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| ID | Type | Description | Link |
|---|---|---|---|
| 97-M-0126 |
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The purpose of this study is to compare the effectiveness and side effects of the drugs clozapine and olanzapine in children and adolescents with schizophrenia and psychoses.
Childhood psychosis is a serious disorder that may have devastating consequences. Effective treatments for the condition are under continual investigation. This study will examine the causes of and offer treatment for childhood psychosis.
Participants in this study will undergo psychological tests, blood and urine tests, electroencephalogram (EEG), electrocardiogram (EKG), and magnetic resonance imaging (MRI) scans of the brain for the first 1 to 2 weeks of the study while taking their regular medications. Participants will then be tapered off their medications over 1 to 3 weeks and will continue to stay off medications for an additional 2 days to 3 weeks. During this time, participants will undergo psychiatric, neurological, and cardiac examinations as well as blood tests. After this period without medications, participants will be randomly assigned to receive either clozapine or olanzapine for 8 weeks. An EEG will be performed prior to treatment and after 6 weeks of study medication. Participants who respond well to the study drugs may continue to receive them through their own physician. Participants who do not respond to either clozapine or olanzapine or cannot tolerate their side effects will be treated individually with other drugs until optimum treatment is identified. Regular telephone updates and in person visits to NIH for repeat testing and MRIs will be conducted.
The purpose of this protocol is to compare efficacy of clozapine and olanzapine in children and adolescents with schizophrenia and psychoses, as well as to learn about side effects of these medication in pediatric population. The underlying hypothesis is that clozapine has superior efficacy over olanzapine.
Children and adolescents, ages 7 to 18 years, meeting DSM-IV criteria for schizophrenia, schizoaffective disorder and psychotic disorder not otherwise specified, with onset of psychosis before their 13th birthday, who have not responded to at least two prior trials with typical or a typical neuroleptics, will be eligible to participate in a double-blind, parallel group, trial of olanzapine-clozapine.
This study will be done in conjunction with the Screening protocol, which will include characterization by clinical phenomenology, eye tracking, MRI brain imaging, plasma biochemistry, and chromosomal analysis.
This study will consist of the following phases 1) Tapering of psychotropic medications (1-4 weeks, depending upon type and dosage). 2) Observation for up to 2 weeks drug free, in order to establish a baseline prior to starting medication trial. 3) An 8 week double-blind trial of either clozapine or olanzapine. Efficacy and tolerability of clozapine and olanzapine will be compared using specified criteria. 4) If desired improvement not achieved or trial is interrupted, an 8 week open trial of the second medication and 5) Discharge following medication optimization for up to 4 weeks, or as clinically appropriate. This protocol also includes a follow-up every 2 to 3 years for a period of 10 years.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Olanzapine | Active Comparator |
| |
| Clozapine | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Olanzapine | Drug | tablet; 5-20mg/day; 8 weeks |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in the Scale for the Assessment of Negative Symptoms | Measures change in affective flattening or blunting, alogia, avolition/apathy, anhedonia/asociality, attention; minimum score = 0; maximum score = 125; lower values are considered a better outcome | 8 week double-blind study period; baseline and 8 weeks |
| Change in the Clinical Global Impression Severity of Symptoms Scale | Measures change in the severity of symptoms; Minimum score = 1; maximum score = 7; lower score is considered a better outcome. | 8 week double-blind study period; baseline and 8 weeks |
| Change in the Brief Psychiatric Rating Scale-24 | A 24-item scale measuring change in interpersonal behaviors, mood, psychosis, anxiety, speech, sleep, orientation and physical activity. Lowest score = 24; highest score = 168; lower score is considered a better outcome. | 8 week double-blind study period; baseline and 8 weeks |
| Change in the Scale for the Assessment of Positive Symptoms | Measures change in hallucinations, delusions, bizarre behavior, and thought organization. Minimum score = 0; maximum score = 170; lower score is considered a better outcome. | 8 week double-blind study period; baseline and 8 weeks |
| Change in the Bunney-Hamburg Rating Scale for Psychosis | Measures change in psychosis severity; Minimum score = 0; maximum score = 7; lower score is considered a better outcome. | 8 week double-blind study period; baseline and 8 weeks |
| Change in Bunney-Hamburg Rating Scale for Depression |
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| Measure | Description | Time Frame |
|---|---|---|
| Change in Weight | 8 week double-blind study period; baseline and 8 weeks | |
| Change in Body Mass Index (BMI) | BMI is calculated by the following formula: weight (in kilograms) divided by the square of the height (in meters) |
Males and females, age 7 to 18 years
Onset of psychotic symptoms before 13th birthday and a DSM-IV diagnosis of either schizophrenia, schizoaffective disorder, MDI syndrome, or psychosis NOS (not otherwise specified).
