Summary ID#4668 Clinical Study Summary: Study B4Z-MC-LYAQ

Transcription

1 CT Registry ID#4668 Page 1 Summary ID#4668 Clinical Study Summary: Study B4Z-MC-LYAQ Date summary approved by Lilly: 09 August 2005 Title of Study: Safety and Efficacy of Atomoxetine or Atomoxetine Plus Fluoxetine in the Treatment of Mixed Attentional and Affective Disorders Investigators: This multicenter study included 21 principal investigators. Study Centers: There were 21 study centers in the US, although only 20 centers enrolled patients. Length of Study: 6 months Phase of Development: 3 Date first patient enrolled: 20 February 2001 Date last patient completed: 24 August 2001 Objectives: The primary objective of Study B4Z-MC-LYAQ (LYAQ) was to assess the tolerability and safety of atomoxetine (formerly called tomoxetine) in doses up to 1.8 mg/kg/day in patients who had a cytochrome P450 2D6 (CYP2D6) poor metabolizer (PM) phenotype. Three secondary objectives were identified for this study: To test the hypothesis that atomoxetine 1.2 mg/kg/day alone is noninferior to atomoxetine 1.2 mg/kg/day plus fluoxetine 20 mg/day in the treatment of mixed attentional and affective symptoms. To compare the safety of the combination of atomoxetine in doses up to 1.8 mg/kg/day and fluoxetine 20 mg/day with that of atomoxetine alone at doses up to 1.8 mg/kg/day. To assess speed of onset of therapeutic effect in the setting of CYP2D6 rapid or poor metabolism as assessed by Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator- Administered and Scored (ADHDRS-IV-Parent:Inv). Study Design: This study comprised three active treatment groups and lasted approximately 12 weeks (approximately 6 weeks atomoxetine exposure). Patients entering the study who were already in treatment for an affective disorder or an anxiety disorder with a stable dose of fluoxetine between 10 mg/day and 40 mg/day entered an open-label combined fluoxetine/atomoxetine therapy. Patients who were not taking fluoxetine at the outset of the study were randomly assigned to a double-blind treatment arm and received either atomoxetine only or combined atomoxetine/fluoxetine therapy. After the treatment period (Study Period II), patients on double-blind therapy were randomly assigned to tapered or nontapered dosing in an approximate 2-week double-blind discontinuation period. Number of Patients: Planned: 80 already taking fluoxetine, 220 not already taking fluoxetine Randomized: 14 atomoxetine/fluoxetine open-label, 127 atomoxetine/fluoxetine double-blind, 46 atomoxetine/placebo double-blind Completed: 11 atomoxetine/fluoxetine open-label, 102 atomoxetine/fluoxetine double-blind, 36 atomoxetine/placebo double-blind

2 CT Registry ID#4668 Page 2 Diagnosis and Main Criteria for Inclusion: Patients were at least 7 years but less than 18 years of age who met DSM-IV criteria for ADHD and had concurrent symptoms of depression or anxiety, or patients met DSM-IV criteria for an anxiety or depressive disorder and had concurrent symptoms of ADHD. Test Product, Dose, and Mode of Administration: Atomoxetine capsules: Target dose of 1.2 mg/kg/day or 1.8 mg/kg/day given as a divided dose. Duration of Treatment: Atomoxetine: Approximately 6 weeks Fluoxetine: Approximately 11 weeks Reference Therapy, Dose, and Mode of Administration: Fluoxetine capsules 10 to 30 mg (for openlabel group) and 20 mg (for double-blind group). Placebo capsules (for double-blind group). Variables: Efficacy: The primary efficacy variable was the change from baseline to endpoint in the Clinical Global Impressions-Severity (CGI-S) rating score. Severity was rated on a 7-point scale with a higher score indicating greater severity of the ADHD, affective, and anxiety symptoms. The primary efficacy analysis was a test of the noninferiority of change in CGI-S in the atomoxetine plus placebo group compared with the atomoxetine plus fluoxetine group. Safety: Analysis of adverse events included the enrolled patients who received at least 1 dose of atomoxetine. Percentages of patients with treatment-emergent adverse events and treatment-emergent out-of-range laboratory analyte values were computed for each treatment group. Changes from baseline (last measurement on or before Visit 4) to endpoint in continuous laboratory values, electrocardiogram (ECG) intervals, and vital signs were computed by treatment group. Percentages of patients meeting categorical criteria for ECG intervals and vital signs were also computed. Pharmacokinetic: Blood samples for determination of plasma atomoxetine concentrations at trough and peak timepoints were obtained from each patient at Visit 8, at which time steady-state was achieved on either the 1.2 mg/kg/day or the 1.8 mg/kg/day atomoxetine treatment. To assess the relationship between atomoxetine plasma concentration and safety measures, the correlation between selected safety measures and plasma concentrations at Visit 8 were computed. In addition, a repeated measures model was utilized to assess any relationship between plasma concentration and safety variables. Evaluation Methods: Statistical: Test for noninferiority: 1-sided 95% confidence interval from an analysis of variance (ANOVA) containing terms for treatment and investigational site. Fisher s exact test to compare the percentage of responders and other categorical variables, ANOVA to compare continuous data, and Wilcoxon signed-rank test to test for within-group changes. Other methods used included 2-sided 95% confidence intervals, Pearson correlation coefficient, and repeated-measures mixed model. Missing data were handled using a last-observation-carried-forward (LOCF) approach for change from baseline to endpoint analyses. Electrocardiogram QT Interval data were corrected using the following three methods: Bazett s correction method (QTcB; division of QT by RR 0.5), Fridericia s correction method (QTcF; division of QT by RR 0.33), and a data correction method proposed by Lilly (QTcD;division of QT by RR 0.39). Summary: Patient Disposition: Four patients (2.1%) discontinued their participation in this study due to adverse events. These 4 patients were patients for whom no pharmacokinetic (PK) data were available, and they did not participate in the comparison of phenotypic poor metabolizer (PM) patients to phenotypic extensive metabolizer (EM) patients. One patient (0.5%) discontinued from the study due to adverse events (coded in the database as discontinued due to physician decision) prior to atomoxetine exposure.

