Bipolar I Disorder, Schizophrenia
Conditions
Keywords
safety, schizophrenia, bipolar I (manic or mixed), adolescents, weight management
Brief summary
Open-label safety study of oral olanzapine treatment in adolescents, aged 13 to 17 years, with bipolar I disorder (manic or mixed episodes) or schizophrenia.
Interventions
DRUGOlanzapine
2.5 milligrams (mg) to 20 mg given orally, daily for 52 weeks
BEHAVIORALStandard behavioral weight intervention
One time counseling and basic counseling information on healthy eating and exercise habits at randomization visit only.
BEHAVIORALIntense behavioral weight intervention
Counseling provided at randomization and at all subsequent study visits by appropriately trained individual regarding healthy lifestyle habits. Participants also provided with simple tools to help enable healthy eating and exercise habits.
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
13 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Participants must have a diagnosis of bipolar I disorder and display an acute manic or mixed episode (with or without psychotic features) or a diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision (DSM-IV-TR)and confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime (K-SADS-PL). * Participants with a diagnosis of schizophrenia must obtain a Brief Psychiatric Rating Scale for Children (BPRS-C) total score \>30, with a minimum score of 3 on at least one of the following items at both screening and randomization - hallucinations, delusions, peculiar fantasies. * Participants with a diagnosis of bipolar I disorder must have a Young Mania Rating Scale (YMRS) total score greater than or equal to 15 at both screening and randomization. * Has given assent (when applicable); and has a parent or authorized legal representative who has given informed consent, is reliable, has a level of understanding sufficient to permit participant to perform all tests and examinations required by the protocol, and understands the nature of the study.
Exclusion criteria
* History of mental retardation, current comorbid autism, or current comorbid Pervasive Developmental Disorder. * Have DSM-IV-TR substance (except nicotine and caffeine) dependence within the past 30 days prior to randomization. * Been judged clinically to be at any suicidal risk. * History of allergic reaction or hypersensitivity to olanzapine. * Receiving current pharmaceutical treatment for weight management or are participating in a structured behavioral diet and/or exercise weight loss program. * Other antipsychotics, mood stabilizers, or anticonvulsants (for mood stabilization) used for the primary study conditions (bipolar I disorder or schizophrenia) * 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 12 months (365 days). * Have had one or more seizures without a clear and resolved etiology. * Baseline alanine aminotransferase (ALT) values greater than or equal to 2 times the upper limit of normal (ULN) of the performing laboratory or aspartate aminotransferase (AST) 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 screening. * Have leukopenia or history of leukopenia without a clear and resolved etiology or known history of agranulocytosis (absolute neutrophil count \<500 cubic millimeter \[mm\^3\], \<0.5 GI/L, or \<0.5 10E\^3/microliters \[μL\]) during the participant's lifetime. * Prolactin level of \>200 nanograms per milliliter (ng/mL) \[\>200 micrograms per liter (ug/L), or \>4228 milli-International unit per liter (mIU/L)\] at screening. * Have QTc (Bazett's) \>450 milliseconds (males) or \>460 milliseconds (females) at screening. * Previously been randomized in this study and/or participated in a clinical trial of another investigational drug, including olanzapine, within 1 month (30 days) prior to screening. * Currently prescribed olanzapine for greater than or equal to 5 days within 1 month (30 days) prior to screening. * Are investigator site personnel directly affiliated with this study and/or their immediate families OR are employed by or representatives of Lilly. * Pregnant or nursing. * Have received treatment within the last 30 days with an investigational new drug that has not received regulatory approval for any indication at the time of study entry. * Treatment with clozapine within 14 days prior to randomization. * Participants who have used olanzapine (that is, oral olanzapine, intramuscular \[IM\] olanzapine, or olanzapine orally disintegrating tablets) and have had treatment withdrawn due to clinically significant and/or intolerable adverse effects, or who have exhibited a lack of efficacy/response to treatment to olanzapine including treatment resistance.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Mean Change From Baseline to 52 Weeks in Body Mass Index (BMI) for All Participants | Baseline, 52 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Event for 7%, 15%, and 25% Weight Gain for All Participants | Baseline up to 52 weeks | Kaplan-Meier methodology used to estimate time to event. Participants who never reached the target weight gain contributed to the set of patients at risk up to the point at which they discontinued from the study and were then censored (i.e., removed from the risk set). |
