Summary ID# Clinical Study Summary: Study B4Z-JE-LYBD

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1 CT Registry ID#5286 Page 1 Summary ID# 5286 Clinical Study Summary: Study B4Z-JE-LYBD An Open Label, Dose-Titration Safety Study of Hydrochloride in Outpatient Japanese Children with Attention-Deficit/Hyperactivity Disorder Date summary approved by Lilly: 27 July 2006 Brief Summary of Results The primary objective of Study B4Z-JE-LYBD (LYBD) was to assess whether treatment with 1.8 mg/kg/day of LY (hereafter referred to as atomoxetine) would be safe and tolerable in a population of Japanese pediatric attention deficit/hyperactivity disorder (ADHD) patients aged 6 through 18 years. The secondary objectives of the study were to investigate the symptom scores in the attention-deficit/hyperactivity disorder rating scale- IV-parent version (investigator administered and scored, translated and validated in Japanese [ADHDRS-IV-J:I] at baseline) with atomoxetine therapy, and to evaluate the plasma concentration of atomoxetine, 4-hydroxyatomoxetine, and N- desmethylatomoxetine. The results were as follows: There were no deaths or serious adverse events (SAEs) in this study. The total rate of discontinuations due to adverse events (AEs) was 8.1%. Two patients (5.4%) discontinued the study due to headache and 1 patient (2.7%) discontinued due to vomiting. Statistically significant mean changes were observed for laboratory values including: hemoglobin (p=.011), erythrocyte count (p=.022), urinalysis specific gravity (p=.038), aspartate transaminase (p<.001), alanine transaminase (p=.009), creatine phosphokinase (p<0.001), alkaline phosphatase (p=.003), thyroxine

2 CT Registry ID#5286 Page 2 (total-t4) (p=.002), urea nitrogen (p=.015), chloride (p=.042), and total protein (p=.009). An analysis of vital signs showed statistically significant changes in pulse, height, and weight (all p<.01). Electrocardiogram (ECG) analysis showed statistically significant mean changes for: heart rate (p<.001), RR interval (p<.001), QRS interval (p<.001), QT Bazett correction (p<.001), and QT data correction (p=.026). Statistically significant mean changes were not observed for QT Fridericia correction. Patients showed statistically significant improvements from baseline to endpoint on the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored. For the ADHDRS-IV-J:I Total score, the mean change in last observation carried forward (LOCF) from baseline to endpoint was a reduction of 18.6; for the hyperactivity-impulsivity subscale, the mean change in LOCF from baseline to endpoint was a reduction of 8.1; and for the inattention subscale, the mean change in LOCF from baseline to endpoint was a reduction of 10.5 (p<.001 for all three). The Clinical Global Impressions Attention-Deficit/Hyperactivity Disorder Severity (CGI-ADHD-S), showed the mean change in LOCF from baseline to endpoint was a reduction of 1.9 (p<.001). According to the LOCF at endpoint for the percentage-of-responder analyses, 83.3% of patients met the response criterion for ADHDRS-IV-J:I, and 25% met the response criterion for CGI-ADHD-S. Title of Study: An Open Label, Dose Titration Safety Study of Hydrochloride in Outpatient Japanese Children with Attention-Deficit/Hyperactivity Disorder Investigator(s): This multicenter study included 21 principal investigators. Study Center(s): This study was conducted at 19 study centers. (There was 1 principal investigator at each site, but the chief investigators at 2 sites changed during the course of the study; hence, the 21 principal investigators.) Length of Study: 7 months Phase of Development: 2 Date of first patient enrolled (first patient visit): 07 April 2003 Date of last patient completed: 20 October 2003 Objectives: The primary objective of this study was to assess whether treatment with 1.8 mg/kg/day of atomoxetine was safe and tolerable in a population of Japanese pediatric ADHD patients aged 6 through 18 years. The secondary objectives of the study were as follows: To investigate the symptom scores in the ADHDRS-IV-J:I at baseline and with atomoxetine therapy To evaluate the plasma concentration of atomoxetine, 4-hydroxyatomoxetine, and N- desmethylatomoxetine. Study Design: This was an open-label, forced titration study through increasing doses to a maximum target dose (low dose 0.5 mg/kg/day up to a maximum target dose 1.8 mg/kg/day). The total daily dose for each patient was administered as a divided dose on a twice-daily dosing schedule. The study consisted of 2 study periods, an entry/screening phase (Study Period I, Visit 1 and Visit 2) and an open-label treatment

