A Study of Olanzapine and Fluoxetine for Treatment-resistant Depression

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of olanzapine and fluoxetine compared to placebo and fluoxetine as treatment for treatment-resistant depression (TRD) in Chinese participants.

Official Title
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A Study to Assess the Short-Term Efficacy and Safety of Olanzapine and Fluoxetine Compared to Placebo and Fluoxetine for Nonpsychotic Treatment-Resistant Depression

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Drug: Olanzapine
* Drug: Fluoxetine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have single or recurrent unipolar major depressive disorder (MDD) without psychotic features by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) clinical assessment Have a total score ≥22 on the 17-item Hamilton Depression Rating Scale (HAM-D17) at screening and randomization Have treatment-resistant depression (TRD), defined as having failed to achieve a satisfactory antidepressant response, in the opinion of the investigator, to separate treatment courses of at least 2 different antidepressants, other than fluoxetine, of adequate dosage and duration (≥6 weeks) within the current major depressive episode Exclusion Criteria: Have a diagnosis of Parkinson's disease or a related disorder Have a current or lifetime diagnosis of any of the following conditions, according to DSM-IV-TR 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 a current diagnosis of post-partum depression or MDD with a seasonal pattern as defined in the DSM-IV-TR Have paranoid, schizoid, schizotypal, antisocial, or borderline personality disorder (Axis II) as a comorbid or primary diagnosis, based on DSM-IV-TR criteria Have DSM-IV-TR substance dependence/abuse or are not willing to avoid use of the substance (not including dependence on nicotine or caffeine) within 30 days of screening Are actively suicidal in the judgment of the investigator Have uncorrected narrow-angle glaucoma Have had one or more seizures without a clear and resolved etiology Have leukopenia Have any acute, serious, or unstable medical conditions Have an increased serum prolactin concentration at screening Have a rate-corrected cardiac QT interval, calculated using Bazett's formula (QTc Bazett's [Rate-corrected cardiac QT interval on electrocardiogram calculated using Bazett's formula(QTcB)]), on Electrocardiogram (ECG) >450 milliseconds (male) or >470 milliseconds (female) at screening Have a history of allergic reaction to olanzapine, fluoxetine, or olanzapine in combination with fluoxetine Have had treatment with olanzapine, fluoxetine, or olanzapine in combination with fluoxetine withdrawn due to clinically significant and/or intolerable adverse effects within 6 months of screening Have received treatment with remoxipride within 6 months of randomization Have received treatment with depot antipsychotics within one dosing interval before randomization Have received electroconvulsive therapy (ECT) or vagus nerve stimulation (VNS) treatment within the current MDD episode, or has a history of failure to respond to adequate treatment courses of ECT or VNS, or is expected to require ECT or VNS at any time during the study Have received previous treatment with clozapine Have received treatment with a monoamine oxidase inhibitor (MAOI) within 14 days of screening, or are expected to need MAOI treatment at any time during the study or up until 5 weeks after study discontinuation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olanzapine + Fluoxetine<br>Olanzapine starting dose is 5 milligram (mg) (1 tablet). May titrate up to 10 mg (2 tablets), or 15 mg (3 tablets) administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks. | Drug: Olanzapine<br>* Administered Orally<br>* Other names: Zyprexa;Drug: Fluoxetine<br>* Administered Orally<br>* Other names: Prozac;|
| Placebo Comparator: Placebo + Fluoxetine<br>Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks. | Drug: Fluoxetine<br>* Administered Orally<br>* Other names: Prozac;Drug: Placebo<br>* Administered Orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to 8 Week Endpoint in Montgomery-Äsberg Depression Rating Scale (MADRS) | The MADRS total score is the sum of the 10 items; therefore the possible MADRS total score ranges from 0 to 60. A higher MADRS total score indicates a greater severity of depressive symptoms. Least square means (LSM) change from baseline, standard error was derived using mixed model repeated measures (MMRM) methodology with factors for treatment, Pooled Investigator, Visit, (Baseline + Treatment)*Visit. | Baseline, 8 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to 8 Week Endpoint in Clinical Global Impressions-Severity of Depression (CGI-S) Scale | CGI-S scale measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). The LS mean (LSM) change from baseline, standard error was derived using MMRM methodology with factors for treatment , Pooled Investigator , Visit , (Baseline + Treatment)*Visit. | Baseline, 8 Weeks | 