| Mean Change From Baseline to 52 Weeks in Adolescent Structured Young Mania Rating Scale (YMRS) for Participants With Bipolar I Disorder | Baseline, 52 weeks | The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 (symptom not present) to 60 (symptom extremely severe). |
| Mean Clinical Global Impression of Improvement (CGI-I) at 52 Weeks for All Participants | 52 weeks | The Clinical Global Impression of Improvement (CGI-I) is used by the clinician to record the improvement of illness at the time of assessment. The score ranges from 1 (very much improved) to 7 (very much worse). |
| Mean Change From Baseline to Endpoint in Body Mass Index (BMI) for Participants With Duration of Treatment of at Least 6 Months | Baseline, 52 weeks | — |
| Mean Change From Baseline to 52 Weeks in Clinical Global Impression - Severity (CGI-S) for All Participants | Baseline, 52 weeks | The CGI-S is used by the clinician to record the severity of illness at the time of assessment. The score ranges from 1 = normal, not at all ill to 7 = among the most extremely ill. |
| Mean Change From Baseline to 52 Weeks in Anchored Version of the Brief Psychiatric Rating Scale for Children (BPRS-C) for Participants With Schizophrenia | Baseline, 52 weeks | The BPRS-C characterizes psychopathology. A total of 21 items are rated on a scale from 0 (not present) to 6 (extremely severe) with a total score ranging from 0 to 126. A decrease in score indicates a reduction in psychopathology. |
| Mean Change From Baseline to 52 Weeks in Waist Circumference for All Participants | Baseline, 52 weeks | — |
Countries
Poland, Puerto Rico, Russia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Olanzapine/Standard Behavioral Weight Intervention Olanzapine: 2.5 mg to 20 mg given orally, daily for 52 weeks.
Standard behavioral weight intervention: One time counseling and basic counseling information on healthy eating and exercise habits at randomization visit only | 102 |
| Olanzapine/Intense Behavioral Weight Intervention Olanzapine: 2.5 mg to 20 mg given orally, daily for 52 weeks.
Intense behavioral weight intervention: Counseling provided at randomization and at all subsequent study visits by appropriately trained individual regarding healthy lifestyle habits. Participants also provided with simple tools to help enable healthy eating and exercise habits | 101 |
| Total | 203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 19 | 15 |
| Overall Study | Clinical Relapse | 0 | 1 |
| Overall Study | Entry Criteria Not Met | 2 | 1 |
| Overall Study | Lack of Efficacy | 10 | 4 |
| Overall Study | Lost to Follow-up | 5 | 11 |
| Overall Study | Parent/Caregiver Decision | 5 | 5 |
| Overall Study | Physician Decision | 2 | 5 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Treatment Non-compliance | 3 | 6 |
| Overall Study | Withdrawal by Subject | 11 | 14 |
Baseline characteristics
| Characteristic | Olanzapine/Standard Behavioral Weight Intervention | Olanzapine/Intense Behavioral Weight Intervention | Total |
|---|---|---|---|
| Age, Continuous | 15.86 years STANDARD_DEVIATION 1.49 | 15.66 years STANDARD_DEVIATION 1.52 | 15.76 years STANDARD_DEVIATION 1.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 9 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 87 Participants | 92 Participants | 179 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 14 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 84 Participants | 80 Participants | 164 Participants |
| Region of Enrollment Germany | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Poland | 6 participants | 12 participants | 18 participants |
| Region of Enrollment Puerto Rico | 13 participants | 7 participants | 20 participants |
| Region of Enrollment Russian Federation | 28 participants | 27 participants | 55 participants |
| Region of Enrollment United States | 53 participants | 54 participants | 107 participants |
| Sex: Female, Male Female | 50 Participants | 47 Participants | 97 Participants |
| Sex: Female, Male Male | 52 Participants | 54 Participants | 106 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 81 / 102 | 81 / 101 |
| serious Total, serious adverse events | 13 / 102 | 20 / 101 |
Outcome results
Primary
Mean Change From Baseline to 52 Weeks in Body Mass Index (BMI) for All Participants
Time frame: Baseline, 52 weeks
Population: All randomized participants who received at least one dose of study drug. Mixed model repeated measures (MMRM) methodology used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Standard Behavioral Weight Intervention | Mean Change From Baseline to 52 Weeks in Body Mass Index (BMI) for All Participants | 3.64 kilograms per meter squared (kg/m^2) | Standard Error 0.39 |
| Olanzapine/Intense Behavioral Weight Intervention | Mean Change From Baseline to 52 Weeks in Body Mass Index (BMI) for All Participants | 2.83 kilograms per meter squared (kg/m^2) | Standard Error 0.4 |
p-value: 0.15Mixed Models Analysis
Secondary
Mean Change From Baseline to 52 Weeks in Adolescent Structured Young Mania Rating Scale (YMRS) for Participants With Bipolar I Disorder
The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 (symptom not present) to 60 (symptom extremely severe).