3 CT Registry ID#4668 Page 3 A total of 148 patients were determined to be either phenotypic EM patients (N=97) or phenotypic PM patients (N=51). All patients for whom a phenotype was determined completed Study Period II. No serious adverse events occurred and no deaths were reported. Patient Demographics: Table LYAQ.1 shows demographic and other patient characteristics for all randomized patients. Two hundred twenty (220) patients entered the study; of these, 187 were enrolled. Comorbid DSM-IV diagnoses were assessed using the Behavioral Disorder (including ADHD), Affective Disorder, Anxiety Disorder, and Post Traumatic Stress Disorder modules of the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS- PL). Efficacy: The primary efficacy variable was the change from baseline to endpoint in the CGI-S rating score. Baseline was defined as the last nonmissing measurement obtained on or prior to Visit 2. The primary efficacy analysis defined in the protocol was a test of the noninferiority of change in CGI-S in the atomoxetine plus placebo group compared with the atomoxetine plus fluoxetine group. As Table LYAQ.2 shows, both atomoxetine plus placebo and atomoxetine plus fluoxetine produced statistically significant reductions (improvements) from baseline to endpoint in the CGI-S rating score. Because the resulting lower limit of the confidence interval for the difference in change between the treatment groups was below an effect size of 0.45 (prospectively specified in the protocol), noninferiority between atomoxetine and atomoxetine plus fluoxetine was not supported. Patients were considered responders if their endpoint CGI-S score was at most 2. Fourteen (14) patients (31.8%) in the atomoxetine plus placebo treatment group and 49 patients (43.4%) in the atomoxetine plus fluoxetine treatment group were responders. The treatment difference was not statistically significant (p = 0.208). Comparisons of the results of the secondary measures between the atomoxetine plus placebo group and the atomoxetine plus fluoxetine group showed a similar pattern to the primary efficacy measure, with differences between the groups not reaching statistical significance (Table LYAQ.3). Analysis of results comparing patients who did or did not meet plasma concentration criteria for PM status did not show any significant differences between EM and PM patients. The results did not support the primary efficacy hypothesis of the study (that atomoxetine alone would be noninferior to atomoxetine plus fluoxetine in reducing overall symptoms). Safety: The percentage of patients discontinuing the study due to an adverse event was 2.1%. Table LYAQ.4 summarizes treatment-emergent adverse events occurring in > 5% of all phenotypic PM versus phenotypic EM patients and Table LYAQ.5 summarizes treatment-emergent adverse events occurring with 5% incidence in all enrolled patients who received at least 1 dose of atomoxetine by treatment group. No statistically significant differences between the double-blind groups were detected. Table LYAQ.6 summarizes data for laboratory analytes for which statistically significant differences were detected in the comparison of phenotypic PM to phenotypic EM patients. Data for all comparisons are shown, with those for which a statistically significant difference was found being indicated in bold. Table LYAQ.7 provides a summary for laboratory analytes for which a statistically significant bytreatment-group difference was detected in the double-blind portion of the study (indicated in table in bold text). P-values for comparisons between the double-blind atomoxetine plus placebo versus the doubleblind atomoxetine plus fluoxetine group are shown. Values (mean change and percent low or high) for the open-label atomoxetine plus fluoxetine group are also shown, but without a statistical comparison. Neither comparison reveals a pattern of abnormalities suggestive of organ toxicity. In the comparison of all phenotypic PM to all phenotypic EM patients (Table LYAQ.8), no statistically significant differences were noted regarding effects on vital signs. A comparison of the increase in mean systolic blood pressure between phenotypic PM patients (+4.65 mm Hg) and all phenotypic EM patients (+1.12 mm Hg) did not reach statistical significance (p=.072).

