITT Sample included all participants in the Randomized Sample who received at least one dose of double-blind trial medication and had at least one post-randomization efficacy evaluation in Phase C.
    Arm/Group Title Phase C: Escitalopram Monotherapy Phase C: Aripiprazole Monotherapy Phase C: Aripiprazole/Escitalopram Combination Therapy
    Arm/Group Description Participants with incomplete response at Week 8 who were randomized to this arm group received escitalopram monotherapy 10 or 20 mg capsule, orally, once daily, whichever dose was taken during the final week of Phase B plus one matching placebo capsule for 6 weeks, in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C. Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily plus one matching placebo capsule for 6 weeks, in Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated. No dose increments were allowed after Week 12; however, doses may have been decreased at any week, based upon tolerability. Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily in combination with the escitalopram 10 or 20 mg orally, once daily plus one matching placebo capsule for 6 weeks, in Phase C. No dose adjustments were allowed for escitalopram during Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated.
    Measure Participants 22 21 23
    Mean (Standard Error) [score on a scale]
    2.4
    (0.3)
    2.3
    (0.2)
    2.3
    (0.2)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase C: Escitalopram Monotherapy, Phase C: Aripiprazole/Escitalopram Combination Therapy
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.856
    Comments
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel Row Mean Scores Test was used to determine the p-value.
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.1
    Confidence Interval (2-Sided) 95%
    -0.7 to 0.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase C: Aripiprazole Monotherapy, Phase C: Aripiprazole/Escitalopram Combination Therapy
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.838
    Comments
    Method Cochran-Mantel-Haenszel
    Comments Cochran-Mantel-Haenszel Row Mean Scores Test was used to determine the p-value.
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value 0.1
    Confidence Interval (2-Sided) 95%
    -0.6 to 0.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title 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)
    Description The 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. All items are rated on an 11-point continuum (0= no impairment to 10= most severe) with the total SDS score ranging from 0 (no impairment) to 30 (most severe). A negative change from Week 8 indicates improvement. Last observation carried forward (LOCF) method was used for analyses.
    Time Frame Week 8 to Week 14

