Summary ID# 5285 Clinical Study Summary: Study B4Z-JE-LYBC ...art45-paediatric-studies-docs.ema.europa.eu/GROUP A... · these 3 dose ranges with that of placebo, and evaluating the

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Atomoxetine Copyright © 2007 Eli Lilly and Company. All rights reserved.

Summary ID# 5285

Clinical Study Summary: Study B4Z-JE-LYBC

A Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Comparison of Fixed-Dose Ranges of Atomoxetine Hydrochloride in Child Outpatients with

Attention-Deficit/Hyperactivity Disorder

Date summary approved by Lilly: 02 August 2007

Brief Summary of Results

The primary objective of this study was to investigate the efficacy of atomoxetine treatment in reducing the severity of attention-deficit/hyperactivity disorder (ADHD) symptoms in Japanese pediatric and adolescent outpatients (6-17 years of age) by testing 3 fixed-dose ranges of atomoxetine (1.8 mg/kg/day, 1.2 mg/kg/day, 0.5 mg/kg/day) compared sequentially with placebo.

The main instrument used to assess efficacy was the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Japanese Version (ADHD RS-IV-J) (DuPaul et al. 1998; Yamazaki et al. 2001), an 18-item scale with 1 item for each of the 18 symptoms contained in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition™ (DSM-IV) diagnosis of ADHD (APA 1994). This scale when used by investigators was designated as the ADHD RS-IV-J:I rating scale. The same scale was also used by the patients' teachers to assess symptoms in the classroom setting; this was designated as the ADHD RS-IV-J:School rating scale. The clinician assessment Clinical Global Impressions-Attention-Deficit/Hyperactivity Disorder-Severity (CGI-AD/HD-S) was used as another measure of efficacy (Guy 1976; NIMH 1985).

The primary efficacy variable used to evaluate atomoxetine treatment was ADHD RS-IV-J:I/School (Sch) total score, a comprehensive assessment in which the primary efficacy measure, the ADHD RS-IV-J:I rating scale, was administered and scored by the investigator in conjunction with teacher scores on the ADHD RS-IV-J:School rating scale. The ADHD RS-IV-J:I total score, ADHD RS-IV-J:School total score and CGI-ADHD-S assessment were used as secondary efficacy variables.

Secondary objectives included comparing the efficacy of each of the above 3-fixed atomoxetine dose ranges with one another and with placebo, comparing the safety of



these 3 dose ranges with that of placebo, and evaluating the plasma concentration of atomoxetine and its main metabolites with respect to dose and patient ability to metabolize atomoxetine based on their CYP2D6 genotype (i.e., EM: Extensive metabolizers, IM: Intermediate metabolizers, PM: Poor metabolizers).

The main results of this study were as follows:

• Atomoxetine 1.8 mg/kg/day was shown to be statistically significant compared with placebo in ameliorating ADHD symptoms in Japanese pediatric ADHD patients (ADHD RS-IV-J:I/Sch total score: p=0.010/one-sided; ADHD RS-IV-J:I total score: p=0.008/one-sided).

• The low 0.5 mg/kg/day dose and intermediate 1.2 mg/kg/day dose were not found to be statistically significant in ameliorating ADHD symptoms compared with placebo.

• A statistically significant linear dose response in efficacy was seen with increasing atomoxetine dose (ADHD RS-IV-J:I/Sch total score: p=0.008; ADHD RS-IV-J:I total score: p=0.007; ADHD RS-IV-J:School total score: p=0.026).

• Measurement of the secondary efficacy variables ADHD RS-IV-J:School total score and CGI-ADHD-S assessment did not show any statistically significant difference between atomoxetine treatment and placebo.

• Analysis of laboratory analytes did not reveal any pattern of abnormalities associated with atomoxetine administration.

• No deaths occurred during this study.

• Two patients discontinued the study due to adverse events.

• One SAE was reported during the course of the study: hospitalization (twice) due to vomiting and headache. This patient recovered and completed the study.

• The most commonly reported treatment-emergent adverse events (TEAEs; ≥10%) in all atomoxetine treatment groups were nasopharyngitis (15.8% : 29/183), headache (14.2% : 26/183), and decreased appetite (12% : 22/183).

• Two adverse events above the 5% level in patients given atomoxetine were statistically significant: decreased appetite in 12% (22/183 : p<0.001) and vomiting in 8.2% (15/183 : p=0.022).

• Statistically significant (p<0.05) increases in mean diastolic blood pressure and heart rate (pulse) were observed at all atomoxetine doses. A statistically significant dose response (p<0.001) was also observed for diastolic blood pressure and heart rate.



• No statistically significant increases in mean QTc interval (Fridericia, Data Driven corrections) were found for any of the atomoxetine treatment groups. All mean increases seen with these two corrections were below 5 msec. Neither the Fridericia nor the Data Driven correction gave any evidence of an atomoxetine linear dose response in QTc mean change.

• Analysis of categorical changes in QTc interval (Fridericia, Data Driven corrections) detected statistically significant trends in QTc prolongation ≥30 msec in 15 (8.2%) patients (Fridericia: p=0.015) and 16 (8.7%) patients (Driven Driven: p=0.034) from the atomoxetine treatment groups. However, there were no prolongation times longer than 450 msec, and none longer than 60 msec. There were no adverse events or study discontinuations related to QTc interval prolongation.

• There were no study discontinuations and no evidence of differences in tolerability among patients with decreased efficiency to metabolize atomoxetine (IM and PM patients with respect to CYP2D6 genotype).

Title of Study: A Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Comparison of Fixed-Dose Ranges of Atomoxetine Hydrochloride in Child Outpatients with Attention-Deficit/Hyperactivity Disorder

Investigator(s): This multicenter study included 41 principal investigators.

Study Center(s): This study was conducted at 41 study centers in one country.

Length of Study: 1 year 7 months Date first patient enrolled: 22 February 2005 Date last patient completed: 29 September 2006

Phase of Development: 2/3

Objectives: Primary objective: To test the efficacy of atomoxetine treatment in reducing the severity of

Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms in Japanese children and adolescents who were at least 6 years of age but less than 18 years of age by testing 1.8, 1.2, and 0.5 mg/kg/day doses of atomoxetine compared

sequentially with placebo as measured by the ADHD RS-IV-J:I/Sch total score. Secondary objectives:

(1) To compare the safety of 3 fixed-dose ranges of atomoxetine with

that of placebo. (2) To assess the relationship between atomoxetine dose and both

efficacy and safety.

(3) To compare the efficacy of each of 3 fixed doses of atomoxetine with one another and with placebo in children who have not had prior treatment with psychostimulants.

(4) To evaluate the plasma concentration of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine with respect to dose and cytochrome P450 2D6 (CYP2D6) metabolic status.



(5) To evaluate during the course of the study the teacher’s assessment as measured by ADHD RS-IV-J:School total score.

Study Design: Randomized, double blind, placebo-controlled study (Figure LYBC.1)

Number of Patients: Planned: 240 60 per treatment group (4 groups): placebo atomoxetine 0.5 mg/kg/day

atomoxetine 1.2 mg/kg/day atomoxetine 1.8 mg/kg/day

Randomized: 245 placebo 62

atomoxetine 0.5 mg/kg/day: 62 atomoxetine 1.2 mg/kg/day: 60 atomoxetine 1.8 mg/kg/day: 61

Completed: 234 placebo: 61 (173: atomoxetine) atomoxetine 0.5 mg/kg/day: 60 atomoxetine 1.2 mg/kg/day: 57 atomoxetine 1.8 mg/kg/day: 56

Diagnosis and Main Criteria for Inclusion: Japanese male and female patients who were at least 6 but less than 18 years of age and who met the criteria for ADHD found in the Diagnostic and Statistical Manual of Mental Disorders (APA 1994) and in the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version: Behavioral Disorders Supplement (K-SADS-PL: Behavioral) module (Kaufman et al. 1997).

Study Drug, Dose, and Mode of Administration: Atomoxetine hydrochloride 4 capsule sizes : 2.5 mg, 5 mg, 10 mg, 20 mg

Combination of capsules given orally twice a day to provide target daily dosage based on patient body weight.

Reference Therapy, Dose, and Mode of Administration: Placebo: Identical in appearance and administration to study drug.

Duration of Treatment: 56 days (planned) 48 – 78 days (allowed)

Variables: Efficacy: Primary: ADHD RS-IV-J:I/Sch total score Secondary: ADHD RS-IV-J:I total score

ADHD RS-IV-J:School total score CGI-AD/HD-S (clinician assessment)

Safety: Adverse events, clinical laboratory tests, vital signs, electrocardiograms

Pharmacokinetic: Concentrations (atomoxetine and its metabolites: 4-hydroxyatomoxetine, and N-desmethylatomoxetine)



Evaluation Methods: Statistical: The primary efficacy variable was the change from baseline to last observation

carried forward (LOCF) endpoint in the ADHD RS-IV-J:I/Sch total score.

ADHD RS-IV-J:I/Sch was defined as the ADHD RS-IV-J:I total score assessed in conjunction with the ADHD RS-IV-J:School total score collected at the same time for a specific visit. For the primary efficacy analysis the Williams’ test was

performed to compare sequentially 1.8 mg/kg/day, 1.2 mg/kg/day, and 0.5 mg/kg/day doses of atomoxetine with placebo in order to determine the minimum effective dose. Statistical significance was p<0.025 (one-sided William's test).

Statistical significance in all other tests was two-sided, p<0.05.

Pharmacokinetic: Blood samples taken with a sparse sampling approach were evaluated by population pharmacokinetics to characterize the pharmacokinetics of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine. Plasma atomoxetine concentrations together with patient characteristics were evaluated using the nonlinear mixed effects modeling program (NONMEM) and graphical analyses. Pharmacokinetics of 4-hydroxyatomoxetine and N-desmethylatomoxetine were evaluated using graphical methods only.

Results:

Study Design

Study LYBC comprised two study periods (Figure LYBC.1):

• Study Period I: Screening, Medication Washout, and Assessment

• Study Period II: Randomized, Double-Blind Acute Treatment

Patients who met entry criteria completed an initial washout, screening, and assessment period of 12-35 days (Study Period I). This was then followed by approximately 8 weeks of acute treatment (Study Period II). At the end of this period dosages were abruptly discontinued.