4 CT Registry ID#4668 Page 4 Table LYAQ.9 summarizes the mean change from baseline to endpoint in vital sign measures for Study Period II for phenotypic PM patients and phenotypic EM patients who received at least 1.2 mg/kg/day of atomoxetine and had both baseline and at least 1 postbaseline measurement. The difference in mean systolic blood pressure changes between phenotypic PM patients (+5.54 mm Hg) and phenotypic EM patients (+1.05 mm Hg) was statistically significant (p=.037). Table LYAQ.10 provides a summary of vital sign changes for all enrolled patients by treatment groups along with p-values for within-group changes and p-values for the comparison between the treatment groups (double-blind atomoxetine versus double-blind atomoxetine plus fluoxetine, and double-blind atomoxetine plus fluoxetine versus open-label atomoxetine plus fluoxetine). The atomoxetine plus fluoxetine group experienced larger and statistically significant changes in dystolic blood pressure, pulse and weight compared to the atomoxetine plus placebo group. Table LYAQ.11 provides a summary of the mean change from baseline to endpoint in ECG intervals and heart rate for Study Period II for all phenotypic PM and phenotypic EM patients who had both baseline and at least 1 postbaseline measurement. Table LYAQ.12 summarizes the mean change from baseline to endpoint in ECG intervals and heart rate for Study Period II for all phenotypic PM and phenotypic EM patients who received at least 1.2 mg/kg/day of atomoxetine and who had both baseline and at least 1 postbaseline measurement. Atomoxetine was associated with increased heart rate in all groups. Changes in the QTcD interval were not statistically significant for either EM or PM patients, nor were there statistically significant differences between treatment groups. As Table LYAQ.13 shows, however, there was an increase in QTcD for the combined group of all patients coadministered fluoxetine compared to the atomoxetine plus placebo group. Among the patients who were coadministered fluoxetine and atomoxetine, there was no difference in mean change in QTcD among those who were phenotypic EM patients and those who were phenotypic PM patients (+5.63 msec, msec, respectively, p=.24), and there was no relationship between plasma atomoxetine concentrations and change in QTcD (slope = , p=.699; Figure LYAQ.1). No effect on QTcD was seen among patients who were administered atomoxetine only. Pharmacokinetic: Forty-six (46) of 112 genotypic EM patients (41%) with plasma atomoxetine concentration data were considered phenotypic PMs when coadministered fluoxetine because their peak plasma atomoxetine concentration was within (or greater than) 2 standard deviations of the mean expected plasma atomoxetine concentration for PM patients. Of the patients who were considered phenotypic PMs, 36 patients achieved doses equal or greater than 1.2 mg/kg/day. Figure LYAQ.2 shows peak plasma concentration data for patients who received atomoxetine plus fluoxetine. Figure LYAQ.3 shows peak plasma concentration data for patients who received atomoxetine only. These 2 figures also show a line representing the mean minus 2 standard deviations for genotyopic PM patients. These figures illustrate the increase in atomoxetine concentration observed with coadministration of fluoxetine. Also shown on these graphs are the 5 genotypic PM patients who participated in this study and their plasma concentration data. Table LYAQ.14 and Table LYAQ.15 summarize the correlation between actual atomoxetine plasma concentration and ECG measurements at Visit 8 (or Visit 9) for patients who received atomoxetine plus fluoxetine and patients who received atomoxetine only. There was a statistically significant correlation between Bazett-corrected QT interval and atomoxetine trough plasma concentration for patients on atomoxetine plus fluoxetine. There were no statistically significant correlations between QTc values using data or Fridericia correction methods and atomoxetine plasma concentrations for patients on either treatment. Results from the repeated measures model indicated that there was no statistically significant relationship between the QTcD interval and plasma atomoxetine concentrations (slope=0.0005, p=.716).