3 CT Registry ID#5286 Page 3 phase (Study Period II, Visit 3 through Visit 6 [see Figure LYBD. 1]). Number of Patients: Planned: 30 Enrolled: 37 Completed: 32 Main Criteria for Inclusion: Eligible participants were male and female Japanese pediatric outpatients, at least 6 years of age and less than 18 years of age at the time of entry, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV ) and the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children - Present and Lifetime Version: Behavioral Disorders Supplement (K-SADS-PL: Behavioral) module criteria for ADHD. Study Drug, Dose, and Mode of Administration: hydrochloride 0.5 mg/kg/day to 1.8 mg/kg/day, given orally, twice daily as a split dose in 2.5, 5, 10, or 20 mg capsules. Reference Therapy, Dose, and Mode of Administration: No reference therapy was used in this study. Duration of Treatment: 8 weeks Variables: Efficacy: ADHDRS-IV-J:I, CGI-ADHD-S Safety: AEs, laboratory tests, vital signs, body weight, height, ECG test Pharmacokinetic: Concentrations (atomoxetine and its metabolites).

4 CT Registry ID#5286 Page 4 Evaluation Methods: Statistical: In general, all statistical analyses, both efficacy and safety included all patients who met entry criteria, took at least 1 dose of study medication, and had a baseline and postbaseline measurement. This set of patients is referred to as the full analysis set (FAS). If not otherwise stated, all statistical tests were performed using a 2-sided, 0.05 significance level. Dropouts and missing data were accounted for using a LOCF approach, wherein the last value obtained from a patient prior to their early discontinuation of the study is carried forward through the end of the study. However, additional data may have been excluded from the efficacy analysis in the following cases: If a patient did not discontinue this study after taking excluded drug(s), the data after that date were excluded from all efficacy analyses. If a patient did not discontinue this study after having 2 visits of noncompliance, the data after the second noncompliant visit were excluded from all efficacy analyses. For both the ADHDRS-IV-J:I Total score and the CGI-ADHD-S score, changes from baseline to endpoint during Study Period II were computed using the LOCF approach and the results were summarized. Baseline was defined as the last nonmissing measurement obtained on or prior to Visit 2 (end of Study Period I). Endpoint score was defined as the last nonmissing measurement obtained after Visit 2 (end of Study Period I) but on or prior to Visit 6 (end of Study Period II). For each of these efficacy measures, a Wilcoxon signed-rank test was used to assess whether the change was significantly different from zero. Additionally, changes from baseline in the ADHDRS-IV-J:I Total score and CGI-ADHD-S were summarized for each visit from Visit 3 through Visit 6 using only observed data. In addition to the above, the percentage of patients responding to treatment was calculated. Two methods were used to define treatment response: [1] ADHDRS-IV-J:I Total score decrease of 25% from baseline. [2] CGI-ADHD-S score of 1 or 2 at endpoint. Adverse events (AEs) occurring for the first time after the first dose of the study drug up to the last observation point were analyzed. To contribute to the analysis of AEs, an event must have either occurred for the first time in the study during the treatment period or occurred during the treatment period at a greater severity than during baseline. Changes from baseline to endpoint scores for laboratory data, vital signs, and ECG intervals were computed. QT corrections were done using several methods. Treatment changes were assessed with paired t-tests or the Wilcoxon signed-rank test. Treatment-emergent out-of-range laboratory values were assessed in a similar fashion as treatment-emergent adverse events (TEAEs). Categorical analyses of changes in ECG intervals and vital signs were also performed and analyzed. Pharmacokinetic/Pharmacodynamic: A single blood sample for determination of atomoxetine plasma concentration was collected at the final visit for all patients. In addition, blood samples for atomoxetine concentration determination may also have been drawn from patients with an SAE or a clinically significant overdose. If a patient was found to have severe neurologic signs or symptoms at any visit following the initiation of therapy, a blood sample for plasma concentration analysis had to be drawn following the procedures that were required to be completed: The date and time of the previous medication dose should have been recorded. The exact date and time that a blood sample was drawn should have been recorded on the laboratory test requisition form. Results:

