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CT Registry ID#8160

Atomoxetine Hydrochloride Copyright © 2005 Eli Lilly and Company. All rights reserved.

Summary ID# 8160

Clinical Study Summary: Study B4Z-TW-S010

Efficacy, Tolerability, and Safety of Once-Daily Atomoxetine Hydrochloride versus Placebo in

Taiwanese Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

Date summary approved by Lilly: 20 October 2005

Brief Summary of Results

• The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-Parent:Inv) total score decreased by 16.9±10.8 (mean±SD change from baseline to Visit 6, p<.001) with atomoxetine treatment. A decrease of 7.5±13.1 (mean±SD change from baseline to Visit 6, p=.002) in the ADHDRS-IV-Parent:Inv total score was observed with placebo treatment. At each visit during the treatment phase, comparison of the mean change from baseline between the two groups showed that atomoxetine was more effective than placebo at decreasing the ADHDRS-IV-Parent:Inv total score (p<.001).

• At each visit during the treatment phase, comparison of the mean change from baseline between the two groups showed that atomoxetine was more effective than placebo at decreasing the ADHDRS-IV-Parent:Inv Inattention subscale score and Hyperactivity/Impulsive subscale scores (p<.01).

• At the end of the treatment phase (Visit 6), 74% of subjects from the atomoxetine group were categorized as responders compared with 38% of subjects from the placebo group (p<.001). A responder was defined as having a >25% reduction from baseline in the ADHDRS-IV-Parent:Inv total score.

CT Registry ID#8160


• Comparison of the mean change from baseline to the end of Study Period II (SPII) between the two groups showed that atomoxetine was more effective than placebo at decreasing the mean Conners’ Parent Rating Scale-Revised: Short Form (CPRS-R:S) total score as well as all mean CPRS-R:S subscale scores (p<.05).

• Comparison of the mean change from baseline to Visit 6 between the two groups showed that atomoxetine was more effective than placebo at decreasing the mean Conners’ Teacher Rating Scale-Revised: Short Form (CTRS-R:S) total score as well as mean CTRS-R:S Cognitive Problems, Hyperactivity, and ADHD Index subscale scores (p<.05). The CTRS-R:S Oppositional subscale score was not statistically significantly altered compared to baseline in either treatment group.

• From the safety population (n=105), 70 (66.7 %) subjects reported one or more TEAE(s) (n=54 from the atomoxetine group, n=16 from the placebo group; p=.004). Of these 70 subjects, 45 (n=40 from the atomoxetine group, n=5 from the placebo group; p<.001) experienced drug-related treatment-emergent adverse events (TEAEs) in the opinion of the investigator. Two serious adverse events (SAEs) were reported during the study, with one being categorized as a serious TEAE. Both were assessed to be related to either study drug or study procedures.

• The most common TEAE reported by subjects from the atomoxetine group was anorexia, which was reported by 26 (36.6 %) subjects from this group compared with five (14.7 %) subjects from the placebo group (p=.02). Nausea was reported by 12 (16.9 %) subjects from the atomoxetine group, while no subjects receiving placebo reported this TEAE (p<.01). Anorexia was the most common drug-related TEAE reported by subjects from the atomoxetine group, with 23 cases categorized as drug-related.

• At all visits, there was a statistically significant weight decrease in the atomoxetine group (p<.001) and a statistically significant weight increase in the placebo group (p<.05). The difference between the two groups was statistically significant at all visits (p<.001). No between-group differences were observed for systolic blood pressure, diastolic blood pressure, heart rate, temperature, or weight.

• Statistically significant differences between treatment groups were observed for mean changes in some laboratory parameters compared to baseline, however these changes were, in the opinion of the treating investigator and the lead clinical research physician, clinically insignificant.

CT Registry ID#8160


Title of Study: Efficacy, Tolerability, and Safety of Once-Daily Atomoxetine Hydrochloride versus Placebo in Taiwanese Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. Investigator(s): This multi-center study included three principal investigators. Study Center(s): This study was conducted at three study centers in one country. Length of Study: 9 months Date of first subject visit: 26 February 2004 Date of last subject visit: 19 November 2004

Phase of Development: IIIb.

Objectives: Primary Objective:

• To test the hypothesis that atomoxetine administered as a single-daily dose provides superior efficacy compared with placebo in Taiwanese children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Assessment was measured by reduction from baseline to endpoint by the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-Parent:Inv) total score in the once-daily atomoxetine- and placebo-treated groups.

Secondary Objectives: • To compare the improvement in symptoms associated with ADHD in children and adolescents

achieved by once-daily dosing of atomoxetine or placebo as defined by a >25% reduction in the ADHDRS-IV-Parent:Inv score and by mean reductions in the Conners’ Parent Rating Scale-Revised: Short Form (CPRS-R:S) and ADHDRS-IV-Parent:Inv subscale scores.

• To compare the reduction in school-related symptoms between atomoxetine and placebo as assessed by the Conners’ Teacher Rating Scale-Revised: Short Form (CTRS-R:S).

• To assess the safety and tolerability of once-daily dosing of atomoxetine. Study Design: This was a multi-center, randomized, double-blind, placebo-controlled study in children and adolescents aged 6 through 16 years who met the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition TM (DSM-IVTM) criteria for ADHD, as well as criteria for enrollment. The protocol comprised three study periods and included an initial randomization of all subjects to acute treatment after an initial screening and washout period. Randomization was performed with 2:1 proportions of subjects being assigned to atomoxetine (target dose: 1.2 mg/kg/day) and placebo. During the acute treatment phase (Study Period II), study drug dosage were adjusted by the physician based on assessment of symptom response and tolerability. Following Study Period II, subjects entered a discontinuation phase comprised of one follow up visit. Number of Subjects: Planned: 70 atomoxetine, 35 placebo. Randomized/Entered: 72 atomoxetine (65 male, 7 female), 34 placebo (29 male, 5 female). Completed: 69 atomoxetine (63 male, 6 female), 29 placebo (24 male, 5 female). Diagnosis and Main Criteria for Inclusion: Subjects were aged 6 through 16 years with ADHD that met the DSM-IVTM disease diagnostic criteria as well as severity criteria. Diagnosis was assessed by clinical evaluation as well as administration of several modules of K-SADS:E-C structured interview. Subjects must also have had a total ADHDRS-IV-Parent:Inv score of at least 25 for boys or 22 for girls, or >12 for their diagnostic subtype at both Visit 1 and Visit 2. In addition, a Clinical Global Impressions-Attention-Deficit/Hyperactivity Disorder-Severity (CGI-ADHD-S) score ≥ 4 at both Visit 1 and Visit 2 was necessary. If subjects had taken any medication used to treat ADHD previously, they had to have completed the appropriate washout procedures. Test Product, Dose, and Mode of Administration: Atomoxetine Hydrochloride, given orally once daily. The target dose was 1.2 mg/kg/day up to a maximal daily dose of 100mg, provided as capsules (2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, and 40 mg).

CT Registry ID#8160


Reference Therapy, Dose, and Mode of Administration: Placebo, given orally once daily as capsules identical in appearance to test product. Duration of Treatment: 6 weeks. Atomoxetine Hydrochloride Frequency: 6 weeks. Placebo Frequency: 6 weeks.

Variables: Efficacy: Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-Parent:Inv) scale. Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scale. Conners’ Parent Rating Scale-Revised: Short Form (CPRS-R:S) scale. Conners’ Teacher Rating Scale-Revised: Short Form (CTRS-R:S) scale. Safety: Vital signs. Adverse events. Clinical laboratory tests. Evaluation Methods: Statistical: Descriptive statistics such as the number of observations, mean, median, standard deviations, minimum, maximum, and 95% confidence interval were used to summarize the continuous variables. Frequency and proportion were used to summarize the categorical variables. All statistical tests for efficacy endpoints and other clinical endpoints were two-sided and evaluated at p=.05 level of significance. The primary analysis for efficacy endpoints were performed based on the intent-to-treat (ITT) population. The last-observation-carried-forward (LOCF) procedure was used to account for missing data among the efficacy parameters. No imputation was done for estimating the missing value for safety variables. For demographic data and baseline characteristics, the comparability between treatment groups was examined by using two-way analysis of variance (ANOVA) with fixed factor treatment and investigator as terms in the model for continuous variables. Fisher’s exact test was used to compare between treatment groups for categorical variables. The primary efficacy endpoint, changes in the ADHDRS-IV-Parent:Inv total score, was compared between treatment groups using an analysis of covariance (ANCOVA) with terms of baseline score, treatment, and investigator in the model. The point estimators and 95% confidence intervals of treatment difference were also provided. The paired t test was used to analyze the change from baseline within each treatment group. The secondary analyses of changes in the ADHDRS-IV-Parent:Inv total score also included an ANOVA (excluding the baseline term from the primary analysis ANCOVA). Secondary efficacy variables, including the ADHDRS-IV-Parent:Inv subscale scores, CGI-ADHD-S, CPRS-R:S total and subscale scores, and CTRS-R:S total and subscale scores were analyzed in a similar fashion as ADHDRS-IV-Parent:Inv total score. The Corchran-Mantel-Haenszel test stratified by site was used to assess the ADHD responder rate. For time to onset of sustained response, treatment differences were assessed using a Cox proportional hazards cure model.

CT Registry ID#8160


Compliance condition was summarized by visits and by treatment groups. All adverse events were coded by the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) code system. The frequency and percentage of treatment-emergent adverse events (TEAEs) during Study Period II were presented for each treatment group. The treatment groups, body systems, COSTART preferred term, and severity were summarized for TEAEs. Fisher’s exact test was used to compare the number of subjects with TEAEs between treatment groups. For the laboratory parameters, the treatment differences in changes from baseline to endpoint (last assessment during Study Period II) scores were computed using ANOVA and within group changes were assessed with paired t tests. Transition tables from baseline to endpoint for laboratory parameters were provided by treatment groups. For vital signs and body weight, the comparison between treatment groups was analyzed based on the change from baseline by using ANOVA and paired t test for within each treatment group. The categorical analyses for vital signs were based on the normal (< 90th percentile), high-normal (90th – 95th percentile), and hypertension (≥95th percentile) ranges (by age group) for blood pressure and the low, normal, and high ranges for heart rates. Transition tables from baseline to each visit for blood pressure and heart rate were summarized.

CT Registry ID#8160


Results:

Subject Demographics

Of all randomized subjects, there were more males than females in both atomoxetine (90.28 % versus 9.72 %) and placebo (85.29 % versus 14.71 %) groups (Table 1). The average age was 8.5 years in the atomoxetine group, and 9.0 years in the placebo group with comparable height and weight. A statistically significant difference was observed in the education level (p=.014), due to different distributions of school grade levels between the two treatment groups.