    Outcome Measure Data

    Analysis Population Description
    ITT Sample included all participants in the Randomized Sample who received at least one dose of double-blind trial medication and had at least one post-randomization efficacy evaluation in Phase C. Number analyzed is the number of participants with data available for analysis.
    Arm/Group Title Phase C: Escitalopram Monotherapy Phase C: Aripiprazole Monotherapy Phase C: Aripiprazole/Escitalopram Combination Therapy
    Arm/Group Description Participants with incomplete response at Week 8 who were randomized to this arm group received escitalopram monotherapy 10 or 20 mg capsule, orally, once daily, whichever dose was taken during the final week of Phase B plus one matching placebo capsule for 6 weeks, in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C. Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily plus one matching placebo capsule for 6 weeks, in Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated. No dose increments were allowed after Week 12; however, doses may have been decreased at any week, based upon tolerability. Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily in combination with the escitalopram 10 or 20 mg orally, once daily plus one matching placebo capsule for 6 weeks, in Phase C. No dose adjustments were allowed for escitalopram during Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated.
    Measure Participants 22 21 23
    Least Squares Mean (Standard Error) [score on a scale]
    -0.9
    (0.5)
    -1.4
    (0.5)
    -1.2
    (0.5)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase C: Escitalopram Monotherapy, Phase C: Aripiprazole/Escitalopram Combination Therapy
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.765
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.2
    Confidence Interval (2-Sided) 95%
    -1.6 to 1.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase C: Aripiprazole Monotherapy, Phase C: Aripiprazole/Escitalopram Combination Therapy
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.760
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value 0.2
    Confidence Interval (2-Sided) 95%
    -1.2 to 1.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame From first dose of study drug through end of study (up to 22 weeks)
    Adverse Event Reporting Description Phase B Sample included all participants who took at least one dose of escitalopram as indicated on the dosing record. Phase B+ Sample included all participants who responded at the end of Phase B (were therefore not randomized) and who continued on single-blind escitalopram beyond Week 8. Randomized Sample included all participants who were randomized in Phase C.
    Arm/Group Title Phase B: Single-blind Prospective Treatment Phase Phase B+: Single-blind Phase B Responders Phase C: Escitalopram Monotherapy Phase C: Aripiprazole Monotherapy Phase C: Aripiprazole/Escitalopram Combination Therapy
    Arm/Group Description Escitalopram 10 mg capsule, orally, once daily increased to 20 mg/day at the end of Week 1 based upon tolerability profile, plus one matching placebo capsule, for 8 weeks. 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+. Participants with response 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) taken during the final week of Phase B plus one matching placebo capsule, for an additional 6 weeks, in Phase B+. Participants with incomplete response at Week 8 who were randomized to this arm group received escitalopram monotherapy 10 or 20 mg capsule, orally, once daily, whichever dose was taken during the final week of Phase B plus one matching placebo capsule for 6 weeks, in Phase C. No dose adjustments were allowed for escitalopram monotherapy during Phase C. Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily plus one matching placebo capsule for 6 weeks, in Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated. No dose increments were allowed after Week 12; however, doses may have been decreased at any week, based upon tolerability. Participants with incomplete response at Week 8 who were randomized to this arm group received aripiprazole 3, 6, or 12 mg capsule, orally, once daily in combination with the escitalopram 10 or 20 mg orally, once daily plus one matching placebo capsule for 6 weeks, in Phase C. No dose adjustments were allowed for escitalopram during Phase C. Participants were titrated to the aripiprazole target dose of 12 mg/day at Week 9 if the initial 6 mg/day dose was tolerated.
    All Cause Mortality
    Phase B: Single-blind Prospective Treatment Phase Phase B+: Single-blind Phase B Responders Phase C: Escitalopram Monotherapy Phase C: Aripiprazole Monotherapy Phase C: Aripiprazole/Escitalopram Combination Therapy
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/237 (0%) 0/54 (0%) 0/22 (0%) 0/21 (0%) 0/23 (0%)
    Serious Adverse Events
    Phase B: Single-blind Prospective Treatment Phase Phase B+: Single-blind Phase B Responders Phase C: Escitalopram Monotherapy Phase C: Aripiprazole Monotherapy Phase C: Aripiprazole/Escitalopram Combination Therapy
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/237 (0.8%) 1/54 (1.9%) 1/22 (4.5%) 0/21 (0%) 0/23 (0%)
    Investigations
    Alanine aminotransferase increased 0/237 (0%) 0/54 (0%) 1/22 (4.5%) 0/21 (0%) 0/23 (0%)
    Psychiatric disorders
    Depression 1/237 (0.4%) 0/54 (0%) 0/22 (0%) 0/21 (0%) 0/23 (0%)
    Respiratory, thoracic and mediastinal disorders
    Asthma 0/237 (0%) 1/54 (1.9%) 0/22 (0%) 0/21 (0%) 0/23 (0%)
    Social circumstances
    Physical assault 1/237 (0.4%) 0/54 (0%) 0/22 (0%) 0/21 (0%) 0/23 (0%)
    Other (Not Including Serious) Adverse Events
    Phase B: Single-blind Prospective Treatment Phase Phase B+: Single-blind Phase B Responders Phase C: Escitalopram Monotherapy Phase C: Aripiprazole Monotherapy Phase C: Aripiprazole/Escitalopram Combination Therapy
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 53/237 (22.4%) 7/54 (13%) 5/22 (22.7%) 10/21 (47.6%) 11/23 (47.8%)
    Gastrointestinal disorders
    Nausea 18/237 (7.6%) 0/54 (0%) 2/22 (9.1%) 1/21 (4.8%) 1/23 (4.3%)
    Constipation 1/237 (0.4%) 0/54 (0%) 2/22 (9.1%) 0/21 (0%) 1/23 (4.3%)
    Diarrhoea 10/237 (4.2%) 2/54 (3.7%) 0/22 (0%) 3/21 (14.3%) 0/23 (0%)
    Infections and infestations
    Upper Respiratory Tract Infection 5/237 (2.1%) 1/54 (1.9%) 0/22 (0%) 2/21 (9.5%) 2/23 (8.7%)
    Investigations
    Weight increased 2/237 (0.8%) 2/54 (3.7%) 0/22 (0%) 0/21 (0%) 2/23 (8.7%)
    Nervous system disorders
    Akathisia 0/237 (0%) 0/54 (0%) 0/22 (0%) 2/21 (9.5%) 2/23 (8.7%)
    Dizziness 8/237 (3.4%) 0/54 (0%) 1/22 (4.5%) 4/21 (19%) 1/23 (4.3%)
    Headache 20/237 (8.4%) 2/54 (3.7%) 1/22 (4.5%) 0/21 (0%) 2/23 (8.7%)
    Psychiatric disorders
    Restlessness 0/237 (0%) 0/54 (0%) 0/22 (0%) 1/21 (4.8%) 2/23 (8.7%)
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain 1/237 (0.4%) 0/54 (0%) 2/22 (9.1%) 0/21 (0%) 1/23 (4.3%)

    Limitations/Caveats

    The study was terminated early due to Sponsor decision, closure of this combination therapy program is unrelated to any safety issues, no signals of concern.

    More Information

    Certain Agreements

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

    A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Global Clinical Development
    Organization Otsuka Pharmaceutical Development & Commercialization, Inc.
    Phone 1-609-524-6788
    Email clinicaltransparency@otsuka-us.com
    Responsible Party:
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    ClinicalTrials.gov Identifier:
    NCT01111552
    Other Study ID Numbers:
    • 31-08-256
    • 2010-018858-12
    First Posted:
    Apr 27, 2010
    Last Update Posted:
    Oct 26, 2021
    Last Verified:
    Sep 1, 2021