| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| conduct disorder (CD), oppositional defiant disorder (ODD) and disruptive behavior disorder not otherwise specified (DBD-NOS) |
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| MedDRA Classification |
| 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 assess the efficacy of the treatment with ziprasidone of conduct problems and aggressive behavior by rating, reflecting and assessing subject’s condition with the Nisonger Child Behavior Rating Form for typical IQ (NCBRF-TIQ). Primary outcome measures are the subscales “Conduct Problem” (such as cruelty to animals, misbehaving, fighting) and “Oppositional Behavior” (such as arguing, disobedience, stubborn). Symptom rating will be done by the subject’s primary caregiver. |
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| E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of the treatment with ziprasidone in children and adolescents.
To assess the efficacy by rating, reflecting and assessing the subject’s condition on the Clinical Global Impressions-Severity of Illness scale (CGI-S) and the Global Impressions-Improvement scale (CGI-I) by the psychiatrist.
To assess the correlation between serum levels and dosage, efficacy and side effects.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Patients enrolled in this study are to meet the following inclusion criteria:
1. The subject and the authorized legal representative must understand the nature of the study and be able to comply with protocol requirements. The representative must sign an Informed Consent Document and the subject must provide Written Assent.
2. The subject (male or female) must be between 7-17 (inclusive) years of age at screening.
3. The subject must have a primary diagnosis of Conduct Disorder [CD] (312.8), Oppositional Defiant Disorder [ODD] (313.81) or Disruptive Behavior Disorder not otherwise specified [DBD-NOS] (312.9) as defined by DSM-IV criteria and confirmed by the Kiddie-SADS-PL.
4. At the screening visit (Visit 1), subjects must have a score of 21 or more on the sum of the scales for conduct problems and for oppositional behaviour in the NCBRF-TIQ.
5. In the investigator's opinion, the subject must be likely to benefit from the therapy.
6. The subject is willing and able to discontinue any medications that are prohibited in this study (see Concomitant Medications table, Section 3.5.1). Any such medications must be discontinued at least 5 half-lives prior to the administration of double-blinded study medication.
Patients who are receiving prohibited medications are to be considered for the protocol only If discontinuation of the medication does not compromise the welfare of the patient and/or alternative medication that is allowed by the protocol is available and appropriate for the patient. Psychotropic medications should be tapered down per accepted medical practice and the specific package insert instead of being abruptly discontinued.
7. Females of childbearing potential may be included provided that they are not pregnant, not nursing, and are practicing effective contraception and meet all of the following criteria:
a. Are instructed and agree to avoid pregnancy during the study.
b. Have a negative pregnancy test (β-HCG) at screening and Visit 2.
c. Use one of the following birth control methods:
• an oral contraceptive agent, an intrauterine device (ILTD), an implantable contraceptive (e.g. Norplant), transdermal hormonal contraceptive (e.g. Ortho-Evra), or an injectable contraceptive (e.g. Depo-Provera) for at least one month prior to entering the study and will continue its use throughout the study; or
• a barrier method of contraception, e.g., condom andlor diaphragm with spermicide while participating in the study.
• abstinence for at least 3 months before the start of the study and intention to abstain from sexual activity during the study period.
8. Subjects must have an IQ > 55 best tested with the HAWIK-III, alternatively with the CFT-20 or K-ABC.
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| E.4 | Principal exclusion criteria |
1. Subjects who are clinically stable on treatment regimens that are being well tolerated and effective.
2. Subjects with any psychotic disorder.
3. Subjects with DSM-IV defined psychoactive substance or alcohol abuse/dependence (does not apply to nicotine or caffeine) within the preceding 1 month.
4. Subjects who are judged by the investigator as being at imminent risk of suicide.
5. Subjects who are judged by the investigator as being at imminent risk of homicide
6. Subjects with autism or other pervasive developmental disorder.
General Medical
7. Subjects with any serious, unstable illness including hepatic, renal, gastrointestinal, respiratory, cardiovascular, endocrinologic (including controlled or uncontrolled Type I diabetes), immunologic, hematologic, dermatological, oncological, or neurological disease (including any history of seizure or epilepsy). Subjects with a history of febrile seizures are eligible if no seizures have occurred during the last 3 years.