Current significant impairment due to the illness (current psychotic symptoms, decline of functioning academically and socially, significant discomfort due to psychotic symptoms).
Failure of two prior trials with antipsychotic medications (either typical or atypical) used at adequate doses (greater than or equal to 100 mg/day in chlorpromazine equivalents) and for adequate duration (at least 4 weeks, unless terminated due to intolerable side effects). Failure is defined as either insufficient response with persistence of symptoms significantly impairing child's functioning, according to child's and parental reports and medical and school records, or intolerable side effects to drugs other than clozapine and olanzapine.
Subjects may be included if their previous trial(s) of olanzapine failed to reach the dose of 20. mg/day or a duration of fewer than four weeks.
Subjects may be included if their previous trial(s) of clozapine failed to reach the dose of 200. mg/day or a duration of fewer than six weeks.
Comorbid psychiatric disorders in the past 12 months are permitted as long as not clinically significant.
EXCLUSION CRITERIA:
Prepsychotic full-scale IQ less than 70.
Unstable major neurological or medical conditions.
Current pregnancy or plan to become pregnant during the first three months (the duration of the study) in woman of childbearing age; breast-feeding in woman with infants.
DSM-IV substance abuse or dependence in the past 6 months.
True non-responders to either olanzapine or clozapine. True non-response is defined as: a) intolerance to either of the medications preventing an adequate trial, or b) only minimal (less than 20%) benefit with the adequate trial of either of the medications. Adequate trial constitutes at least 8 weeks of the medication with the dose of 20 mg on olanzapine or 200 mg of clozapine.
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| Name | Affiliation | Role |
|---|---|---|
| Judith L Rapoport, M.D. | Child Psychiatry Branch, NIMH, NIH | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | 20892 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 7701277 | Background | Gordon CT, Frazier JA, McKenna K, Giedd J, Zametkin A, Zahn T, Hommer D, Hong W, Kaysen D, Albus KE, et al. Childhood-onset schizophrenia: an NIMH study in progress. Schizophr Bull. 1994;20(4):697-712. doi: 10.1093/schbul/20.4.697. | |
| 10578456 | Background | Nicolson R, Rapoport JL. Childhood-onset schizophrenia: rare but worth studying. Biol Psychiatry. 1999 Nov 15;46(10):1418-28. doi: 10.1016/s0006-3223(99)00231-0. |
| Label | URL |
|---|---|
| NIH Clinical Center Detailed Web Page | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Olanzapine Group | All medications were given by mouth, in identical tablet form. Day 1, patient was given 5mg olanzapine or 12.5mg clozapine. Clozapine dose was then increased every other day, the first increase by 12.5mg (to a total dose of 25mg/day) and then in steps of 25mg. When the clozapine dose reached 150mg/day, the olanzapine dose was increased to 10mg/day. When the clozapine dose reached 300mg/day, the olanzapine dose was increased to 15mg/day. Further increases were guided by clinical judgment to a maximum of 20mg/day of olanzapine and 900mg/day of clozapine. |
| FG001 | Clozapine Group | All medications were given by mouth, in identical tablet form. Day 1, patient was given 5mg olanzapine or 12.5mg clozapine. Clozapine dose was then increased every other day, the first increase by 12.5mg (to a total dose of 25mg/day) and then in steps of 25mg. When the clozapine dose reached 150mg/day, the olanzapine dose was increased to 10mg/day. When the clozapine dose reached 300mg/day, the olanzapine dose was increased to 15mg/day. Further increases were guided by clinical judgment to a maximum of 20mg/day of olanzapine and 900mg/day of clozapine. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Olanzapine Group | All medications were given by mouth, in identical tablet form. Day 1, patient was given 5mg olanzapine or 12.5mg clozapine. Clozapine dose was then increased every other day, the first increase by 12.5mg (to a total dose of 25mg/day) and then in steps of 25mg. When the clozapine dose reached 150mg/day, the olanzapine dose was increased to 10mg/day. When the clozapine dose reached 300mg/day, the olanzapine dose was increased to 15mg/day. Further increases were guided by clinical judgment to a maximum of 20mg/day of olanzapine and 900mg/day of clozapine. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in the Scale for the Assessment of Negative Symptoms | Measures change in affective flattening or blunting, alogia, avolition/apathy, anhedonia/asociality, attention; minimum score = 0; maximum score = 125; lower values are considered a better outcome | Posted | Mean | 95% Confidence Interval | Scores on a scale | 8 week double-blind study period; baseline and 8 weeks |