5 CT Registry ID#4668 Page 5 Table LYAQ.1. Summary of Demographics and Other Patient Characteristics All Randomized Patients OL_ATXFL DB_ATXFL DB_ATXPL Total Variable (N=14) (N=127) (N=46) (N=187) Sex: No. (%) Female 5 (35.7) 32 (25.2) 16 (34.8) 53 (28.3) Male 9 (64.3) 95 (74.8) 30 (65.2) 134 (71.7) Origin: No. (%) African Descent 1 (7.1) 6 (4.7) 6 (13.0) 13 (7.0) Caucasian 12 (85.7) 106 (83.5) 39 (84.8) 157 (84.0) East/Southeast A 0 1 (0.8) 0 1 (0.5) Hispanic 0 6 (4.7) 1 (2.2) 7 (3.7) Other 1 (7.1) 8 (6.3) 0 9 (4.8) Age: yrs. Mean Median Standard Dev Minimum Maximum CYP2D6 EXTN 13 (92.9) 125 (98.4) 42 (95.5) 180 (97.3) SLOW 1 (7.1) 2 (1.6) 2 (4.5) 5 (2.7) Unspecified Height: cm Mean Median Standard Dev Minimum Maximum Weight: kg No. Patients Mean Median Standard Dev Minimum Maximum Unspecified DSM-IV ADHD Subtype HYP/IMP 0 5 (4.0) 0 5 (2.7) INATTV 4 (28.6) 33 (26.2) 7 (15.2) 44 (23.7) MIXED 10 (71.4) 88 (69.8) 39 (84.8) 137 (73.7) Unspecified Family History-ADHD-Mother N 8 (57.1) 93 (74.4) 25 (54.3) 126 (68.1) U 2 (14.3) 8 (6.4) 11 (23.9) 21 (11.4) Y 4 (28.6) 24 (19.2) 10 (21.7) 38 (20.5) Unspecified (continued)

6 CT Registry ID#4668 Page 6 Table LYAQ.1. Summary of Demographics and Other Patient Characteristics All Randomized Patients (continued) OL_ATXFL DB_ATXFL DB_ATXPL Total Variable (N=14) (N=127) (N=46) (N=187) Family History-ADHD-Father N 8 (57.1) 73 (58.4) 20 (43.5) 101 (54.6) U 3 (21.4) 15 (12.0) 13 (28.3) 31 (16.8) Y 3 (21.4) 37 (29.6) 13 (28.3) 53 (28.6) Unspecified Family History-ADHD-Grandparents N 10 (71.4) 96 (76.8) 29 (63.0) 135 (73.0) U 4 (28.6) 16 (12.8) 14 (30.4) 34 (18.4) Y 0 13 (10.4) 3 (6.5) 16 (8.6) Unspecified Family History-ADHD-Siblings N 6 (42.9) 78 (62.4) 20 (43.5) 104 (56.2) N/A 0 7 (5.6) 1 (2.2) 8 (4.3) U 1 (7.1) 4 (3.2) 11 (23.9) 16 (8.6) Y 7 (50.0) 36 (28.8) 14 (30.4) 57 (30.8) Unspecified Family History-Anxiety-Mother N 9 (64.3) 76 (60.8) 28 (60.9) 113 (61.1) U 2 (14.3) 7 (5.6) 9 (19.6) 18 (9.7) Y 3 (21.4) 42 (33.6) 9 (19.6) 54 (29.2) Unspecified Family History-Anxiety-Father N 12 (85.7) 90 (72.0) 30 (65.2) 132 (71.4) U 2 (14.3) 15 (12.0) 10 (21.7) 27 (14.6) Y 0 20 (16.0) 6 (13.0) 26 (14.1) Unspecified Family History-Anxiety-Grandparents N 8 (57.1) 87 (69.6) 26 (56.5) 121 (65.4) U 2 (14.3) 10 (8.0) 10 (21.7) 22 (11.9) Y 4 (28.6) 28 (22.4) 10 (21.7) 42 (22.7) Unspecified Family History-Anxiety-Siblings N 9 (64.3) 94 (75.2) 33 (71.7) 136 (73.5) N/A 0 7 (5.6) 1 (2.2) 8 (4.3) U 2 (14.3) 8 (6.4) 6 (13.0) 16 (8.6) Y 3 (21.4) 16 (12.8) 6 (13.0) 25 (13.5) Unspecified Family History-Affective-Mother N 7 (50.0) 69 (55.2) 24 (52.2) 100 (54.1) U 2 (14.3) 9 (7.2) 6 (13.0) 17 (9.2) Y 5 (35.7) 47 (37.6) 16 (34.8) 68 (36.8) Unspecified (continued)