5 CT Registry ID#5286 Page 5 Study Design Figure LYBD.1 illustrates the study design for Study LYBD. Figure LYBD.1. Study design. Patient Demographics Table LYBD.1 summarizes the patient demographics and other baseline characteristics for Study LYBD. Of the 37 enrolled patients, 100% were East/Southeast Asian, 86.5% were male and 13.5% were female. The mean age was years (range 6.21 years to years). Prior stimulant exposure was noted in 51.4% of the patients. One hundred percent of the patients were determined to be cytochrome P450 2D6 (CYP2D6) extensive metabolizer (EM) patients. (For the pharmacokinetic analysis, 2 patients were classified as ultra-rapid metabolizer (UM) patients; for all other analyses, these UM patients were included in the EM group.) The most common ADHD subtype diagnosis was the predominantly inattentive subtype (62.2%), followed by the combined ADHD subtype (35.1%), and the hyperactive-impulsive subtype (2.7%).

6 CT Registry ID#5286 Page 6 Table LYBD.1. Variable (N=37) Sex: No. (%) No. Patients 37 Female 5 (13.5) Male 32 (86.5) Origin: No. (%) No. Patients 37 East/Southeast A 37 (100) Age: yrs. No. Patients 37 Mean Median Standard Dev Minimum 6.21 Maximum Height: cm No. Patients 37 Mean Median Standard Dev Minimum Maximum Weight: kg No. Patients 37 Mean Median Standard Dev Minimum Maximum Summary of Demographics and Other Patient Characteristics Variable (N=37) CYP2D6 No. Patients 37 EXTN 37 (100) DSM-IV ADHD Subtype No. Patients 37 HYP/IMP 1 (2.7) INATTV 23 (62.2) MIXED 13 (35.1) Prior Stimulant Exposure No. Patients 37 N 18 (48.6) Y 19 (51.4) WISC full scale IQ No. Patients 35 Mean Median Standard Dev Minimum Maximum Population: Full Analysis Set Initial Visit ONLY Patient Disposition This study consisted of 2 study periods: an entry/screening phase (Study Period I, Visit 1 and Visit 2) and an open-label treatment phase (Study Period II, Visit 3 through Visit 6). Figure LYBD.2 shows the patient disposition.

7 CT Registry ID#5286 Page 7 Abbreviations: N = number. Figure LYBD.2. Patient disposition. Thirty-eight patients entered the study and 1 patient discontinued prior to receiving atomoxetine because the patient did not meet protocol criteria. Of the 37 patients who were enrolled in the study, 5 patients discontinued during Study Period II. Three patients discontinued due to AEs, 1 due to physician decision, and 1 due to a protocol violation. The AEs leading to discontinuation were headache (2 patients) and vomiting (1 patient). The physician decision for discontinuation was due to the inability to determine safety and efficacy information from a patient s mother, and the protocol violation leading to discontinuation was due to patient noncompliance. Thirty-two patients completed the study. Primary Endpoint Safety The primary objective of this study is to assess whether treatment with 1.8 mg/kg/day of atomoxetine will be safe and tolerable in a population of Japanese pediatric ADHD patients aged 6 through 18 years. The safety evaluation included an analysis of AE data,

8 CT Registry ID#5286 Page 8 and contains the analyses of changes in laboratory measurements, vital sign measurements, and ECG data. Treatment-emergent adverse events (TEAEs) and treatment-emergent abnormal laboratory values were assessed. Adverse Events No deaths or SAEs were reported during the study. In this study, 33 patients (89.2%) given atomoxetine reported at least 1 TEAE. The most commonly reported AEs ( 10%) were: abdominal pain, constipation, diarrhea, nasopharyngitis, decrease in weight, decrease in appetite, anorexia, headache, and somnolence. Table LYBD.2 summarizes the TEAEs of 5%. The rate of discontinuations due to AEs was 8.1%. Two patients (5.4%) discontinued the study due to headache and 1 patient (2.7%) discontinued due to vomiting.

