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Assessment of Safety and Efficacy of Therapy for the Prevention of Weight Gain Associated With Olanzapine

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00401973
Recruitment Status : Completed
First Posted : November 22, 2006
Results First Posted : September 30, 2009
Last Update Posted : October 6, 2009
Sponsor:
Information provided by:
Eli Lilly and Company

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Prevention
Conditions Schizophrenia
Schizoaffective Disorders
Interventions Drug: olanzapine
Drug: amantadine
Drug: metformin
Drug: zonisamide
Behavioral: Wellness education
Enrollment 199
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Hide Arm/Group Description olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Period Title: Overall Study
Started 50 76 73
Completed 39 50 50
Not Completed 11 26 23
Reason Not Completed
Adverse Event             2             8             4
Clinical Relapse             0             1             1
Lack of Efficacy             0             0             3
Lost to Follow-up             2             2             2
Physician Decision             2             0             1
Protocol Violation             1             2             3
Sponsor Decision             0             1             0
Withdrawal by Subject             4             12             9
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin Total
Hide Arm/Group Description olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Total of all reporting groups
Overall Number of Baseline Participants 50 76 73 199
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 50 participants 76 participants 73 participants 199 participants
38.7  (12.89) 38.2  (11.40) 38.7  (12.01) 38.5  (11.95)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 50 participants 76 participants 73 participants 199 participants
Female
19
  38.0%
30
  39.5%
30
  41.1%
79
  39.7%
Male
31
  62.0%
46
  60.5%
43
  58.9%
120
  60.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 50 participants 76 participants 73 participants 199 participants
United States 13 22 21 56
Mexico 7 9 11 27
Puerto Rico 5 8 5 18
Israel 5 8 9 22
Russian Federation 11 15 14 40
Korea, Republic of 9 14 13 36
Race/Ethnicity  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 50 participants 76 participants 73 participants 199 participants
African 2 10 4 16
Caucasian 23 30 34 87
East Asian 10 15 14 39
Hispanic 14 20 18 52
Native American 0 0 1 1
West Asian 1 1 2 4
Type of Diagnosis  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 50 participants 76 participants 73 participants 199 participants
Schizoaffective 8 15 18 41
Schizophrenia 42 61 55 158
Body Mass Index (BMI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Kilograms/square meter (kg/m^2)
Number Analyzed 50 participants 76 participants 73 participants 199 participants
27.0  (4.53) 27.3  (4.67) 27.0  (4.84) 27.1  (4.68)
[1]
Measure Description: Body mass index is an estimate of body fat based on body weight divided by height squared.
Onset Age  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 50 participants 76 participants 73 participants 199 participants
24.35  (8.42) 26.44  (9.98) 24.40  (9.18) 25.15  (9.32)
Previous Number of Episodes  
Mean (Standard Deviation)
Unit of measure:  Number of episodes
Number Analyzed 50 participants 76 participants 73 participants 199 participants
1.53  (1.02) 2.19  (5.90) 2.22  (5.77) 2.04  (5.06)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kilograms
Number Analyzed 50 participants 76 participants 73 participants 199 participants
77.0  (16.33) 79.1  (17.27) 76.2  (16.22) 77.5  (16.62)
1.Primary Outcome
Title Change From Baseline to Endpoint in Weight
Hide Description [Not Specified]
Time Frame Baseline to endpoint (22 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with baseline and at least one postbaseline measurement.
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Hide Arm/Group Description:
olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Overall Number of Participants Analyzed 40 50 51
Least Squares Mean (Standard Error)
Unit of Measure: kilograms
2.76  (0.75) 2.40  (0.65) 0.65  (0.63)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine, Olanzapine + Metformin
Comments To detect a difference between treatment arms of 3.06 kg in mean weight change from baseline to endpoint, 150 patients must be enrolled in stepped intervention arm and 50 in control arm. Assuming a standard deviation of 6.87 kg, there is 80% power to detect a difference between treatment arms on a 1-sided 2-sample t-test at the 5% significance level. Primary analysis was the comparison of mean weight change for 'olanzapine only' versus pooled 'olanzapine & adjunctive treatment' arm at Week 22.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.065
Comments P-value for Olanzapine versus pooled olanzapine+amantadine and olanzapine+metformin.
Method Mixed Models Analysis
Comments Repeated Measures Analysis
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine
Comments Hypothesis=weight gain associated with olanzapine can be prevented or mitigated with an adjunctive pharmacological algorithm.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.113
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated Measures Analysis
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.036
Comments [Not Specified]
Method Mixed Models Analysis