7 CT Registry ID#4668 Page 7 Table LYAQ.1. Summary of Demographics and Other Patient Characteristics All Randomized Patients (concluded) OL_ATXFL DB_ATXFL DB_ATXPL Total Variable (N=14) (N=127) (N=46) (N=187) Family History-Affective-Father N 10 (71.4) 82 (65.6) 31 (67.4) 123 (66.5) U 2 (14.3) 15 (12.0) 9 (19.6) 26 (14.1) Y 2 (14.3) 28 (22.4) 6 (13.0) 36 (19.5) Unspecified Family History-Affective-Grandparents N 7 (50.0) 67 (53.6) 27 (58.7) 101 (54.6) U 3 (21.4) 12 (9.6) 9 (19.6) 24 (13.0) Y 4 (28.6) 46 (36.8) 10 (21.7) 60 (32.4) Unspecified Family History-Affective-Siblings N 10 (71.4) 92 (73.6) 31 (67.4) 133 (71.9) N/A 0 7 (5.6) 1 (2.2) 8 (4.3) U 1 (7.1) 6 (4.8) 8 (17.4) 15 (8.1) Y 3 (21.4) 20 (16.0) 6 (13.0) 29 (15.7) Unspecified Prior Stimulant Exposure N 4 (28.6) 38 (30.2) 13 (28.3) 55 (29.6) Y 10 (71.4) 88 (69.8) 33 (71.7) 131 (70.4) Unspecified Grade in School (5.5) 2 (4.3) 9 (4.8) 10 1 (7.1) 5 (3.9) 1 (2.2) 7 (3.7) (1.6) 2 (4.3) 4 (2.1) (1.6) 0 2 (1.1) (15.0) 2 (4.3) 21 (11.2) 3 2 (14.3) 16 (12.6) 8 (17.4) 26 (13.9) 4 2 (14.3) 16 (12.6) 7 (15.2) 25 (13.4) 5 4 (28.6) 17 (13.4) 6 (13.0) 27 (14.4) 6 1 (7.1) 17 (13.4) 7 (15.2) 25 (13.4) 7 2 (14.3) 10 (7.9) 7 (15.2) 19 (10.2) 8 1 (7.1) 14 (11.0) 3 (6.5) 18 (9.6) 9 1 (7.1) 2 (1.6) 1 (2.2) 4 (2.1) U = Unknown Population: All Enrolled Patients. Double Blind or Open Label Visits 1-11

8 Table LYAQ.2. Clinical Global Impressions-Severity Score Primary Efficacy Analysis Change from Baseline to Endpoint Double-Blind Atomoxetine versus Atomoxetine-plus-Fluoxetine Study Period II Baseline Endpoint Change p-value(a) p-value(b) Treatment Group n Mean SD Mean SD Mean SD Atomoxetine-Fluoxetine < Placebo-Atomoxetine < Difference(1-sided 95% C.I.) -0.41(-0.77, --- ) Mean Squared Error 1.47 Effect size(1-sided 95% C.I.) -0.33(-0.63, --- ) Abbreviations: C.I. = Confidence Interval; SD = standard deviation. (a) p-value is from Wilcoxon signed-rank test. (b) Between treatment group p-values are from mean change from baseline to endpoint (LOCF) scores using least squares means from an ANOVA model with term for treatment and pooled investigator. All qualified patients included. CT Registry ID#4668 Page 8

9 Table LYAQ.3. Summary of Secondary Efficacy Analyses Change from Baseline to Endpoint on Total Scores All Qualified Patients Study Period II Baseline Endpoint Change p-value(a) p-value(b) Treatment Group n Mean SD Mean SD Mean SD ADHDRS Atomoxetine-Fluoxetine < Placebo-Atomoxetine < CDI 95% C.I.: (-8.23, 1.16 ) Atomoxetine-Fluoxetine < Placebo-Atomoxetine < CDRS 95% C.I.: (-7.02, 0.15 ) Atomoxetine-Fluoxetine < Placebo-Atomoxetine < GSAS 95% C.I.: (-7.37, 1.85 ) Atomoxetine-Fluoxetine < Placebo-Atomoxetine < % C.I.: (-3.82, 0.98 ) (continued) CT Registry ID#4668 Page 9