Forty-one (56.94 %) and 20 (58.82 %) subjects from the atomoxetine group and the placebo group respectively, had received treatment of psychostimulants before entering the study. Forty-three (59.72 %) and 20 (58.82 %) subjects from the atomoxetine group and the placebo group respectively, had previous ADHD therapy. Eighteen (25 %) subjects from the atomoxetine group and 12 (35.29 %) subjects from the placebo group were categorized as “inattention” for their ADHD subtype in accordance with DSM-IV criteria, while 54 (75 %) subjects from the atomoxetine group and 22 (64.71 %) subjects from the placebo group, had “combined” ADHD subtypes. The mean age of onset among subjects from both atomoxetine and placebo groups was 5.4 years. No statistically significant differences were observed.

The Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version: Behavioral Disorders Supplement (KSADS-PL:Behavioral) includes ADHD, oppositional disorder, and conduct disorder, and subjects may have more than one of the disorders. From the atomoxetine group, 71 (98.61 %) subjects had ADHD, 14 (19.44 %) subjects had oppositional disorder, and seven (9.72 %) subjects had conduct disorder. From the placebo group, all subjects had ADHD, three (8.82 %) subjects had oppositional disorder, and two (5.88 %) subjects had conduct disorder. There were no cases of KSADS-PL Affective Disorder or KSADS-PL Anxiety Disorder in either treatment group.

CT Registry ID#8160


Table 1. Baseline Demographics

Atomoxetine Placebo Difference Characteristic Statistics (N=72) (N=34)

Sex Female 7 (9.72%) 5 (14.71%) 0.516a

Male 65 (90.28%) 29 (85.29%)

Age (year) N 72 34 Mean ± SD

8.5 ±2.0 9.0 ±2.5 -0.5

Median 8.0 8.5

Min - Max 6.0 - 13.0 6.0 - 15.0 95% CI 8.1 - 9.0 8.1 - 9.9 -1.3 - 0.4

P-value 0.284b

Origin East/Southern Asian 72 (100.0%) 34 (100.0%)

Education Kindergarten

3 (4.17%) 0 (0.00%) 0.014 a

Elementary School Grade 1 11 (15.28%) 7 (20.59%) Elementary School Grade 2 17 (23.61%) 7 (20.59%) Elementary School Grade 3 12 (16.67%) 5 (14.71%) Elementary School Grade 4 10 (13.89%) 6 (17.65%) Elementary School Grade 5 12 (16.67%) 0 (0.00%) Elementary School Grade 6 0 (0.00%) 3 (8.82%) Junior High School Grade 1 3 (4.17%) 3 (8.82%) Junior High School Grade 2 4 (5.56%) 1 (2.94%) Junior High School Grade 3 0 (0.00%) 2 (5.88%)

Family History c Mother 0 (0.00%) 0 (0.00%) Father 5 (6.94%) 1 (2.94%) Grandparents 1 (1.39%) 0 (0.00%) Siblings 7 (9.72%) 4 (11.76%)

Height (cm) N 72 34

Mean ±SD 133.5 ±11.8 133.9 ±13.2 -0.4

Median 132.0 128.9

Min - Max 114.3 - 168.0 115.5 - 168.0 95% CI 130.8 - 136.3 129.3 - 138.5 -5.4 - 4.7

P-value 0.843 b

Weight (kg) d N 72 34

Mean ±SD 31.3 ±8.9 32.3 ±9.1 -1

Median 29.5 28.5

Min - Max 20.0 - 57.6 20.0 - 54.0 95% CI 29.2 - 33.4 29.1 - 35.5 -4.7 - 2.8

P-value 0.530 b

(continued)

CT Registry ID#8160


Table 1. Baseline Demographics (continued)


Previous Psychostimulants Yes 41 (56.94%) 20 (58.82%) 1.000 a

No 31 (43.06%) 14 (41.18%)

Previous ADHD Therapy Yes 43 (59.72%) 20 (58.82%) 1.000 a

No 29 (40.28%) 14 (41.18%)

DSM-IV ADHD Subtype Inattention

18 (25.00%) 12 (35.29%) 0.356 a

Hyperactivity 0 (0.00%) 0 (0.00%) Combined

54 (75.00%) 22 (64.71%)

Age at Onset of ADHD (year) N

72 34

Mean ±SD 5.4 ±1.3 5.4 ±1.3 0.0

Median 5.5 5.3

Min - Max 1.0 - 7.0 2.0 - 7.0 95% CI 5.1 – 5.7 5.0 – 5.9 -0.5 - 0.5

P-value 0.942 b

KSADS-PL Behavior

Disorders c ADHD 71 (98.61%) 34 (100.0%)

Oppositional Defiant 14 (19.44%) 3 (8.82%) Conduct Disorder 7 (9.72%) 2 (5.88%)

KSADS-PL Affective Disorders c

Major Depressive Disorder 0 (0.00%) 0 (0.00%)

Seasonal Pattern

0 (0.00%) 0 (0.00%)

Dysthymia 0 (0.00%) 0 (0.00%)

Adjustment Disorder 0 (0.00%) 0 (0.00%)

Any Other Depressive Disorder

0 (0.00%) 0 (0.00%)

(continued)

CT Registry ID#8160


Table 1. Baseline Demographics (concluded)


KSADA-PL Anxiety Disorders c

Panic Disorder 0 (0.00%) 0 (0.00%)

Separation Anxiety Disorder 0 (0.00%) 0 (0.00%)

Avoidant Disorder/Social Phobia

0 (0.00%) 0 (0.00%)

Agoraphobia and Specific Phobias

0 (0.00%) 0 (0.00%)

Overanxious/Generalized Anxiety Disorder

0 (0.00%) 0 (0.00%)

Obsessive Compulsive Disorder

0 (0.00%) 0 (0.00%)

Abbreviations: ADHD = attention-deficit/hyperactivity disorder; CI = confidence interval; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; KSADS-PL Affective Disorders = Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version: Affective Disorders Supplement; KSADA-PL Anxiety Disorders = ;KSADS-PL Behavior Disorders = Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version: Behavioral Disorders Supplement; SD = standard deviation.

a p-value from Fisher’s exact test. b p-value between treatment groups was using ANOVA with terms of treatment and investigator. c Subjects may choose more than one answer. d Weight was assessed at Visit 2.

Subject Disposition

A total of 114 subjects were entered into the screening phase. Of these, eight subjects were screen failures, and the remaining 106 subjects were randomized to receive treatment of atomoxetine hydrochloride (n=72) or placebo (n=34). Table 2 shows the number of subjects at each visit during the study. From the atomoxetine group, 69 (95.83 %) subjects completed Study Period II, compared with 29 (85.29 %) subjects from the placebo group (p=.107). All of these subjects proceeded into Study Period III, with the exception of one subject from the atomoxetine group.

Table 3 summarizes the reasons given for early discontinuation from Study Period II. Of those subjects who discontinued early from the atomoxetine group, one (1.39 %) subject discontinued due to an adverse event (dizziness), one (1.39 %) subject discontinued due to a lack of efficacy based on subject/caregiver’s perception, and one (1.39 %) subject discontinued due to personal conflict or other subject/caregiver decision. From the placebo group, four (11.76 %) subjects withdrew due to a lack of efficacy based on subject/caregiver’s perception and one (2.94 %) subject withdrew due to a lack of efficacy based on subject/caregiver and physician’s perception.

CT Registry ID#8160


Table 2. Subject Disposition by Visit

Atomoxetine Placebo Total Number of Subjects at Each Visit (N=72) (N=34) (N=106)

Visit 1 (Screening) 72 34 106

Visit 2 (Baseline) 72 34 106

Visit 3 (Week 1) 72 34 106

Visit 4 (Week 2) 71 34 105

Visit 5 (Week 4) 69 32 101

Visit 6 (Week 6) 69 29 98

Visit 7 (Study Period III) 68 29 97

Table 3. Reasons for Discontinuation

Atomoxetine Placebo (N=72) (N=34) p-value*

Completed Study Period II 69 (95.83%) 29 (85.29%) 0.107

Early Discontinued Study Period II 3 (4.17%) 5 (14.71%) Reason for Early Discontinuation Adverse event 1 (1.39%) 0 (0.00%) Lack of efficacy, subject/caregiver perception 1 (1.39%) 4 (11.76%) Lack of efficacy, subject/caregiver and physician perception 0 (0.00%) 1 (2.94%) Personal conflict or other subject/caregiver decision 1 (1.39%) 0 (0.00%)

* p-value is from Fisher’s exact test.

CT Registry ID#8160


Primary Efficacy Measure

The primary efficacy measure was the mean change in Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-Parent:Inv) total score from baseline to Visits 3, 4, 5, and 6 (Table 4). At baseline, the mean total score for ADHDRS-IV-Parent:Inv was 36.7±6.7 for the atomoxetine group and 37.1±6.4 for the placebo group (p=.741). At Visit 3, the mean total score for ADHDRS-IV-Parent:Inv had decreased by 12.2±9.7 (p<.001) and 5.5±7.2 (p<.001) compared to baseline for the atomoxetine and placebo groups respectively. At Visit 4, these decreases were 14.3±10.4 (p<.001) and 7.5±11.0 (p<.001) for the atomoxetine and placebo groups respectively. At Visit 5 and Visit 6, the mean decreases from baseline in ADHDRS-IV-Parent:Inv total score were 15.5±10.2 (p<.001) and 16.9±10.8 (p<.001) respectively in the atomoxetine group. For the placebo group, the mean decreases from baseline in ADHDRS-IV-Parent:Inv total score were 5.8±12.1 (p<.001) and 7.5±13.1 (p=.002) at Visit 5 and Visit 6 respectively. At each visit, the differences observed between the two groups were statistically significant (p<.001).