Comments Repeated Measures Analysis
2.Secondary Outcome
Title Mean Change From Baseline to Endpoint in Fasting Triglycerides
Hide Description [Not Specified]
Time Frame Baseline to endpoint (22 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with baseline and at least one postbaseline measurement. Last post-baseline measurement carried forward.
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Hide Arm/Group Description:
olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Overall Number of Participants Analyzed 42 49 56
Mean (Standard Deviation)
Unit of Measure: millimoles per Liter (mmol/L)
Baseline 1.58  (0.81) 1.61  (0.76) 1.68  (1.00)
Change from Baseline 0.33  (1.01) 0.35  (0.88) 0.06  (0.64)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.498
Comments P-value for Change from Baseline for Olanzapine versus pooled olanzapine+amantadine and olanzapine+metformin.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.637
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.125
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
3.Secondary Outcome
Title Mean Change From Baseline to Endpoint in Fasting Total Cholesterol
Hide Description [Not Specified]
Time Frame Baseline to endpoint (22 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with baseline and at least one postbaseline measurement. Last post-baseline measurement carried forward.
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Hide Arm/Group Description:
olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Overall Number of Participants Analyzed 42 49 56
Mean (Standard Deviation)
Unit of Measure: millimole per Liter (mmol/L)
Baseline 5.01  (1.00) 5.03  (1.09) 4.91  (1.21)
Change from Baseline 0.36  (0.84) 0.01  (1.06) -0.08  (0.92)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.173
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.016
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.029
Comments P-value for Change from Baseline for Olanzapine versus pooled olanzapine+amantadine and olanzapine+metformin.
Method ANCOVA
Comments [Not Specified]
4.Secondary Outcome
Title Mean Change From Baseline to Endpoint in Fasting High Density Lipoprotein (HDL) Cholesterol
Hide Description [Not Specified]
Time Frame Baseline to endpoint (22 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Number of randomized participants with a baseline and at least one post-baseline measurement. Last post-baseline measurement carried forward.
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Hide Arm/Group Description:
olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Overall Number of Participants Analyzed 46 63 64
Mean (Standard Deviation)
Unit of Measure: millimole per liter (mmol/L)
Baseline 1.25  (0.29) 1.26  (0.36) 1.22  (0.35)
Change from Baseline -0.00  (0.23) -0.11  (0.25) -0.08  (0.24)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.017
Comments P-value for Change from Baseline for Olanzapine versus pooled olanzapine+amantadine and olanzapine+metformin.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.015
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.071
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
5.Secondary Outcome
Title Mean Change From Baseline to Endpoint in Fasting Low Density Lipoprotein (LDL) Cholesterol
Hide Description [Not Specified]
Time Frame Baseline to endpoint (22 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with baseline and at least one postbaseline measurement. Last post-baseline measurement carried forward.
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Hide Arm/Group Description:
olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Overall Number of Participants Analyzed 40 47 55
Mean (Standard Deviation)
Unit of Measure: millimole per Liter (mmol/L)
Baseline 3.02  (0.88) 3.06  (1.03) 2.91  (0.93)
Change from Baseline 0.16  (0.60) -0.04  (0.95) -0.02  (0.84)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.152
Comments P-value for Change from Baseline for Olanzapine versus pooled olanzapine+amantadine and olanzapine+metformin.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.350
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.123
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
6.Secondary Outcome
Title Mean Change From Baseline to Endpoint in Fasting Glucose
Hide Description [Not Specified]
Time Frame Baseline to endpoint (22 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with baseline and at least one postbaseline measurement. Last post-baseline measurement carried forward.
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Hide Arm/Group Description:
olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Overall Number of Participants Analyzed 44 59 64
Mean (Standard Deviation)
Unit of Measure: millimole per Liter (mmol/L)
Baseline 5.32  (0.46) 5.25  (0.78) 5.28  (0.63)
Change from Baseline 0.26  (0.99) 0.10  (0.48) 0.01  (0.58)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.499
Comments P-value for Change from Baseline for Olanzapine versus pooled olanzapine+amantadine and olanzapine+metformin.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.833
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.339
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
7.Secondary Outcome
Title Mean Change From Baseline to Endpoint in Hemoglobin A1c
Hide Description [Not Specified]