9 CT Registry ID#5286 Page 9 Table LYBD.2. Summary of Treatment-Emergent Adverse Events with 5% Incidence - Full Analysis Set Preferred Term n % (N = 37) Tachycardia Nausea Vomiting Pyrexia Arthralgia Insomnia Cough Rash Stomatitis Malaise Pharyngitis Upper respiratory tract inflammation Diarrhoea Constipation Nasopharyngitis Weight decreased Somnolence Anorexia Abdominal pain Decreased appetite Headache Patients with one or more TESS Patients with NO TESS Population: Full Analysis Set Baseline: Visits 1-2, Endpoint: Visits 3-6 TESS: Treatment Emergent Signs and Symptoms Laboratory Values Table LYBD.3 summarizes mean changes from baseline to endpoint for each laboratory analyte. Statistically significant mean changes were observed for laboratory values including: hemoglobin (p=.011), erythrocyte count (p=.022), urinalysis specific gravity (p=.038), aspartate transaminase (p<.001), alanine transaminase (p=.009), creatine phosphokinase (p<.001), alkaline phosphatase (p=.003), thyroxine (total-t4) (p=.002), urea nitrogen (p=.015), chloride (p=.042), and total protein (p=.009). Table LYBD.4 shows the percentage of patients with treatment-emergent abnormally high or low analyte values. For a given analyte value to be considered treatment-

10 CT Registry ID#5286 Page 10 emergent abnormally high, it must occur after treatment with atomoxetine has started and the corresponding analyte value should not have been high at baseline. Likewise, low values seen after dosing will only be counted if the corresponding value at baseline was not low.

11 Table LYBD.3. Summary of Laboratory Data (CN) Mean Change from Baseline to Endpoint by Analyte - Full Analysis Set Baseline Change p-value Lab Test Lab Unit N Mean SD Mean SD increased decreased HEMATOCRIT % HEMOGLOBIN g/dl ERYTHROCYTE COUNT E4/mm LEUKOCYTE COUNT CELLS/UL NEUTROFILS % LYMPHOCYTES % MONOCYTES % EOSINOPHILS % BASOPHILS % MEAN CELL VOLUME (MCV) fl PLATELET COUNT E4/mm UA-SPECIFIC GRAVITY NO UNITS AST/SGOT U/L <0.001 ALT/SGPT U/L CREATINE PHOSPHOKINASE U/L <0.001 ALKALINE PHOSPHATASE U/L GGT (GGPT/SGGT/YGGT) U/L THYROXINE, TOTAL-T4 ug/dl THYROID STIM. HORMONE uiu/ml UREA NITROGEN mg/dl CREATININE mg/dl CALCIUM mg/dl INORGANIC PHOSPHORUS mg/dl SODIUM meq/l POTASSIUM meq/l CHLORIDE meq/l TOTAL PROTEIN g/dl ALBUMIN g/dl GLUCOSE, FASTING mg/dl URIC ACID mg/dl CHOLESTEROL mg/dl BILIRUBIN, TOTAL mg/dl Abbreviations: N = number of patients with a baseline and at least one post baseline measurement. SD = standard deviation, p Value is from Wilcoxon signed rank test Change = endpoint - baseline, Baseline: Visit 1-2, Endpoint: Visit 3-6 CT Registry ID#5286 Page 11

12 Table LYBD.4. Summary of Laboratory (CN) Data Frequency of Patients with Abnormal Laboratory Values with Treatment-Emergent Adverse Event (TEAE) Option - Full Analysis Set ATOMOXETINE Lab Incidence (Total=37) Test Group N n (%) ATOMOXETINE Lab Incidence (Total=37) Test Group N n (%) HEMATOCRIT HIGH 36 5 (13.9) HEMOGLOBIN HIGH 36 5 (13.9) ERYTHROCYTE COUNT HIGH 36 1 (2.8) LEUKOCYTE COUNT LOW 34 1 (2.9) NEUTROPHILS LOW 19 7 (36.8) HIGH 29 3 (10.3) LYMPHOCYTES LOW 33 4 (12.1) HIGH 22 7 (31.8) MONOCYTES LOW 34 4 (11.8) HIGH 31 1 (3.2) EOSINOPHILS LOW 26 3 (11.5) HIGH 24 2 (8.3) MEAN CELL VOLUME LOW 36 2 (5.6) UA-SPECIFIC GRAVITY HIGH 26 7 (26.9) UA-WBC ABNORMAL 34 3 (8.8) UA-PROTEIN ABNORMAL 36 1 (2.8) AST/SGOT HIGH 32 1 (3.1) ALT/SGPT HIGH 31 4 (12.9) UREA NITROGEN HIGH 32 1 (3.1) INORGANIC PHOSPHORUS HIGH 33 1 (3.0) CHLORIDE LOW 36 3 (8.3) TOTAL PROTEIN HIGH 36 2 (5.6) URIC ACID LOW 34 1 (2.9) BILIRUBIN, TOTAL HIGH 34 1 (2.9) CREATININE HIGH 36 1 (2.8) GLUCOSE, FASTING LOW 34 1 (2.9) HIGH 32 4 (12.5) Population: Full Analysis Set Baseline: Visits 1-2, Endpoint: Visits 3-6 Total = Total number of patients in the treatment group having both baseline and endpoint visits. N = Total number of at risk patients with the lab test. n = Total number of at risk patients with the specific lab result (e.g. HIGH). CT Registry ID#5286 Page 12