Visit

Study Period I Screening, Washout,

and Assessment

Study Period II Double-Blind Acute

Treatment

Atomoxetine 1.8 mg/kg/day



2 643 5

14 (12-35 allowed)

Placebo

Suggested Interval Between Visits (Days)

1

Dose titration 0.8 mg/kg/day

14 (12-18 allowed)

14 (12-18 allowed)

14 (12-21 allowed)

14 (12-21 allowed)

Figure LYBC.1. Study design.

Patient Demographics

Table LYBC.1 shows patient demographics at baseline for the 243 patients in the Full Analysis Set (FAS: see section on Efficacy).

All of the treatment groups were balanced with respect to patient demographics with no major imbalances among treatment groups for any characteristic. Patients ranged from 6 to 17 years of age (mean: 10.53 years). There were 155 (85.6%) males and 26 (14.4%) females in the atomoxetine treatment groups, and of these 181 patients, 100 (55.2%) had prior stimulant use. Two (1.1%) of the patients in the atomoxetine treatment groups were classified as poor metabolizers (PM) with respect to CYP2D6 genotype: 1 patient in the low dose group (atomoxetine 0.5 mg/kg/day) and 1 in the intermediate dose group (atomoxetine 1.2 mg/kg/day). With regards to ADHD subtype, 61.3% (149/243) of the patients were Inattentive, 4.5% (11/243) Hyperactive/Impulsive, and 34.2% (83/243) Mixed.

The severity of disease at baseline for all patients in the Full Analysis Set is summarized in Table LYBC.2. All of the treatment groups were well balanced for each measure of disease severity. No statistically significant difference between groups in mean baseline score was seen for any measure.

In order to better understand the effect of CYP2D6 genotype on the metabolism, efficacy, and safety of atomoxetine, two IM (intermediate metabolizer) patient categories (Category 1, Category 2) based on CYP2D6 allele type were defined as subsets of the EM (extensive metabolizer) patients. The number of EM, IM, and PM patients in each treatment group for the Full Analysis Set is shown in Table LYBC.3 by metabolizer type.



No statistically significant difference was observed between treatment groups with respect to the number of EM / IM / PM patients in each group.



Table LYBC.1. Patient Demographic Characteristics at Baseline Full Analysis Set

__________________________________________________________________________________________________________________________________ Placebo ATMX 0.5 ATMX 1.2 ATMX 1.8 ATMX all All p-value (N=62) (N=62) (N=59) (N=60) (N=181) (N=243) __________________________________________________________________________________________________________________________________ Gender Male 52( 83.9) 52( 83.9) 51( 86.4) 52( 86.7) 155( 85.6) 207( 85.2) 0.953 * Female 10( 16.1) 10( 16.1) 8( 13.6) 8( 13.3) 26( 14.4) 36( 14.8) __________________________________________________________________________________________________________________________________ Origin EastAsian 62(100.0) 62(100.0) 59(100.0) 60(100.0) 181(100.0) 243(100.0) - __________________________________________________________________________________________________________________________________ Age No.patients 62 62 59 60 181 243 0.725 ** Mean 10.76 10.25 10.53 10.58 10.45 10.53 SD 2.03 2.57 2.72 2.70 2.65 2.51 Min 7.20 6.63 6.50 6.11 6.11 6.11 Median 10.59 9.34 9.89 10.87 9.89 10.18 Max 15.77 16.21 17.60 17.62 17.62 17.62 __________________________________________________________________________________________________________________________________ Age:Yrs 6 0( 0.0) 3( 4.8) 2( 3.4) 3( 5.0) 8( 4.4) 8( 3.3) - 7 5( 8.1) 9( 14.5) 9( 15.3) 10( 16.7) 28( 15.5) 33( 13.6) 8 10( 16.1) 11( 17.7) 8( 13.6) 6( 10.0) 25( 13.8) 35( 14.4) 9 8( 12.9) 14( 22.6) 11( 18.6) 5( 8.3) 30( 16.6) 38( 15.6) 10 13( 21.0) 3( 4.8) 9( 15.3) 7( 11.7) 19( 10.5) 32( 13.2) 11 8( 12.9) 8( 12.9) 3( 5.1) 13( 21.7) 24( 13.3) 32( 13.2) 12 8( 12.9) 4( 6.5) 7( 11.9) 6( 10.0) 17( 9.4) 25( 10.3) 13 7( 11.3) 2( 3.2) 3( 5.1) 4( 6.7) 9( 5.0) 16( 6.6) 14 2( 3.2) 3( 4.8) 3( 5.1) 2( 3.3) 8( 4.4) 10( 4.1) 15 1( 1.6) 3( 4.8) 0( 0.0) 1( 1.7) 4( 2.2) 5( 2.1) 16 0( 0.0) 2( 3.2) 1( 1.7) 2( 3.3) 5( 2.8) 5( 2.1) 17 0( 0.0) 0( 0.0) 3( 5.1) 1( 1.7) 4( 2.2) 4( 1.6) __________________________________________________________________________________________________________________________________ CYP2D6 EM 62(100.0) 61( 98.4) 58( 98.3) 60(100.0) 179( 98.9) 241( 99.2) 0.616 ** Genotype PM 0( 0.0) 1( 1.6) 1( 1.7) 0( 0.0) 2( 1.1) 2( 0.8) __________________________________________________________________________________________________________________________________



Table LYBC.1. Patient Demographic Characteristics at Baseline Full Analysis Set (Concluded)

__________________________________________________________________________________________________________________________________ Placebo ATMX 0.5 ATMX 1.2 ATMX 1.8 ATMX all All p-value (N=62) (N=62) (N=59) (N=60) (N=181) (N=243) __________________________________________________________________________________________________________________________________ AD/HD Inattentive 37( 59.7) 38( 61.3) 35( 59.3) 39( 65.0) 112( 61.9) 149( 61.3) 0.840 ** Subtype Hyp/Imp 1( 1.6) 3( 4.8) 4( 6.8) 3( 5.0) 10( 5.5) 11( 4.5) Mixed 24( 38.7) 21( 33.9) 20( 33.9) 18( 30.0) 59( 32.6) 83( 34.2) __________________________________________________________________________________________________________________________________ Prior Yes 32( 51.6) 34( 54.8) 33( 55.9) 33( 55.0) 100( 55.2) 132( 54.3) 0.966 * Stimulant No 30( 48.4) 28( 45.2) 26( 44.1) 27( 45.0) 81( 44.8) 111( 45.7) Exposure __________________________________________________________________________________________________________________________________ V1 Height No.patients 62 62 59 60 181 243 0.822 ** Mean 139.45 138.00 138.99 140.41 139.12 139.20 SD 11.88 14.63 14.63 15.50 14.87 14.15 Min 121.40 115.80 114.40 112.70 112.70 112.70 Median 137.20 133.35 136.00 139.05 136.50 136.80 Max 171.70 169.10 169.40 173.00 173.00 173.00 __________________________________________________________________________________________________________________________________ V1 Weight No.patients 62 62 59 60 181 243 0.693 ** Mean 35.48 34.22 35.58 36.72 35.49 35.49 SD 9.73 11.50 11.96 12.51 11.97 11.42 Min 22.90 19.80 20.30 18.20 18.20 18.20 Median 33.15 29.85 33.10 33.75 32.70 32.70 Max 62.00 69.00 68.50 68.30 69.00 69.00 __________________________________________________________________________________________________________________________________ WISC-III No.patients 62 61 56 58 175 237 0.939 ** Mean 100.21 99.34 99.61 100.91 99.95 100.02 SD 16.00 12.84 14.97 14.32 13.98 14.50 Min 67.00 71.00 67.00 63.00 63.00 63.00 Median 100.00 100.00 100.50 100.00 100.00 100.00 Max 138.00 122.00 133.00 137.00 137.00 138.00 __________________________________________________________________________________________________________________________________ *Frequencies are analyzed using Fisher Exact test. **Means are analyzed using a Type III Sum of Square Analysis of Variance. Abbreviations: AD/HD = attention deficit/hyperactivity disorder; ATMX = atomoxetine; EM = extensive metabolizer; Hyp/Imp = hyperactive/impulsive; Max = maximum; min = minimum; N = total number of patients; No = number; PM = poor metabolizer; SD = standard deviation; V = visit; WISC-III = Wechsler Intelligence Scale for Children-III; Yrs = years.



Table LYBC.2. Severity of Disease at Baseline Full Analysis Set

__________________________________________________________________________________________________________________________________ Placebo ATMX 0.5 ATMX 1.2 ATMX 1.8 ATMX all All p-value* (N=62) (N=62) (N=59) (N=60) (N=181) (N=243) __________________________________________________________________________________________________________________________________ Baseline No. Patients 61 62 59 60 181 242 0.798 ADHD RS-IV-J:I/Sch Mean 32.3 32.3 33.1 31.5 32.3 32.3 Total score SD 9.6 8.4 8.9 7.8 8.4 8.7 Min 17 16 16 17 16 16 Median 31.0 32.0 31.0 30.0 31.0 31.0 Max 50 51 52 51 52 52 __________________________________________________________________________________________________________________________________ __________________________________________________________________________________________________________________________________ Baseline No. Patients 62 62 59 60 181 243 0.799 ADHD RS-IV-J:I Mean 32.2 32.3 33.1 31.5 32.3 32.3 Total score SD 9.5 8.4 8.9 7.8 8.4 8.7 Min 17 16 16 17 16 16 Median 31.0 32.0 31.0 30.0 31.0 31.0 Max 50 51 52 51 52 52 __________________________________________________________________________________________________________________________________ Baseline No. Patients 61 62 59 60 181 242 0.538 ADHD RS-IV-J:School Mean 20.7 20.3 21.8 18.4 20.1 20.3 Total score SD 13.7 12.3 14.2 11.6 12.7 12.9 Min 0 0 0 0 0 0 Median 19.0 19.0 22.0 19.0 19.0 19.0 Max 50 48 54 47 54 54 __________________________________________________________________________________________________________________________________ Baseline No. Patients 62 62 59 60 181 243 0.586 CGI-AD/HD-S Mean 4.8 4.6 4.7 4.6 4.6 4.7 SD 0.9 1.0 0.9 0.9 1.0 0.9 Min 3 3 3 3 3 3 Median 5.0 5.0 5.0 5.0 5.0 5.0 Max 6 7 7 7 7 7 __________________________________________________________________________________________________________________________________ *Means are analyzed using a Type III Sum of Square Analysis of Variance. Abbreviations: ADHD RS-IV-J:I/Sch = Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored/School; ATMX = atomoxetine; CGI-AD/HD-S = Clinical Global Impressions-Attention-Deficit/Hyperactivity Disorder-Severity; Max = maximum; min = minimum; N = total number of patients; No = number; SD = standard deviation.



