A Study in Relapse Prevention of Treatment-resistant Depression

Official Title: “A Study to Assess the Long-Term Efficacy and Safety of Olanzapine and Fluoxetine Combination Versus Fluoxetine Only in the Relapse Prevention of Stabilized Patients With Treatment-Resistant Depression”

The purpose of this study is to determine whether olanzapine and fluoxetine combination (OFC) if used for a long time (47 weeks) makes patients suffering from Treatment Resistant Depression stable, determine if OFC is safe when used to treat patients with Treatment Resistant Depression for a long time (up to 47 weeks), to determine whether olanzapine and fluoxetine combination or fluoxetine alone is better to treat Treatment Resistant Depression when treated for a long time ( up to 47 weeks) and to assess the quality of life during treatment.

This is a multicenter, randomized, double-blind, active comparator-controlled, parallel study of patients with Treatment Resistant Depression (TRD), comparing the efficacy and safety of olanzapine and fluoxetine Combination (OFC) versus fluoxetine in relapse prevention of stabilized patients with TRD. The study will consist of 4 phases: a screening phase; a 6- to 8-week open-label acute treatment phase; a 10- to 12-week open-label stabilization phase; and a 27- to 29-week double-blind relapse prevention treatment phase.

Patients who demonstrate response to open-label OFC during the acute treatment phase will continue into the stabilization phase. Patients who remain stable while receiving open-label OFC during this phase will be randomized to receive either OFC or fluoxetine during the double-blind relapse prevention phase. Investigators and patients will be blinded to the precise duration of the stabilization period, the definition of remission, and the criteria for entry into the relapse prevention phase; this information is described in a supplement given to Ethical Review Boards (ERBs) and regulatory authorities.

Intervention(s) in this Clinical Trial

• Drug: Olanzapine and Fluoxetine combination
  • Open label acute phase: introductory dose for 4 days then 3/25, 6/25, 12/25, 6/50, 12/50 or 18/50mg, oral, daily, for 6-8 weeks. Open label stabilization phase: 6/25, 12/25, 6/50, 12/50 or 18/50 mg, oral, daily for 16-20 weeks. Double blind relapse prevention phase: dose determined during stabilization phase at week 17, oral, daily, for 27 weeks.
• Drug: Fluoxetine
  • 25 or 50mg/day fixed dosing for 27 weeks

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Olanzapine and Fluoxetine combination
• Active Comparator: Fluoxetine

Primary Measures

• Time to relapse by any criteria
  • Time Frame: baseline to 47 weeks
    Safety Issue?: No

Secondary Measures

• Percentage of patients who relapse by any criteria
  • Time Frame: baseline to 47 weeks
    Safety Issue?: No
• Rate of relapse based on Montgomery-Åsberg Depression Rating Scale (MADRS) score with concomitant Clinical Global Impressions—Severity of Depression (CGI-Severity) score
  • Time Frame: baseline to 47 weeks
    Safety Issue?: No
• Rate of relapse as measured by Hospitalization for depression or suicidality
  • Time Frame: baseline to 47 weeks
    Safety Issue?: No
• Rate of relapse as measured by Discontinuation due to lack of efficacy/worsening of depression/suicidality
  • Time Frame: baseline to 47 weeks
    Safety Issue?: No
• Time to relapse based on the Montgomery-Åsberg Depression Rating Scale (MADRS) score with concomitant Clinical Global Impressions—Severity of Depression (CGI-Severity) score
  • Time Frame: baseline to 47 weeks
    Safety Issue?: No
• Time to relapse as measured by Hospitalization for depression or suicidality
  • Time Frame: baseline to 47 weeks
    Safety Issue?: No
• Time to relapse as measured by Discontinuation due to lack of efficacy/worsening of depression/suicidality
  • Time Frame: baseline to 47 weeks
    Safety Issue?: No
• Percentage of responders
  • Time Frame: week 6 to week 20
    Safety Issue?: No
• Percentage of patients maintaining response
  • Time Frame: week 20 to 47 weeks
    Safety Issue?: No
• Percentage of patients achieving remission
  • Time Frame: week 6 to week 20
    Safety Issue?: No
• Percentage of patients maintaining remission
  • Time Frame: week 20 to 47 weeks
    Safety Issue?: No
• Mean change from baseline to each visit using MMRM analysis in Montgomery-Asberg Depression Rating Scale (MADRS)
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: No
• Mean change from baseline to each visit and endpoint using LOCF analysis in Montgomery-Asberg Depression Rating Scale (MADRS)
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: No
• Mean change from baseline to each subsequent visit using MMRM in Clinical Global Impressions - Severity of Depression (CGI-Severity)
  • Time Frame: baseline to 47 weeks
    Safety Issue?: No
• Resource Utilization
  • Time Frame: baseline to 47 weeks
    Safety Issue?: No
• Change from baseline to endpoint in the Sheehan Disability Scale (SDS)
  • Time Frame: baseline to 47 weeks
    Safety Issue?: No
• Percent of Participants with Treatment-Emergent Akathisia
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Percent of Participants with Treatment-Emergent Parkinsonism
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Percent of Participants with Treatment-Emergent Dyskinesia
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Mean Change in Fasting Total Cholesterol
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Percent of Participants with Treatment-Emergent High Fasting Total Cholesterol
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Mean Change in Fasting LDL Cholesterol
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Percent of Participants with Treatment-Emergent High Fasting LDL Cholesterol
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Mean Change in Fasting HDL Cholesterol
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Percent of Participants with Treatment-Emergent Low Fasting HDL Cholesterol
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Percent of Participants with Treatment-Emergent Hepatic Events
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Mean Change in Fasting Triglycerides
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Percent of Participants with Treatment-Emergent High Fasting Triglycerides
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Mean Change in Fasting Glucose
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Percent of Participants with Treatment-Emergent High Fasting Glucose
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Mean Change in Weight
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Percent of Participants with Baseline-to-Endpoint Change in Weight of at Least 7%
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Percent of Participants with Suicide-Related Outcomes
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Mean Change in corrected (for rate) cardiac QT interval on electrocardiogram(QTc)
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Percent of Participants with Treatment-Emergent corrected (for rate) cardiac QT interval on electrocardiogram (QTc) >500 ms
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes
• Percent of Participants with a 60 ms increase in corrected (for rate) cardiac QT interval on electrocardiogram (QTc)
  • Time Frame: week 6 to 47 weeks
    Safety Issue?: Yes

