| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| children and adolescents with disruptive behavioral symptoms associated with Pervasive Developmental Disorders (PDD) |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10061345 |
| E.1.2 | Term | Pervasive developmental disorder |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| to test the hypothesis that olanzapine is superior to placebo in the maintenance of effect on disruptive behavioral symptoms associated with PDDs over 12 weeks of double-blind treatment among children and adolescents who meet criteria for response during treatment with olanzapine over 12 weeks of open-label olanzapine treatment. |
|
| E.2.2 | Secondary objectives of the trial |
To test the hypothesis that olanzapine is superior to placebo in maintenance of effect during study period III using: Proportions of patients who meet criteria for symptom recurrence, ABC total score and the subscale scores and CGI-S and to test effect on functional outcomes during study period III: CGAS, RPP-PDD-Parent and RPP-PDD-Teacher, KIDSCREEN-27 and NCBRF total and subscale scores
To assess
-effect of olanzapine, compared with placebo, on cognitive outcomes during study period III
-time to response for partial responder
-the safety and tolerability
-the reversibility of potential adverse effects of olanzapine upon discontinuation of drug
-the efficacy of olanzapine and to assess improvement on efficacy and functional outcomes and effect on cognition during study period II
- longer-term efficacy, functional outcome, and cognition results during study period IV
To characterize olanzapine PK in children and adolescents |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Patients must be at least 6 years of age and not more than 16.5 years (defined as 180 days past 16th birthday) of age at Visit 1.
[2] Patients must meet DSM-IV-TR diagnostic criteria for one of the following PDD disorders as diagnosed by the investigator using symptom information obtained using the ADI-R (Lord et al. 1994):
-Autistic Disorder,
-Asperger’s Disorder,
-PDD-NOS.
[3] Patients must demonstrate a minimum level of disease symptomatology as assessed using symptom categories and cut-off scores established by the ADI-R. Minimal symptoms for the purposes of this study are defined as meeting or exceeding cut-off scores for symptom category D (Abnormality of Development Evident at or Before 36 Months) and meeting or exceeding cut-off scores in 2 of the following 3 symptom categories:
-A (Qualitative Abnormalities in Reciprocal Social Interactions)
-B (Qualitative Abnormalities in Communication); for this category, patients can meet or exceed the cut-off scores for either B(V) (Verbal Total) or B(NV) (Nonverbal Total)
-C (Restricted, Repetitive and Stereotyped Patterns of Behavior)
[4] Patients must score ≥18 on the Irritability Subscale of the ABC at Visits 1, 2, and 3.
[5] Patients must score ≥4 on the CGI-S rating scale at Visits 1, 2, and 3.
[6] All female patients of childbearing potential must test negative for pregnancy based on a serum pregnancy test at the time of enrollment and agree to use an acceptable method of birth control during the study and for 60 days post participation.
[7] Patients must have a weight of at least 15 kg at study entry.
[8] Patients must be able to swallow whole capsules and tablets.
[9] The patient’s parent and, when possible, the patient, must understand the nature of the study and have a level of understanding sufficient to allow performance of tests and examinations (including venipuncture) required by the protocol and must be judged by the investigator as reliable to keep appointments for clinic visits. |
|
| E.4 | Principal exclusion criteria |
[10] Meets the DSM-IV-TR diagnostic criteria for Rett’s disorder or childhood disintegrative disorder
[11] Is immediate family of investigator site personnel directly affiliated with this study or of a Lilly employee (Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.)