Table LYBC.3. CYP2D6 (EM/IM/PM) at Baseline Full Analysis Set

__________________________________________________________________________________________________________________________________ Placebo ATMX 0.5 ATMX 1.2 ATMX 1.8 ATMX all All p-value (N=62) (N=62) (N=59) (N=60) (N=181) (N=243) __________________________________________________________________________________________________________________________________ CYP2D6 EM 51( 82.3) 46( 74.2) 44( 74.6) 49( 81.7) 139( 76.8) 190( 78.2) 0.768 * EM/IM/PM IM 11( 17.7) 15( 24.2) 14( 23.7) 11( 18.3) 40( 22.1) 51( 21.0) Category 1 PM 0( 0.0) 1( 1.6) 1( 1.7) 0( 0.0) 2( 1.1) 2( 0.8) __________________________________________________________________________________________________________________________________ CYP2D6 EM 46( 74.2) 42( 67.7) 40( 67.8) 46( 76.7) 128( 70.7) 174( 71.6) 0.782 * EM/IM/PM IM 16( 25.8) 19( 30.6) 18( 30.5) 14( 23.3) 51( 28.2) 67( 27.6) Category 2 PM 0( 0.0) 1( 1.6) 1( 1.7) 0( 0.0) 2( 1.1) 2( 0.8) __________________________________________________________________________________________________________________________________ *Frequencies are analyzed using Fisher Exact test. Abbreviations: ATMX = atomoxetine; EM = extensive metabolizer; IM = intermediate metabolizer; N = total number of patients; PM = poor metabolizer.



Patient Disposition

An overview of patient disposition is shown in Figure LYBC.2.

Patients Entered N=270

Patients Randomized N=245

Placebo N=62

Screen Failure: N=25 Reason: Entry Criteria Exclusion 23 Protocol Violation 1 Patient Decision 1

ATMX 0.5 N=62

ATMX 1.2 N=60

ATMX 1.8 N=61

Discontinuation N=1

Reason: Sponsor Decision 1

Discontinuation N=2

Reason: Lack of Efficacy 1 Protocol Violation 1

Discontinuation N=3

Reason: Adverse Event 1 Protocol Violation 1 Patient Decision 1

Discontinuation N=5

Reason: Protocol Violation 2 Adverse Event 1 Entry Criteria Exclusion 1 Physician Decision 1

Study Completed N=61




Abbreviations: ATMX = atomoxetine; N = total number of patients.

Figure LYBC.2. Patient disposition.

Of the 270 patients who entered the study, 25 failed the initial screening procedures and were discontinued prior to randomization.

Table LYBC.4 shows the percentage of enrolled patients who discontinued from Study Period II for specific reasons. Of the 245 randomized patients, 11 (4.5%) discontinued the study. The single patient who discontinued for lack of efficacy was in the low dose treatment group (atomoxetine 0.5 mg/kg/day). Two patients (0.8%) discontinued the study because of adverse events.

Of the 183 patients in the three atomoxetine treatment groups, 173 (94.5%) completed Study Period II. In the placebo treatment group 61 (98.4%) patients completed Study Period II.



Table LYBC.4. Primary Reason for Study Discontinuation All Randomized Patients

____________________________________________________________________________________________________________________________ Placebo ATMX 0.5 ATMX 1.2 ATMX 1.8 ATMX all Reason for Discontinuation (N=62) (N=62) (N=60) (N=61) (N=183) p-value* n (%) n (%) n (%) n (%) n (%) ____________________________________________________________________________________________________________________________ Patients Completed 61 (98.4) 60 (96.8) 57 (95.0) 56 (91.8) 173 (94.5) 0.314 Adverse event 0 ( 0.0) 0 ( 0.0) 1 ( 1.7) 1 ( 1.6) 2 ( 1.1) 0.369 Death 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Lost to Follow up 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Protocol entry exclusion 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 1.6) 1 ( 0.5) 0.494 Protocol violation 0 ( 0.0) 1 ( 1.6) 1 ( 1.7) 2 ( 3.3) 4 ( 2.2) 0.568 Patient decision/Parent decision 0 ( 0.0) 0 ( 0.0) 1 ( 1.7) 0 ( 0.0) 1 ( 0.5) 0.245 Physician decision 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 1.6) 1 ( 0.5) 0.494 Sponsor decision 1 ( 1.6) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1.000 Lack of efficacy 0 ( 0.0) 1 ( 1.6) 0 ( 0.0) 0 ( 0.0) 1 ( 0.5) 1.000 ____________________________________________________________________________________________________________________________ * P-value derived from Fisher Exact test Abbreviations: ATMX = atomoxetine; N = total number of patients.



Efficacy

Datasets analyzed for efficacy are shown in Figure LYBC.3. All efficacy analyses were performed for patients who met the study inclusion criteria, took at least one dose of the study medication, and had a baseline and post-baseline measurement. This set of patients was designated as the Full Analysis Set (FAS).

All randomized patients (245) met the study inclusion criteria, took at least one dose of the study medication (placebo or atomoxetine), and had a baseline and post-baseline measurement. Two of these patients took prohibited drugs prior to the first visit after randomization and were excluded from the efficacy analysis. Thus, 243 patients were included in the efficacy analysis. These patients comprised the Full Analysis Set.

Only ADHD RS-IV-J:I scores that were used to assess patients in conjunction with teacher scores on the ADHD RS-IV-J:School rating scale were included in the primary efficacy analysis. These were designated as ADHD RS-IV-J:I/Sch scores, and only patients with these scores for Visit 2 and at least their final visit (Visit 6, or prior visit LOCF) were included in the ADHD RS-IV-J:I/Sch data set. Two of the 243 patients included in the Full Analysis Set lacked either baseline or post-baseline scores on the ADHD RS-IV-J:School rating scale and were thus excluded from the ADHD RS-IV-J:I/Sch data set. Therefore, 241 patients were included in the primary efficacy analysis (ADHD RS-IV-J:I/Sch data set).



ADHD RS-IV-J:I/Sch Placebo 61 ATMX 0.5 62 ATMX 1.2 58 ATMX 1.8 60

ADHD RS-IV-J:I Placebo 62 ATMX 0.5 62 ATMX 1.2 59 ATMX 1.8 60

ADHD RS-IV-J:School Placebo 61 ATMX 0.5 62 ATMX 1.2 58 ATMX 1.8 60

CGI-AD/HD-S Placebo 62 ATMX 0.5 62 ATMX 1.2 59 ATMX 1.8 60

Full Analysis Set Placebo 62 ATMX 0.5 62 ATMX 1.2 59 ATMX 1.8 60

Patients Excluded Placebo 0 ATMX 0.5 0 ATMX 1.2 1 ATMX 1.8 1

Patients who took at least 1 dose of

study medication Placebo 62 ATMX 0.5 62 ATMX 1.2 60 ATMX 1.8 61

All Randomized Patients Placebo 62 ATMX 0.5 62 ATMX 1.2 60 ATMX 1.8 61

Patients who took no study medication

Placebo 0 ATMX 0.5 0 ATMX 1.2 0 ATMX 1.8 0

Abbreviations: ADHD RS-IV-J:I/Sch = Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-

Parent Version: Investigator-Administered and Scored/School; ATMX = atomoxetine; CGI-AD/HD-S = Clinical Global Impressions-Attention-Deficit/Hyperactivity Disorder-Severity.

Figure LYBC.3. Patients included in the efficacy analyses.

Primary Outcome Measure

The primary efficacy variable was the ADHD RS-IV-J:I/Sch total score.

Table LYBC.5 contains the mean baseline, endpoint (LOCF), and change from baseline to endpoint in mean ADHD RS-IV-J:I/Sch total score. Atomoxetine 1.8 mg/kg/day showed a statistically significant overall improvement in mean change of ADHD RS-IV-J:I/Sch total score from baseline to endpoint (-11.6: SD=8.8, p=0.010/one-sided) compared with placebo. There was no statistically significant difference between atomoxetine 1.2 mg/kg/day and placebo. However, decreases from baseline in mean



ADHD RS-IV-J:I/Sch total score did show a statistically significant linear response with increasing atomoxetine dose (p=0.008).