Inclusion Criteria:

• Have single or recurrent unipolar (Major Depressive Disorder) MDD, without psychotic features by DSMIV- TR clinical assessment, confirmed by the structured clinician Interview for DSM-IV Axis 1 disorders.
• If female and of childbearing potential, test negative for pregnancy and agree to abstain from sexual activity or use a medically accepted means of contraception during the study. Use of any oral or injectable contraception must be initiated prior to receiving treatment.
• Have 17-item (Hamilton Depression) HAM-D score greater than or equal to 18 at screening and the day treatment is due to be received for the first time.
• Have treatment-resistant depression, as defined by having demonstrated failure to achieve satisfactory antidepressant response to adequate separate treatment courses of at least 2 different antidepressants within the current episode of MDD.

Exclusion Criteria:

• Have a diagnosis of Parkinson's disease or related disorders.
• Have a current or lifetime diagnosis of any of the following according to DSM-IV criteria: Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Psychotic Disorder Not Otherwise Specified, Bipolar Disorder I or II, Delirium of any type, Dementia of any type, Amnestic Disorder, any
• Substance-Induced Disorder, or any Psychotic Disorder due to a General Medical
• Condition.
• Have current diagnosis of post-partum depression, MDD with atypical features, or MDD with a seasonal pattern as defined in the DSM-IV.
• Have paranoid, schizoid, schizotypal, antisocial, and borderline personality disorders (Axis II) as a comorbid or primary diagnosis, based on DSM-IV criteria.
• Have had psychotic symptoms within 1 month prior to Screening or demonstrate psychotic features at screening and on the day treatment is due to be assigned for the first time as determined by the investigator.
• Have DSM-IV substance dependence/abuse or not willing to avoid use of the substance (not including dependence on nicotine or caffeine), as defined by the SCID-I, within the past 30 days.
• Are actively suicidal in the judgment of the investigator.
• Have had one or more seizures without a clear and resolved etiology.
• Have leukopenia or history of leukopenia without a clear and resolved etiology, or known history of agranulocytosis during the patient's lifetime.
• Have ALT/SGPT values greater than or equal to 2 times the upper limit of normal (ULN) of the performing laboratory or AST/SGOT values greater than or equal to 2 times the ULN or total bilirubin values greater than or equal to 1.5 times the ULN at any time during screening.
• Have acute, serious, or unstable medical conditions.
• Have any illness such that death is anticipated within 1 year or intensive care unit hospitalization for the illness is anticipated within 6 months.
• Have elevated prolactin levels at screening.
• Have QTc Bazett's greater than 450 milliseconds (male) or greater than 470 milliseconds (female) at screening and when treatment is due to be received for the first time.
• Have received electroconvulsive therapy (ECT) or vagus nerve stimulation (VNS) treatment within the current episode; have a history of failure to adequate treatment courses of ECT or VNS; or will require ECT or VNS at any time during study participation.
• If receiving psychotherapy, light therapy, or both, are anticipated to require changes in frequency/intensity of treatment regimen or to cease treatment regimen over the duration of the study. Patients who are not receiving any of these therapies upon study entry may not begin any of these therapies during screening, or during any treatment phases of the study.
• Have received previous treatment with clozapine.
• Have used a monoamine oxidase inhibitor (MAOI) within 14 days prior to screening or are expected to need MAOI treatment at any time during this study through 5 weeks after the patient discontinues from the study.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Eli Lilly and Company Industry

Overall Clinical Trial Officials and Contacts

Call 1-877-CTLILLY (1-877-285-4559) Mon-Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) Study Director Eli Lilly and Company  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00958568

Study ID Number: 12115

ClinicalTrials.gov Identifier: NCT00958568

Health Authority: United States: Food and Drug Administration