13 CT Registry ID#5286 Page 13 Vital Signs Vital signs were examined to determine if treatment with atomoxetine was associated with changes in heart rate (pulse) or blood pressure. The following analyses were performed: analyses of mean change from baseline to endpoint categorical analyses of change in each variable. Table LYBD.5 summarizes the mean change from baseline to endpoint in vital sign measures. There were statistically significant changes in pulse, height, and weight (all p<.001). Table LYBD.6 summarizes the categorical changes in heart rate (pulse) and weight for atomoxetine-treated patients, and Table LYBD.7 summarizes the categorical changes in blood pressure for atomoxetine-treated patients. The criteria for the analysis of blood pressure were obtained from the Guidelines for the Management of Hypertension (Japan Society of Hypertension 2000). Five patients (13.5%) exhibited high diastolic blood pressure, and 1 patient (2.70%) exhibited high systolic pressure.

14 Table LYBD.5. Summary of Vital Sign Data Change from Baseline to Endpoint - Full Analysis Set Treatment Baseline Endpoint Change p-value* ATMX n Mean Median SD Mean Median SD Mean Median SD LCI UCI Pulse <0.001 Height <0.001 Weight <0.001 Systolic Blood Pressure Diastolic Blood Pressure Abbreviations: ATMX: atomoxetine; n = number of patients with a baseline and at least one post baseline measurement; SD = standard deviation; Change = endpoint-baseline; C.I. = 95% 2-sided Confidence Interval of Change; LCI = Lower bound of 95% C.I.; UCI = Upper bound of 95% C.I.; Baseline: Visit 1-2; Endpoint: Visit 3-6. * p-value is from Wilcoxon signed-rank test CT Registry ID#5286 Page 14

15 CT Registry ID#5286 Page 15 Table LYBD.6. Summary of Vital Sign Data Categorical Changes in Heart Rate (Pulse) and Weight - Full Analysis Set N=37 Criteria n (%) A % B % C % D % A=Maximum heart rate(visits 3-6) of >=110 bpm. B=Change to maximum heart rate of >=25 bpm. C=A and B. D=Weight loss from baseline to endpoint of 3.5%. N=number of randomized patients with at least one dose of study drug. Patients with a baseline heart rate of >=100 bpm are excluded from analyses A and C. Table LYBD.7. Summary of Vital Sign Data Categorical Changes in Blood Pressure - Full Analysis Set ATOMOX Incidence (N=37) Test group N n (%) Sitting Avg. Systolic BP (mmhg) HIGH 37 1 (2.70) Sitting Avg. Systolic BP (mmhg) NORMAL (97.30) Sitting Avg. Diastolic BP (mmhg) HIGH 37 5 (13.51) Sitting Avg. Diastolic BP (mmhg) NORMAL (86.49) Population: Enrolled patients who took at least 1 dose of study drug. Hypertension assessment criteria: The Guideline for the Management of Hypertension (The Japanese Society of Hypertension) Baseline: Visits 1-2(LOCF), Endpoint: Visits 3-6 N = Number of patients Normal at Baseline. n = Number of patients in the Incidence Group Post Baseline. Electrocardiograms (ECGs) Table LYBD.8 summarizes the mean change for ECG intervals and heart rate from baseline to endpoint. For QT correction, Bazett s formula, Fridericia s formula, and a data-driven approach were used. Because Bazett s formula overcorrects for heart rate effects (thereby erroneously suggesting a prolongation of the QTc interval in the setting of a chronotropic drug, such as atomoxetine), Fridericia s formula or the data-driven approach would be more appropriate to assess the QT prolongation by atomoxetine treatment. Electrocardiogram (ECG) analysis showed statistically significant mean