Table 4. ADHDRS-IV-Parent:Inv Total Score Change from Baseline to Visits 3, 4, 5, and 6

Atomoxetine Placebo

Visit Statistics (N=72) (N=34) Difference P-valuea P-valueb

Baseline N 72 34

Mean ±SD 36.7 ±6.7 37.1 ±6.4 -0.4

Median 36.5 37.5

Min - Max 23.0 - 50.0 25.0 - 52.0

95% CI 35.2 - 38.3 34.8 - 39.3 -3.1 - 2.4

P-value 0.741

Visit 3 N 72 34

Mean ±SD 24.5 ±9.3 31.6 ±7.4 -7.1

Median 25.5 32.5

Min - Max 4.0 - 45.0 13.0 - 46.0

95% CI 22.3 - 26.7 29.0 - 34.2 -10.7 - -3.5

(continued)

CT Registry ID#8160


Table 4. ADHDRS-IV-Parent:Inv Total Score Change from Baseline to Visits 3, 4, 5, and 6 (continued)

Atomoxetine Placebo


Change from Baseline to Visit 3

N 72 34

Mean ±SD -12.2 ±9.7 -5.5 ±7.2 -6.7

Median -10.5 -3.0

Min - Max -40.0 - 4.0 -27.0 - 4.0

95% CI -14.5 - -9.9 -8.0 - -3.0 -10.1 - -3.4

P-valuec < 0.001 < 0.001 < 0.001 < 0.001

Visit 4 N 72 34

Mean ±SD 22.4 ±10.1 29.6 ±10.8 -7.2

Median 21.0 31.0

Min - Max 1.0 - 44.0 10.0 - 45.0

95% CI 20.0 - 24.7 25.8 - 33.4 -11.5 - -3.0


N 72 34

Mean ±SD -14.3 ±10.4 -7.5 ±11.0 -6.9

Median -16.0 -5.0

Min - Max -44.0 - 7.0 -32.0 - 9.0

95% CI -16.8 - -11.9 -11.3 - -3.6 -11.3 - -2.5

P-valuec < 0.001 < 0.001 < 0.001 0.002

Visit 5 N 72 34

Mean ±SD 21.2 ±10.1 31.3 ±11.9 -10.0

Median 21.0 35.0

Min - Max 1.0 - 42.0 6.0 - 46.0

95% CI 18.9 - 23.6 27.1 - 35.4 -14.4 - -5.6

(continued)

CT Registry ID#8160


Table 4. ADHDRS-IV-Parent:Inv Total Score Change from Baseline to Visits 3, 4, 5, and 6 (concluded)

Atomoxetine Placebo



N 72 34

Mean ±SD -15.5 ±10.2 -5.8 ±12.1 -9.7

Median -15.5 -3.0

Min - Max -40.0 - 7.0 -37.0 - 10.0

95% CI -17.9 - -13.1 -10.0 - -1.6 -14.1 - -5.2

P-valuec < 0.001 0.008 < 0.001 < 0.001

Visit 6 N 72 34

Mean ±SD 19.8 ±10.7 29.6 ±12.6 -9.8

Median 18.5 34.5

Min - Max 0.0 - 54.0 6.0 - 52.0

95% CI 17.3 - 22.3 25.2 - 34.0 -14.5 - -5.2


N 72 34

Mean ±SD -16.9 ±10.8 -7.5 ±13.1 -9.5

Median -18.5 -5.5

Min - Max -40.0 - 7.0 -39.0 - 11.0

95% CI -19.5 - -14.4 -12.0 - -2.9 -14.2 - -4.7

P-valuec < 0.001 0.002 < 0.001 < 0.001

Abbreviations: ADHDRS-IV-Parent:Inv = Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored; CI = confidence interval; SD = standard deviation.

a p-value between treatment groups using ANCOVA with terms of baseline score, treatment, and investigator.

b p-value between treatment groups using ANOVA with terms of treatment and investigator. c p-value within each treatment group was derived from paired t test.

CT Registry ID#8160


Secondary Efficacy Measures

Table 5 shows the ADHDRS-IV-Parent:Inv Inattention subscale scores at each visit for both treatment groups. Baseline scores were not statistically significantly different between the two groups (p=.455). Mean scores from the atomoxetine group statistically significantly decreased from baseline by 6.6±5.7 (p<.001), 7.5±6.3 (p<.001), 8.0±6.1 (p<.001), and 8.5±6.2 (p<.001) at Visit 3, Visit 4, Visit 5, and Visit 6 respectively. For the placebo group, the mean scores at Visit 3, Visit 4, Visit 5, and Visit 6 had decreased by 3.1±4.5 (p<.001), 4.1±5.8 (p<.001), 3.2±6.3 (p=.005), and 4.1±7.2 (p=.002) respectively, compared to baseline. Statistically significant differences were observed between the two groups in the changes from baseline at each visit (p<.01).

Table 5. ADHDRS-IV-Parent:Inv Inattention Subscale Score

Atomoxetine Placebo


Baseline N 72 34

Mean ±SD 19.7 ±3.8 20.2 ±3.4 -0.5

Median 19.0 19.5

Min - Max 8.0 - 27.0 14.0 - 27.0

95% CI 18.8 - 20.6 19.0 - 21.4 -2.0 - 1.0

P-value 0.455

Visit 3 N 72 34

Mean ±SD 13.0 ±4.6 17.1 ±4.2 -4.1

Median 13.5 17.5

Min - Max 3.0 - 23.0 7.0 - 25.0

95% CI 11.9 - 14.1 15.6 - 18.5 -5.9 - -2.2

(continued)

CT Registry ID#8160


Table 5. ADHDRS-IV-Parent:Inv Inattention Subscale Score (continued)

Atomoxetine Placebo



N 72 34

Mean ±SD -6.6 ±5.7 -3.1 ±4.5 -3.6

Median -6.0 -2.0

Min - Max -24.0 - 4.0 -17.0 - 2.0

95% CI -8.0 - -5.3 -4.7 - -1.5 -5.7 - -1.4

P-valuec < 0.001 < 0.001 < 0.001 0.002

Visit 4 N 72 34

Mean ±SD 12.2 ±5.6 16.0 ±5.7 -3.9

Median 12.0 17.5

Min - Max 0.0 - 24.0 3.0 - 25.0

95% CI 10.8 - 13.5 14.0 - 18.0 -6.2 - -1.6


N 72 34

Mean ±SD -7.5 ±6.3 -4.1 ±5.8 -3.4

Median -7.0 -2.5

Min - Max -27.0 - 6.0 -21.0 - 4.0

95% CI -9.0 - -6.0 -6.2 - -2.1 -5.9 - -0.8

P-valuec < 0.001 < 0.001 0.002 0.010

Visit 5 N 72 34

Mean ±SD 11.6 ±5.4 16.9 ±6.5 -5.3

Median 10.5 20.0

Min - Max 1.0 - 25.0 4.0 - 25.0

95% CI 10.4 - 12.9 14.7 - 19.2 -7.7 - -2.9

(continued)

CT Registry ID#8160


Table 5. ADHDRS-IV-Parent:Inv Inattention Subscale Score (concluded)

Atomoxetine Placebo



N 72 34

Mean ±SD -8.0 ±6.1 -3.2 ±6.3 -4.8

Median -8.0 -2.0

Min - Max -21.0 - 5.0 -19.0 - 7.0

95% CI -9.5 - -6.6 -5.4 - -1.0 -7.3 - -2.2

P-valuec < 0.001 0.005 < 0.001 < 0.001

Visit 6 N 72 34

Mean ±SD 11.2 ±5.8 16.0 ±6.5 -4.8

Median 10.0 18.5

Min - Max 0.0 - 27.0 4.0 - 27.0

95% CI 9.8 - 12.6 13.8 - 18.3 -7.3 - -2.3


N 72 34

Mean ±SD -8.5 ±6.2 -4.1 ±7.2 -4.3

Median -9.5 -2.0

Min - Max -20.0 - 5.0 -22.0 - 7.0

95% CI -9.9 - -7.0 -6.7 - -1.6 -7.0 - -1.6

P-valuec < 0.001 0.002 < 0.001 0.002




CT Registry ID#8160


Table 6 shows the ADHDRS-IV-Parent:Inv Hyperactivity/Impulsive subscale scores at each visit for both treatment groups. Baseline scores were not statistically significantly different between the two groups (p=.885). Mean scores for the Hyperactivity/Impulsive subscale from the atomoxetine group statistically significantly decreased compared to baseline by 5.6±5.0 (p<.001), 6.8±5.1 (p<.001), 7.5±4.9 (p<.001), and 8.5±5.5 (p<.001) at Visit 3, Visit 4, Visit 5, and Visit 6 respectively. For the placebo group, the mean scores at Visit 3, Visit 4, Visit 5, and Visit 6 had decreased by 2.4±4.1 (p=.002), 3.3±5.9 (p=.002), 2.6±6.3 (p=.022), and 3.3±6.7 (p=.007) respectively compared to baseline. Statistically significant differences were observed between the two groups in the changes from baseline to the scores at each visit (p<0.01).

Table 6. ADHDRS-IV-Parent:Inv Hyperactivity/Impulsive Subscale Score

Atomoxetine Placebo


Baseline N 72 34

Mean ±SD 17.1 ±4.8 16.9 ±4.6 0.1

Median 16.0 18.0

Min - Max 5.0 - 26.0 9.0 - 26.0

95% CI 15.9 - 18.2 15.3 - 18.5 -1.8 - 2.1

P-valuec 0.885

Visit 3 N 72 34

Mean ±SD 11.5 ±5.5 14.5 ±4.4 -3.0

Median 11.5 15.0

Min - Max 1.0 - 25.0 6.0 - 22.0

95% CI 10.2 - 12.8 13.0 - 16.0 -5.2 - -0.9


N 72 34

Mean ±SD -5.6 ±5.0 -2.4 ±4.1 -3.2

Median -5.0 -2.0

Min - Max -16.0 - 4.0 -13.0 - 4.0

95% CI -6.8 - -4.4 -3.8 - -1.0 -5.1 - -1.2

P-valuec < 0.001 0.002 0.001 0.002

(continued)

CT Registry ID#8160


Table 6. ADHDRS-IV-Parent:Inv Hyperactivity/Impulsive Subscale Score (continued)

Atomoxetine Placebo


Visit 4 N 72 34

Mean ±SD 10.2 ±5.5 13.6 ±6.1 -3.4

Median 10.0 12.0

Min - Max 0.0 - 22.0 3.0 - 24.0

95% CI 8.9 - 11.5 11.5 - 15.7 -5.7 - -1.0


N 72 34

Mean ±SD -6.8 ±5.1 -3.3 ±5.9 -3.5

Median -7.0 -3.5

Min - Max -17.0 - 5.0 -17.0 - 5.0

95% CI -8.0 - -5.6 -5.4 - -1.3 -5.7 - -1.3

P-valuec < 0.001 0.002 0.001 0.002

Visit 5 N 72 34

Mean ±SD 9.6 ±5.6 14.3 ±6.2 -4.7

Median 9.0 14.5

Min - Max 0.0 - 21.0 2.0 - 24.0

95% CI 8.3 - 10.9 12.2 - 16.5 -7.1 - -2.3


N 72 34

Mean ±SD -7.5 ±4.9 -2.6 ±6.3 -4.9

Median -7.0 -1.0

Min - Max -19.0 - 2.0 -18.0 - 7.0

95% CI -8.6 - -6.3 -4.8 - -0.4 -7.1 - -2.7

P-valuec < 0.001 0.022 < 0.001 < 0.001

(continued)

