Comparison of Atomoxetine Versus Placebo in Children and Adolescents With ADHD and Comorbid ODD in Germany

Study Overview
=================
Brief Summary
-----------------
A three-arm, randomized, double-blind, placebo-controlled, Phase 4, multicenter study to compare the efficacy and safety of atomoxetine versus placebo in children and adolescents aged 6 through 17 years with attention-deficit/hyperactivity disorder (ADHD) and comorbid oppositional defiant disorder (ODD) who are treated as outpatients in Germany. After an initial 3- to 28-day screening and washout phase, participants will be assigned to double-blind treatment with atomoxetine or placebo. A 2 week up-titration period will be succeeded by a 7 week treatment period at the target dose. The primary efficacy measure will be the Swanson, Nolan and Pelham Rating Scale Revised (SNAP-IV) ODD subscale score.

Official Title
-----------------
A Randomized, Double-Blind Comparison of Atomoxetine Versus Placebo in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder and Comorbid Oppositional Defiant Disorder

Conditions
-----------------
Attention Deficit Hyperactivity Disorder, Oppositional Defiant Disorder

Intervention / Treatment
-----------------
* Drug: Atomoxetine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female outpatients who are at least 6 years of age, and who will not have reached their 18th birthday Diagnosis of ADHD and presence of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria A through C for ODD (NOTE: diagnosis for conduct disorder not exclusionary) Normal intelligence Able to swallow capsules Exclusion Criteria: Weigh less than 20 kilogram (kg) or more than 90 kg at study entry Prior treatment with atomoxetine History of seizure disorder, suicidal risk, alcohol or drug abuse within the past 3 months History of severe allergies or multiple adverse drug reactions Cardiovascular disorders: hypertension, unexplained cardiac signs or symptoms, QT (measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle) prolongation , inherited cardiac disorders

