A Double-Blind, Placebo-Controlled Study of Aripiprazole Adjunctive to Antidepressant Therapy

Major Depressive Disorder Clinical Trial

Official title:

A Double-Blind, Placebo-Controlled Study of Aripiprazole Adjunctive to Antidepressant Therapy (ADT) Among Outpatients With Major Depressive Disorder Who Have Responded Inadequately to Prior ADT

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00683852
• Other study ID #: BMS - 2008A053242
• Status: Completed
• Phase: Phase 3
• First received: May 22, 2008
• Last updated: August 11, 2010
• Start date: July 2008
• Est. completion date: September 2009

Study information

• Verified date: August 2010
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether a reduced dose of aripiprazole is effective in treating patients with major depressive disorder

Description:

This is a 60-day, multi-center, double-blind, placebo-controlled study on the efficacy of aripiprazole (Abilify) augmentation of selective serotonin reuptake inhibitors (SSRIs) or selective serotonin norepinephrine uptake inhibitors (SNRIs) venlafaxine in patients with MDD who have responded inadequately to treatment with ADTs. The purpose of our study is to evaluate the efficacy and tolerability of low-dose (2 mg/day) aripiprazole (Abilify) as an augmentation strategy in MDD non-responding to ADT with SSRIs or the SNRI venlafaxine.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 224
• Est. completion date: September 2009
• Est. primary completion date: September 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Patients able to give informed consent, and/or consent obtained from a legally acceptable representative (as required by IRB/IEC), prior to the initiation of any protocol required procedures.

2. Patients must be able to understand the nature of the study, agree to comply with the prescribed dosage regimens, report for regularly scheduled office visits, and communicate to study personnel about adverse events and concomitant medication use.

3. Patients with a diagnosis of major depressive episode as defined by DSM-IV-TR criteria, based on the SCID-I/P; their major depressive episode must be deemed "valid" using the SAFER criteria interview administered by remote, independent raters.

4. Patients who have reported a history for the current depressive episode of an inadequate response to at least one and no more than three adequate antidepressant treatments. An inadequate response is defined as less than a 50% reduction in depressive symptom severity, as assessed by the MGH ATRQ administered by remote, independent raters. An adequate trial is defined as an antidepressant treatment for at least 6 weeks duration at least at a minimum dose as specified in the MGH ATRQ.

5. Patients must have a HAM-D17 = 18 at the end of the screening phase to qualify for inclusion. The HAM-D17 will be administered by the study clinicians at the screening and baseline visits, and by remote, independent raters during the screening phase at the time of the SAFER interview.

6. Patients must be able to be reliably rated on the psychiatric scales required by the protocol.

7. Men and women, ages 18 to 65 Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.

WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea ³ 12 consecutive months; or women on hormone replacement therapy [HRT] with documented serum follicle stimulating hormone [FSH] level > 35 mIU/mL). Even women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential.

WOCBP must have a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.

8. Meet DSM-IV criteria (by Structured Clinical Interview for DSM-IV - SCID-I/P) for MDD, current;

9. Quick Inventory of Depressive Symptomatology - Self-Rated (QIDS-SR) (22) score of at least 16 at both screen and baseline visits;

10. Treated with an SSRI at adequate doses (defined as 20mg/day or more of fluoxetine, citalopram; paroxetine 30mg/day or more or 37.5 mg/day or more of paroxetine CR; 10 mg/day or more of escitalopram, 50mg/day or more of sertraline, and 150 mg/day or more of venlafaxine) during the current episode for at least 8 weeks, with the same, adequate dose over the last 4 weeks;

11. Between the screen and baseline visit, patients must be documented prospectively to have received a stable dose of their SSRI or venlafaxine for at least 2 weeks.

Additional criteria for defining response and non-response for patients in Phase 2 eligible for the pooling of the data with all the patients in Phase 1. Among patients pre-randomized to receive placebo in both phases or to receive placebo in Phase 1 and aripiprazole in phase 2, only those meeting non-response criteria will be added to the primary efficacy sample:

• Placebo non-responders are defined as those patients who failed to achieve a 50% decrease in their MADRS score at visit 3,

• Have a MADRS score of > 16 at visit 3

Exclusion Criteria:

1. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period [and for up to 4 weeks after the last dose of investigational product].