16 CT Registry ID#5286 Page 16 changes for heart rate (p<.001), RR interval (p<.001), QRS interval (p<.001), QT Bazett correction (p<.001), and QT data correction (p=.026). Statistically significant mean changes were not observed for QT Fridericia correction. For this study, ECGs were single, clinical ECGs and were not collect at specific times of day.

17 Table LYBD.8. Summary of Changes from Baseline to Endpoint for ECG and Heart Rate Treatment Baseline Endpoint Change p-value* ATMX n Mean Median SD Mean Median SD Mean Median SD LCI UCI Heart Rate <0.001 RR Interval <0.001 QRS Interval <0.001 QT BAZETT CORRECTION <0.001 QT Data CORRECTION QT FRIDERICIA CORRECTION Abbreviations: ATMX: atomoxetine; n = number of patients with a baseline and at least one post baseline measurement; SD = standard deviation; Change = endpoint-baseline; C.I. = 95% 2-sided Confidence Interval of Change; LCI = Lower bound of 95% C.I.; UCI = Upper bound of 95% C.I.; Baseline: Visit 1-2; Endpoint: Visit 3-6. * p-value is from Wilcoxon signed-rank test CT Registry ID#5286 Page 17

18 CT Registry ID#5286 Page 18 Secondary Endpoints Efficacy and Pharmacokinetics Secondary endpoints included an analysis of the symptom scores in the ADHDRS-IV-J:I at baseline and with atomoxetine therapy and an evaluation of the plasma concentration of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine. Efficacy The summary of the efficacy analyses is divided into 2 sections: Analyses of the ADHDRS-IV-J:I Total score: The primary analysis of the ADHDRS-IV-J:I Total score consisted of a Wilcoxon signed-rank test of changes from baseline to endpoint score. Change was computed using a last visit carried forward approach. Additionally, ADHDRS-IV-J:I subscales for Inattention and Hyperactivity-Impulsivity were analyzed in the same manner as the ADHDRS-IV-J:I Total score. Analyses of the CGI-ADHD-S: The CGI-ADHD-S was analyzed in the same manner as the ADHDRS-IV-J:I. Additionally, patients were categorized as responders using multiple definitions specified in the protocol: patients with a 25% decrease from baseline to endpoint in the ADHDRS- IV-J:I Total score patients with an endpoint CGI-ADHD-S score of at most 2. Table LYBD.9 gives the results of change from baseline to endpoint for the ADHDRS- IV-J:I (Total score, hyperactivity-impulsivity subscale, and inattention subscale). For the ADHDRS-IV-J:I Total score, the mean change in LOCF from baseline to endpoint was a reduction of 18.6; for the inattention subscale, the mean change in LOCF from baseline to endpoint was a reduction of 10.5; and for the hyperactivity-impulsivity subscale, the mean change in LOCF was a reduction of 8.1 from baseline to endpoint. All 3 of these changes are statistically significant (p<0.001). Table LYBD.10 summarizes the analysis of the changes from baseline to endpoint in CGI-ADHD-S. The mean change in LOCF from baseline to endpoint was a reduction of 1.9, a statistically significant (p<.001) change. Table LYBD.11 contains the results of the percentage-of-responder analyses. According to the LOCF at endpoint, 83.3% of the patients met the response criterion for ADHDRS- IV-J:I and 25% of the patients met the response criterion for CGI-ADHD-S. Table LYBD.12 contains the analyses of scores obtained from the ADHDRS-IV-J:I performed separately for patients falling into each of the ADHD subtypes (hyperactiveimpulsive, inattentive, and mixed). The changes from baseline to endpoint for the

19 CT Registry ID#5286 Page 19 inattentive and combined ADHD subtypes were statistically significant (p<.001). For the inattentive subgroup, the mean change from baseline to endpoint was a reduction of 18.0; for the combined subgroup, the mean change from baseline to endpoint was a reduction of 19.2.