Time frame: Baseline, 52 weeks
Population: All randomized participants with bipolar I disorder, who received at least one dose of study drug. Mixed model repeated measures (MMRM) methodology.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Standard Behavioral Weight Intervention | Mean Change From Baseline to 52 Weeks in Adolescent Structured Young Mania Rating Scale (YMRS) for Participants With Bipolar I Disorder | -17.66 units on a scale | Standard Error 1.75 |
| Olanzapine/Intense Behavioral Weight Intervention | Mean Change From Baseline to 52 Weeks in Adolescent Structured Young Mania Rating Scale (YMRS) for Participants With Bipolar I Disorder | -12.05 units on a scale | Standard Error 1.92 |
p-value: 0.008Mixed Models Analysis
Secondary
Mean Change From Baseline to 52 Weeks in Anchored Version of the Brief Psychiatric Rating Scale for Children (BPRS-C) for Participants With Schizophrenia
The BPRS-C characterizes psychopathology. A total of 21 items are rated on a scale from 0 (not present) to 6 (extremely severe) with a total score ranging from 0 to 126. A decrease in score indicates a reduction in psychopathology.
Time frame: Baseline, 52 weeks
Population: All randomized participants with schizophrenia who received at least one dose of study drug. Mixed model repeated measures (MMRM) methodology.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Standard Behavioral Weight Intervention | Mean Change From Baseline to 52 Weeks in Anchored Version of the Brief Psychiatric Rating Scale for Children (BPRS-C) for Participants With Schizophrenia | -28.00 units on a scale | Standard Error 2.83 |
| Olanzapine/Intense Behavioral Weight Intervention | Mean Change From Baseline to 52 Weeks in Anchored Version of the Brief Psychiatric Rating Scale for Children (BPRS-C) for Participants With Schizophrenia | -30.96 units on a scale | Standard Error 2.67 |
p-value: 0.436Mixed Models Analysis
Secondary
Mean Change From Baseline to 52 Weeks in Clinical Global Impression - Severity (CGI-S) for All Participants
The CGI-S is used by the clinician to record the severity of illness at the time of assessment. The score ranges from 1 = normal, not at all ill to 7 = among the most extremely ill.