10 Table LYAQ.3. Summary of Secondary Efficacy Analyses Change from Baseline to Endpoint on Total Scores All Qualified Patients Study Period II (concluded) Baseline Endpoint Change p-value(a) p-value(b) Treatment Group n Mean SD Mean SD Mean SD MASC Atomoxetine-Fluoxetine < Placebo-Atomoxetine < % C.I.: (-8.10, 4.06 ) Abbreviations: ADHDRS = Attention Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored; CDI = Children's Depression Inventory; CDRS = Children's Depression Rating Scale; GSAS = Global Severity Assessment of Affective, Anxiety and Attentional Symptoms; MASC = Multidimensional Anxiety Scale for Children. (a) p-value is from Wilcoxon signed-rank test. (b) Between treatment group p-values are from baseline to endpoint (LOCF) scores using least squares means from an ANOVA model with terms for investigator, treatment. All qualified patients included. CT Registry ID#4668 Page 10

11 CT Registry ID#4668 Page 11 Table LYAQ.4. Summary of Treatment-Emergent Adverse Events with Incidence 5% by Phenotype Study Period II PHENO_PM PHENO_EM Total p-value* (N=51) (N=97) (N=148) Event Classification n (%) n (%) n (%) PATIENTS WITH >= 1 TESS 38 (74.5) 63 (64.9) 101 (68.2).269 PATIENTS WITH NO TESS 13 (25.5) 34 (35.1) 47 (31.8).269 ANOREXIA 13 (25.5) 11 (11.3) 24 (16.2).035 HEADACHE 4 (7.8) 16 (16.5) 20 (13.5).206 ASTHENIA 7 (13.7) 11 (11.3) 18 (12.2).792 INSOMNIA 9 (17.6) 9 (9.3) 18 (12.2).185 ABDOMINAL PAIN 6 (11.8) 8 (8.2) 14 (9.5).558 ACCIDENTAL INJURY 5 (9.8) 7 (7.2) 12 (8.1).752 SOMNOLENCE 7 (13.7) 4 (4.1) 11 (7.4).048 NAUSEA 5 (9.8) 5 (5.2) 10 (6.8).314 RASH 4 (7.8) 5 (5.2) 9 (6.1).496 RHINITIS 3 (5.9) 5 (5.2) 8 (5.4) 1.00 DYSPEPSIA 2 (3.9) 5 (5.2) 7 (4.7) 1.00 NERVOUSNESS 2 (3.9) 5 (5.2) 7 (4.7) 1.00 VOMITING 4 (7.8) 3 (3.1) 7 (4.7).234 ALLERGIC REACTION 1 (2.0) 5 (5.2) 6 (4.1).665 DIZZINESS 1 (2.0) 5 (5.2) 6 (4.1).665 PHARYNGITIS 3 (5.9) 3 (3.1) 6 (4.1).415 CHEST PAIN 3 (5.9) 1 (1.0) 4 (2.7).118 TREMOR 3 (5.9) 0 3 (2.0).039 Population: Phenotypic EMs AND Phenotypic PMs Double Blind or Open Label Baseline: Visits 1-4, Endpoint: Visits 5-9 * Frequencies are analyzed using a Fisher's Exact test.