CT Registry ID#8160


Table 6. ADHDRS-IV-Parent:Inv Hyperactivity/Impulsive Subscale Score (concluded)

Atomoxetine Placebo


Visit 6 N 72 34

Mean ±SD 8.6 ±5.5 13.6 ±6.8 -5.0

Median 8.5 14.5

Min - Max 0.0 - 27.0 0.0 - 25.0

95% CI 7.3 - 9.9 11.2 - 16.0 -7.5 - -2.6


N 72 34

Mean ±SD -8.5 ±5.5 -3.3 ±6.7 -5.2

Median -9.0 -4.0

Min - Max -21.0 - 3.0 -21.0 - 8.0

95% CI -9.8 - -7.2 -5.7 - -1.0 -7.6 - -2.7

P-valuec < 0.001 0.007 < 0.001 < 0.001




Table 7 shows the Clinical Global Impressions-Attention-Deficit/Hyperactivity Disorder-Severity (CGI-ADHD-S) scores at each visit for both treatment groups. Baseline scores were not statistically significantly different between the two groups (p=.703). Mean CGI-ADHD-S scores from the atomoxetine group had decreased compared to baseline by 1.3±1.0 (p<.001), 1.6±1.1 (p<.001), 1.7±1.2 (p<.001), and 2.0±1.3 (p<.001) at Visit 3, Visit 4, Visit 5, and Visit 6 respectively. For the placebo group, the mean scores at Visit 3, Visit 4, Visit 5, and Visit 6 had decreased compared to baseline by 0.5±1.0 (p=.006), 0.5±1.2 (p=.016), 0.5±1.4 (p=.029), and 0.8±1.5 (p=.003) respectively. Statistically significant differences were observed between the two groups in the changes from baseline to the scores at each visit (p<.05).

CT Registry ID#8160


Table 7. CGI-ADHD-S Score

Atomoxetine Placebo


Baseline N 72 34

Mean ±SD 5.3 ±0.8 5.2 ±0.8 0.1

Median 5.0 5.0

Min - Max 4.0 - 7.0 4.0 - 7.0

95% CI 5.1 - 5.5 4.9 - 5.5 -0.3 - 0.4

P-valuec 0.703

Visit 3 N 72 34

Mean ±SD 4.0 ±1.0 4.7 ±1.0 -0.7

Median 4.0 5.0

Min - Max 2.0 - 6.0 3.0 - 6.0

95% CI 3.7 - 4.2 4.4 - 5.1 -1.2 - -0.3


N 72 34

Mean ±SD -1.3 ±1.0 -0.5 ±1.0 -0.8

Median -1.0 0.0

Min - Max -3.0 - 1.0 -4.0 - 1.0

95% CI -1.5 - -1.1 -0.8 - -0.2 -1.2 - -0.4

P-valuec < 0.001 0.006 < 0.001 < 0.001

Visit 4 N 72 34

Mean ±SD 3.7 ±1.1 4.7 ±1.2 -1.0

Median 4.0 5.0

Min - Max 1.0 - 6.0 2.0 - 7.0

95% CI 3.4 - 3.9 4.3 - 5.1 -1.5 - -0.6

(continued)

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Table 7. CGI-ADHD-S Score (continued)

Atomoxetine Placebo



N 72 34

Mean ±SD -1.6 ±1.1 -0.5 ±1.2 -1.1

Median -2.0 0.0

Min - Max -4.0 - 1.0 -4.0 - 1.0

95% CI -1.9 - -1.4 -1.0 - -0.1 -1.6 - -0.6

P-value < 0.001 0.016 < 0.001 < 0.001

Visit 5 N 72 34

Mean ±SD 3.6 ±1.1 4.7 ±1.3 -1.1

Median 3.0 5.0

Min - Max 1.0 - 6.0 2.0 - 7.0

95% CI 3.3 - 3.8 4.2 - 5.1 -1.6 - -0.6


N 72 34

Mean ±SD -1.7 ±1.2 -0.5 ±1.4 -1.2

Median -2.0 0.0

Min - Max -4.0 - 1.0 -4.0 - 2.0

95% CI -2.0 - -1.5 -1.0 - -0.1 -1.7 - -0.7

P-value < 0.001 0.029 < 0.001 < 0.001

Visit 6 N 72 34

Mean ±SD 3.3 ±1.3 4.4 ±1.4 -1.1

Median 3.0 4.5

Min - Max 1.0 - 6.0 2.0 - 7.0

95% CI 3.0 - 3.6 3.9 - 4.9 -1.6 - -0.6

(continued)

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Table 7. CGI-ADHD-S Score (concluded)

Atomoxetine Placebo



N 72 34

Mean ±SD -2.0 ±1.3 -0.8 ±1.5 -1.2

Median -2.0 -0.5

Min - Max -5.0 - 1.0 -5.0 - 2.0

95% CI -2.3 - -1.7 -1.3 - -0.3 -1.7 - -0.6

P-value < 0.001 0.003 < 0.001 < 0.001

Abbreviations: CGI-ADHD-S = Clinical Global Impressions-Attention-Deficit/Hyperactivity Disorder-Severity; CI = confidence interval; SD = standard deviation.



The change in Conners’ Parent Rating Scale-Revised: Short Form (CPRS-R:S) total score from baseline to the end of Study Period II for each treatment group is presented in Table 8. Baseline scores were not statistically significantly different between the two groups (p=.614). At the end of Study Period II, the mean CPRS-R:S total scores had decreased by 12.2±11.3 (p<.001) in the atomoxetine group, while the decrease of 3.5±15.3 in the placebo group was not statistically significant (p=.193). The difference between the score changes in the two treatment groups was statistically significant (p=.002).

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Table 8. CPRS-R:S Total Score

Atomoxetine Placebo


Baseline N 69 33

Mean ±SD 44.6 ±13.0 43.2 ±15.2 1.4

Median 45.0 42.0

Min - Max 15.6 - 68.0 7.0 - 65.4

95% CI 41.5 - 47.7 37.8 - 48.6 -4.4 - 7.2

P-value 0.614

SPII N 69 33

Mean ±SD 32.4 ±14.8 39.7 ±18.0 -7.2

Median 33.0 38.0

Min - Max 0.0 - 73.0 7.0 - 73.0

95% CI 28.9 - 36.0 33.3 - 46.1 -13.9 - -0.6

Change from Baseline to SPII N 69 33

Mean ±SD -12.2 ±11.3 -3.5 ±15.3 -8.6

Median -10.0 0.0

Min - Max -46.0 - 11.7 -50.0 - 23.0

95% CI -14.9 - -9.4 -9.0 - 1.9 -14.6 - -2.6

P-value < 0.001 0.193 0.002 0.002

Abbreviations: CPRS-R:S = Conners’ Parent Rating Scale-Revised: Short Form; CI = confidence interval; SD = standard deviation; SPII = Study Period II.



The change in CPRS-R:S Oppositional subscale score from baseline to the end of Study Period II for each treatment group is presented in Table 9. Baseline scores were not statistically different between the two groups (p=.069). At the end of Study Period II, the mean CPRS-R:S Oppositional subscale score had decreased by 1.1±3.4 (p<.01) in the atomoxetine group, while the decrease of 0.6±3.8 in the placebo group was not statistically significant (p=.403). The difference between the score changes in the two treatment groups was not statistically significant when analyzed using ANCOVA with terms of baseline score, treatment, and investigator in the model (p=.098), however this

CT Registry ID#8160


difference was statistically significant when analyzed using ANOVA with terms of treatment and investigator in the model (p=.027).

Table 9. CPRS-R:S Oppositional Subscale Score

Atomoxetine Placebo


Baseline N 71 34

Mean ±SD 8.2 ±3.8 6.8 ±3.9 1.5

Median 8.0 7.0

Min - Max 0.0 - 17.0 0.0 - 16.0

95% CI 7.3 - 9.1 5.4 - 8.1 -0.1 - 3.0

P-valuec 0.069

SPII N 71 34

Mean ±SD 7.1 ±3.9 7.3 ±4.8 -0.2

Median 7.0 6.0

Min - Max 0.0 - 18.0 0.0 - 18.0

95% CI 6.2 - 8.0 5.6 - 9.0 -2.0 - 1.5


Mean ±SD -1.1 ±3.4 0.6 ±3.8 -1.7

Median -1.0 1.0

Min - Max -10.0 - 6.0 -9.0 - 8.0

95% CI -1.9 - -0.3 -0.8 - 1.9 -3.2 - -0.2

P-valuec 0.006 0.403 0.098 0.027




CT Registry ID#8160


The change in CPRS-R:S Cognitive Problems subscale score from baseline to the end of Study Period II for each treatment group is presented in Table 10. Baseline scores were not statistically different between the two groups (p=.961). At the end of Study Period II, the mean CPRS-R:S Cognitive Problems subscale score had decreased by 3.5±3.6 (p<.001) in the atomoxetine group, while the decrease of 0.8±4.6 in the placebo group was not statistically significant (p=.316). The difference between the score changes in the two treatment groups was statistically significant (p<.001).

Table 10. CPRS-R:S Cognitive Problems Subscale Score

Atomoxetine Placebo


Baseline N 71 34

Mean ±SD 10.4 ±3.8 10.5 ±4.4 -0.1

Median 11.0 11.0

Min - Max 1.2 - 18.0 1.0 - 18.0

95% CI 9.5 - 11.4 9.0 - 12.0 -1.7 - 1.6

P-value 0.961

SPII N 71 34

Mean ±SD 7.0 ±4.2 9.7 ±4.8 -2.7

Median 7.0 9.5

Min - Max 0.0 - 18.0 1.0 - 18.0

95% CI 6.0 - 8.0 8.0 - 11.4 -4.5 - -0.9


Mean ±SD -3.5 ±3.6 -0.8 ±4.6 -2.7

Median -3.0 -0.6

Min - Max -13.2 - 5.0 -13.0 - 7.0

95% CI -4.3 - -2.6 -2.4 - 0.8 -4.3 - -1.1

P-value < 0.001 0.316 < 0.001 0.001




CT Registry ID#8160


The change in CPRS-R:S Hyperactivity subscale score from baseline to the end of Study Period II for each treatment group is presented in Table 11. Baseline scores were not statistically different between the two groups (p=.688). At the end of Study Period II, the mean CPRS-R:S Hyperactivity subscale scores had decreased by 3.1±3.3 (p<.001) in the atomoxetine group and 1.5±3.2 (p=.011) in the placebo group. The difference between the score changes in the two treatment groups was statistically significant (p<.05).