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atomoxetine Fast Titration<br>0.5 milligram per kilogram (mg/kg) daily dose taken orally for 1 week, then 1.2 mg/kg daily dose taken orally for 8 weeks | Drug: Atomoxetine<br>* Dosage form for the atomoxetine fast and slow titration arms consists of 2.5 mg, 10 mg, 20 mg, 25 mg, and 40 mg capsules. Double-blind treatment will consist of 3 capsules taken once per day for approximately 9 weeks.<br>* Other names: Strattera;|
| Experimental: Atomoxetine Slow Titration<br>0.5 mg/kg daily dose taken orally for 1 week, then 0.8 mg/kg daily dose taken orally for 1 week, then 1.2 mg/kg daily dose taken orally for 7 weeks | Drug: Atomoxetine<br>* Dosage form for the atomoxetine fast and slow titration arms consists of 2.5 mg, 10 mg, 20 mg, 25 mg, and 40 mg capsules. Double-blind treatment will consist of 3 capsules taken once per day for approximately 9 weeks.<br>* Other names: Strattera;|
| Placebo Comparator: Placebo<br>matching placebo daily dose taken orally | Drug: Placebo<br>* Double-blind treatment will consist of 3 matching placebo capsules taken once per day by mouth for approximately 9 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Swanson, Nolan and Pelham Rating Scale Revised (SNAP-IV) Oppositional Defiant Disorder: (ODD) Score | The SNAP-IV, a 26-item scale, includes 1 item for each of the 18 symptoms contained in the DSM-IV diagnosis of ADHD and 1 item for each of the 8 symptoms contained in the DSM-IV diagnosis of ODD. Each item is scored on a 0 to 3 scale (0=Not at All, 1=Just a Little, 2=Pretty Much, 3=Very Much). The SNAP-IV yields scores in three domains: Inattention (items 1-9: subscore range=0-27), Hyperact-ivity/Impulsivity (items 10-18: subscale range=0-27), and Oppositional (items 19-26: subscale range=0-24). SNAP-IV: ADHD Combined Scale score (inattention + hyperactivity/impulsivity) ranges from 0-54. | 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Swanson, Nolan & Pelham Rating Scale - Revised (SNAP-IV): ADHD Combined Score | The SNAP-IV: ADHD Combined Subscale for inattention (items 1-9) and hyperactivity/impulsivity (items 11-19) scores the intensity of each item during the last seven days on a 0 to 3 scale (0=not at all, 1=just a little, 2=pretty much, 3=very much). The lowest possible score is 0; highest is 54. | 9 weeks | 
| Swanson, Nolan & Pelham Rating Scale - Revised (SNAP-IV): ADHD Inattention Score | The SNAP-IV: ADHD Inattention Subscale (items 1-9) scores the intensity of each item during the last seven days on a 0 to 3 scale (0=not at all, 1=just a little, 2=pretty much, 3=very much). The lowest possible score is 0; highest is 27. | 9 weeks | 
| Swanson, Nolan & Pelham Rating Scale - Revised (SNAP-IV): Hyperactivity/Impulsivity Score | The SNAP-IV: ADHD Hyperactivity/Impulsivity Subscale (items 10-18) scores the intensity of each item during the last seven days on a 0 to 3 scale (0=not at all, 1=just a little, 2=pretty much, 3=very much). The lowest possible score is 0; highest is 27. | 9 weeks | 
| Parent-Rated Attention-Deficit Scale (FBB-HKS), Total Score: Severity | FBB-HKS (Fremdbeurteilungsbogen fur Hyperkinetische Storungen), the German, parent-rated scale for attention-deficit, is a 20-item rating scale which describes ADHD symptom criteria of DSM-IV and is grouped based upon the 3 ADHD domains: inattention (items 1-9); hyperactivity (items 10-16); impulsivity (items 17-20). Parents rated symptom severity of each item during the last 7 days on a 0 to 3 scale (0=not at all to 3=very much). The total score was calculated for ADHD overall (sum of ratings for items 1-20, divided by 20). Higher scores indicate higher severity of symptoms. | 9 weeks | 
| Parent-Rated Oppositional Defiant/Conduct Disorders Scale (FBB-SSV): Total Score, Severity | FBB-SSV (Fremdbeurteilungsbogen fur Storungen des Sozialverhaltens), the German, parent-rated oppositional defiant/conduct disorders scale, covers 23 criteria for ODD and 25 for conduct disorder (CD) in four sections. Parents rated symptom severity of each item during the last 7 days on a 0 to 3 scale (0=not at all to 3=very much). The total score was calculated for ODD/CD overall (sum of ratings for items 1-17, divided by 17). Higher scores indicate higher severity of symptoms. | 9 weeks | 
| Investigator-Rated Individual Target Behaviors (ITB-Inv): Intensity Score | ITB-Inv assesses frequency and intensity of individually-defined target behaviors. The investigator defines 3 individual behavior problems based on interviews and additional information. Those most impairing for the child or stressful for the parents will be chosen as target behavior. Intensity during the last 7 days is rated on a 10-point scale (0=no problems to 9=most severe problems) with the lowest possible score of 0 and the highest possible of 27. | 9 weeks | 
| Investigator-Rated Individual Target Behaviors (ITB-Inv): Frequency Score | ITB-Inv assesses frequency and intensity of individually-defined target behaviors. The investigator defines 3 individual behavior problems based on interviews and additional information. Those most impairing for the child or stressful for the parents will be chosen as target behavior. Frequency of each target behavior during the last 7 days is rated on a 6-point scale (0=never to 5=always) with 0 as lowest possible score and 15 the highest possible score. | 9 weeks | 
| Impact on Family Scale (FaBel), Total Impact Score | Family burden is assessed by the FaBel questionnaire (German version of the Impact on Family Scale). Questionnaire is answered by participant's caregiver and contains 33 Likert-scaled items to assess general negative impact (of a disability, disorder, disease) on parents, description of social relationships, concern for siblings, financial impact, problems in coping as well as a total score. Each item is rated on a 4-point scale (1=fully applies, 4=applies not at all). Total scores range from 24-96. Higher scores correspond to higher family burden. | 9 weeks | 
| Clinical Global Impressions - Severity (CGI-S): ADHD Score | The physician-rated CGI-S ADHD measures the participant's overall severity of ADHD symptoms (1=normal, not at all ill; 7=among the most extremely ill patients) during the last 7 days. | 9 weeks | 
| Clinical Global Impressions - Severity (CGI-S): ODD Score | The physician-rated CGI-S ODD measures the participant's overall severity of ODD symptoms (1=normal, not at all ill; 7=among the most extremely ill patients) during the last 7 days. | 9 weeks | 
