| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Attention Deficit Hyperactivity Disorder |
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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 | 10003735 |
| E.1.2 | Term | Attention deficit-hyperactivity disorder |
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| 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 is to test the hypothesis that atomoxetine given at individually titrated doses for 6 months is superior to other early standard therapy in improving quality of life as measured by the mean change in the achievement domain of the Child Health and Illness Profile – Child Edition, Parent Report Form (CHIP-CE PRF), in pharmacologically naïve children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are as follows:
• to compare atomoxetine with other early standard therapy at 4 months in patients with ADHD as measured by mean change in the achievement domain of the CHIP-CE PRF
• to compare atomoxetine with other early standard therapy at 4 and 6 months in patients with ADHD as measured by change in the CHIP-CE PRF total score and domains (satisfaction, comfort, resilience and risk avoidance)
• to compare atomoxetine with other early standard therapy at 4 months and 6 months in patients with Attention-Deficit/Hyperactivity Disorder (ADHD) in the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P)
• to compare atomoxetine with other early standard therapy at 4 months and 6 months in patients with Attention-Deficit/Hyperactivity Disorder (ADHD) as measured by the ADHD-RS-IV Parent:Inv
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional Protocol Sample Banking Addendum B4Z- EW-LYDY(1)
A Randomized, Controlled, Open-Label Study of the Long-Term Impact on Functioning using Atomoxetine Hydrochloride Compared to Other Early Standard Care in the Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in Treatment-Naïve Children and Adolescents.
(ADHD-LIFE Study) - Protocol Addendum (1) Approved by Lilly: 23 October 2006
This addendum is to be performed in addition to all procedures required by protocol B4Z-EW-LYDY or any subsequent amendments to that protocol. This addendum is optional.
Eli Lilly and Company has established a program, Combined Specimen Banking (CSB), to bank samples (collectively called Banked Samples) from patients enrolled in studies sponsored by Eli Lilly and Company. The Banked Samples are collected and banked for research to identify the genes associated with diseases and/or response to clinical trial medication or other medication taken during the trial. For example, in Study B4Z-EW-LYDY, approximately 400 ADHD diagnosed patients from 6 to 17 years of age will be included to evaluate the efficacy of atomoxetine versus other early standard therapy in the long term period.
The research performed on the Banked Samples is limited to the clinical information collected on the case report form (CRF) and provided by laboratory analysis. Information regarding these genetic factor may benefit patients in the future through the development of new and more specific therapeutics developed as a result of genetic analyses.
Although the Banked Sample(s) will be stored for research purposes, the sample(s) will be used only until the Banked Sample(s) collected in the trial is/are exhausted. The blood cells will not be made to grow indefinitely in the laboratory (immortalized). In addition, the patient’s entire genetic makeup will not be determined from the sample.
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| 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 must be at least 6 years of age, but must not have reached their 17th birthday at Visit 1.
[2] Patients must meet the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition Text Revision™ (DSM-IV-TR™) diagnostic criteria for ADHD. For the purposes of this study the diagnosis of ADHD will be confirmed during Visit 1 by administering the K-SADS-PL. Patients must also have an ADHD-RS-IV Parent:Inv score at least 1.5 standard deviations above the age norm for their diagnostic subtype at both Visit 1 and Visit 2. In addition, they must have a CGI-ADHD-S score 4 at both Visit 1 and Visit 2.
[3] Patients must be pharmacological naive at Visit 1. Pharmacological naive is defined as not having received more than seven consecutive days of any dose of pharmacotherapy for ADHD during the patient’s lifetime and having not received more than two consecutive days of any dose of pharmacotherapy for ADHD within 30 days before Visit 1.
[4] Patients must be able to swallow capsules.
[5] Patients must be of normal intelligence as assessed by the investigator (that is, without a general impairment of intelligence and likely, in the investigator’s judgment, to achieve a score of 80 on an 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.
[6] Patients and parents/legal guardians have been judged by the investigator to be reliable to keep appointments for clinic visits and all tests and examinations required by the protocol.
[7] Patients and parents must be able to communicate adequately with the investigator and site personnel.
[8] This inclusion criterion applies to females of child-bearing potential only.
Test negative for pregnancy at the time of entry (Visit 1) based on a urine pregnancy test. If local law, an ERB and/or regulatory bodies have different requirements then these requirements take precedence.
[9] Each patient (and/or legally authorized patient representative where required by local law) must understand the nature of the study and must sign an ICD.
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| E.4 | Principal exclusion criteria |
[10] Patients who weigh less than 20 kg at study entry (Visit 1).
[11] Patients who have a documented history of bipolar disorder, any history of psychosis or pervasive development disorder (autistic spectrum disorder). If the investigator believes that such a diagnosis has previously been made in error, he/she should contact Lilly and discuss the case history with the Lilly physician responsible for the study prior to allowing the patient to enter the study.
[12] Patients with a history of any seizure disorder (other than febrile seizures) or patients who have taken (or are currently taking) anticonvulsants for seizure control are not eligible to participate.
[13] Patients at serious suicidal risk as assessed by the investigator. (This evaluation must include the items a, b, c, d and e of K- SADS-PL’s depression module, and there can not be a score of 3 in any of these items).