Time frame: Baseline, 52 weeks
Population: All randomized participants who received at least one dose of study drug. Mixed model repeated measures (MMRM) methodology.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Standard Behavioral Weight Intervention | Mean Change From Baseline to 52 Weeks in Clinical Global Impression - Severity (CGI-S) for All Participants | -2.06 units on a scale | Standard Error 0.14 |
| Olanzapine/Intense Behavioral Weight Intervention | Mean Change From Baseline to 52 Weeks in Clinical Global Impression - Severity (CGI-S) for All Participants | -1.74 units on a scale | Standard Error 0.14 |
p-value: 0.103Mixed Models Analysis
Secondary
Mean Change From Baseline to 52 Weeks in Waist Circumference for All Participants
Time frame: Baseline, 52 weeks
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Standard Behavioral Weight Intervention | Mean Change From Baseline to 52 Weeks in Waist Circumference for All Participants | 7.22 centimeters (cm) | Standard Error 1.06 |
| Olanzapine/Intense Behavioral Weight Intervention | Mean Change From Baseline to 52 Weeks in Waist Circumference for All Participants | 7.31 centimeters (cm) | Standard Error 1.11 |
p-value: 0.954Mixed Models Analysis
Secondary
Mean Change From Baseline to Endpoint in Body Mass Index (BMI) for Participants With Duration of Treatment of at Least 6 Months
Time frame: Baseline, 52 weeks
Population: All randomized participants who received at least one dose of study drug and who had at least 6 months of data. Last observation carried forward (LOCF) methodology.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Standard Behavioral Weight Intervention | Mean Change From Baseline to Endpoint in Body Mass Index (BMI) for Participants With Duration of Treatment of at Least 6 Months | 3.36 kg/m^2 | Standard Error 0.41 |
| Olanzapine/Intense Behavioral Weight Intervention | Mean Change From Baseline to Endpoint in Body Mass Index (BMI) for Participants With Duration of Treatment of at Least 6 Months | 2.99 kg/m^2 | Standard Error 0.4 |
p-value: 0.52ANCOVA
Secondary
Mean Clinical Global Impression of Improvement (CGI-I) at 52 Weeks for All Participants
The Clinical Global Impression of Improvement (CGI-I) is used by the clinician to record the improvement of illness at the time of assessment. The score ranges from 1 (very much improved) to 7 (very much worse).
Time frame: 52 weeks
Population: All randomized participants who received at least one dose of study drug. Mixed model repeated measures (MMRM) methodology.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine/Standard Behavioral Weight Intervention | Mean Clinical Global Impression of Improvement (CGI-I) at 52 Weeks for All Participants | 2.04 units on a scale | Standard Error 0.15 |
| Olanzapine/Intense Behavioral Weight Intervention | Mean Clinical Global Impression of Improvement (CGI-I) at 52 Weeks for All Participants | 2.29 units on a scale | Standard Error 0.16 |
p-value: 0.266Mixed Models Analysis
Secondary
Time to Event for 7%, 15%, and 25% Weight Gain for All Participants
Kaplan-Meier methodology used to estimate time to event. Participants who never reached the target weight gain contributed to the set of patients at risk up to the point at which they discontinued from the study and were then censored (i.e., removed from the risk set).
Time frame: Baseline up to 52 weeks
Population: 65 participants (32%; 34% in Standard Group \[SG\], 30% in Intense Group \[IG\]) did not meet 7% weight gain criterion \[WGC\] by the time they discontinued.~122 participants (60%; 58% in SG, 62% in IG) did not meet 15% WGC by the time they discontinued.~161 participants (79%; 76% in SG, 82% in IG) did not meet 25% WGC by the time they discontinued.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Olanzapine/Standard Behavioral Weight Intervention | Time to Event for 7%, 15%, and 25% Weight Gain for All Participants | Time to First 7% Weight Gain | 57 days |
| Olanzapine/Standard Behavioral Weight Intervention | Time to Event for 7%, 15%, and 25% Weight Gain for All Participants | Time to First 15% Weight Gain | 197 days |
| Olanzapine/Standard Behavioral Weight Intervention | Time to Event for 7%, 15%, and 25% Weight Gain for All Participants | Time to First 25% Weight Gain | NA days |
| Olanzapine/Intense Behavioral Weight Intervention | Time to Event for 7%, 15%, and 25% Weight Gain for All Participants | Time to First 7% Weight Gain | 57 days |
| Olanzapine/Intense Behavioral Weight Intervention | Time to Event for 7%, 15%, and 25% Weight Gain for All Participants | Time to First 15% Weight Gain | 198 days |
| Olanzapine/Intense Behavioral Weight Intervention | Time to Event for 7%, 15%, and 25% Weight Gain for All Participants | Time to First 25% Weight Gain | NA days |