| Clinical Global Impressions - Severity (CGI-S): Combined ADHD and ODD Scores | The physician-rated CGI-S Combined ADHD and ODD measures the participant's overall severity of both ADHD and ODD symptoms (1=normal, not at all ill; 7=among the most extremely ill patients) during the last 7 days. | 9 weeks | 
| German Revised Children's Quality of Life Questionnaire (KINDL-R): Total Quality of Life Score | KINDL-R (Revidierter KINDer Lebensqualitatsfragebogen, revised version), a validated German quality of life (QOL) questionnaire, provides parents' views on their child's emotional QOL. It consists of 24 items covering 6 QOL related dimensions (subscales) and 7 additional items assessing chronic illness. Each item is rated on a 5-point scale (1= never; 5= all the time). The lowest possible score in the Total QOL score is 0; the highest possible score is 100. Scores were normalized between 0 and 100, irrespective of the number of items per subscore. Higher score indicates better QOL. | 9 weeks | 
| German Revised Children's Quality of Life Questionnaire (KINDL-R): Physical Well-Being Score | KINDL-R (Revidierter KINDer Lebensqualitatsfragebogen, revised version), a validated German quality of life (QOL) questionnaire, provides parents' views on their child's emotional QOL. It consists of 24 items covering 6 QOL related dimensions (subscales) and 7 additional items assessing chronic illness. Each item is rated on a 5-point scale (1= never; 5= all the time). The lowest possible score on the Physical Well-Being subscale is 0; highest possible score is 100. Scores were normalized between 0 and 100, irrespective of the number of items per subscore. Higher scores indicate better QOL. | 9 weeks | 
| German Revised Children's Quality of Life Questionnaire (KINDL-R): Emotional Well-Being Score | KINDL-R (Revidierter KINDer Lebensqualitatsfragebogen, revised version), a validated German quality of life (QOL) questionnaire, provides parents' views on their child's emotional QOL. It consists of 24 items covering 6 QOL related dimensions (subscales) and 7 additional items assessing chronic illness. Each item is rated on a 5-point scale (1= never; 5= all the time).The lowest possible score for the Emotional Well-Being subscale is 0; highest possible score is 100. Scores were normalized between 0 and 100, irrespective of the number of items per subscore. Higher scores indicate better QOL. | 9 weeks | 
| German Revised Children's Quality of Life Questionnaire (KINDL-R): Self Esteem Score | KINDL-R (Revidierter KINDer Lebensqualitatsfragebogen, revised version), a validated German quality of life (QOL) questionnaire, provides parents' views on their child's emotional QOL. It consists of 24 items covering 6 QOL related dimensions (subscales) and 7 additional items assessing chronic illness. Each item is rated on a 5-point scale (1= never; 5= all the time). The lowest possible score on the Self Esteem subscale is 0; the highest possible score is 100. Scores were normalized between 0 and 100, irrespective of the number of items per subscore. Higher scores indicate better QOL. | 9 weeks | 
| German Revised Children's Quality of Life Questionnaire (KINDL-R): Family Score | KINDL-R (Revidierter KINDer Lebensqualitatsfragebogen, revised version), a validated German quality of life (QOL) questionnaire, provides parents' views on their child's emotional QOL. It consists of 24 items covering 6 QOL related dimensions (subscales) and 7 additional items assessing chronic illness. Each item is rated on a 5-point scale (1=never; 5=all the time). The lowest possible score on the Family subscale is 0; the highest possible score is 100. Scores were normalized between 0 and 100, irrespective of the number of items per subscore. Higher scores indicate better QOL. | 9 weeks | 
| German Revised Children's Quality of Life Questionnaire (KINDL-R): Friends Score | KINDL-R (Revidierter KINDer Lebensqualitatsfragebogen, revised version), a validated German quality of life (QOL) questionnaire, provides parents' views on their child's emotional QOL. It consists of 24 items covering 6 QOL related dimensions (subscales) and 7 additional items assessing chronic illness. Each item is rated on a 5-point scale (1= never; 5= all the time). The lowest possible score on the Friends subscale is 0; the highest possible score is 100. Scores were normalized between 0 and 100, irrespective of the number of items per subscore. Higher scores indicate better QOL. | 9 weeks | 
| German Revised Children's Quality of Life Questionnaire (KINDL-R): School Score | KINDL-R (Revidierter KINDer Lebensqualitatsfragebogen, revised version), a validated German quality of life (QOL) questionnaire, provides parents' views on their child's emotional QOL. It consists of 24 items covering 6 QOL related dimensions (subscales) and 7 additional items assessing chronic illness. Each item is rated on a 5-point scale (1= never; 5= all the time). The lowest possible score on the School subscore is 0; the highest possible score is 100. Scores were normalized between 0 and 100, irrespective of the number of items per subscore. Higher scores indicate better QOL. | 9 weeks | 
| Number of Participants Discontinuing Treatment | Originally, time to treatment discontinuation was analyzed, deeming participants 'censored' if they reached the end of the observation period, were lost to followup, or withdrew informed consent. Because the median was not reached, the number of participants who discontinued (i.e., those who were not censored) is reported here. | 9 weeks | 
| Number of Patients Who Experienced Clinically Relevant Categories of Adverse Events During Initial Three Weeks of Study Treatment | Number of participants who experienced pre-specified categories of clinically relevant adverse events during the initial three-weeks of study treatment. NOTE: this is a subset of the overall adverse events which are reported by participant and event. | 3 weeks | 
| Number of Patients Who Experienced Clinically Relevant Categories of Adverse Events During Nine-Week Study Treatment Period | Number of participants who experienced pre-specified categories of clinically relevant adverse events during the nine-week study treatment period. NOTE: this is a subset of the overall adverse events which are reported by participant and event. | 9 weeks |