[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 which the investigator considers indicative of abuse
[15] Patients with significant prior or current medical conditions (for example human immunodeficiency virus (HIV+), surgically corrected congenital heart defects, or malignancy.
[16] Patients who have a medical condition that would increase sympathetic nervous system activity markedly (for example, catecholamine-secreting neural tumor) or who are taking a medication on a daily basis that has sympathomimetic activity (for example, albuterol, inhalation aerosols, pseudoephedrine). Such medications can be taken on an occasional basis.
[17] Patients with a history of hyperthyroidism or hypothyroidism will be excluded. However, patients who were previously diagnosed with hyperthyroidism or hypothyroidism, who have been treated with a stable dose of thyroid supplement for at least the past 3 months, and who are clinically and chemically euthyroid will be allowed to participate in the study.
[18] Patients with acute closed angle glaucoma.
[19] Use of monoamine oxidase inhibitors (MAOIs) during the 2 weeks (14 days) prior to Visit 2.
[20] Current or past history of hypertension. For the purposes of this protocol, hypertension will be defined as average systolic or diastolic blood pressure measured on at least 2 separate occasions, greater than or equal to the 95th percentile for age and sex defined by the National Heart and Lung Institute (National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents 1996). The accuracy of historical diagnoses will be determined by the investigator.
[21] Patients with cardiovascular disease, prolonged QT interval or other conditions that could be aggravated by an increased heart rate or increased blood pressure.
[22] Pregnant or breastfeeding females are excluded from the study.
[23] Sexually active females who do not use a medically acceptable method of contraception are also excluded from the study. For this study, medically acceptable methods of contraception include barrier methods (condom or diaphragm with spermicidal agent) or oral contraception. The rhythm method (abstinence during predicted times of ovulation with unprotected intercourse at other times) or coitus interruptus prior to ejaculation by the male partner are not acceptable means of contraception.
[24] Patients with a history of severe allergies to more than one class of medications or have had multiple adverse drug reactions.
[25] Patients who at any time during the study period II are likely to begin a structured psychotherapy aimed at ADHD. Psychotherapy initiated at least 1 month prior to study participation is acceptable; however during study period II, after study participation has begun only supportive or educational therapy is permitted.
[26] Patients who are taking any psychotropic medication as detailed in Attachment LYDY.5 on a regular basis must have a washout equal to a minimum of 5 half-lives of that medication prior to randomization. If the half-life of a medication is unknown, the Lilly physician should be consulted prior to entering the patient into the study.
[27] Patients who are seeking ADHD treatment solely for improvement of school performance.
[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) |
6.1. Primary Outcome Variable, Quality of Life Measure
The Child Health and Illness Profile (CHIP) is a validated, generic health-status survey developed to assess the overall health of children and adolescents. There is a parent-rated version for children (CHIP-CE PRF) and 2 self-rating versions, one for children and one for adolescents. The Child Edition (CHIP-CE CRF) is for ages 6 to 11 and the Adolescent Edition (CHIP-AE) is for ages 12 and older. The Parent Report Form for Children (CHIP-CE PRF) will be rated by the parents of both children and adolescents in this study. The parent-rated version has been selected as the primary outcome measure while the self-rated versions constitute secondary outcome measures in this study.
Scores from the CHIP are reported at the domain level and as a profile-type. “Average”’ health on the CHIP domains is within 0.6 of a standard deviation of the mean of 50. That is, average/good health is in the range from 44 to 56 points (+/- 6 points, since the CHIP standard deviation is 10). A score of 43 or below indicates poor health in that domain. A score of 57 or higher indicates excellent health. The achievement domain describes the developmentally appropriate role functioning in school and with peers. It includes academic performance (5 items) and peer relations (5 items) sub domains.
The CHIP instruments were developed and validated by Drs. Barbara Starfield, Anne Riley and their colleagues at the Johns Hopkins Bloomberg School of Public Health (Riley et al. 1998, Starfield et al. 2000, Riley et al. 2004a, Riley et al. 2004b, Rajmil et al. 2003). The CHIP-CE PRF has already been shown to be sensitive to changes in patients with ADHD (B4Z-BP-LYBS study).
6.1.1. Child Health and Illness Profile – Child Edition – Parent Report Form (CHIP–CE PRF)
The CHIP-CE, Parent Report Form (CHIP-CE PRF), will be rated by the parents of both children and adolescents at Visits 2, 4, 5, 6, 7, 10 and at early discontinuation The CHIP-CE PRF, is a parent rated assessment of a child’s health status and level of functioning. It consists of 76 items and takes approximately 20 minutes to complete. It is a validated and comprehensive measure of a child’s functioning and examines the following domains: Satisfaction, Comfort, Risk Avoidance, Resilience, and Achievement. The majority of items assess frequency of activities or feelings using a five-point response format (for example: 'How good is your child at making friends?' (1=never, 5=always).
The total score will be calculated by summing the domain raw means and dividing by 5 (the number of domains).
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | 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 | 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) | 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 | Yes |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| 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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| 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 |
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| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| 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 | 4 |
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