2. WOCBP using a prohibited contraceptive method.

3. Women who are pregnant or breastfeeding.

4. Women with a positive pregnancy test on enrollment or prior to investigational product administration.

5. Sexually active fertile men not using effective birth control if their partners are WOCBP.

6. Patients who report an inadequate response (less than 50% decrease in depressive symptom severity) to more than two adequate trials of antidepressant treatments during the current depressive episode (including monotherapy treatment and distinct combination regimens) at a therapeutic dose (as defined by the ATRQ) and for an adequate duration (minimum six weeks for any monotherapy).

7. Patients who report treatment with adjunctive antipsychotic medication with an antidepressant for a minimum of two weeks during the current depressive episode.

8. Patients with a current need for involuntary commitment or who have been hospitalized within four weeks of the Screening Visit for the current major depressive episode.

9. Patients who have received ECT during the current episode.

10. Patients who have a current Axis I diagnosis of:

1. Delirium, dementia, amnestic, or other cognitive disorder;

2. Schizophrenia or other psychotic disorder, based on the SCID-I/P;

3. Bipolar I or II disorder, based on the SCID-I/P;

11. Patients with a clinically significant Axis II (DSM-IV-TR) diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal or histrionic personality disorder.

12. Patients experiencing hallucinations, delusions, or any psychotic symptomatology in the current depressive episode.

13. Patients who have met DSM-IV-TR criteria for any significant substance use disorder within the past six months, based on the SCID-I/P.

14. Patients receiving new onset psychotherapy within 6 weeks of screening, or at any time during participation in the trial.

15. Patients who have been previously randomized in an aripiprazole clinical trial (lifetime).

16. Patients who have participated in any clinical trial with an investigational drug or device within the past month.

17. Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease;

18. Patients who, in the investigator's judgment represent a significant risk of committing suicide during the course of the trial based on history or evaluation of current mental status

19. Patients who have a history or evidence of a medical condition that would expose them to an undue risk of a significant adverse event or interfere with assessments of safety or efficacy during the course of the trial

20. Patients with thyroid pathology (unless condition has been stabilized with medications for at least the past three months)

21. Patients with a lifetime history of neuroleptic malignant syndrome or serotonin syndrome

22. Patients with a significant history of a seizure disorder

23. Patients with detectable levels of cocaine, heroin or opioids in the urine drug screen

24. Diastolic blood pressure > 105 mmHg

25. Any signs or symptoms that in the investigator's judgment are medically significant, in that it would impact the patients safety.

1. Patients who are known to be allergic or hypersensitive to aripiprazole or other dihydrocarbostyrils (e.g. carteolol, vesnarinone, and cilostazol)

2. Patients previously treated with and not responding to aripiprazole

3. Monoamine oxidase inhibitors (e.g., Nardil, phenelzine, Parnate, tranylcypromine, Marplan, isocarboxazid) treatment within the two weeks prior to enrollment

4. Patients who would likely require prohibited concomitant medication during the trial

5. Prisoners or subjects who are involuntarily incarcerated

6. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness

7. Patients who no longer meet DSM-IV criteria for MDD during the baseline visit;

8. Patients who demonstrate a greater than 25% decrease in depressive symptoms as reflected by the QIDS-SR or HAM-D17 total score from screen visit to baseline visit;

9. Patients with a history of antidepressant-induced hypomania.

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

Intervention

Drug:
• Aripiprazole
Tablet dose of aripiprazole will be 2 mg/day during the first phase (30 days) of the study, and 5 mg/day in the second phase (30 days)
• Aripiprazole
For patients randomly assigned to the placebo/drug sequence, the dose of aripiprazole will be 2 mg/day during the second phase of the study (30 days)
• Placebo
for patients randomly assigned to the placebo/placebo sequence, study medication will be placebo during both phases of the study (60 days)

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Massachusetts General Hospital	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

References & Publications (2)

Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK, Khan A. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007 Jun;68(6):843-53. — View Citation

Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon JS, Trivedi MH, Thase ME, Berman RM. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008 Apr;28(2):156-65. doi: 10.1097/JCP.0b013e31816774f9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary outcome will be the difference in rate of response (decrease in MADRS total score of at least 50%) between patients treated with adjunctive aripiprazole 2 mg and adjunctive placebo using the sequential parallel comparison design.		30 days, 60 days	No
Secondary	To document the safety and tolerability of low doses of aripiprazole augmentation		30 days, 60 days	Yes