Table LYBC.5. ADHD RS-IV-J:I/Sch Change from Baseline to LOCF Endpoint Full Analysis Set

___________________________________________________________________________________________________________ Baseline Endpoint Change 95%CI** ------------ ------------ ------------ ------------ P-value* P-value** n Mean SD Mean SD Mean SD Diff** LCL UCL Williams ANCOVA ___________________________________________________________________________________________________________ ADHD RS-IV-J:I/Sch : Total score Placebo 61 32.3 9.6 24.2 11.4 -8.1 7.1 ATMX 0.5 62 32.3 8.4 22.7 11.4 -9.6 9.1 -1.5 -4.3 1.3 - 0.280 ATMX 1.2 58 33.3 8.7 22.5 10.3 -10.8 6.8 -2.5 -5.4 0.3 0.037 0.078 ATMX 1.8 60 31.5 7.8 19.8 9.0 -11.6 8.8 -3.7 -6.5 -0.8 0.010 0.011 Dose Response *** Linear: P = 0.008 Quadratic: P = 0.837 ----------------------------------------------------------------------------------------------------------- ADHD RS-IV-J:I/Sch : Inattentive Subscale Placebo 61 19.9 3.7 15.2 6.1 -4.7 4.7 ATMX 0.5 62 19.4 4.1 13.6 6.1 -5.7 5.8 -1.2 -3.0 0.7 - 0.209 ATMX 1.2 58 20.5 4.0 14.1 5.4 -6.3 4.9 -1.4 -3.3 0.4 0.059 0.133 ATMX 1.8 60 20.0 3.8 13.2 5.8 -6.8 5.8 -2.1 -3.9 -0.2 0.019 0.030 Dose Response *** Linear: P = 0.032 Quadratic: P = 0.676 ----------------------------------------------------------------------------------------------------------- ADHD RS-IV-J:I/Sch : Hyperactive/Impulsive Subscale Placebo 62 12.3 7.1 8.9 6.7 -3.4 3.3 ATMX 0.5 62 13.0 6.7 9.1 6.7 -3.9 4.7 -0.4 -1.7 1.0 - 0.599 ATMX 1.2 58 12.9 7.2 8.4 6.3 -4.5 4.0 -1.0 -2.3 0.4 - 0.149 ATMX 1.8 60 11.5 6.0 6.7 4.7 -4.8 4.4 -1.7 -3.0 -0.3 0.033 0.014 Dose Response *** Linear: P = 0.009 Quadratic: P = 0.731 ___________________________________________________________________________________________________________ N:number of patients who are included in Full Analysis Set. * P-value(One sided) is derived from Williams test. ** Unadjusted p-value, treatment difference, the confidence interval is derived from pairwise treatment comparison vs Placebo using ANCOVA model. *** Dose Response p-value is derived from then contrasts of the least-square means from ANCOVA model. ANCOVA model: change = baseline + treatment Linear Contrast: -3 -1 1 3, Quadratic Contrast: 1 -1 -1 1 Abbreviations: ADHD RS-IV-J:I/Sch = Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored/School; ANCOVA = analysis of covariance; ATMX = atomoxetine; CI = confidence interval; Diff = difference; LCL = lower control limit; n = number of patients; SD = standard deviation; UCL = upper control limit.



Figure LYBC.4 shows the mean reduction from baseline to endpoint in ADHD RS-IV-J:I/Sch total score for all treatment groups. The reduction in both the atomoxetine 1.2 mg/kg/day and 1.8 mg/kg/day groups was larger than that of placebo; however only those reductions observed in the 1.8 mg/kg/day group were statistically significant (p<0.025/one-sided).

*

Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ATMX = atomoxetine. * p<0.025.

Figure LYBC.4. Mean reduction from baseline to endpoint in ADHD RS-IV-J:I/Sch Total Scores for all atomoxetine treatment groups in the full analysis set.

Secondary Outcome Measures

The principal secondary efficacy variables were:

• ADHD RS-IV-J:I total score • ADHD RS-IV-J:School total score • CGI-AD/HD-S clinician assessment.



In order to better understand the effect of atomoxetine on inattention symptoms compared with hyperactivity-impulsivity symptoms, the following subscale scale scores were also used as secondary efficacy variables:

• ADHD RS-IV-J:I/Sch Inattentive subscale score • ADHD RS-IV-J:I/Sch Hyperactive/Impulsive subscale score • ADHD RS-IV-J:I Inattentive subscale score • ADHD RS-IV-J:I Hyperactive/Impulsive subscale score • ADHD RS-IV-J:School Inattentive subscale score • ADHD RS-IV-J:School Hyperactive/Impulsive subscale score

The 18-item ADHD RS-IV-J:I rating scale is designed such that odd-numbered items focus on inattention symptoms and even-numbered items on hyperactivity-impulsive symptoms. Total scores for these specific subsets were used for the above subscale scores.

The following results were obtained for secondary measure outcomes:

• A statistically significant decrease from baseline in mean ADHD RS-IV-J:I/Sch Inattentive subscale score (p=0.019/one-sided) compared with placebo was seen in the atomoxetine 1.8 mg/kg/day group (Table LYBC.5).

• Statistically significant decreases from baseline in both mean ADHD RS-IV-J:I total score (p=0.008/one-sided) and mean ADHD RS-IV-J:I Inattentive subscale score (p=0.016/one-sided) compared with placebo were seen in the atomoxetine 1.8 mg/kg/day group (Table LYBC.6).

• A statistically significant (p≤0.05) linear dose response with increasing atomoxetine dose was observed for all secondary measure outcomes with the exception of ADHD RS-IV-J:School Hyperactive/Impulsive subscale score and CGI-AD/HD-S clinician assessment (Tables LYBC.5~8).

• No statistically significant differences from baseline were seen in mean ADHD RS-IV-J:School total score, nor were any seen in mean ADHD RS-IV-J:School Inattentive or Hyperactive/Impulsive subscale scores compared with placebo (Table LYBC.7).

• No statistically significant differences were seen in mean CGI-AD/HD-S change from baseline (Table LYBC.8).



Table LYBC.6. ADHD RS-IV-J:I Change from Baseline to LOCF Endpoint Full Analysis Set

___________________________________________________________________________________________________________ Baseline Endpoint Change 95%CI** ------------ ------------ ------------ ------------ P-value* P-value** n Mean SD Mean SD Mean SD Diff** LCL UCL Williams ANCOVA ___________________________________________________________________________________________________________ ADHD RS-IV-J:I: Total score Placebo 62 32.2 9.5 24.2 11.3 -8.0 7.1 ATMX 0.5 62 32.3 8.4 22.7 11.4 -9.6 9.1 -1.6 -4.4 1.2 - 0.258 ATMX 1.2 59 33.1 8.9 22.1 10.6 -10.9 7.0 -2.8 -5.6 0.1 0.027 0.056 ATMX 1.8 60 31.5 7.8 19.8 9.0 -11.6 8.8 -3.7 -6.6 -0.9 0.008 0.010 Dose Response *** Linear: P = 0.007 Quadratic: P = 0.756 ----------------------------------------------------------------------------------------------------------- ADHD RS-IV-J:I: Inattentive Subscale Placebo 62 19.9 3.7 15.3 6.0 -4.6 4.7 ATMX 0.5 62 19.4 4.1 13.6 6.1 -5.7 5.8 -1.3 -3.1 0.6 - 0.183 ATMX 1.2 59 20.3 4.0 14.0 5.6 -6.4 5.0 -1.6 -3.5 0.3 0.045 0.094 ATMX 1.8 60 20.0 3.8 13.2 5.8 -6.8 5.8 -2.1 -4.0 -0.3 0.016 0.025 Dose Response *** Linear: P = 0.025 Quadratic: P = 0.593 ----------------------------------------------------------------------------------------------------------- ADHD RS-IV-J:I: Hyperactive/Impulsive Subscale Placebo 62 12.3 7.1 8.9 6.7 -3.4 3.3 ATMX 0.5 62 13.0 6.7 9.1 6.7 -3.9 4.7 -0.4 -1.7 1.0 - 0.599 ATMX 1.2 59 12.7 7.3 8.2 6.4 -4.5 4.0 -1.1 -2.4 0.3 - 0.114 ATMX 1.8 60 11.5 6.0 6.7 4.7 -4.8 4.4 -1.7 -3.0 -0.3 0.033 0.014 Dose Response *** Linear: P = 0.008 Quadratic: P = 0.803 ___________________________________________________________________________________________________________ N:number of patients who are included in Full Analysis Set. * P-value(One sided) is derived from Williams test. ** Unadjusted p-value, treatment difference, the confidence interval is derived from pairwise treatment comparison vs Placebo using ANCOVA model. *** Dose Response p-value is derived from then contrasts of the least-square means from ANCOVA model. ANCOVA model: change = baseline + treatment Linear Contrast: -3 -1 1 3, Quadratic Contrast: 1 -1 -1 1 Abbreviations: ADHD RS-IV-J:I = Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored; ANCOVA = analysis of covariance; ATMX = atomoxetine; CI = confidence interval; Diff = difference; LCL = lower control limit; n = number of patients; SD = standard deviation; UCL = upper control limit.



Table LYBC.7. ADHD RS-IV-J:School Change from Baseline to LOCF Endpoint Full Analysis Set

___________________________________________________________________________________________________________ Baseline Endpoint Change 95%CI** ------------ ------------ ------------ ------------ P-value* P-value** n Mean SD Mean SD Mean SD Diff** LCL UCL Williams ANCOVA ___________________________________________________________________________________________________________ ADHD RS-IV-J:School: Total score Placebo 61 20.7 13.7 18.6 13.2 -2.2 6.4 ATMX 0.5 62 20.3 12.3 17.1 12.2 -3.2 7.3 -1.1 -3.5 1.3 - 0.359 ATMX 1.2 58 22.1 14.1 17.7 12.6 -4.4 8.2 -2.0 -4.4 0.5 - 0.119 ATMX 1.8 60 18.4 11.6 14.0 10.8 -4.3 7.5 -2.7 -5.1 -0.2 0.062 0.034 Dose Response *** Linear: P = 0.026 Quadratic: P = 0.808 ----------------------------------------------------------------------------------------------------------- ADHD RS-IV-J:School: Inattentive Subscale Placebo 61 12.2 6.9 11.2 7.1 -1.1 4.0 ATMX 0.5 62 11.7 6.2 10.1 6.5 -1.6 3.9 -0.6 -2.0 0.8 - 0.396 ATMX 1.2 58 12.4 7.0 10.1 6.6 -2.4 4.6 -1.2 -2.7 0.2 - 0.089 ATMX 1.8 60 11.1 6.7 8.6 6.5 -2.5 4.2 -1.6 -3.0 -0.2 0.042 0.026 Dose Response *** Linear: P = 0.017 Quadratic: P = 0.816 ----------------------------------------------------------------------------------------------------------- ADHD RS-IV-J:School: Hyperactive/Impulsive Subscale Placebo 62 8.4 7.7 7.3 7.1 -1.1 3.3 ATMX 0.5 62 8.6 7.2 7.0 6.6 -1.6 4.1 -0.5 -1.8 0.8 - 0.446 ATMX 1.2 58 9.7 8.1 7.6 6.8 -2.1 4.6 -0.7 -2.0 0.6 - 0.322 ATMX 1.8 60 7.3 6.0 5.4 5.5 -1.9 4.1 -1.1 -2.3 0.2 0.145 0.107 Dose Response *** Linear: P = 0.108 Quadratic: P = 0.922 ___________________________________________________________________________________________________________ N:number of patients who are included in Full Analysis Set. * P-value(One sided) is derived from Williams test. ** Unadjusted p-value, treatment difference, the confidence interval is derived from pairwise treatment comparison vs Placebo using ANCOVA model. *** Dose Response p-value is derived from then contrasts of the least-square means from ANCOVA model. ANCOVA model: change = baseline + treatment Linear Contrast: -3 -1 1 3, Quadratic Contrast: 1 -1 -1 1 Abbreviations: ADHD RS-IV-J:School = Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: School; ANCOVA = analysis of covariance; ATMX = atomoxetine; CI = confidence interval; Diff = difference; LCL = lower control limit; n = number of patients; SD = standard deviation; UCL = upper control limit.