Table 11. CPRS-R:S Hyperactivity Subscale Score

Atomoxetine Placebo


Baseline N 71 34

Mean ±SD 9.1 ±3.8 8.8 ±4.3 0.3

Median 9.0 9.0

Min - Max 0.0 - 17.0 0.0 - 17.0

95% CI 8.2 - 10.0 7.3 - 10.3 -1.4 - 1.9

P-valuec 0.688

SPII N 71 34

Mean ±SD 5.9 ±3.8 7.3 ±4.4 -1.4

Median 6.0 6.0

Min - Max 0.0 - 17.0 0.0 - 16.0

95% CI 5.0 - 6.8 5.8 - 8.9 -3.1 - 0.2


Mean ±SD -3.1 ±3.3 -1.5 ±3.2 -1.7

Median -3.0 -1.0

Min - Max -12.0 - 6.0 -11.0 - 5.0

95% CI -3.9 - -2.4 -2.6 - -0.4 -3.0 - -0.3

P-valuec < 0.001 0.011 0.014 0.016




CT Registry ID#8160


The change in CPRS-R:S ADHD Index subscale score from baseline to the end of Study Period II for each treatment group is presented in Table 12. Baseline scores were not statistically different between the two groups (p=.938). At the end of Study Period II, the mean CPRS-R:S ADHD Index subscale score had decreased by 6.6±5.8 (p<.001) in the atomoxetine group, while the decrease of 2.3±7.6 in the placebo group was not statistically significant (p=.100). The difference between the score changes in the two treatment groups was statistically significant (p<.01).

Table 12. CPRS-R:S ADHD Index Subscale Score

Atomoxetine Placebo


Baseline N 70 33

Mean ±SD 22.1 ±6.1 22.2 ±6.8 -0.1

Median 22.0 23.0

Min - Max 7.6 - 32.0 6.0 - 33.0

95% CI 20.6 - 23.6 19.8 - 24.6 -2.8 - 2.5

P-valuec 0.938

SPII N 70 33

Mean ±SD 15.5 ±7.1 20.0 ±8.6 -4.5

Median 15.0 21.0

Min - Max 0.0 - 36.0 5.0 - 34.0

95% CI 13.8 - 17.1 16.9 - 23.0 -7.7 - -1.3


Mean ±SD -6.6 ±5.8 -2.3 ±7.6 -4.4

Median -5.1 0.0

Min - Max -25.0 - 4.4 -24.0 - 9.0

95% CI -8.0 - -5.3 -5.0 - 0.5 -7.1 - -1.7

P-valuec < 0.001 0.100 0.001 0.002




CT Registry ID#8160


The change in Conners’ Teacher Rating Scale-Revised: Short Form (CTRS-R:S) total score from baseline to Visit 6 for each treatment group is presented in Table 13. Baseline scores were not statistically different between the two groups (p=.161). At Visit 6, the mean CTRS-R:S total score had decreased by 6.8±16.9 (p=.004) in the atomoxetine group, while the decrease of 0.8±10.3 in the placebo group was not statistically significant (p=.699). The difference between the score changes in the two treatment groups was statistically significant (p<.05).

Table 13. CTRS-R:S Total Score

Atomoxetine Placebo


Baseline N 57 28

Mean ±SD 33.8 ±16.1 39.6 ±15.6 -5.8

Median 34.0 38.2

Min - Max 0.0 - 74.0 10.0 - 69.0

95% CI 29.5 - 38.1 33.5 - 45.6 -13.1 - 1.5

P-valuec 0.161

Visit 6 N 57 28

Mean ±SD 27.0 ±14.9 40.4 ±15.9 -13.4

Median 29.0 42.0

Min - Max 0.0 - 65.0 10.0 - 68.0

95% CI 23.1 - 31.0 34.3 - 46.6 -20.4 - -6.4


N 57 28

Mean ±SD -6.8 ±16.9 0.8 ±10.3 -7.6

Median -6.0 1.5

Min - Max -47.0 - 47.0 -23.4 - 19.0

95% CI -11.3 - -2.3 -3.1 - 4.8 -13.5 - -1.7

P-valuec 0.004 0.669 < 0.001 0.028

Abbreviations: CTRS-R:S = Conners’ Teacher Rating Scale-Revised: Short Form; CI = confidence interval; SD = standard deviation.



CT Registry ID#8160


The change in CTRS-R:S Oppositional subscale score from baseline to Visit 6 for each treatment group is presented in Table 14. Baseline scores were not statistically different between the two groups (p=.365). At Visit 6, there were no statistically significant changes in the mean CTRS-R:S Oppositional subscale score compared to baseline in either treatment group (p=.765 for atomoxetine and p=.814 for placebo). The between-group difference was also statistically insignificant.

Table 14. CTRS-R:S Oppositional Subscale Score

Atomoxetine Placebo


Baseline N 61 29

Mean ±SD 2.9 ±3.2 3.6 ±3.9 -0.8

Median 1.0 2.0

Min - Max 0.0 - 11.0 0.0 - 13.0

95% CI 2.0 - 3.7 2.1 - 5.1 -2.3 - 0.8

P-value 0.365

Visit 6 N 61 29

Mean ±SD 2.7 ±3.1 3.8 ±3.4 -1.0

Median 1.0 4.0

Min - Max 0.0 - 11.0 0.0 - 15.0

95% CI 1.9 - 3.5 2.5 - 5.1 -2.5 - 0.4


N 61 29

Mean ±SD -0.1 ±3.0 0.1 ±3.1 -0.3

Median 0.0 0.0

Min - Max -10.0 - 7.0 -6.0 - 7.0

95% CI -0.9 - 0.6 -1.1 - 1.3 -1.6 - 1.1

P-value 0.765 0.814 0.339 0.719




CT Registry ID#8160


The change in CTRS-R:S Cognitive Problems subscale score from baseline to Visit 6 for each treatment group is presented in Table 15. Baseline scores were not statistically different between the two groups (p=.437). At Visit 6, the mean CTRS-R:S Cognitive Problems subscale score had decreased by 0.8±3.0 (p=.047) in the atomoxetine group, while the mean increase of 0.6±2.2 in the placebo group was not statistically significant (p=.189). The difference between the score changes in the two treatment groups was statistically significant (p<.05).

Table 15. CTRS-R:S Cognitive Problems Subscale Score

Atomoxetine Placebo


Baseline N 61 28

Mean ±SD 5.6 ±4.2 6.4 ±3.4 -0.8

Median 5.0 6.3

Min - Max 0.0 - 15.0 1.0 - 15.0

95% CI 4.5 - 6.7 5.1 - 7.8 -2.6 - 1.0

P-valuec 0.437

Visit 6 N 61 28

Mean ±SD 4.8 ±3.9 7.0 ±3.7 -2.2

Median 4.0 7.0

Min - Max 0.0 - 15.0 0.0 - 15.0

95% CI 3.8 - 5.8 5.6 - 8.4 -3.9 - -0.4


N 61 28

Mean ±SD -0.8 ±3.0 0.6 ±2.2 -1.3

Median 0.0 1.0

Min - Max -8.0 - 10.0 -6.3 - 4.0

95% CI -1.6 - -0.0 -0.3 - 1.4 -2.5 - -0.2

P-valuec 0.047 0.189 0.010 0.034




CT Registry ID#8160


The change in CTRS-R:S Hyperactivity subscale score from baseline to Visit 6 for each treatment group is presented in Table 16. Baseline scores were not statistically different between the two groups (p=.328). At Visit 6, the mean CTRS-R:S Hyperactivity subscale score had decreased by 2.3±4.8 (p<.001) in the atomoxetine group, while the mean increase of 0.2±3.5 in the placebo group was not statistically significant (p=.726). The difference between the score changes in the two treatment groups was statistically significant (p<.05).

Table 16. CTRS-R:S Hyperactivity Subscale Score

Atomoxetine Placebo


Baseline N 58 29

Mean ±SD 8.6 ±4.9 9.9 ±4.8 -1.3

Median 9.0 10.0

Min - Max 0.0 - 21.0 0.0 - 20.0

95% CI 7.3 - 9.9 8.0 - 11.7 -3.5 - 0.9

P-valuec 0.328

Visit 6 N 58 29

Mean ±SD 6.3 ±4.6 10.1 ±4.6 -3.8

Median 6.5 10.0

Min - Max 0.0 - 17.0 0.0 - 18.0

95% CI 5.1 - 7.5 8.4 - 11.8 -5.9 - -1.7


N 58 29

Mean ±SD -2.3 ±4.8 0.2 ±3.5 -2.5

Median -1.5 0.0

Min - Max -15.0 - 13.0 -8.0 - 6.0

95% CI -3.5 - -1.0 -1.1 - 1.6 -4.3 - -0.7

P-valuec < 0.001 0.726 < 0.001 0.013




CT Registry ID#8160


The change in CTRS-R:S ADHD Index subscale score from baseline to Visit 6 for each treatment group is presented in Table 17. Baseline scores were not statistically different between the two groups (p=.281). At Visit 6, the mean CTRS-R:S ADHD Index subscale score had decreased by 3.6±8.5 (p=.002) in the atomoxetine group, while the mean increase of 0.7±5.6 in the placebo group was not statistically significant (p=.485). The difference between the score changes in the two treatment groups was statistically significant (p<.05).