12 CT Registry ID#4668 Page 12 Table LYAQ.5. Summary of Treatment-Emergent Adverse Events Incidence 5% by Treatment Group Study Period II OL_ATXFL DB_ATXFL DB_ATXPL Total (N=14) (N=115) (N=44) (N=173) Event Classification n (%) n (%) n (%) n (%) PATIENTS WITH >= 1 TESS 10 (71.4) 81 (70.4) 25 (56.8) 116 (67.1) PATIENTS WITH NO TESS 4 (28.6) 34 (29.6) 19 (43.2) 57 (32.9) ANOREXIA 1 (7.1) 23 (20.0) 3 (6.8) 27 (15.6) HEADACHE 3 (21.4) 17 (14.8) 6 (13.6) 26 (15.0) INSOMNIA 1 (7.1) 16 (13.9) 5 (11.4) 22 (12.7) ASTHENIA 1 (7.1) 14 (12.2) 5 (11.4) 20 (11.6) ABDOMINAL PAIN 2 (14.3) 13 (11.3) 3 (6.8) 18 (10.4) ACCIDENTAL INJURY 0 9 (7.8) 3 (6.8) 12 (6.9) SOMNOLENCE 0 11 (9.6) 1 (2.3) 12 (6.9) NAUSEA 3 (21.4) 6 (5.2) 2 (4.5) 11 (6.4) RHINITIS 1 (7.1) 8 (7.0) 2 (4.5) 11 (6.4) RASH 1 (7.1) 7 (6.1) 1 (2.3) 9 (5.2) NERVOUSNESS 1 (7.1) 5 (4.3) 2 (4.5) 8 (4.6) VOMITING 1 (7.1) 7 (6.1) 0 8 (4.6) DIZZINESS 1 (7.1) 3 (2.6) 3 (6.8) 7 (4.0) DYSPEPSIA 0 6 (5.2) 1 (2.3) 7 (4.0) PHARYNGITIS 2 (14.3) 2 (1.7) 3 (6.8) 7 (4.0) ALLERGIC REACTION 0 3 (2.6) 3 (6.8) 6 (3.5) COUGH INCREASED 1 (7.1) 4 (3.5) 0 5 (2.9) CHEST PAIN 1 (7.1) 2 (1.7) 1 (2.3) 4 (2.3) EMOTIONAL LABILITY 1 (7.1) 2 (1.7) 1 (2.3) 4 (2.3) HYPERTENSION 1 (7.1) 3 (2.6) 0 4 (2.3) INFECTION 1 (7.1) 2 (1.7) 1 (2.3) 4 (2.3) TREMOR 1 (7.1) 3 (2.6) 0 4 (2.3) AMBLYOPIA 1 (7.1) 2 (1.7) 0 3 (1.7) TACHYCARDIA 2 (14.3) 1 (0.9) 0 3 (1.7) APATHY 1 (7.1) (0.6) EYE PAIN 1 (7.1) (0.6) FLU SYNDROME 1 (7.1) (0.6) POSTURAL HYPOTENSION 1 (7.1) (0.6) TWITCHING 1 (7.1) (0.6) Population: All Enrolled Patients who received at least 1 dose of atomoxetine. Double Blind or Open Label Baseline: Visits 1-4, Endpoint: Visits 5-9

13 CT Registry ID#4668 Page 13 Table LYAQ.6. Summary of Laboratory Data Analytes With a Statistically Significant Between-Group Difference, Phenotypic PM Patients versus Phenotypic EM Patients Study Period II MEAN CHANGE TO ENDPOINT PERCENT HIGH/LOW Patients All High-dose All High-dose GGT ppm /0 0/0 p-val na/na na/na pem /0 0/0 URIC ACID ppm /0 0/0 p-val na/.552 na/.551 pem / /3.5 BILIRIBIN ppm /0 0/0 p-val na/na na/na pem /0 1.2/0 BICARBONATE ppm /2.0 0/2.6 p-val na/1.0 na/.525 pem /1.1 0/1.1 Note: p-values comparing PMs and EMs are based on an analysis of variance on ranks of change from baseline scores with terms for treatment and phenotype. Abbreviations: EM = extensive metabolizer; GGT = gamma glutamyltransferase; PM = poor metabolizer; pem = phenotypic extensive metabolizer; ppm = phenotypic poor metabolizer; p-val = p-value.

14 CT Registry ID#4668 Page 14 Table LYAQ.7. Summary of Laboratory Data Analytes With a Statistically Significant Between Group Difference, Double Blind Phase, Study Period II Mean Change to Endpoint Percent Low/High ALKPH (U/L) DB_ATXFL /3.1 p-val <.001 na/1.00 DB_ATXPL /2.9 OL_ATXFL /0 CPK (U/L) DB_ATXFL /1.9 p-val.463 na/.046 DB_ATXPL /10.3 OL_ATXFL /0 CHOL (mmol/l) DB_ATXFL /5.0 p-val /.322 DB_ATXPL /0 OL_ATXFL /10.0 Abbreviations: ALT=alanine aminotransferase, ALKPH=alkaline phosphatase, CPK=creatine phosphokinase, CHOL=cholesterol p-val=p-value