Table LYBC.8. CGI-AD/HD-S Change from Baseline to LOCF Endpoint Full Analysis Set

___________________________________________________________________________________________________________ Baseline Endpoint Change 95%CI** ------------ ------------ ------------ ------------ P-value* P-value** n Mean SD Mean SD Mean SD Diff** LCL UCL Williams ANCOVA ___________________________________________________________________________________________________________ CGI-AD/HD-S Placebo 62 4.8 0.9 4.2 1.1 -0.6 0.8 ATMX 0.5 62 4.6 1.0 4.0 1.1 -0.6 0.8 -0.1 -0.4 0.2 - 0.562 ATMX 1.2 59 4.7 0.9 4.1 1.1 -0.6 0.8 -0.1 -0.4 0.2 - 0.579 ATMX 1.8 60 4.6 0.9 3.8 0.9 -0.8 1.0 -0.3 -0.6 0.0 0.076 0.047 Dose Response *** Linear: P = 0.060 Quadratic: P = 0.543 ___________________________________________________________________________________________________________ N:number of patients who are included in Full Analysis Set. * P-value(One sided) is derived from Williams test. ** Unadjusted p-value, treatment difference, the confidence interval is derived from pairwise treatment comparison vs Placebo using ANCOVA model. *** Dose Response p-value is derived from then contrasts of the least-square means from ANCOVA model. ANCOVA model: change = baseline + treatment Linear Contrast: -3 -1 1 3, Quadratic Contrast: 1 -1 -1 1 Abbreviations: ANCOVA = analysis of covariance; ATMX = atomoxetine; CGI-AD/HD-S = Clinical Global Impressions-Attention-Deficit/Hyperactivity Disorder-Severity; CI = confidence interval; Diff = difference; LCL = lower control limit; n = number of patients; SD = standard deviation; UCL = upper control limit.



Safety

Of the 245 patients who entered this study, 183 received at least one dose of atomoxetine. There were no patient deaths. One SAE was reported: hospitalization (twice) due to headache and vomiting. Two patients discontinued the study because of adverse events (affect lability and headache).

Treatment-Emergent Adverse Events

TEAEs were those adverse events that emerged or deteriorated during the study drug administration period. Table LYBC.9 summarizes TEAEs that occurred in at least 5% of patients who took at least one dose of study medication (placebo or atomoxetine).

At least one TEAE was reported for 78.7% (144/183) of the patients given atomoxetine. The most commonly reported events (≥10%) in all atomoxetine treatment groups were nasopharyngitis, headache, and decreased appetite. Two adverse events above the 5% level were found to have a statistically significant (p<0.05) relationship to dose: decreased appetite in 12% (22/183 : p<0.001) and vomiting in 8.2% (15/183 : p=0.022) of patients given atomoxetine.

Treatment-Emergent Adverse Drug Reactions (ADRs)

ADRs were those TEAEs indicated by the investigator to be related or possibly related to atomoxetine administration. Table LYBC.10 summarizes ADRs that occurred in at least 5% of patients who took at least one dose of study medication.

At least one ADR was reported for 50.3% (92/183) of the patients given atomoxetine. In these patients the ADR incidence rate was found to have a statistically significant relationship (p=0.003) with increasing atomoxetine dose. The most commonly reported ADRs (≥10%) were decreased appetite and headache. Decreased appetite in 11.5% (21/183) of the atomoxetine-treated patients was found to have a statistically significant (p<0.001) dose response.



Table LYBC.9. Treatment-Emergent Adverse Events Experienced By at Least 5% of Patients - MedDRA preferred Term Patients Who Took at Least 1 Dose of Study Medication

__________________________________________________________________________________________________________________________________ Event Classification Placebo ATMX 0.5 ATMX 1.2 ATMX 1.8 ATMX all p-value (N=62) (N=62) (N=60) (N=61) (N=183) CA Trend N (%) N (%) N (%) N (%) N (%) Test* __________________________________________________________________________________________________________________________________ Patient with>=1 TEAE 43 ( 69.4) 49 ( 79.0) 47 ( 78.3) 48 ( 78.7) 144 ( 78.7) 0.284 Patient without TEAE 19 ( 30.6) 13 ( 21.0) 13 ( 21.7) 13 ( 21.3) 39 ( 21.3) Nasopharyngitis 10 ( 16.1) 11 ( 17.7) 7 ( 11.7) 11 ( 18.0) 29 ( 15.8) 0.965 Headache 4 ( 6.5) 7 ( 11.3) 10 ( 16.7) 9 ( 14.8) 26 ( 14.2) 0.108 Decreased appetite 2 ( 3.2) 3 ( 4.8) 6 ( 10.0) 13 ( 21.3) 22 ( 12.0) <0.001 Somnolence 4 ( 6.5) 4 ( 6.5) 6 ( 10.0) 8 ( 13.1) 18 ( 9.8) 0.142 Nausea 3 ( 4.8) 4 ( 6.5) 6 ( 10.0) 6 ( 9.8) 16 ( 8.7) 0.222 Vomiting 0 ( 0.0) 3 ( 4.8) 7 ( 11.7) 5 ( 8.2) 15 ( 8.2) 0.022 Abdominal pain 5 ( 8.1) 5 ( 8.1) 4 ( 6.7) 2 ( 3.3) 11 ( 6.0) 0.257 Diarrhoea 2 ( 3.2) 1 ( 1.6) 6 ( 10.0) 4 ( 6.6) 11 ( 6.0) 0.133 __________________________________________________________________________________________________________________________________ *P-value is derived from Cochran Armitage Trend test. MedDRA Version 9.1 Abbreviations: ATMX = atomoxetine; N = number of patients; TEAE = treatment-emergent adverse event.



Table LYBC.10. Treatment-Emergent Adverse Drug Reactions Experienced By at Least 5% of Patients - MedDRA preferred Term Patients Who Took at Least 1 Dose of Study Medication

__________________________________________________________________________________________________________________________________ Event Classification Placebo ATMX 0.5 ATMX 1.2 ATMX 1.8 ATMX all p-value (N=62) (N=62) (N=60) (N=61) (N=183) CA Trend N (%) N (%) N (%) N (%) N (%) Test* __________________________________________________________________________________________________________________________________ Patient with>=1 ADR 19 ( 30.6) 25 ( 40.3) 35 ( 58.3) 32 ( 52.5) 92 ( 50.3) 0.003 Patient without ADR 43 ( 69.4) 37 ( 59.7) 25 ( 41.7) 29 ( 47.5) 91 ( 49.7) Decreased appetite 2 ( 3.2) 3 ( 4.8) 6 ( 10.0) 12 ( 19.7) 21 ( 11.5) <0.001 Headache 3 ( 4.8) 5 ( 8.1) 8 ( 13.3) 8 ( 13.1) 21 ( 11.5) 0.076 Somnolence 3 ( 4.8) 3 ( 4.8) 6 ( 10.0) 8 ( 13.1) 17 ( 9.3) 0.051 Nausea 3 ( 4.8) 4 ( 6.5) 5 ( 8.3) 4 ( 6.6) 13 ( 7.1) 0.622 __________________________________________________________________________________________________________________________________ *P-value is derived from Cochran Armitage Trend test. MedDRA Version 9.1 Abbreviations: ADR = adverse drug reaction; ATMX = atomoxetine; N = number of patients.



Serious Adverse Events (SAEs)

One SAE was reported during the course of the study: an 8-year old Japanese male randomized to the atomoxetine 1.8 mg/kg/day group was hospitalized twice due to headache and vomiting. The patient recovered from these events and completed the study.

Study Discontinuations Due to Adverse Events

Two patients discontinued the study because of adverse events: a 10-year-old Japanese male (atomoxetine 1.8 mg/kg/day group; affect lability), and a 14-year-old Japanese female (atomoxetine 1.2 mg/kg/day group; headache).

Clinical Laboratory Values

As determined by the Sponsor, analysis of laboratory analytes did not reveal any pattern of abnormalities associated with atomoxetine administration.

Vital Signs

Mean change from baseline to LOCF endpoint in vital sign measures are shown in Table LYBC.11. There were no study discontinuations related to changes in vital signs.

A statistically significant (p<0.05) increase in mean diastolic blood pressure from baseline to endpoint was observed for all atomoxetine doses. The difference between treatment groups was statistically significant (p=0.003), and the dose-response was found to have a statistically significant (p<0.001) linear component.

A statistically significant linear dose-response (p=0.029) was also observed for mean systolic blood pressure. No statistically significant difference was found between treatment groups.

A statistically significant (p≤0.001) increase was also observed in mean heart rate (pulse) for all atomoxetine doses. The difference between treatment groups was statistically significant (p<0.001) as was the linearity of the dose response (p<0.001). These results were not unexpected given the pharmacologic action of this drug.

With regards to mean height, a statistically significant dose response was observed with the quadratic contrast from the ANCOVA model (p=0.036). However, there was no statistically significant difference between treatment groups.

Changes in mean weight among treatment groups and the linearity of dose response were both statistically significant (p<0.001). When baseline and endpoint values were compared, statistically significant decreases in weight were seen for both the atomoxetine 1.2 mg/kg/day (p=0.002) and 1.8 mg/kg/day (p<0.001) groups. Dose response was also found to have a statistically significant (p<0.001) linear component.