|
8 week-double-blind study period
All adverse side effects are reported.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Olanzapine Group | All medications were given by mouth, in identical tablet form. Day 1, patient was given 5mg olanzapine or 12.5mg clozapine. Clozapine dose was then increased every other day, the first increase by 12.5mg (to a total dose of 25mg/day) and then in steps of 25mg. When the clozapine dose reached 150mg/day, the olanzapine dose was increased to 10mg/day. When the clozapine dose reached 300mg/day, the olanzapine dose was increased to 15mg/day. Further increases were guided by clinical judgment to a maximum of 20mg/day of olanzapine and 900mg/day of clozapine. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abnormal white blood count | Blood and lymphatic system disorders | Systematic Assessment | Total white blood count > 2000; absolute neutrophil count between 1000 and 1500 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Enuresis | Renal and urinary disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Judith L. Rapoport, M.D. | National Institute of Mental Health | 301-496-6080 | rapoporj@mail.nih.gov |
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| ID | Term |
|---|---|
| D012561 | Schizophrenia, Childhood |
| D011618 | Psychotic Disorders |
| D012559 | Schizophrenia |
| ID | Term |
|---|---|
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
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| ID | Term |
|---|---|
| D000077152 | Olanzapine |
| D003024 | Clozapine |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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| Clozapine | Drug | tablet; 12.5-900mg/day; 8 weeks |
|
|
Measures change in severity of depression; Minimum score = 0; maximum score = 7; lower score is considered a better outcome.
| 8 week double-blind study period; baseline and 8 weeks |
| Change in Bunney-Hamburg Rating Scale for Mania | Measures change in the severity of mania; Minimum score = 0; maximum score = 7; lower score is considered a better outcome. | 8 week double-blind study period; baseline and 8 weeks |
| Change in the Bunney-Hamburg Rating Scale for Anxiety | Measures change in the severity of anxiety; Minimum score = 0; maximum score = 7; lower score is considered a better outcome. | 8 week double-blind study period; baseline and 8 weeks |
| 8 week double-blind study period; baseline and 8 weeks |
| Change in Extrapyramidal Movements as Measured by the Abnormal Involuntary Movements Scale (AIMS) | minimum score = 10; maximum score = 50; lower score is considered a more favorable outcome | 8 week double-blind study period; baseline and 8 weeks |
| Change in Extrapyramidal Movements as Measured by the Simpson Angus Scale Score | minimum score = 10; maximum score = 90; lower score considered a more favorable outcome | 8 week double-blind study period; baseline and 8 weeks |
| 16818861 | Result | Shaw P, Sporn A, Gogtay N, Overman GP, Greenstein D, Gochman P, Tossell JW, Lenane M, Rapoport JL. Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry. 2006 Jul;63(7):721-30. doi: 10.1001/archpsyc.63.7.721. |
| BG001 | Clozapine Group | All medications were given by mouth, in identical tablet form. Day 1, patient was given 5mg olanzapine or 12.5mg clozapine. Clozapine dose was then increased every other day, the first increase by 12.5mg (to a total dose of 25mg/day) and then in steps of 25mg. When the clozapine dose reached 150mg/day, the olanzapine dose was increased to 10mg/day. When the clozapine dose reached 300mg/day, the olanzapine dose was increased to 15mg/day. Further increases were guided by clinical judgment to a maximum of 20mg/day of olanzapine and 900mg/day of clozapine. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Clozapine Group | All medications were given by mouth, in identical tablet form. Day 1, patient was given 5mg olanzapine or 12.5mg clozapine. Clozapine dose was then increased every other day, the first increase by 12.5mg (to a total dose of 25mg/day) and then in steps of 25mg. When the clozapine dose reached 150mg/day, the olanzapine dose was increased to 10mg/day. When the clozapine dose reached 300mg/day, the olanzapine dose was increased to 15mg/day. Further increases were guided by clinical judgment to a maximum of 20mg/day of olanzapine and 900mg/day of clozapine. |
|
|
|
| Primary | Change in the Clinical Global Impression Severity of Symptoms Scale | Measures change in the severity of symptoms; Minimum score = 1; maximum score = 7; lower score is considered a better outcome. | Posted | Mean | 95% Confidence Interval | Scores on a scale | 8 week double-blind study period; baseline and 8 weeks |
|
|
|
|