20 Table LYBD.9. ADHDRS-IV-J:I Total Score Change from Baseline to Endpoint Baseline Endpoint Change Visit n Mean SD Mean SD Mean SD p-value* p-value** <.001 < <.001 < <.001 < <.001 <.001 LOCF at Endpoint <.001 < INATTENTIVE LOCF at Endpoint <.001 HYPERACTIVE/IMPULSIVE LOCF at Endpoint <.001 *p-value based on Wilcoxon signed rank test from analysis of changes from baseline for the LOCF Change from baseline to endpoint (visit 6). **p-value based on a paired t-test from analysis of change from baseline. Population: Full Analysis Set CT Registry ID#5286 Page 20

21 Table LYBD.10. CGI-ADHD-S Change from Baseline to Endpoint Baseline Endpoint Change Visit n Mean SD Mean SD Mean SD p-value* p-value** <.001 < <.001 < <.001 < <.001 <.001 LOCF at Endpoint <.001 <.001 *p-value based on Wilcoxon signed rank test from analysis of change from baseline to endpoint (visit 6). **p-value based on a paired t-test from analysis of change from baseline to endpoint. Population: Full Analysis Set CT Registry ID#5286 Page 21

22 CT Registry ID#5286 Page 22 Table LYBD.11. Percentage of Responders ADHDRS-J:I CGI-ADHD-S Response* Response** Visit N n % N n % % % % % % % % % LOCF at Endpoint % % * Responder is defined as having 25% or greater decrease from baseline to endpoint in the ADHDRS-J:I total score. ** Responder is defined as having an endpoint score of 1 or 2 on the CGI-ADHD-Severity score. All patients with a baseline and at least one post baseline measurement who also took at least one dose of study medication were included.

23 Table LYBD.12. ADHDRS-IV-J:I Total Score Change from Baseline to Endpoint by Subtype Baseline Endpoint Change Subtype: n Mean SD Mean SD Mean SD p-value* p-value** Hyperactive/Impulsive Inattentive <.001 <.001 Mixed <.001 <.001 *p-value based on Wilcoxon signed rank test from analysis of changes from baseline for the LOCF Change from baseline to endpoint (visit 6). **p-value based on a paired t-test from analysis of change from baseline. Population: Full Analysis Set CT Registry ID#5286 Page 23

24 CT Registry ID#5286 Page 24 Pharmacokinetic Analysis A blood sample was drawn from 36 of the 37 patients receiving atomoxetine for measurement of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine in plasma. One patient had an additional sample drawn at Visit 5 (after approximately 6 weeks of treatment) when it was thought that he would discontinue at Visit 5; however, he continued in the study and had a sample drawn at Visit 6 as well. Thus, 37 concentration results were available from 36 patients. Of the 37 results, 36 were quantifiable for atomoxetine, 34 for 4-hydroxyatomoxetine, and 32 for N-desmethylatomoxetine. Of the 36 patients with a plasma sample, 34 were CYP2D6 EM patients. Two patients were classified as UMs. No CYP2D6 poor metabolizer patients were identified. Concentration results are shown in Figure LYBD.3, Figure LYBD.4, and Figure LYBD.5 below. For comparison purposes, concentrations were normalized for most recent dose (mg/kg). Concentrations are shown on both Cartesian and semilog scales as shown in Figure LYBD.3 and Figure LYBD.5.

25 CT Registry ID#5286 Page 25 Upper plot is shown with and without (inset) break in y-axis. Figure LYBD.3. Dose-weight normalized atomoxetine plasma concentrations versus time in Japanese EM and UM children on Cartesian (upper panel) and semilog (lower panel) scales, B4Z-JE-LYBD.

26 CT Registry ID#5286 Page 26 Figure LYBD.4. Dose-weight normalized 4-hydroxyatomoxetine plasma concentrations versus time in Japanese EM and UM children on Cartesian (upper panel) and semilog (lower panel) scales, B4Z-JE-LYBD.

27 CT Registry ID#5286 Page 27 Figure LYBD.5. Dose-weight normalized N-desmethylatomoxetine plasma concentrations versus time in Japanese EM children on Cartesian (upper panel) and semilog (lower panel) scales, B4Z-JE-LYBD.