8. Subjects with a history of syncopal episodes (sudden loss of consciousness with loss of postural tone and not preceded by a pre-syncopal phase) or unexplained loss of consciousness. Subjects with a history of occasional syncopes ofp robable vasovagal origin (onset not sudden but preceded by a pre-syncopal phase, presence of predisposing factors such as blood sampling procedure, standing, hot shower, hair curling, etc) are eligible.
9. Subjects with any medical condition or dietary habit that has a significant potential to alter the absorption of the study drug; or subjects taking any medication that may alter drug absorption. (e.g. anorexia nervosa, bulimia, chronic use of laxatives).
10. Subjects with uncorrected hypothyroidism or hyperthyroidism or whose thyroid function and medication regimen have been stable less than 1 month.
11. Subjects with any screening laboratory value that deviates significantly from the upper or lower limits of the normal reference range. SGOT and SGPT must be within 2 X and total bilirubin must be within 1.5 X times of the upper limits of the reference range. Subjects with an isolated increase of unconjugated bilirubin (Gilbert's syndrome) are eligible.
12. Subjects with screening K+, Mg++ or Ca++ below the normal range.
13. Subjects with a history of chronic hepatitis, known serologic evidence of acute hepatitis or chronic hepatitis (positive HbsAg), or subjects with known hepatitis C antibodies and elevated LFTs.
14. Subjects known to be HIV positive.
Cardiovascular
15. Subjects with a history of significant cardiovascular disease, including conditions that have previously required treatment or acute evaluation, or significant concurrent cardiovascular disease, including uncontrolled hypertension (sitting diastolic pressure >90 mm Hg and/or sitting systolic pressure > 140 mm Hg with or without treatment), congestive heart failure, or congenital heart disease.
Non-clinically significant sinus bradycardia or sinus tachycardia will not be considered significant medical illnesses and would not exclude a subject from the study. Isolated atrial septal defect (ASD), ventricular septal defect (VSD, or patent ductus arteriosus (PDA) will not be considered significant medical illnesses if they are surgically corrected.
16. Subjects with a history of cardiac arrhythmias, conduction abnormalities or known personal history of QT prolongation (including congenital long QT syndrome).
17. Subjects with a known genetic risk for prolonged QT syndrome
18. Subjects with a clinically significant ECG abnormality at Screening or Baseline
19. Subjects with persistent QTc (Fridericia) ≥ 460 msec at Screening or Baseline.
Medications
20. Subjects taking any medications not allowed by the Concomitant Medication Table (Section 3.5.1). Medications should be avoided that may mask or exacerbate adverse effects, or have psychotropic properties which would exacerbate symptoms (e.g., sympathomimetics) or obscure study drug effect (e.g., antihistamines).
21. Subjects who have received clozapine within 12 weeks, a depot antipsychotic within 4 weeks or a monoamine oxidase inhibitor within 2 weeks prior to Baseline.
22. Subjects known by medical history or hospitalization records to have used phencyclidine within the 30 days prior to Screening.
23. Subjects requiring treatment with drugs which have been consistently observed to prolong the QT interval (see Section 3.5.2).
24. Subjects who received an investigational drug within 4 weeks of Baseline.
25. Subjects who received ziprasidone in a previous clinical trial.
26. Subjects known to be allergic to ziprasidone.
27. Subjects with history of antipsychotic-induced EPS that does not respond to antiparkinsonian medication.
28. Subjects with prior episode of neuroleptic malignant syndrome or prior hypersensitivity to antipsychotic agents.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is change from baseline in the NCBRF-TIQ conduct and oppositional behavior sub-score. The primary time point is Week 9. |
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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 | Information not present in EudraCT |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
|
| The end of the trial is defined as the last visit of the last subject undergoing the trial. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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