[12] Has received treatment within the 30 days before Visit 1 with a drug that has not received regulatory approval for any indication at the time of study entry
[13] Has previously completed or withdrawn from this study or any other study investigating olanzapine or has been previously identified as being a nonresponder to or intolerant of olanzapine
[14] Has a current diagnosis (within 6 months of the start of the study) or lifetime DSM-IV-TR diagnosis of schizophrenia-related disorders, schizophrenia, bipolar disorder, or major depressive disorder
[15] Takes a stimulant or any psychotropic medication on a regular basis, including health-food supplements that the investigator feels could affect central nervous system activity (for example, St. John’s wort or melatonin), or any other excluded concomitant medication (as discussed in Section 5.7) and is unwilling to stop taking it
[16] Has any acute or unstable medical condition, including (but not limited to) inadequately controlled diabetes [hemoglobin A1c (HbA1c) >8%] or impaired glucose control; severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL); hepatic insufficiency (specifically any degree of jaundice); recent cerebrovascular accidents; uncontrolled seizure disorders; serious acute systemic infection or immunologic disease; unstable cardiovascular disorders (including ischemic heart disease); uncorrected hypothyroidism or hyperthyroidism; renal, gastroenterological, respiratory, endocrinologic, neurological, immunologic, or hematologic diseases (specifically current absolute neutrophil count <1,500 mm3); current leukopenia or history of leukopenia without a clear and resolved etiology; history of agranulocytosis (absolute neutrophil count <500 mm3); or a prolactin level (>200 ng/mL [200 µg/L])
[17] Has any acute or unstable medical or psychiatric condition for which intensive care unit hospitalization is anticipated during the course of the study
[18] Has any clinical condition at study entry that, in the judgment of a physician, should preclude his or her participation
[19] Has laboratory results, including serum chemistry, hematology, or urinalysis, that show clinically significant abnormalities (Clinically significant is defined as laboratory values requiring acute medical intervention, indicating serious medical illness, or requiring further medical evaluation in the judgment of the investigator.)
[20] Has alanine transaminase (ALT) ≥2 times the upper limit of normal (ULN) of the central laboratory standard, aspartate transaminase (AST) value ≥3 times the ULN of central laboratory standard, or total bilirubin values ≥1.5 times the ULN of central laboratory standard at Visit 2
[21] Has a history of tardive dyskinesia, hypersensitivity to neuroleptics, or neuroleptic malignant syndrome
[22] Has a history of alcohol or drug abuse on a repeated basis within the past 3 months. (Patients who have used alcohol or drugs on isolated occasions are eligible. Whether use is isolated or repeated will be determined by the patient’s history and the investigator’s clinical judgment. Patients who are currently using alcohol, drugs of abuse, or any prescribed or over-the-counter medication in a manner considered by the investigator as indicative of abuse are excluded.)
[23] Has a seizure disorder for which he or she receives more than 1 anticonvulsant or has had a seizure in the past 3 months
[24] Has QTc interval >440 msec (Bazett's correction) at Visit 1
[25] Has used monoamine oxidase inhibitors (MAOIs) within 14 days before Visit 1 or has the potential to use an MAOI at any time during the study
[26] Has a documented genetic disease such as fragile X syndrome. (Patients with any other genetic disorder must be assessed for eligibility by Lilly.)
[27] Is pregnant or nursing
[28] Has a documented history of allergic reaction to olanzapine
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Irritability Subscale of the Aberrant Behavior Checklist
The Irritability Subscale is one of 5 subscales of the ABC (Aman et al. 1985), a 58-item rating scale developed to assess inappropriate and maladaptive behavior in individuals with mental retardation or other developmental disabilities. Scores on each item range from 0 (not at all a problem) to 3 (the problem is severe in degree).
The ABC relies on clinical observations of activity and behavior without regard to underlying diagnosis or purpose of the observed behaviors. The 15-item Irritability Subscale includes questions about aggression, self-injury, tantrums, agitation, and unstable mood, making it a reasonable measure of disruptive behavioral symptoms for use in this patient population. The 15 items result in a subscale score of 0 to 45, with higher scores indicating greater severity of problem behaviors. The measure has favorable psychometric properties; validity and reliability of the total and subscales have been reported (Aman and Singh 1994; Brown et al. 2002).
This scale will be administered by the investigator at the investigative site, based on an interview with the patients’ parents (see Section 9.3.1 of Protocol for a description of investigator qualifications).
-Clinical Global Impressions-Severity
The CGI-S is a single-item rating of the clinician’s assessment of symptom severity in relation to the clinician’s total experience with PDD patients (Guy 1976, NIMH 1985). Severity is rated on a 7-point scale (1 = normal, not at all ill; 7 = among the most extremely ill). All CGI-S evaluations must be performed by the investigator.
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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