Table 17. CTRS-R:S ADHD Index Subscale Score

Atomoxetine Placebo


Baseline N 58 29

Mean ±SD 18.5 ±7.9 20.6 ±7.2 -2.1

Median 19.0 21.0

Min - Max 0.0 - 36.0 5.0 - 33.0

95% CI 16.4 - 20.6 17.8 - 23.3 -5.6 - 1.4

P-value 0.281

Visit 6 N 58 29

Mean ±SD 14.9 ±7.3 21.3 ±7.9 -6.4

Median 14.0 22.0

Min - Max 0.0 - 33.0 6.0 - 34.0

95% CI 13.0 - 16.8 18.3 - 24.3 -9.8 - -3.0


N 58 29

Mean ±SD -3.6 ±8.5 0.7 ±5.6 -4.3

Median -4.0 0.0

Min - Max -24.0 - 25.0 -12.0 - 13.2

95% CI -5.8 - -1.3 -1.4 - 2.8 -7.3 - -1.3

P-value 0.002 0.485 < 0.001 0.016




CT Registry ID#8160


A summary of the distribution of responders and non-responders at each visit is presented in Table 18. A responder was defined as having a >25% reduction from baseline in the ADHDRS-IV-Parent:Inv total score. At Visit 3, 41 (56.9%) out of 72 subjects from the atomoxetine group were classified as responders compared with six (17.6%) out of 34 subjects from the placebo group (p<.001). At Visit 4, Visit 5, and Visit 6, there were 50 (69.4%), 52 (72.2%), and 53 (73.6%) subjects respectively, from the atomoxetine group who were classified as responders. These proportions were statistically significantly different from the placebo group, from which there were 14 (41.2%), 11 (32.4%), and 13 (38.2%) subjects classified as responders at Visit 4, Visit 5, and Visit 6 respectively (p<.01 for all visits).

Table 18. By-visit Summary of Responders and Non-responders

Atomoxetine Placebo Visit Responder (N=72) (N=34) P-value*

Visit 3 YES 41 ( 56.9%) 6 ( 17.6%) < 0.001

NO 31 ( 43.1%) 28 ( 82.4%) Visit 4 YES 50 ( 69.4%) 14 ( 41.2%) 0.006 NO 22 ( 30.6%) 20 ( 58.8%) Visit 5 YES 52 ( 72.2%) 11 ( 32.4%) < 0.001 NO 20 ( 27.8%) 23 ( 67.6%) Visit 6 YES 53 ( 73.6%) 13 ( 38.2%) < 0.001 NO 19 ( 26.4%) 21 ( 61.8%) * p-value from Cochran-Mantel-Haenszel test, stratified by site.

CT Registry ID#8160


Safety

During the period from subject enrolled to the end of Study Period II, a total of 262 adverse events (AEs) were reported (204 AEs in the atomoxetine group and 58 AEs in the placebo group). Of these, 208 were treatment-emergent adverse events (TEAE): 164 events in the atomoxetine group and 44 events in the placebo group. There were 103 events that were classified as drug-related TEAEs with 96 of these events occurring in the atomoxetine group and the remaining seven events occurring in placebo group. One serious adverse event (SAE) was reported during this period and it was determined to be not related to study treatment.

Table 19 shows that 80 (76.2 %) of the 105 subjects who comprised the safety population reported one or more AE(s) (59 subjects receiving atomoxetine and 21 subjects receiving placebo; p=.026). Of these, 70 (66.7%) subjects reported their AE(s) after treatment administration (54 subjects receiving atomoxetine and 16 subjects receiving placebo; p=.004). Of these 70 subjects, 45 (42.9%) experienced drug-related TEAE(s) (40 subjects receiving atomoxetine and five subjects receiving placebo; p<.001). One subject from the atomoxetine group discontinued due to dizziness.

Two SAEs were reported during the study by subjects receiving atomoxetine. One was an acute asthma attack requiring hospitalization and was considered to be a serious TEAE because it was reported during Study Period II. The other SAE was reported during Study Period III when a subject suffered from an upper respiratory infection and fever and was then admitted to a local clinic with bronchiolitis. In the opinion of the investigator in both cases, these events were not related to either the study medication or to protocol procedures.

CT Registry ID#8160


Table 19. Distribution of Subjects Reporting Adverse Events by Category

Atomoxetine Placebo Total Category (N=71) (N=34) (N=105)

n (%) n (%) n (%) P-value* Number of Subjects with Adverse Events 59 (83.1%) 21 (61.8%) 80 (76.2%) 0.026 Number of Subjects with Treatment-Emergent Adverse Events

54 (76.1%) 16 (47.1%) 70 (66.7%) 0.004

Number of Subjects with Serious Adverse Events

1 (1.4%) 0 (0.0%) 1 (1.0%) 1.000

Number of Subjects with Serious Treatment-Emergent Adverse Events

1 (1.4%) 0 (0.0%) 1 (1.0%) 1.000

Number of Subjects with Drug-Related Adverse Events

40 (56.3%) 6 (17.6%) 46 (43.8%) < 0.001

Number of Subjects with Drug-Related Treatment-Emergent Adverse Events

40 (56.3%) 5 (14.7%) 45 (42.9%) < 0.001

Number of Subjects with Drug-Related Serious Adverse Events

0 (0.0%) 0 (0.0%) 0 (0.0%)

Number of Subjects with Drug-Related Serious Treatment-Emergent Adverse Events

0 (0.0%) 0 (0.0%) 0 (0.0%)

* p-value: Comparisons between treatment groups by Fisher’s exact test.

TEAEs that were reported by >10% of subjects receiving atomoxetine were anorexia, somnolence, nausea, and increased cough. The most common TEAE reported by subjects from the atomoxetine group was anorexia, which was reported by 26 (36.6%) subjects from this group, compared with five (14.7%) subjects from the placebo group (p=.02; Table 20). Nausea was reported by 12 (16.9 %) subjects from the atomoxetine group, while no subjects receiving placebo reported this TEAE (p<.01). The frequencies of other TEAEs were not statistically significantly different between the two treatment groups (Table 20).

Table 21 presents those TEAEs that were categorized as drug-related in the opinion of the investigator. Anorexia was the most common drug-related TEAE reported by subjects from the atomoxetine group. Of the 26 cases of anorexia reported by subjects from the atomoxetine group, 23 were categorized as drug-related. Nineteen of the 22 cases of somnolence and nine of the 12 cases of nausea, reported by subjects from the atomoxetine group, were categorized as drug-related.

CT Registry ID#8160


Table 20. Treatment Emergent Adverse Events in Decreasing Frequency for the Atomoxetine Group

TEAE Atomoxetine (N=71)

Placebo (N=34)

P-value*

Anorexia 26 (36.6%) 5 (17.4%) 0.02 Somnolence 22 (31.0%) 4 (11.8%) 0.05 Nausea 12 (16.9%) 0 (0.0%) <0.01 Cough increased 9 (12.7%) 7 (20.6%) 0.38 Headache 7 (9.9%) 2 (5.9%) 0.71 Dizziness 7 (9.9%) 1 (2.9%) 0.43 Asthenia 7 (9.9%) 0 (0.0%) 0.09 Rhinitis 6 (8.5%) 5 (14.7%) 0.33 Abdominal pain 6 (8.5%) 0 (0.0%) 0.17 Pharyngitis 5 (7.0%) 4 (11.8%) 0.47 Vomiting 5 (7.0%) 2 (5.9%) 1.00 Diarrhea 4 (5.6%) 0 (0.0%) 0.30 Weight Loss 4 (5.6%) 0 (0.0%) 0.30 Fever 3 (4.2%) 5 (14.7%) 0.11 Twitching 1 (1.4%) 2 (5.9%) 0.24 * p-value: Comparisons between treatment groups by Fisher’s exact test.


CT Registry ID#8160

Table 21 Number of Subjects with One or More Drug-Related Treatment-Emergent Adverse Events by Body System, COSTART Term, and Severity

Atomoxetine (N=71) Placebo (N=34) Body System

COSTART Preferred Term

Mild Moderate Severe Total Mild Moderate Severe Total

Body as a Whole Abdominal Pain 3 (4.2%) 1 (1.4%) 0 (0.0%) 4 (5.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Asthenia 5 (7.0%) 1 (1.4%) 0 (0.0%) 6 (8.5%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Headache 3 (4.2%) 0 (0.0%) 0 (0.0%) 3 (4.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)

Total 11 (15.5%) 0 (0.0%) Cardiovascular System

Palpitation 1 (1.4%) 0 (0.0%) 0 (0.0%) 1 (1.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Tachycardia 1 (1.4%) 0 (0.0%) 0 (0.0%) 1 (1.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)

Total 2 (2.8%) 0 (0.0%) Digestive System

Anorexia 17 (23.9%) 6 (8.5%) 0 (0.0%) 23 (32.4%) 3 (8.8%) 0 (0.0%) 0 (0.0%) 3 (8.8%) Diarrhea 3 (4.2%) 0 (0.0%) 0 (0.0%) 3 (4.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Nausea 6 (8.5%) 3 (4.2%) 0 (0.0%) 9 (12.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Vomiting 4 (5.6%) 0 (0.0%) 0 (0.0%) 4 (5.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)

Total 29 (40.8%) 3 (8.8%) Metabolic and Nutritional Disorders

Weight Loss 4 (5.6%) 0 (0.0%) 0 (0.0%) 4 (5.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Total 4 (5.6%) 0 (0.0%) Nervous System

Dizziness 5 (7.0%) 1 (1.4%) 0 (0.0%) 6 (8.5%) 1 (2.9%) 0 (0.0%) 0 (0.0%) 1 (2.9%) Insomnia 2 (2.8%) 0 (0.0%) 0 (0.0%) 2 (2.8%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Somnolence 18 (25.4%) 1 (1.4%) 0 (0.0%) 19 (26.8%) 3 (8.8%) 0 (0.0%) 0 (0.0%) 3 (8.8%)

Total 24 (33.8%) 4 (11.8%)

CT Registry ID#8160


Systolic blood pressure (Table 22), diastolic blood pressure (Table 23), heart rate (Table 24), temperature (Table 25), and weight (Table 26) were measured at baseline, Visit 3, Visit 4, Visit 5, and Visit 6. At all visits, there was a statistically significant weight decrease in the atomoxetine group (p<.001) and a statistically significant weight increase in the placebo group (p<.05). Furthermore, at all visits, the difference between the two groups was statistically significant (p<.001). No between-group differences were observed for systolic blood pressure, diastolic blood pressure, heart rate, temperature, or weight.

Serum levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, gamma-glutamyl transferase (GGT), creatine kinase (CK), total bilirubin, blood urea nitrogen (BUN), creatinine, glucose, uric acid, calcium, phosphorus, total protein, albumin, sodium, potassium, chloride, bicarbonate, cholesterol, and HbA1C were also measured. The following statistically significant changes from baseline to endpoint were observed in the atomoxetine group: ALT (U/L) decreased by 2.1±4.4 (mean±SD, p<.001), alkaline phosphatase (U/L) decreased by 15.9±56.5 (mean±SD, p=.021), total bilirubin (mg/dL) increased by 0.06±0.17 (mean±SD, p=.007), uric acid (mg/dL) decreased by 0.33±0.96 (mean±SD, p=.006), calcium (mmol/L) increased by 0.09±0.33 (mean±SD, p=.031), albumin (g/dL) increased by 0.10±0.23 (mean±SD, p<.001), and bicarbonate (mEq/L) increased by 1.45±2.39 (mean±SD, p<.001). In the placebo group, the following statistically significant changes from baseline to endpoint were observed: random glucose (mg/dL) increased by 5.5±13.1 (mean±SD, p=.022), chloride (mmol/L) increased by 1.1±1.0 (mean±SD, p=.002), and bicarbonate (mEq/L) decreased by 1.18±2.09 (mean±SD, p=.015). Statistically significant differences between treatments were observed in the changes from baseline to endpoint of alkaline phosphatase (p=.029), GGT (p=.046), calcium (p=.046), phosphorus (p=.035), chloride (p=.007), and bicarbonate (p<.001). All values that were outside of the normal range were, in the opinion of the treating investigator and the lead clinical research physician, clinically insignificant.