| Primary | Change in the Brief Psychiatric Rating Scale-24 | A 24-item scale measuring change in interpersonal behaviors, mood, psychosis, anxiety, speech, sleep, orientation and physical activity. Lowest score = 24; highest score = 168; lower score is considered a better outcome. | Posted | Mean | 95% Confidence Interval | Scores on a scale | 8 week double-blind study period; baseline and 8 weeks |
|
|
|
|
| Primary | Change in the Scale for the Assessment of Positive Symptoms | Measures change in hallucinations, delusions, bizarre behavior, and thought organization. Minimum score = 0; maximum score = 170; lower score is considered a better outcome. | Posted | Mean | 95% Confidence Interval | Scores on a scale | 8 week double-blind study period; baseline and 8 weeks |
|
|
|
|
| Primary | Change in the Bunney-Hamburg Rating Scale for Psychosis | Measures change in psychosis severity; Minimum score = 0; maximum score = 7; lower score is considered a better outcome. | Posted | Mean | 95% Confidence Interval | Scores on a scale | 8 week double-blind study period; baseline and 8 weeks |
|
|
|
|
| Primary | Change in Bunney-Hamburg Rating Scale for Depression | Measures change in severity of depression; Minimum score = 0; maximum score = 7; lower score is considered a better outcome. | Posted | Mean | 95% Confidence Interval | Scores on a scale | 8 week double-blind study period; baseline and 8 weeks |
|
|
|
|
| Primary | Change in Bunney-Hamburg Rating Scale for Mania | Measures change in the severity of mania; Minimum score = 0; maximum score = 7; lower score is considered a better outcome. | Posted | Mean | 95% Confidence Interval | Scores on a scale | 8 week double-blind study period; baseline and 8 weeks |
|
|
|
|
| Primary | Change in the Bunney-Hamburg Rating Scale for Anxiety | Measures change in the severity of anxiety; Minimum score = 0; maximum score = 7; lower score is considered a better outcome. | Posted | Mean | 95% Confidence Interval | Scores on a scale | 8 week double-blind study period; baseline and 8 weeks |
|
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|
|
| Other Pre-specified | Change in Weight | Posted | Mean | Standard Deviation | kilograms | 8 week double-blind study period; baseline and 8 weeks |
|
|
|
|
| Other Pre-specified | Change in Body Mass Index (BMI) | BMI is calculated by the following formula: weight (in kilograms) divided by the square of the height (in meters) | Posted | Mean | Standard Deviation | kg/m² | 8 week double-blind study period; baseline and 8 weeks |
|
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|
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| Other Pre-specified | Change in Extrapyramidal Movements as Measured by the Abnormal Involuntary Movements Scale (AIMS) | minimum score = 10; maximum score = 50; lower score is considered a more favorable outcome | Posted | Median | Full Range | scores on a scale | 8 week double-blind study period; baseline and 8 weeks |
|
|
|
| Other Pre-specified | Change in Extrapyramidal Movements as Measured by the Simpson Angus Scale Score | minimum score = 10; maximum score = 90; lower score considered a more favorable outcome | Posted | Median | 95% Confidence Interval | scores on a scale | 8 week double-blind study period; baseline and 8 weeks |
|
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|
| 1 |
| 13 |
| 13 |
| 13 |
| EG001 | Clozapine Group | All medications were given by mouth, in identical tablet form. Day 1, patient was given 5mg olanzapine or 12.5mg clozapine. Clozapine dose was then increased every other day, the first increase by 12.5mg (to a total dose of 25mg/day) and then in steps of 25mg. When the clozapine dose reached 150mg/day, the olanzapine dose was increased to 10mg/day. When the clozapine dose reached 300mg/day, the olanzapine dose was increased to 15mg/day. Further increases were guided by clinical judgment to a maximum of 20mg/day of olanzapine and 900mg/day of clozapine. | 2 | 12 | 12 | 12 |
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| Increased appetite | Metabolism and nutrition disorders | Systematic Assessment |
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| Hypersalivation | Gastrointestinal disorders | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Difficulty concentrating | Nervous system disorders | Systematic Assessment |
|
| Somnolence | Nervous system disorders | Systematic Assessment |
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| Insomnia | Nervous system disorders | Systematic Assessment |
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| Hypertension | Cardiac disorders | Systematic Assessment |
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| tachycardia >100 beats/min (supine) | Cardiac disorders | Systematic Assessment |
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| Tachycardia >120 beats/min (supine) | Cardiac disorders | Systematic Assessment |
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| D006571 | Heterocyclic Compounds |
| D003984 | Dibenzazepines |
| D006575 | Heterocyclic Compounds, 3-Ring |