Clinical trial NCT00035321: The Study of Olanzapine Plus Fluoxetine in Combination for Treatment of Treatment Resistant Depression
Official title: The Study of Olanzapine Plus Fluoxetine in Combination for Treatment-Resistant Depression Without Psychotic Features
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Major Depressive Disorder
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2002-05-03
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purposes of this study are to determine:

* Whether olanzapine plus fluoxetine in combination will help patients with treatment-resistant major depression.
* The safety of olanzapine plus fluoxetine in combination, plus and any side effects that might be associated with the combination.
* The effectiveness of olanzapine plus fluoxetine compared to olanzapine and fluoxetine alone.


Eligibility criteria: Inclusion Criteria:

* Male or female patients, 18 - 65 years of age.
* Each patient must have a level of understanding sufficient to perform all tests and examinations required by the protocol, and must be considered reliable according to the investigator's clinical judgement
* Patients must fulfill the criteria for recurrent MDD without psychotic features as defined by the DSM-IV, based on clinical assessment and confirmed by Structured Clinical Interview for DSM-IV Axis I Disorders - Clinical Version (SCID-I) plus the Major Depressive Disorder Specifiers included in the Research Version of the SCID-I. This includes at least one of the following diagnoses: 296.31, 296.32, and 296.33
* Female patients of childbearing potential must be using a medically accepted means of contraception throughout the course of the study. Use of any oral or injectable contraception must be initiated prior to visit 2
* Failure to achieve satisfactory antidepressant response to an adequate trial of an antidepressant (except fluoxetine), for at least 6 weeks at an acceptable dose or greater, occurring within the current episode of MDD

Exclusion Criteria:

* Treatment with a drug within the last 30 days that has not received regulatory approval at the time of study entry
* Exposure to OFC in a Lilly-sponsored clinical trial investigating OFC, and any patients historically failing to respond to olanzapine and fluoxetine in combination under any circumstance
* Persons who have previously entered any Lilly-sponsored study which was investigating olanzapine
* Female patients who are either pregnant or nursing
* Serious, unstable illnesses for which death is anticipated within 1 year of intensive care unit hospitalization for the disease is anticipated within 6 months. This includes hepatic (specifically any degree of jaundice), renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic diseases (specifically current agranulocytosis with an absolute neutrophil count \< 500 mm_3)