Table LYBC.11. Vital Signs Mean Change from Baseline to LOCF Endpoint Patients Who Took at Least 1 Dose of Study Medication

__________________________________________________________________________________________________________________________________ Baseline Endpoint Change p-value __________________________________________________________________________________________________________________________________ Therapy n Mean SD Mean SD Mean SD Within* Between** __________________________________________________________________________________________________________________________________ Systolic Placebo 62 101.63 12.44 102.34 10.94 0.71 13.02 0.669 0.148 Blood Pressure ATMX 0.5 62 103.06 10.27 103.60 11.34 0.53 11.98 0.728 ATMX 1.2 60 102.13 10.15 105.70 9.92 3.57 10.16 0.009 ATMX 1.8 61 102.20 10.27 105.84 10.02 3.64 12.35 0.025 Dose Response*** Linear: P=0.029 Quadratic: P=0.807 __________________________________________________________________________________________________________________________________ Diastolic Placebo 62 57.23 10.22 57.92 8.80 0.69 9.81 0.580 0.003 Blood Pressure ATMX 0.5 62 58.40 9.83 61.21 8.84 2.81 9.81 0.028 ATMX 1.2 60 57.73 8.72 61.98 7.52 4.25 9.17 <0.001 ATMX 1.8 61 57.93 9.35 63.20 8.79 5.26 10.76 <0.001 Dose Response*** Linear: P=<0.001 Quadratic: P=0.388 __________________________________________________________________________________________________________________________________ Heart Rate(Pulse) Placebo 62 80.60 11.91 80.97 10.27 0.37 12.10 0.810 <0.001 ATMX 0.5 62 81.08 12.34 86.10 10.75 5.02 11.55 0.001 ATMX 1.2 60 81.43 12.34 89.97 13.98 8.53 16.59 <0.001 ATMX 1.8 61 84.00 13.18 92.07 14.60 8.07 13.09 <0.001 Dose Response*** Linear: P=<0.001 Quadratic: P=0.181 __________________________________________________________________________________________________________________________________ Height Placebo 61 139.65 11.87 140.84 11.92 1.19 0.69 <0.001 0.062 ATMX 0.5 62 138.00 14.63 138.88 14.47 0.89 0.72 <0.001 ATMX 1.2 60 139.39 14.83 140.11 14.92 0.72 1.32 <0.001 ATMX 1.8 61 140.13 15.53 141.07 15.66 0.93 0.98 <0.001 Dose Response*** Linear: P=0.092 Quadratic: P=0.036 __________________________________________________________________________________________________________________________________



Table LYBC.11. Vital Signs Mean Change from Baseline to LOCF Endpoint Patients Who Took at Least 1 Dose of Study Medication (Concluded)

__________________________________________________________________________________________________________________________________ Baseline Endpoint Change p-value __________________________________________________________________________________________________________________________________ Therapy n Mean SD Mean SD Mean SD Within* Between** __________________________________________________________________________________________________________________________________ Weight Placebo 62 35.68 9.69 36.59 9.83 0.91 0.97 <0.001 <0.001 ATMX 0.5 62 34.62 11.56 34.66 11.66 0.05 0.94 0.705 ATMX 1.2 60 36.16 12.00 35.62 11.85 -0.53 1.26 0.002 ATMX 1.8 61 36.77 12.35 35.99 11.80 -0.78 1.32 <0.001 Dose Response*** Linear: P=<0.001 Quadratic: P=0.026 __________________________________________________________________________________________________________________________________ N: number of patients who took at least one dose of study medication * Within p-value is derived from paired t-test. ** Between p-value is derived from ANCOVA. *** Dose Response p-value is derived from the contrasts of the least-square means from ANCOVA model. ANCOVA model: change = baseline + treatment Linear Contrast -3 -1 1 3 Quadratic Contrast 1 -1 -1 1 Abbreviations: ATMX = atomoxetine; n = number of patients; SD = standard deviation.



Table LYBC.12 summarizes the categorical analysis results of changes in blood pressure (systolic and diastolic), heart rate (pulse), and weight for atomoxetine- and placebo-treated patients. For each criterion the percentage of patients meeting the criteria in a treatment-emergent manner (at any Study Period II visit) was computed for each treatment group.

With the exception of systolic and diastolic blood pressure, all trends were statistically significant (p<0.05). Increased heart rate (pulse) was not unexpected due to atomoxetine’s noradrenergic mechanism of action.



Table LYBC.12. Summary of Vital Signs Data Analysis of Categorical Changes in Blood Pressure, Heart Rate(Pulse) and Weight Patients Who Took at Least 1 Dose of Study Medication

__________________________________________________________________________________________________________________________________ Placebo ATMX 0.5 ATMX 1.2 ATMX 1.8 ATMX all p-value (N=62) (N=62) (N=60) (N=61) (N=183) CA Trend Criteria. N n (%) N n (%) N n (%) N n (%) N n (%) Test* __________________________________________________________________________________________________________________________________ A 61 3 4.9 60 6 10.0 60 10 16.7 59 11 18.6 179 27 15.1 0.012 B 62 6 9.7 62 10 16.1 60 21 35.0 61 13 21.3 183 44 24.0 0.019 C 61 2 3.3 60 2 3.3 60 5 8.3 59 7 11.9 179 14 7.8 0.030 D 62 0 0.0 62 4 6.5 60 16 26.7 61 20 32.8 183 40 21.9 <0.001 E 62 0 0.0 62 1 1.6 60 0 0.0 61 0 0.0 183 1 0.5 0.755 F 62 4 6.5 62 5 8.1 60 5 8.3 59 6 10.2 181 16 8.8 0.493 __________________________________________________________________________________________________________________________________ Criteria: A: Maximum heart rate (Pulse)�Visits 3-6� of >=110bpm B: Change to Maximum Heart rate (Pulse) of >= 25 bpm C: A and B D: Weight Loss from baseline to endpoint of >= 3.5% E: Sitting Max. Systolic BP of >= Hypertension Assessment Criteria F: Sitting Max. Diastolic BP of >= Hypertension Assessment Criteria *p-value is derived from Cochran Armitage Trend test. Abbreviations: ATMX = atomoxetine; N = number of patients; n = number of patients meeting the criteria; TEAE = treatment-emergent adverse event.



Electrocardiograms

Summaries of the mean change from baseline to LOCF endpoint in electrocardiogram (ECG) intervals and heart rate are shown in Table LYBC.13.

Mean increases in heart rate were observed for all atomoxetine treatment groups compared with placebo. These leveled off at atomoxetine 1.2 mg/kg/day, but all increases were statistically significant (p<0.05). Differences between treatment groups were also statistically significant (p<0.001).

Relative to placebo, all doses of atomoxetine were also associated with mean decreases in QT interval. On the other hand, the Bazett correction for QT interval, showed a statistically significant (p<0.05) prolongation of the mean QTc interval for each atomoxetine treatment group.

However, for drugs associated with increased heart rate, the Bazett correction is known to over-correct for heart rate effects. In this case the Fridericia or Data Driven correction is more appropriate. Analyses of the ECG results using the Fridericia correction showed a mean decrease in QT interval for the atomoxetine 1.2 mg/kg/day and 1.8 mg/kg/day groups. A 2.07 msec prolongation was still seen in the atomoxetine 0.5 mg/kg/day group, but this was less than half of that seen with the Bazett correction. Data driven correction resulted in mean increases of QTc interval for all atomoxetine treatment groups, but none of the observed increases were found to be statistically significant, either with the Data Driven or Fridericia correction. All mean increases seen with either of these two QT interval corrections were below 5 msec. Also, unlike the Bazett correction, neither the Fridericia nor the Data Driven correction gave any evidence of a statistically significant linear dose response.

Table LYBC.14 summarizes categorical changes in QTc intervals using Food and Drug Administration (FDA) criteria. Even though statistically significant trends were observed for criterion D (increase from baseline ≥30 msec) for both the Fridericia (p=0.015) and Data Driven (p=0.034) corrected QTc intervals, no cases were reported for a QTc interval >450 msec (criteria A, B, C), nor were any cases reported for a QTc increase from baseline ≥60 msec (criteria E). The number of patients in the atomoxetine treatment groups with QTc prolongation between 30 msec and 60 msec seen with both correction methods were: Fridericia (8.2% : 15/183), Data Driven (8.7% : 16/183).

No serious adverse events due to QTc interval prolongation were reported during the study.



Table LYBC.13. Electrocardiograms Mean Change from Baseline to LOCF Endpoint Patients Who Took at Least 1 Dose of Study Medication

__________________________________________________________________________________________________________________________________ Baseline Endpoint Change p-value __________________________________________________________________________________________________________________________________ Therapy n Mean SD Mean SD Mean SD Within* Between** __________________________________________________________________________________________________________________________________ Heart Rate Placebo 62 73.60 11.16 72.56 10.34 -1.03 10.65 0.448 <0.001 ATMX 0.5 62 77.82 13.53 81.47 13.16 3.65 11.97 0.020 ATMX 1.2 60 75.08 11.10 87.02 13.14 11.93 13.13 <0.001 ATMX 1.8 61 74.95 11.58 86.25 14.61 11.30 11.79 <0.001 Dose Response*** Linear: P=<0.001 Quadratic: P=0.011 __________________________________________________________________________________________________________________________________ RR Interval Placebo 62 833.26 123.47 841.78 108.29 8.52 112.20 0.552 <0.001 ATMX 0.5 62 793.00 132.62 754.66 116.34 -38.35 110.93 0.008 ATMX 1.2 60 816.97 125.11 705.97 112.63 -111.00 129.66 <0.001 ATMX 1.8 61 819.98 131.04 715.46 122.09 -104.52 118.99 <0.001 Dose Response*** Linear: P=<0.001 Quadratic: P=0.003 __________________________________________________________________________________________________________________________________ PR Interval Placebo 62 144.98 26.28 146.82 22.13 1.84 19.29 0.456 0.822 ATMX 0.5 62 146.95 17.86 146.85 20.46 -0.10 14.98 0.960 ATMX 1.2 60 147.30 19.96 146.23 19.64 -1.07 15.28 0.591 ATMX 1.8 61 141.10 15.23 142.16 14.34 1.07 12.74 0.516 Dose Response*** Linear: P=0.375 Quadratic: P=0.732 __________________________________________________________________________________________________________________________________



Table LYBC.13. Electrocardiograms Mean Change from Baseline to LOCF Endpoint Patients Who Took at Least 1 Dose of Study Medication (Continued)