Time Frame Baseline to endpoint (22 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with baseline and at least one postbaseline measurement. Last post-baseline measurement carried forward.
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Hide Arm/Group Description:
olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Overall Number of Participants Analyzed 44 63 63
Mean (Standard Deviation)
Unit of Measure: percent hemoglobin A1c
Baseline 5.51  (0.46) 5.48  (0.39) 5.53  (0.37)
Change from Baseline 0.09  (0.45) 0.10  (0.37) -0.03  (0.25)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.278
Comments P-value for Change from Baseline for Olanzapine versus pooled olanzapine+amantadine and olanzapine+metformin.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.976
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.049
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline to Endpoint in Brief Psychiatric Rating Scale (BPRS) Total Score
Hide Description The BPRS is an 18-item clinician-administered scale used to assess the degree of severity of a subject's general psychopathological symptoms. Each item is rated on a scale from 1 (symptom not present) to 7 (symptom extremely severe). The BPRS total score ranges from 18 to 126.
Time Frame Baseline to endpoint (22 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants with a baseline and at least one post baseline measurement. Last post-baseline measurement carried forward.
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Hide Arm/Group Description:
olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Overall Number of Participants Analyzed 45 67 72
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline 48.24  (15.98) 45.90  (12.44) 47.00  (14.18)
Change from Baseline -13.89  (18.61) -9.90  (11.24) -9.72  (14.15)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.122
Comments P-value for Change from Baseline for Olanzapine versus pooled olanzapine+amantadine and olanzapine+metformin.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.225
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.124
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
9.Secondary Outcome
Title Change From Baseline to Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
Hide Description The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
Time Frame Baseline to endpoint (22 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants with a baseline and at least one post baseline measurement. Last post-baseline measurement carried forward.
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Hide Arm/Group Description:
olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Overall Number of Participants Analyzed 46 67 72
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline 12.76  (8.08) 14.22  (11.14) 15.40  (9.21)
Change from Baseline -6.39  (8.37) -4.12  (7.20) -4.36  (7.47)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.020
Comments P-value for Change from Baseline for Olanzapine versus pooled olanzapine+amantadine and olanzapine+metformin.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.037
Comments P-value for Change from Baseline
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.038
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
10.Secondary Outcome
Title Change From Baseline to Endpoint in Clinical Global Impression - Severity Scale (CGI-S)
Hide Description 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 patients).
Time Frame Baseline to endpoint (22 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants with a baseline and at least one post baseline measurement. Last post-baseline measurement carried forward.
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Hide Arm/Group Description:
olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Overall Number of Participants Analyzed 47 72 73
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline 4.06  (1.24) 4.03  (1.07) 4.00  (1.13)
Change from Baseline -0.98  (1.13) -0.72  (1.14) -0.79  (1.03)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.474
Comments P-value for Change from Baseline for Olanzapine versus pooled olanzapine+amantadine and olanzapine+metformin.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Amantadine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.404
Comments P-value for Change from Baseline.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Olanzapine, Olanzapine + Metformin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.652
Comments P-value for Change from Baseline
Method ANCOVA
Comments [Not Specified]
11.Secondary Outcome
Title Correlations Between Weight Changes and Changes in Eating Inventory (EI) and Food Craving Inventory (FCI) at 2 Weeks and 22 Weeks
Hide Description To understand the drivers of weight gain as indicated by the correlation between weight changes and changes in the Eating Inventory (EI) and Food Craving Inventory (FCI). The EI is a 51-item inventory that measures dietary restraint, disinhibition, and perceived hunger. The FCI is a 28-item instrument measuring the frequency over the past month of general cravings and cravings for specific types of foods, namely: high fats, sweets, carbohydrates/starches, and fast-food fats. Correlations were computed on the combined treatment groups.
Time Frame Baseline to endpoint (22 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
N=Pairs of Observations for the combined treatment groups.
Arm/Group Title 2 Weeks 22 Weeks
Hide Arm/Group Description:

Combined treatment groups:

olanzapine plus behavioral information [olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks].

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information [olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms)].

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information [olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms)].

Combined treatment groups:

olanzapine plus behavioral information [olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks].

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information [olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms)].

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information [olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms)].

Overall Number of Participants Analyzed 66 41
Measure Type: Number
Unit of Measure: correlation
EI: Disinhibition -0.034 0.285
EI: Cognitive Restraint -0.273 -0.038
EI: Hunger -0.150 0.148
FCI: Carbohydrates/Starches (N=186, N=141) 0.013 -0.064
FCI: Fast Food Fats (N=188, N=140) -0.019 0.047
FCI: High Fats (N=186, N=138) 0.051 0.043
FCI: Sweets (N=187, N=140) 0.022 -0.008
FCI: Total Score (N=184, N=137) 0.039 -0.000
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Hide Arm/Group Description olanzapine plus behavioral information. olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks.

Olanzapine and Pharmacological Algorithm 1a - amantadine first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. amantadine: 100 mg, oral, twice a day. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

Olanzapine and Pharmacological Algorithm 1b - metformin first plus behavioral information.

olanzapine: 5-20 milligrams (mg), oral, daily for 22 weeks. metformin: 500 mg, oral, twice a day for 2 weeks, titrated to 500 mg three times a day thereafter. zonisamide: 100-400 mg, oral, daily (only if patient gained greater than 3 kilograms).

All-Cause Mortality
Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5      4      4    
General disorders       
Chest pain  1  0/50 (0.00%)  0 0/76 (0.00%)  0 1/73 (1.37%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Squamous cell carcinoma  1  0/50 (0.00%)  0 1/76 (1.32%)  1 0/73 (0.00%)  0
Nervous system disorders       
Akathisia  1  0/50 (0.00%)  0 1/76 (1.32%)  1 0/73 (0.00%)  0
Psychiatric disorders       
Hallucination  1  0/50 (0.00%)  0 1/76 (1.32%)  1 2/73 (2.74%)  2
Panic attack  1  0/50 (0.00%)  0 1/76 (1.32%)  1 0/73 (0.00%)  0
Psychotic disorder  1  1/50 (2.00%)  1 0/76 (0.00%)  0 0/73 (0.00%)  0
Schizophrenia  1  3/50 (6.00%)  3 0/76 (0.00%)  0 0/73 (0.00%)  0
Suicidal ideation  1  1/50 (2.00%)  1 0/76 (0.00%)  0 0/73 (0.00%)  0
Suicide attempt  1  0/50 (0.00%)  0 0/76 (0.00%)  0 1/73 (1.37%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA11.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 4%
Olanzapine Olanzapine + Amantadine Olanzapine + Metformin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   26      38      46    
Gastrointestinal disorders       
Constipation  1  0/50 (0.00%)  0 3/76 (3.95%)  3 3/73 (4.11%)  3
Diarrhoea  1  0/50 (0.00%)  0 3/76 (3.95%)  3 10/73 (13.70%)  11
Dry mouth  1  2/50 (4.00%)  2 4/76 (5.26%)  4 0/73 (0.00%)  0
Nausea  1  2/50 (4.00%)  2 3/76 (3.95%)  3 5/73 (6.85%)  6
Vomiting  1  0/50 (0.00%)  0 1/76 (1.32%)  1 5/73 (6.85%)  5
General disorders       
Asthenia  1  1/50 (2.00%)  1 0/76 (0.00%)  0 3/73 (4.11%)  3
Fatigue  1  1/50 (2.00%)  1 2/76 (2.63%)  2 3/73 (4.11%)  3
Infections and infestations       
Nasopharyngitis  1  0/50 (0.00%)  0 4/76 (5.26%)  4 0/73 (0.00%)  0
Urinary tract infection  1  2/50 (4.00%)  2 0/76 (0.00%)  0 0/73 (0.00%)  0
Injury, poisoning and procedural complications       
Overdose  1  2/50 (4.00%)  2 0/76 (0.00%)  0 0/73 (0.00%)  0
Investigations       
Weight increased  1  2/50 (4.00%)  3 4/76 (5.26%)  4 4/73 (5.48%)  4
Metabolism and nutrition disorders       
Increased appetite  1  3/50 (6.00%)  4 1/76 (1.32%)  1 3/73 (4.11%)  3
Nervous system disorders       
Akathisia  1  2/50 (4.00%)  2 3/76 (3.95%)  3 2/73 (2.74%)  2
Dizziness  1  2/50 (4.00%)  2 1/76 (1.32%)  1 2/73 (2.74%)  2
Headache  1  2/50 (4.00%)  2 2/76 (2.63%)  2 4/73 (5.48%)  4
Sedation  1  0/50 (0.00%)  0 4/76 (5.26%)  4 2/73 (2.74%)  2
Somnolence  1  4/50 (8.00%)  4 5/76 (6.58%)  5 8/73 (10.96%)  10
Psychiatric disorders       
Anxiety  1  2/50 (4.00%)  2 3/76 (3.95%)  3 2/73 (2.74%)  2
Insomnia  1  5/50 (10.00%)  5 4/76 (5.26%)  5 1/73 (1.37%)  3
Sleep disorder  1  2/50 (4.00%)  2 0/76 (0.00%)  0 1/73 (1.37%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA11.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Chief Medical Officer
Organization: Eli Lilly and Company
Phone: 800-545-5979
Responsible Party: Chief Medical Officer, Eli Lilly
ClinicalTrials.gov Identifier: NCT00401973     History of Changes
Other Study ID Numbers: 10768
F1D-US-HGMM
First Submitted: November 17, 2006
First Posted: November 22, 2006
Results First Submitted: August 27, 2009
Results First Posted: September 30, 2009
Last Update Posted: October 6, 2009