No statistically significant differences were observed between treatments for the following hematological parameters: hemoglobin, hematocrit, platelets, mean cell volume (MCV), red blood cell (RBC) count and white blood cell (WBC) count and differentiation. In the atomoxetine group, the following statistically significant changes from baseline to endpoint were observed: hemoglobin (g/dL) increased by 0.19±0.57 (mean±SD, p=.006), hematocrit (%) increased by 0.63±1.80 (mean±SD, p=.004), RBC (106/cmm) increased by 0.091±0.187 (mean±SD, p<.001), and lymphocytes (%) decreased by 2.90±10.08 (mean±SD, p=.025). Any hematological parameters that were found in subjects to be lower or higher than normal values were deemed clinically insignificant by the treating investigator and the lead clinical research physician.

Urinalysis parameters, including specific gravity, protein, glucose, occult blood, and sediments for RBC, WBC, and epithelial, were also measured at baseline and endpoint and no clinically significant changes were observed.


CT Registry ID#8160

Table 22. By-Visit Summary of Systolic Blood Pressure (mmHg) and Change from Baseline Variable Visit Statistics Atomoxetine Placebo Difference P-value _____________________ _________________________________ ______________ ________________ ________________ ______________ _________ Systolic BP (mmHg) Baseline N 71 34 Mean (SD) 95.5 (8.9) 95.4 (10.0) 0.1 Median 95.0 96.0 Min - Max 79.0 - 125.0 71.0 - 110.0 95% CI 93.4 - 97.6 91.9 - 98.9 -3.7 - 3.9 P-value 0.941 Visit 3 N 71 34 Mean (SD) 98.4 (10.3) 95.0 (7.9) 3.4 Median 98.0 94.0 Min - Max 78.0 - 127.0 79.0 - 109.0 95% CI 96.0 - 100.8 92.2 - 97.8 -0.5 - 7.4 Change from Baseline to Visit 3 N 71 34 Mean (SD) 2.9 (10.8) -0.4 (7.3) 3.3 Median 1.0 -2.0 Min - Max -19.0 - 42.0 -18.5 - 16.0 95% CI 0.4 - 5.5 -2.9 - 2.1 -0.2 - 6.9 P-value 0.026 0.743 0.092 Visit 4 N 70 34 Mean (SD) 95.9 (9.5) 94.1 (7.9) 1.8 Median 95.0 95.0 Min - Max 70.0 - 123.0 70.0 - 109.0 95% CI 93.7 - 98.2 91.4 - 96.9 -1.9 - 5.5 Change from Baseline to Visit 4 N 70 34 Mean (SD) 0.3 (9.1) -1.3 (6.1) 1.6 Median 0.8 -1.0 Min - Max -18.0 - 38.0 -13.0 - 9.0 95% CI -1.8 - 2.5 -3.4 - 0.9 -1.4 - 4.6 P-value 0.753 0.233 0.321 ______________________________________________________________________________________________________________________________________

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CT Registry ID#8160

Table 22. By-Visit Summary of Systolic Blood Pressure (mmHg) and Change from Baseline (concluded) Variable Visit Statistics Atomoxetine Placebo Difference P-value _____________________ _________________________________ ______________ ________________ ________________ ______________ _________ Systolic BP (mmHg) Visit 5 N 69 32 Mean (SD) 97.6 (9.0) 96.6 (8.8) 1.1 Median 98.0 97.0 Min - Max 80.0 - 120.0 71.0 - 112.0 95% CI 95.5 - 99.8 93.4 - 99.8 -2.8 - 4.9 Change from Baseline to Visit 5 N 69 32 Mean (SD) 1.9 (8.7) 1.3 (9.7) 0.6 Median 2.0 0.0 Min - Max -22.0 - 23.0 -22.0 - 21.0 95% CI -0.2 - 4.0 -2.2 - 4.8 -3.2 - 4.4 P-value 0.074 0.451 0.707 Visit 6 N 69 29 Mean (SD) 97.8 (8.5) 96.7 (6.4) 1.1 Median 98.0 99.0 Min - Max 79.0 - 122.5 80.0 - 106.0 95% CI 95.8 - 99.8 94.3 - 99.2 -2.4 - 4.5 Change from Baseline to Visit 6 N 69 29 Mean (SD) 2.1 (9.2) 1.0 (8.8) 1.1 Median 1.0 -1.0 Min - Max -21.0 - 26.0 -13.5 - 18.0 95% CI -0.1 - 4.3 -2.4 - 4.3 -2.9 - 5.1 P-value 0.066 0.554 0.575 ______________________________________________________________________________________________________________________________________ N=Number of observations SD=Standard Deviation CI=Confidence Interval BP=Blood Pressure Baseline is defined as the last value collected prior to first dose of study drug. Only subjects with a baseline and at least one post-baseline assessment were included. P-value between treatment groups was using ANOVA with terms of treatment and investigator. P-value within each treatment group was derived from paired t test.


CT Registry ID#8160

Table 23. By-Visit Summary of Diastolic Blood Pressure (mmHg) and Change from Baseline Variable Visit Statistics Atomoxetine Placebo Difference P-value _____________________ _________________________________ ______________ ________________ ________________ ______________ _________ Diastolic BP (mmHg) Baseline N 71 34 Mean (SD) 61.1 (9.5) 60.0 (8.0) 1.1 Median 60.0 59.0 Min - Max 39.0 - 90.0 46.0 - 80.0 95% CI 58.9 - 63.4 57.2 - 62.8 -2.6 - 4.9 P-value 0.532 Visit 3 N 71 34 Mean (SD) 65.6 (8.7) 60.5 (10.3) 5.1 Median 65.0 60.0 Min - Max 37.0 - 90.0 40.0 - 83.0 95% CI 63.6 - 67.7 56.9 - 64.1 1.3 - 9.0 Change from Baseline to Visit 3 N 71 34 Mean (SD) 4.5 (10.6) 0.5 (11.0) 4 Median 3.0 -0.3 Min - Max -27.0 - 35.0 -19.0 - 29.5 95% CI 2.0 - 7.0 -3.3 - 4.3 -0.4 - 8.4 P-value < 0.001 0.798 0.085 Visit 4 N 70 34 Mean (SD) 65.0 (9.0) 60.9 (9.2) 4.1 Median 64.5 59.5 Min - Max 40.0 - 85.0 45.0 - 80.0 95% CI 62.8 - 67.1 57.7 - 64.1 0.3 - 7.8 Change from Baseline to Visit 4 N 70 34 Mean (SD) 4.0 (9.4) 0.9 (10.1) 3.1 Median 3.8 2.0 Min - Max -15.0 - 30.0 -17.5 - 25.0 95% CI 1.7 - 6.2 -2.6 - 4.4 -0.9 - 7.0 P-value < 0.001 0.607 0.129 ______________________________________________________________________________________________________________________________________

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CT Registry ID#8160

Table 23. By-Visit Summary of Diastolic Blood Pressure (mmHg) and Change from Baseline (concluded) Variable Visit Statistics Atomoxetine Placebo Difference P-value _____________________ _________________________________ ______________ ________________ ________________ ______________ _________ Diastolic BP (mmHg) Visit 5 N 69 32 Mean (SD) 66.4 (8.4) 62.8 (10.2) 3.6 Median 66.0 64.0 Min - Max 45.0 - 88.0 35.0 - 82.0 95% CI 64.4 - 68.4 59.1 - 66.5 -0.2 - 7.4 Change from Baseline to Visit 5 N 69 32 Mean (SD) 5.2 (8.8) 2.7 (10.9) 2.5 Median 6.0 3.5 Min - Max -20.0 - 25.0 -25.0 - 23.0 95% CI 3.0 - 7.3 -1.2 - 6.6 -1.6 - 6.5 P-value < 0.001 0.172 0.249 Visit 6 N 69 29 Mean (SD) 64.9 (9.3) 65.1 (7.6) -0.1 Median 65.0 65.0 Min - Max 45.0 - 84.0 45.0 - 80.0 95% CI 62.7 - 67.2 62.2 - 67.9 -4.0 - 3.8 Change from Baseline to Visit 6 N 69 29 Mean (SD) 3.7 (9.0) 5.0 (9.9) -1.3 Median 3.0 8.0 Min - Max -15.0 - 24.0 -13.0 - 22.0 95% CI 1.5 - 5.8 1.2 - 8.8 -5.4 - 2.7 P-value 0.001 0.011 0.504 ______________________________________________________________________________________________________________________________________ N=Number of observations SD=Standard Deviation CI=Confidence Interval BP=Blood Pressure Baseline is defined as the last value collected prior to first dose of study drug. Only subjects with a baseline and at least one post-baseline assessment were included. P-value between treatment groups was using ANOVA with terms of treatment and investigator. P-value within each treatment group was derived from paired t test.