__________________________________________________________________________________________________________________________________ Baseline Endpoint Change p-value __________________________________________________________________________________________________________________________________ Therapy n Mean SD Mean SD Mean SD Within* Between** __________________________________________________________________________________________________________________________________ QRS Interval Placebo 62 87.37 8.91 87.05 8.64 -0.32 4.53 0.577 0.472 ATMX 0.5 62 86.47 7.43 87.00 8.01 0.53 4.79 0.385 ATMX 1.2 60 86.02 6.85 87.22 6.22 1.20 4.98 0.067 ATMX 1.8 61 86.84 9.02 87.79 7.82 0.95 6.07 0.226 Dose Response*** Linear: P=0.142 Quadratic: P=0.574 __________________________________________________________________________________________________________________________________ QT Interval Placebo 62 370.39 25.22 371.53 24.60 1.15 20.63 0.664 <0.001 ATMX 0.5 62 359.05 26.46 355.10 23.23 -3.95 19.65 0.118 ATMX 1.2 60 365.28 26.85 346.75 23.10 -18.53 23.74 <0.001 ATMX 1.8 61 365.02 23.52 348.54 25.66 -16.48 23.51 <0.001 Dose Response*** Linear: P=<0.001 Quadratic: P=0.017 __________________________________________________________________________________________________________________________________ Corrected Placebo 62 407.47 18.68 406.29 16.97 -1.18 18.93 0.626 0.010 QT Interval ATMX 0.5 62 405.29 21.71 410.94 21.96 5.65 20.00 0.030 (Bazett) ATMX 1.2 60 406.07 20.56 415.02 21.15 8.95 22.47 0.003 ATMX 1.8 61 405.44 21.07 414.33 18.90 8.89 20.32 0.001 Dose Response*** Linear: P=0.002 Quadratic: P=0.173 __________________________________________________________________________________________________________________________________



Table LYBC.13. Electrocardiograms Mean Change from Baseline to LOCF Endpoint Patients Who Took at Least 1 Dose of Study Medication (Concluded)

__________________________________________________________________________________________________________________________________ Baseline Endpoint Change p-value __________________________________________________________________________________________________________________________________ Therapy n Mean SD Mean SD Mean SD Within* Between** __________________________________________________________________________________________________________________________________ Corrected Placebo 62 394.46 16.38 394.08 15.88 -0.38 14.83 0.841 0.786 QT Interval ATMX 0.5 62 389.07 18.00 391.14 17.35 2.07 14.78 0.275 (Fridericia) ATMX 1.2 60 391.63 18.48 390.50 16.83 -1.13 17.16 0.613 ATMX 1.8 61 391.13 16.66 390.80 15.58 -0.33 16.79 0.878 Dose Response*** Linear: P=0.401 Quadratic: P=0.851 __________________________________________________________________________________________________________________________________ Corrected Placebo 62 398.80 16.53 398.13 15.71 -0.67 15.75 0.737 0.868 QT Interval ATMX 0.5 62 394.54 18.52 397.73 18.27 3.19 15.99 0.122 (Data Driven) ATMX 1.2 60 396.39 18.62 398.58 17.70 2.19 18.31 0.359 ATMX 1.8 61 395.86 17.54 398.60 15.81 2.74 17.34 0.221 Dose Response*** Linear: P=0.482 Quadratic: P=0.693 __________________________________________________________________________________________________________________________________ N: number of patients who took at least one dose of study medication * Within p-value is derived from paired t-test. ** Between p-value is derived from ANCOVA. *** Dose Response p-value is derived from the contrasts of the least-square means from ANCOVA model. ANCOVA model: change = baseline + treatment Linear Contrast -3 -1 1 3 Quadratic Contrast 1 -1 -1 1 Abbreviations: ATMX = atomoxetine; n = number of patients; SD = standard deviation.



Table LYBC.14. Summary of ECG Data Analysis of Categorical Changes in QTc Using FDA Criteria Patients Who Took at Least 1 Dose of Study Medication

__________________________________________________________________________________________________________________________________ Placebo ATMX 0.5 ATMX 1.2 ATMX 1.8 ATMX all p-value (N=62) (N=62) (N=60) (N=61) (N=183) CA Trend Criteria N n (%) N n (%) N n (%) N n (%) N n (%) Test* __________________________________________________________________________________________________________________________________ Corrected A 62 0 0.0 62 0 0.0 59 0 0.0 61 0 0.0 182 0 0.0 QT Interval B 62 0 0.0 62 0 0.0 60 0 0.0 61 0 0.0 183 0 0.0 (Fridericia) C 62 0 0.0 62 0 0.0 60 0 0.0 61 0 0.0 183 0 0.0 D 62 2 3.2 62 2 3.2 60 5 8.3 61 8 13.1 183 15 8.2 0.015 E 62 0 0.0 62 0 0.0 60 0 0.0 61 0 0.0 183 0 0.0 __________________________________________________________________________________________________________________________________ Corrected A 62 0 0.0 62 0 0.0 59 0 0.0 61 0 0.0 182 0 0.0 QT Interval B 62 0 0.0 62 0 0.0 59 0 0.0 61 0 0.0 182 0 0.0 (Data Driven) C 62 0 0.0 62 0 0.0 60 0 0.0 61 0 0.0 183 0 0.0 D 62 3 4.8 62 2 3.2 60 6 10.0 61 8 13.1 183 16 8.7 0.034 E 62 0 0.0 62 0 0.0 60 0 0.0 61 0 0.0 183 0 0.0 __________________________________________________________________________________________________________________________________ N: Number of patients who did not meet the criterion at baseline n: Number of patients who met the criterion at postbaseline * p-value is derived from Cochran Armitage Trend test. Criteria: A: QTc interval of > 450 msec B: QTc interval of > 480 msec C: QTc interval of > 500 msec D: QTc interval increases from baseline >= 30 msec E: QTc interval increases from baseline >= 60 msec Abbreviations: ATMX = atomoxetine; N = number of patients; n = number of patients meeting the criteria.



Corrected QT intervals (Fridericia, Data Driven) summarized by CYP2D6 metabolic status for EM and PM patients are shown in Table LYBC.15. Analyses of corrected QT intervals (Fridericia, Data Driven) for EM and IM patients (Categories 1, 2) are shown in Tables LYBC.16~17.

No statistically significant trends in mean changes of QTc interval (Fridericia, Data Driven) were observed in either EM or IM (Categories 1, 2) patients with increasing dose, nor was any relationship found between CYP2D6 metabolic status and QTc prolongation when EM and IM patients were compared.

There were no discontinuations due to adverse events, and no evidence of statistically significant differences in atomoxetine tolerability from EM patients among the subgroup of patients with a CYP2D6 genotype consistent with decreased efficiency to metabolize atomoxetine (IM and PM patients).



Table LYBC.15. Corrected QT interval by Subgroup(CYP2D6 EM/PM) Mean Change from Baseline to LOCF Endpoint Patients Who Took at Least 1 Dose of Study Medication

_____________________________________________________________________________________________________________________ Baseline Endpoint Change 95%CI** CYP2D6 ------------ ------------ ------------ ------------ EM/PM n Mean SD Mean SD Mean SD Diff LCL UCL p-value* _____________________________________________________________________________________________________________________ Corrected EM Placebo 62 394.46 16.38 394.08 15.88 -0.38 14.83 QT Interval ATMX 0.5 61 389.37 18.00 391.26 17.46 1.90 14.84 -0.13 -5.02 4.77 0.959 (Fridericia) ATMX 1.2 59 392.06 18.34 390.73 16.88 -1.33 17.24 -2.08 -7.00 2.84 0.405 ATMX 1.8 61 391.13 16.66 390.80 15.58 -0.33 16.79 -1.52 -6.41 3.36 0.539 ----------------------------------------------------------------------------------------------------- PM Placebo 0 ATMX 0.5 1 371.03 383.51 12.47 ATMX 1.2 1 366.35 377.00 10.65 ATMX 1.8 0 ----------------------------------------------------------------------------------------------------- P-value for Subgroup effect: ** 0.929 P-value for Subgroup * therapy interaction: ** 0.915 _____________________________________________________________________________________________________________________ Corrected EM Placebo 62 398.80 16.53 398.13 15.71 -0.67 15.75 QT Interval ATMX 0.5 61 394.91 18.43 397.85 18.39 2.94 16.00 1.68 -3.46 6.83 0.520 (Data Driven) ATMX 1.2 59 396.85 18.44 398.82 17.75 1.97 18.39 1.68 -3.50 6.85 0.524 ATMX 1.8 61 395.86 17.54 398.60 15.81 2.74 17.34 1.95 -3.18 7.09 0.454 ----------------------------------------------------------------------------------------------------- PM Placebo 0 ATMX 0.5 1 371.72 390.09 18.36 ATMX 1.2 1 369.56 384.26 14.69 ATMX 1.8 0 ----------------------------------------------------------------------------------------------------- P-value for Subgroup effect: ** 0.883 P-value for Subgroup * therapy interaction: ** 0.818 _____________________________________________________________________________________________________________________ N:number of patients who took at least 1 dose of medication * P-value is derived from ANCOVA model. Model: Change = baseline + treatment ** P-value of subgroup effect and subgroup*treatment interaction are derived from ANCOVA model. Model: Change = baseline + treatment + subgroup + subgroup*treatment interaction Abbreviations: ATMX = atomoxetine; CI = confidence interval; Diff = difference; EM = extensive metabolizer; LCL = lower control limit; n = number of patients; PM = poor metabolizer; SD = standard deviation; UCL = upper control limit.