| Mean Change From Baseline to 8 Week Endpoint in the Simpson-Angus Scale (SAS) | SAS scale consists of 10 items including 7 items that address bradykinesia-rigidity and additional single items for tremor, glabellar tap,and salivation. Each item represents a specific physical condition and is rated on a 5-point category rating scale ranging from 0 (complete absence of the condition) to 4 (the condition is present to an extreme degree).The total score is obtained by adding the scores for the 10 individual items making the maximum possible score is 40. Higher scores are indicative of more severe Parkinsonian-type symptoms. | Baseline, 8 Weeks | 
| Mean Change From Baseline to 8 Week Endpoint in the Short-Form 36 Health Survey (SF-36) | SF-36, version 2 is a generic participant-rated questionnaire and consists of 36 questions covering the following 8 health domains (subscales): general health, role limitations because of physical problems, role limitations due to emotional problems, physical functioning, bodily pain, mental health, social functioning, and vitality. Each subscale is scored by summing the individual items and transforming the scores into a 0 to 100 scale, with higher scores indicating better health status or functioning. Two summary scores, the physical component summary (PCS) and the mental component summary (MCS) were constructed based on the eight SF-36 subscales. Both PCS and MCS range from 0-100 with higher scores indicating better health or functioning. | Baseline, 8 Weeks | 
| Mean Change From Baseline to 8 Week Endpoint in the Sheehan Disability Scale (SDS) | SDS consists of 3 items (work/school, social life/leisure activities, and family life/home responsibilities). Total scores range from 0 to 30 with higher values indicating greater disruption. Individual Item scores range from 0 to 10 with higher values indicating greater disruption. | Baseline, 8 Weeks | 
| Percentage of Participants Who Achieve a Response Based on a ≥50% Reduction From Baseline in MADRS Total Score | The MADRS total score is the sum of the 10 items; therefore the possible MADRS total score ranges from 0 to 60. A higher MADRS total score indicates a greater severity of depressive symptoms. | Baseline,8 Weeks | 
| Percentage of Participants Who Achieve Remission Based on MADRS Total Score ≤10 at 8 Weeks | The MADRS consists of 10 items with each item rated on a scale ranging from 0 to 6. Fixed descriptors appear along the scale for each item at points 0, 2, 4, and 6, to standardize the gradation of response along the scale. The MADRS total score is the sum of the 10 items; therefore the possible MADRS total score ranges from 0 to 60. A higher MADRS total score indicates a greater severity of depressive symptoms. | Baseline, 8 Weeks | 
| Mean Change From Baseline to 8 Week Endpoint in the Barnes Akathisia Scale (BAS) | BAS is used to rate observable, restless movements of drug induced akathisia and the subjective awareness of restlessness and any distress associated with the akathisia. The BAS consists of the following 3 items: an objective assessment of akathisia symptoms; a subjective assessment of the patient's awareness of inner restlessness; and a global clinical assessment of akathisia. The first two items are rated on a 4-point scale ranging from 0 (no abnormal movements or the absence of inner restlessness) to 3 (severe akathisia or the awareness of intense compulsion to move most of the time). The last item, the global clinical assessment of akathisia, is rated on a 5-point scale, ranging from 0 (no evidence of akathisia) to 5 (severe akathisia). Total BAS score ranges from 0 to 14 with a higher score representing worse results. | Baseline, 8 Weeks | 
| Mean Change From Baseline to 8 Week Endpoint in the Abnormal Involuntary Movement Scale (AIMS) | AIMS is a 12-item scale. Items 1 to 8 are rated on a 5-point scale ranging from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Item 9 assesses the participant's incapacitation due to abnormal movements, and item 10 assesses the participant's awareness of the abnormal movements and associated distress. Items 9 and 10 are rated on 5-point scales ranging from 0 (none or no awareness) to 4 (severe or aware, severe distress). Items 11 and 12 are yes/no questions regarding the dental status of the participant. The total score is the sum of the scores for the 12 items and the possible total score ranges from 0 to 42. A higher total score is indicative of more severe dyskinetic movements. | Baseline, 8 Weeks |