CT Registry ID#8160

Table 24. By-Visit Summary of Heart Rate (bpm) and Change from Baseline Variable Visit Statistics Atomoxetine Placebo Difference P-value _____________________ _________________________________ ______________ ________________ ________________ ______________ _________ Heart Rate (bmp) Baseline N 71 34 Mean (SD) 84.3 (10.8) 82.9 (10.5) 1.5 Median 84.0 81.0 Min - Max 62.0 - 118.0 68.0 - 116.0 95% CI 81.8 - 86.9 79.2 - 86.6 -3.0 - 5.9 P-value 0.535 Visit 3 N 71 34 Mean (SD) 87.1 (12.6) 82.4 (9.4) 4.7 Median 86.0 83.5 Min - Max 62.0 - 118.0 66.0 - 98.0 95% CI 84.1 - 90.1 79.1 - 85.7 0.3 - 9.0 Change from Baseline to Visit 3 N 71 34 Mean (SD) 2.7 (10.7) -0.5 (10.9) 3.2 Median 1.0 1.5 Min - Max -18.0 - 38.0 -24.0 - 20.0 95% CI 0.2 - 5.3 -4.3 - 3.3 -1.2 - 7.7 P-value 0.035 0.802 0.168 Visit 4 N 70 34 Mean (SD) 85.1 (10.9) 83.6 (10.9) 1.5 Median 86.0 82.0 Min - Max 58.0 - 106.0 66.0 - 110.0 95% CI 82.5 - 87.7 79.8 - 87.4 -3.0 - 6.0 Change from Baseline to Visit 4 N 70 34 Mean (SD) 0.7 (11.3) 0.7 (12.5) 0 Median 2.0 0.5 Min - Max -34.0 - 28.0 -34.0 - 34.0 95% CI -2.0 - 3.4 -3.7 - 5.0 -4.9 - 4.8 P-value 0.620 0.755 0.967 ______________________________________________________________________________________________________________________________________

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CT Registry ID#8160

Table 24. By-Visit Summary of Heart Rate (bpm) and Change from Baseline (concluded) Variable Visit Statistics Atomoxetine Placebo Difference P-value _____________________ _________________________________ ________________ ______________ ________________ ______________ _________ Heart Rate (bmp) Visit 5 N 69 32 Mean (SD) 87.4 (10.8) 85.1 (9.5) 2.3 Median 86.0 86.0 Min - Max 62.0 - 122.0 72.0 - 106.0 95% CI 84.7 - 90.0 81.7 - 88.5 -2.2 - 6.7 Change from Baseline to Visit 5 N 69 32 Mean (SD) 3.1 (11.2) 2.2 (10.3) 0.9 Median 2.5 2.0 Min - Max -22.5 - 28.0 -18.0 - 25.0 95% CI 0.4 - 5.7 -1.5 - 5.9 -3.8 - 5.5 P-value 0.027 0.237 0.701 Visit 6 N 69 29 Mean (SD) 88.1 (12.1) 86.6 (10.1) 1.5 Median 89.0 88.0 Min - Max 62.0 - 112.0 66.0 - 110.0 95% CI 85.2 - 91.0 82.8 - 90.5 -3.6 - 6.6 Change from Baseline to Visit 6 N 69 29 Mean (SD) 3.8 (12.5) 2.6 (9.9) 1.2 Median 4.5 2.0 Min - Max -31.0 - 36.0 -16.0 - 22.0 95% CI 0.8 - 6.8 -1.1 - 6.4 -4.0 - 6.3 P-value 0.014 0.165 0.704 ______________________________________________________________________________________________________________________________________ N=Number of observations SD=Standard Deviation CI=Confidence Interval BP=Blood Pressure Baseline is defined as the last value collected prior to first dose of study drug. Only subjects with a baseline and at least one post-baseline assessment were included. P-value between treatment groups was using ANOVA with terms of treatment and investigator. P-value within each treatment group was derived from paired t test.


CT Registry ID#8160

Table 25. By-Visit Summary of Temperature (°C) and Change from Baseline Variable Visit Statistics Atomoxetine Placebo Difference P-value _____________________ _________________________________ ________________ ______________ ________________ ______________ _________ Temperature (C) Baseline N 71 34 Mean (SD) 36.25 (0.67) 36.31 (0.52) -0.06 Median 36.30 36.35 Min - Max 34.60 - 37.60 35.30 - 37.20 95% CI 36.09 - 36.41 36.13 - 36.49 -0.32 - 0.20 P-value 0.533 Visit 3 N 71 34 Mean (SD) 36.24 (0.62) 36.22 (0.67) 0.02 Median 36.30 36.30 Min - Max 34.50 - 37.30 34.10 - 37.30 95% CI 36.09 - 36.39 35.99 - 36.45 -0.24 - 0.28 Change from Baseline to Visit 3 N 71 34 Mean (SD) -0.01 (0.59) -0.09 (0.59) 0.08 Median -0.10 -0.10 Min - Max -1.60 - 1.80 -1.30 - 1.10 95% CI -0.15 - 0.13 -0.29 - 0.12 -0.17 - 0.32 P-value 0.920 0.404 0.535 Visit 4 N 70 34 Mean (SD) 36.31 (0.68) 36.26 (0.85) 0.05 Median 36.40 36.45 Min - Max 34.10 - 39.60 34.30 - 37.90 95% CI 36.15 - 36.48 35.97 - 36.56 -0.26 - 0.36 Change from Baseline to Visit 4 N 70 34 Mean (SD) 0.07 (0.72) -0.04 (0.80) 0.11 Median 0.00 0.00 Min - Max -1.50 - 3.10 -2.20 - 2.40 95% CI -0.10 - 0.24 -0.32 - 0.24 -0.20 - 0.42 P-value 0.436 0.751 0.459 ______________________________________________________________________________________________________________________________________

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CT Registry ID#8160

Table 25. By-Visit Summary of Temperature (°C) and Change from Baseline (concluded) Variable Visit Statistics Atomoxetine Placebo Difference P-value _____________________ _________________________________ ______________ ________________ ________________ ______________ _________ Temperature (C) Visit 5 N 69 32 Mean (SD) 36.26 (0.79) 36.17 (0.52) 0.09 Median 36.30 36.30 Min - Max 34.00 - 39.50 34.30 - 37.10 95% CI 36.07 - 36.45 35.98 - 36.35 -0.17 - 0.36 Change from Baseline to Visit 5 N 69 32 Mean (SD) 0.02 (0.81) -0.14 (0.58) 0.16 Median 0.00 -0.10 Min - Max -1.90 - 3.20 -1.80 - 0.90 95% CI -0.18 - 0.21 -0.35 - 0.07 -0.12 - 0.44 P-value 0.860 0.174 0.258 Visit 6 N 69 29 Mean (SD) 36.22 (0.61) 36.20 (0.54) 0.02 Median 36.20 36.20 Min - Max 34.40 - 37.70 35.20 - 37.30 95% CI 36.07 - 36.37 36.00 - 36.41 -0.24 - 0.28 Change from Baseline to Visit 6 N 69 29 Mean (SD) -0.02 (0.65) -0.10 (0.45) 0.08 Median 0.00 -0.10 Min - Max -1.10 - 1.80 -1.10 - 0.90 95% CI -0.18 - 0.13 -0.27 - 0.07 -0.15 - 0.31 P-value 0.783 0.244 0.560 ______________________________________________________________________________________________________________________________________ N=Number of observations SD=Standard Deviation CI=Confidence Interval BP=Blood Pressure Baseline is defined as the last value collected prior to first dose of study drug. Only subjects with a baseline and at least one post-baseline assessment were included. P-value between treatment groups was using ANOVA with terms of treatment and investigator. P-value within each treatment group was derived from paired t test.


CT Registry ID#8160

Table 26. By-Visit Summary of Weight (kg) and Change from Baseline Variable Visit Statistics Atomoxetine Placebo Difference P-value _____________________ _________________________________ ______________ ________________ ________________ ______________ _________ Weight (kg) Baseline N 71 34 Mean (SD) 31.37 (9.00) 32.30 (9.12) -0.93 Median 29.50 28.50 Min - Max 20.00 - 57.60 20.00 - 54.00 95% CI 29.24 - 33.50 29.12 - 35.48 -4.66 - 2.81 P-value 0.549 Visit 3 N 71 34 Mean (SD) 31.05 (8.81) 32.50 (9.08) -1.45 Median 29.10 28.30 Min - Max 20.00 - 56.40 20.00 - 54.50 95% CI 28.97 - 33.14 29.33 - 35.67 -5.13 - 2.23 Change from Baseline to Visit 3 N 71 34 Mean (SD) -0.32 (0.59) 0.20 (0.54) -0.52 Median -0.30 0.00 Min - Max -1.90 - 0.80 -0.70 - 1.40 95% CI -0.46 - -0.18 0.01 - 0.39 -0.76 - -0.28 P-value < 0.001 0.038 < 0.001 Visit 4 N 70 34 Mean (SD) 30.91 (8.86) 32.63 (9.25) -1.72 Median 29.10 28.40 Min - Max 19.50 - 56.00 20.00 - 54.80 95% CI 28.79 - 33.02 29.40 - 35.86 -5.45 - 2.01 Change from Baseline to Visit 4 N 70 34 Mean (SD) -0.46 (0.64) 0.33 (0.56) -0.79 Median -0.55 0.10 Min - Max -2.20 - 1.40 -0.40 - 1.80 95% CI -0.61 - -0.30 0.14 - 0.52 -1.04 - -0.53 P-value < 0.001 0.002 < 0.001 ______________________________________________________________________________________________________________________________________

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CT Registry ID#8160

Table 26. By-Visit Summary of Weight (kg) and Change from Baseline (concluded) Variable Visit Statistics Atomoxetine Placebo Difference P-value _____________________ _________________________________ ______________ ________________ ________________ ______________ _________ Weight (kg) Visit 5 N 69 32 Mean (SD) 30.62 (8.85) 32.50 (9.23) -1.88 Median 29.00 28.45 Min - Max 19.50 - 55.00 20.50 - 54.00 95% CI 28.49 - 32.75 29.17 - 35.83 -5.68 - 1.93 Change from Baseline to Visit 5 N 69 32 Mean (SD) -0.70 (0.89) 0.48 (0.80) -1.18 Median -0.60 0.40 Min - Max -3.00 - 1.40 -1.00 - 2.20 95% CI -0.91 - -0.48 0.19 - 0.77 -1.54 - -0.81 P-value < 0.001 0.002 < 0.001 Visit 6 N 69 29 Mean (SD) 30.48 (8.85) 32.84 (9.39) -2.36 Median 28.70 29.00 Min - Max 19.80 - 56.00 20.00 - 54.00 95% CI 28.35 - 32.60 29.27 - 36.41 -6.32 - 1.60 Change from Baseline to Visit 6 N 69 29 Mean (SD) -0.84 (1.02) 0.52 (0.74) -1.36 Median -0.80 0.40 Min - Max -4.00 - 1.40 -0.60 - 2.20 95% CI -1.08 - -0.59 0.24 - 0.80 -1.73 - -1.00 P-value < 0.001 < 0.001 < 0.001 ______________________________________________________________________________________________________________________________________ N=Number of observations SD=Standard Deviation CI=Confidence Interval BP=Blood Pressure Baseline is defined as the last value collected prior to first dose of study drug. Only subjects with a baseline and at least one post-baseline assessment were included. P-value between treatment groups was using ANOVA with terms of treatment and investigator. P-value within each treatment group was derived from paired t test.

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