| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Children and adolescents with ADHD (Attention-Deficit/Hyperactivity Disorder) and comorbid ODD (Oppositional Defiant Disorder). |
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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 |
The primary objective of this study is to test the hypothesis that atomoxetine, given once daily for approximately 9 weeks (target dose of 1.2 mg/kg per day), using either fast or slow titration, is superior to placebo in the outpatient treatment of ODD symptoms in children and adolescents with ADHD and comorbid ODD.
ODD symptoms reduction will be measured primarily using the investigator-rated oppositional subscale of the Swanson, Nolan and Pelham Rating Scale-Revised (SNAP IV). For the primary analysis, the data of the two atomoxetine treatment arms combined (fast plus slow titration) will be tested versus placebo (for details refer to Section 8.2.6).
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| E.2.2 | Secondary objectives of the trial |
are to compare atomoxetine using fast & slow titration vs. placebo in children & adolescents with ADHD & comorbid ODD with respect to:
• Reduction of ODD, CD & ADHD symptoms as measured by various scales (details see protocol 2.2, page 14).
• Changes in the child’s perspective of quality of life, as assessed by the parent-rated KINDLR questionnaire
• Development of family burden, as assessed by the parent-rated FaBel questionnaire
• Time to treatment discontinuation
• Safety & tolerability, as assessed by adverse events (AEs) elicited during open-ended questioning, & the derived rates of clinically relevant adverse events (such as gastrointestinal or central nervous events) during the initial 3 weeks of treatment & during the complete 9-week treatment period.
For sec.analyses s. protocol p.14/15)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1] Patients are male or female outpatients who are at least 6 years of age, and who will not have reached their 18th birthday at the date of signature of their lastly signed informed consent/assent document.
[2] Patients must meet DSM-IV diagnostic criteria for ADHD and fulfil DSM-IV diagnostic criteria A) through C) for ODD, as detailed in Section 4.1.1 (Disease Diagnostic Criteria).
[3] Patients and parents (or legal representatives) must have an educational level and degree of understanding sufficient to communicate suitably with the investigator and study coordinator.
[4] Patients must be of normal intelligence in the judgment of the investigator (that is, without a general impairment of intelligence and likely, in the investigator’s judgment, a score of 70 on an Intelligence Quotient [IQ] test). The administration of a formal IQ test is not an entry requirement for this study. Specific learning disabilities are not considered general impairments of intelligence.
[5] Patients and parents must have been judged by the investigator to be reliable to keep appointments for study visits and all tests and examinations required by the protocol.
[6] Patients must be able to swallow capsules (study drug).
4.1.1. Disease Diagnostic Criteria
All patients must meet the following criteria according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition:
• criteria for ADHD and
• Criteria A) through C) for ODD,
as determined by a physician investigator’s clinical assessment.
Patients meeting ADHD combined type, predominantly inattentive type, and predominantly hyperactive-impulsive type according to DSM-IV criteria are eligible for the study. However, patients meeting “ADHD not further specified” criteria according to DSM-IV are not eligible.
The presence of additional Conduct Disorder symptoms according to DSM-IV criteria is not exclusionary.
The validated diagnosis will be based on the structured instruments DCL-HKS and DCL SSV of the DISYPS-KJ (Döpfner and Lehmkuhl 2000). The use of these German language instruments for diagnoses of ADHD and ODD/CD is common clinical practice in Germany. They provide ADHD and ODD/CD diagnoses based on the DSM-IV criteria, but also confirm the diagnoses along the ICD-10 criteria, which are commonly used in Germany.
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| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
[7] Patients who weigh less than 20 kg or greater than 90 kg at study entry (Visit 1). If a patient’s weight changes after Visit 1 to a value outside of the stated range, the patient will still be eligible, and the weight should be rounded to the nearest value within the above range for dosing purposes in Study Period II.
[8] Patients who at any time received prior atomoxetine treatment, including patients who have completed or were withdrawn from this study or any other study investigating atomoxetine.
[9] Patients with current or past history of Bipolar I or II disorder, psychosis, or pervasive developmental disorder.
[10] Patients who have a history of any seizure disorder (other than febrile seizures) or prior electroencephalogram (EEG) abnormalities related to epilepsy, or patients who have taken (or are currently taking) anticonvulsants for seizure control.
[11] Patients who are at serious suicidal risk, as determined by the investigator.
[12] Patients with a history of severe allergies to more than one class of medications or multiple adverse drug reactions.
[13] Patients with Narrow Angle (Angle-Closure) Glaucoma.
[14] Patients with a history of alcohol or drug abuse within the past 3 months (excessive or compulsive use as judged by the investigator), or who are currently using alcohol, drugs of abuse, or any prescribed or over-the-counter medication in a manner that the investigator considers indicative of abuse.
[15] Patients with acute or unstable medical conditions, including (but not limited to) inadequately controlled diabetes, hepatic insufficiency (specifically any degree of jaundice), uncorrected hypothyroidism or hyperthyroidism, acute systemic infection, renal, gastroenterologic, respiratory, endocrinologic, neurologic, immunologic or hematologic disease.
[16] Patients who have hypertension or are currently taking an antihypertensive agent for blood pressure control, or have any other cardiovascular disorder, including prior surgery for congenital cardiovascular disorders (e.g. tetralogy of Fallot).
[17] Patients with any unexplained cardiac signs or symptoms (e.g. systolic ejection murmurs suggesting hypertrophic cardiomyopathy).
[18] Patients with congenital or acquired long QT, or with a family history of QT prolongation or other significant inherited cardiac disorders (e.g. family history of hypertrophic cardiomyopathy).
[19] Patients who have a medical condition that would increase sympathetic nervous system activity (e.g. catecholamine-secreting neural tumor), or who are taking a medication on a daily basis (e.g. albuterol, inhalation aerosols, pseudoephedrine) that has sympathomimetic activity. Such medications can be taken on an as-needed basis.
[20] Patients who are at any time of the study likely to need psychotropic medications apart from the drugs under study, including over the counter medication that in the investigator’s opinion have central nervous system activity (e.g. St. John’s Wort, [“Johanniskraut”], ephedrine).
[21] Patients who at any time during the study are likely to begin a structured psychotherapy. Psychotherapy initiated prior to study participation is acceptable. However, after study participation has begun, only supportive or educational therapy is permitted.
[22] Patients who have used a monoamine oxidase inhibitor (MAOI) during the 2 weeks (14 days) prior to Visit 2.
[23] Female patients who are pregnant or breast-feeding. Sexually active females must use a medically acceptable method of contraception. Females of childbearing potential (defined as first menses occurred) who are sexually abstinent may enter the study, providing they agree that if they become sexually active they will use a reliable method of contraception, such as implants, injectables, combined oral contraceptives, intrauterine devices, vasectomized partner.
[24] Patients who are investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.
[25] Patients who are Lilly employees.
[26] Patients who have received treatment within the last 30 days with a drug that has not received regulatory approval in any country for any indication at the time of study entry.
[27] Patients whose families anticipate a move outside the geographic range of the investigative site within the anticipated duration of the study.
[28] Patients who, in the opinion of the investigator, are unsuitable in any other way to participate in this study.
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| E.5 End points |
| E.5.1 | Primary end point(s) | |
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
| 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 | 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
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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 | 3 |
| E.8.9.1 | In the Member State concerned days | 5 |
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