Primary outcomes:
measure: To assess the efficacy of up to 8 weeks of treatment with OFC versus olanzapine and fluoxetine monotherapies, in patients with recurrent MDD without psychotic features
measure: who meet study criteria for TRD, as measured by last observation carried forward (LOCF) mean change from baseline to endpoint in the MADRS total score
measure: Treatment-resistant depression will be defined as:historic failure to achieve satisfactory response to an antidepressant (other than fluoxetine) during the current MDD episode
measure: when treated with an acceptable antidepressant drug and dose for at least 6 weeks
measure: prospective failure to achieve a satisfactory response to fluoxetine monotherapy during the 8 week study lead-in phase
Secondary outcomes:
measure: To compare the efficacy, safety, and quality of life results of up to 8 weeks of OFC therapy(treatment phase) with fluoxetine and olanzapine monotherapies using the following assessments:
measure: Onset of action as measured by time to achieve and initial response (greater than or equal to 25% reduction from baseline in MADRS total score
measure: Efficacy in the treatment of co-morbid anxiety symptoms as measured by LOCF mean change from baseline to endpoint in Hamilton Psychiatric Rating Scale for Anxiety (HAM-A)total score
measure: Study-defined response and remission rates including time to achieve a full response (defined as greater than or equal to 50% reduction in MADRS total score)
measure: and time to achieve remission (defined as MADRS total score less than or equal to 10 at endpoint)
measure: LOCF mean change from baseline to endpoint in Clinical Global Impression - Severity of Depression score
measure: (CGI-Severity of Depression), individual MADRS questions,and HAM-A item scores
measure: Repeated measures analyses of post-baseline MADRS and HAM-A total scores
measure: The incidence and severity of treatment-emergent adverse events and EPS. The Barnes Akathisia Scale,Simpson-Angus Scale, and the Abnormal Involuntary Movement Scale (AIMS) will be used to assess EPS
measure: The Brief Psychiatric Rating Scale (BPRS) to evaluate the emergence of psychosis
measure: Changes in vital signs and weight, laboratory analytes, and electrocardiograms (ECG)),Quality of life as measured by the LOCF mean change from baseline to endpoint on the Sheehan Disability Scale (SDS) score and the Short Form 36 Health Survey
measure: Additional secondary objectives are to assess the efficacy, safety, and quality of life results of up to 8 additional weeks of open-label OFC therapy (after the treatment phase)using the following measures:
measure: LOCF mean change from baseline to endpoint in MADRS, HAM-A, and CGI-Severity of Depression scores and study-defined rates of response and remission
measure: Safety as measured by the incidence and severity of treatment-emergent adverse events, and EPS using the Barnes Akithisia Scale, Simpson Angus Scale and the AIM
measure: The BPRS to examine the emergence of psychosis
measure: Changes in vital signs and weight, laboratory analytes, and ECG
Other outcomes:
Locations:
city: Oceanside
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: California
city: San Marcos
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: California
city: Torrance
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: California
city: New London
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Connecticut
city: Coral springs
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Florida
city: North Miami
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Florida
city: St. Petersburg
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Florida
city: Atlanta
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Georgia
city: Marietta
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Georgia
city: Chicago
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Illinois
city: Libertyville
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Illinois
city: Oak Brook
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Illinois
city: New Orleans
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Louisiana
city: Baltimore
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Maryland
city: Glen Burnie
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Maryland
city: Westminster
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Maryland
city: Pittsfield
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Massachusetts
city: Columbia
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Missouri
city: Clementon
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: New Jersey
city: Moorestown
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: New Jersey
city: Toms River
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: New Jersey
city: Dayton
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Ohio
city: Medford
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Oregon
city: Salem
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Oregon
city: Sellersville
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Pennsylvania
city: Lincoln
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Rhode Island
city: Dallas
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Texas
city: Salt Lake City
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Utah
city: Richmond
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Virginia
city: Waukesha
country: United States
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Wisconsin
city: St John's
country: Canada
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Newfoundland and Labrador
city: Kingston
country: Canada
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
state: Ontario
city: St. John
country: Canada
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
Study officials:
affiliation: Eli Lilly and Company
name: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon-Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
role: STUDY_DIRECTOR
References:
citation: Houston JP, Kohler J, Bishop JR, Ellingrod VL, Ostbye KM, Zhao F, Conley RR, Poole Hoffmann V, Fijal BA. Pharmacogenomic associations with weight gain in olanzapine treatment of patients without schizophrenia. J Clin Psychiatry. 2012 Aug;73(8):1077-86. doi: 10.4088/JCP.11m06916.
citation: Houston JP, Lau K, Aris V, Liu W, Fijal BA, Heinloth AN, Perlis RH. Association of common variations in the norepinephrine transporter gene with response to olanzapine-fluoxetine combination versus continued-fluoxetine treatment in patients with treatment-resistant depression: a candidate gene analysis. J Clin Psychiatry. 2012 Jun;73(6):878-85. doi: 10.4088/JCP.10m06744. Epub 2012 Mar 6.
citation: Houston J, Dharia S, Bishop JR, Ellingrod VL, Fijal B, Jacobson JG, Hoffmann VP. Association of DRD2 and ANKK1 polymorphisms with prolactin increase in olanzapine-treated women. Psychiatry Res. 2011 May 15;187(1-2):74-9. doi: 10.1016/j.psychres.2010.10.020. Epub 2010 Nov 20.
citation: Tohen M, Case M, Trivedi MH, Thase ME, Burke SJ, Durell TM. Olanzapine/fluoxetine combination in patients with treatment-resistant depression: rapid onset of therapeutic response and its predictive value for subsequent overall response in a pooled analysis of 5 studies. J Clin Psychiatry. 2010 Apr;71(4):451-62. doi: 10.4088/JCP.08m04984gre. Epub 2010 Feb 23.
citation: Thase ME, Corya SA, Osuntokun O, Case M, Henley DB, Sanger TM, Watson SB, Dube S. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. J Clin Psychiatry. 2007 Feb;68(2):224-36. doi: 10.4088/jcp.v68n0207.