Table LYBC.16. Corrected QT interval by Subgroup(CYP2D6 EM/IM :Category 1) Mean Change from Baseline to LOCF Endpoint Patients Who Took at Least 1 Dose of Study Medication

_____________________________________________________________________________________________________________________ Baseline Endpoint Change 95%CI** CYP2D6 ------------ ------------ ------------ ------------ EM/IM *** n Mean SD Mean SD Mean SD Diff LCL UCL p-value* _____________________________________________________________________________________________________________________ Corrected EM Placebo 51 393.57 16.46 392.84 16.13 -0.73 15.08 QT Interval ATMX 0.5 46 389.81 17.57 392.20 16.87 2.39 14.56 1.41 -4.10 6.92 0.614 (Fridericia) ATMX 1.2 45 393.22 19.48 390.01 17.85 -3.21 17.56 -2.64 -8.16 2.88 0.347 ATMX 1.8 50 390.58 16.80 392.08 15.94 1.51 16.01 0.88 -4.51 6.26 0.748 ----------------------------------------------------------------------------------------------------- IM Placebo 11 398.56 16.09 399.82 13.87 1.26 14.20 ATMX 0.5 15 388.01 19.83 388.41 19.50 0.40 16.12 -6.43 -17.46 4.59 0.246 ATMX 1.2 14 388.31 14.00 393.06 13.58 4.75 15.16 -1.93 -13.10 9.24 0.730 ATMX 1.8 11 393.64 16.60 384.95 12.88 -8.69 18.48 -12.55 -24.15 -0.94 0.035 ----------------------------------------------------------------------------------------------------- P-value for Subgroup effect: ** 0.853 P-value for Subgroup * therapy interaction: ** 0.076 _____________________________________________________________________________________________________________________ Corrected EM Placebo 51 397.92 16.55 397.08 16.13 -0.84 16.24 QT Interval ATMX 0.5 46 395.06 18.45 399.01 17.83 3.95 15.57 3.43 -2.36 9.23 0.244 (Data Driven) ATMX 1.2 45 397.62 19.43 397.63 18.82 0.02 18.48 0.71 -5.11 6.53 0.810 ATMX 1.8 50 395.36 17.52 399.51 16.16 4.15 16.60 3.77 -1.90 9.45 0.191 ----------------------------------------------------------------------------------------------------- IM Placebo 11 402.87 16.59 402.96 13.16 0.09 13.93 ATMX 0.5 15 394.46 19.03 394.29 20.25 -0.16 17.45 -5.12 -16.67 6.44 0.377 ATMX 1.2 14 394.37 15.17 402.64 13.64 8.27 17.25 3.26 -8.46 14.99 0.578 ATMX 1.8 11 398.11 18.34 394.47 14.02 -3.64 19.97 -6.48 -18.76 5.79 0.293 ----------------------------------------------------------------------------------------------------- P-value for Subgroup effect: ** 0.929 P-value for Subgroup * therapy interaction: ** 0.134 _____________________________________________________________________________________________________________________ N:number of patients who took at least 1 dose of medication * P-value is derived from ANCOVA model. Model: Change = baseline + treatment ** P-value of subgroup effect and subgroup*treatment interaction are derived from ANCOVA model. Model: Change = baseline + treatment + subgroup + subgroup*treatment interaction *** PM patients are excluded in the analysis

Abbreviations: ATMX = atomoxetine; CI = confidence interval; Diff = difference; EM = extensive metabolizer; IM = intermediate metabolixer; LCL = lower control limit; n = number of patients; SD = standard deviation; UCL = upper control limit.



Table LYBC.17. Corrected QT interval by Subgroup(CYP2D6 EM/IM :Category 2) Mean Change from Baseline to LOCF Endpoint Patients Who Took at Least 1 Dose of Study Medication

_____________________________________________________________________________________________________________________ Baseline Endpoint Change 95%CI** CYP2D6 ------------ ------------ ------------ ------------ EM/IM *** n Mean SD Mean SD Mean SD Diff LCL UCL p-value* _____________________________________________________________________________________________________________________ Corrected EM Placebo 46 393.99 17.00 392.59 16.82 -1.41 15.46 QT Interval ATMX 0.5 42 389.65 18.02 391.82 17.11 2.17 14.66 1.58 -4.23 7.40 0.592 (Fridericia) ATMX 1.2 41 390.91 14.65 388.27 16.54 -2.64 17.12 -2.65 -8.49 3.19 0.371 ATMX 1.8 47 390.14 17.13 391.25 15.34 1.12 15.60 0.76 -4.89 6.40 0.792 ----------------------------------------------------------------------------------------------------- IM Placebo 16 395.80 14.87 398.38 12.23 2.57 12.82 ATMX 0.5 19 388.74 18.41 390.04 18.65 1.30 15.63 -4.87 -14.16 4.41 0.298 ATMX 1.2 18 394.67 25.14 396.35 16.72 1.68 17.62 -1.47 -10.79 7.85 0.753 ATMX 1.8 14 394.46 15.10 389.27 16.87 -5.19 20.16 -8.45 -18.38 1.48 0.094 ----------------------------------------------------------------------------------------------------- P-value for Subgroup effect: ** 0.496 P-value for Subgroup * therapy interaction: ** 0.208 _____________________________________________________________________________________________________________________ Corrected EM Placebo 46 398.41 16.97 396.71 16.66 -1.70 16.39 QT Interval ATMX 0.5 42 394.86 19.01 398.73 18.00 3.87 15.82 3.82 -2.20 9.84 0.212 (Data Driven) ATMX 1.2 41 395.73 15.05 395.73 17.02 0.01 18.25 0.38 -5.67 6.44 0.901 ATMX 1.8 47 395.05 18.01 398.72 15.20 3.67 15.98 3.71 -2.14 9.57 0.212 ----------------------------------------------------------------------------------------------------- IM Placebo 16 399.92 15.68 402.20 12.10 2.28 13.79 ATMX 0.5 19 395.03 17.58 395.90 19.60 0.87 16.64 -3.94 -14.00 6.11 0.436 ATMX 1.2 18 399.40 24.84 405.86 17.81 6.46 18.44 3.90 -6.23 14.04 0.444 ATMX 1.8 14 398.55 16.19 398.18 18.32 -0.37 21.68 -3.36 -14.16 7.44 0.536 ----------------------------------------------------------------------------------------------------- P-value for Subgroup effect: ** 0.346 P-value for Subgroup * therapy interaction: ** 0.153 _____________________________________________________________________________________________________________________ N:number of patients who took at least 1 dose of medication * P-value is derived from ANCOVA model. Model: Change = baseline + treatment ** P-value of subgroup effect and subgroup*treatment interaction are derived from ANCOVA model. Model: Change = baseline + treatment + subgroup + subgroup*treatment interaction *** PM patients are excluded in the analysis

Abbreviations: ATMX = atomoxetine; CI = confidence interval; Diff = difference; EM = extensive metabolizer; IM = intermediate metabolizer; LCL = lower control limit; n = number of patients; SD = standard deviation; UCL = upper control limit.



Pharmacokinetic Outcomes

Body weight and CYP2D6 EM sub-class (heterozygous EM, homozygous EM or IM) exhibited a statistically significant (p<0.001) effect on atomoxetine clearance. Mean atomoxetine apparent clearance (CL/F) increased with body weight, and was lower in IMs compared with other EMs. No other demographic or patient factors were found to have a statistically significant effect on atomoxetine pharmacokinetics.

The distribution of dose-weight normalized atomoxetine concentrations and individual predicted atomoxetine CL/F overlapped between homozygous EMs, heterozygous EMs, and IMs. Although some IMs exhibited atomoxetine CL/F towards the lower end of the distribution of other EMs, no EM subcategory was uniquely different from the other in terms of atomoxetine PK. In contrast, the decrease in CL/F was statistically significant (p<0.001) in PMs (Figure LYBC.5).

0 6 12 18 24Time from Dose (h)

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Abbreviations: Conc = concentration; EM = extensive metabolizer; h = hour; IM = intermediate metabolizer; PM = poor metabolizer; UM = ultra-rapid metabolizer.

Figure LYBC.5. Observed dose-weight normalized atomoxetine concentrations stratified by CYP2D6 genotype.

The plot shows a few EM observations from two patients that were atypically high (5 upper open circles at ~10 hours). Initially the genotype data on these patients indicated that they were EMs, however because of their atypically high dose-weight normalized concentrations their respective genotypes were reanalyzed. Results indicated that these two patients actually had genotypes consistent with PMs. The concentration data on these patients was excluded from the Population Pharmacokinetic Analysis.



Two metabolites of atomoxetine, N-desmethylatomoxetine and 4-hydroxyatomoxetine, were evaluated graphically. These results are shown in Figure LYBC.6 and, as with the observed concentration evaluations of atomoxetine shown in Figure LYBC.5, include observations from PMs and the two excluded patients.

As shown in the upper panel, the N-desmethylatomoxetine dose-weight normalized concentrations showed a large overlap between various genotype subgroups, and as with atomoxetine, some IMs were at the higher end of the distribution of other EMs. Furthermore, PMs exhibited dose-weight normalized concentrations that were higher than other genotypes.

In case of the 4-hydroxyatomoxetine metabolite (lower panel), dose-weight normalized concentrations were much lower than those observed for atomoxetine. There were also no overt differences in dose-weight normalized 4-hydroxyatomoxetine concentrations between the various genotype subgroups.




Dos

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c [(

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Figure LYBC.6. Observed dose-weight normalized N-desmethylatomoxetine and 4-hydroxyatomoxetine concentrations stratified by CYP2D6 status.



References

[APA] American Psychiatric Association. 1994. Attention-deficit and disruptive behavior disorders. In: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association. p.78-85.

DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. 1998. Reliability and validity. In: ADHD Rating Scale-IV. Checklists, norms, and clinical interpretations. New York, NY: Guilford Press. p. 28-42.

Guy W. 1976. ECDEU assessment manual for psychopharmacology, revised. Bethesda (MD): U.S. Department of Health, Education, and Welfare.

Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, et al. 1997. Schedule for affective disorders and schizophrenia for school-age-children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36(7):980-988.

[NIMH] National Institutes of Mental Health. 1985. Psychopharmacology Bulletin 21:839-943.

Yamazaki K, Kimura T, Koishi S, Asakura A, Ohya A, Hayashida H, et al. 2001. Preparation of the ADHD Rating Scale-IV Japanese Version and its discriminative capability. Normative data of ADHDRS-IV: Japanese Version (Preparation of the diagnostic and treatment guideline for ADHD based on empirical research: research for psychiatric and neurological disorders funded by Ministry of Health and Welfare in 2001).

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Summary ID# 5285 Clinical Study Summary: Study B4Z-JE-LYBC ...art45-paediatric-studies-docs.ema.europa.eu/GROUP A... · these 3 dose ranges with that of placebo, and evaluating the