15 Table LYAQ.8. Summary of Vital Signs Change from Baseline to Endpoint Phenotypic PM Patients versus Phenotypic EM Patients Study Period II -----Baseline Change within Subgroup Measure Subgroup N Mean SD Mean SD p-value(a) p-value(b) Diastolic BP PM Patients < EM Patients <.001 Systolic BP PM Patients < EM Patients Pulse PM Patients < EM Patients <.001 Weight (kg) PM Patients < EM Patients <.001 Height (cm) PM Patients EM Patients <.001 Temperature PM Patients EM Patients Abbreviations: BP = blood pressure; EM = extensive metabolizer; PM = poor metabolizer. (a) Within group p-values are based on Wilcoxon's Signed Rank Test. (b) Subgroup p-values comparing PMs and EMs are based on an ANOVA on change from baseline scores with terms for treatment and subgroup. Population: Phenotypic PMs and EMs. CT Registry ID#4668 Page 15

16 Table LYAQ.9. Summary of Vital Signs Change from Baseline to Endpoint Phenotypic PM Patients versus Phenotypic EM Patients Who Received 1.2 mg/kg/day of Atomoxetine Study Period II -----Baseline Change within Subgroup Measure Subgroup N Mean SD Mean SD p-value(a) p-value(b) Diastolic BP PM Patients < EM Patients <.001 Systolic BP PM Patients < EM Patients Pulse PM Patients < EM Patients <.001 Weight (kg) PM Patients < EM Patients <.001 Height (cm) PM Patients EM Patients <.001 Temperature PM Patients EM Patients Abbreviations: BP = blood pressure; EM = extensive metabolizer; PM = poor metabolizer. (a) Within group p-values are based on Wilcoxon's Signed Rank Test. (b) Subgroup p-values comparing PMs and EMs are based on an ANOVA on change from baseline scores with terms for treatment and subgroup. Population: Phenotypic PMs and EMs who received at least 1.2 mg/kg/day. CT Registry ID#4668 Page 16

17 Table LYAQ.10. Summary of Vital Signs Change from Baseline to Endpoint All Enrolled Patients By Treatment Group -----Baseline Change within Between Between Measure Subgroup N Mean SD Mean SD p-value(a) p-value(b) p-value(c) Diastolic BP DB Atx+Flx < DB Atx+Pla OL Atx+Flx Systolic BP DB Atx+Flx < DB Atx+Pla OL Atx+Flx Pulse DB Atx+Flx < DB Atx+Pla OL Atx+Flx <.001 Weight (kg) DB Atx+Flx < DB Atx+Pla OL Atx+Flx <.001 Height (cm) DB Atx+Flx < DB Atx+Pla <.001 OL Atx+Flx Temperature DB Atx+Flx DB Atx+Pla OL Atx+Flx Abbreviations: BP = blood pressure; DB Atx+Flx = double-blind atomoxetine plus fluoxetine; DB Atx+Pla = double-blind atomoxetine plus placebo; OL Atx+Flx = open-label atomoxetine plus fluoxetine. (a) Within group p-values are based on Wilcoxon's Signed Rank Test. (b,c) Between treatment group p-values are based on an ANOVA on change from baseline scores with terms for investigator and treatment. P-value(b) is for comparison between double-blinded atomox.+fluox. and atomox.+placebo. P-value(c) is for comparison between double-blinded and open-label atomox.+fluox. Population: enrolled patients with both baseline and at least one post-baseline measurement. CT Registry ID#4668 Page 17

18 Table LYAQ.11. Summary of ECG Data Change from Baseline to Endpoint All Phenotypic PM Patients versus Phenotypic EM Patients Study Period II -----Baseline Change within Subgroup Measure Subgroup N Mean SD Mean SD p-value(a) p-value(b) PR Interval PM Patients EM Patients <.001 QRS Interval PM Patients EM Patients QT Interval PM Patients < EM Patients <.001 QTcB PM Patients < EM Patients <.001 QTcF PM Patients EM Patients QTcD PM Patients EM Patients Heart Rate PM Patients < EM Patients <.001 Abbreviations: EM = extensive metabolizer; PM = poor metabolizer; QTcB = QT interval Bazett correction; QTcD = QT interval data correction; QTcF = QT interval Fridericia correction. (a) Within group p-values are based on Wilcoxon's Signed Rank Test. (b) Subgroup p-values comparing PMs and EMs are based on an ANOVA on change from baseline scores with terms for treatment and subgroup. Population: Phenotypic PM and EM patients. CT Registry ID#4668 Page 18

19 Table LYAQ.12. Summary of ECG Data Change from Baseline to Endpoint Phenotypic PM Patients versus Phenotypic EM Patients Who Received 1.2 mg/kg/day of Atomoxetine Study Period II -----Baseline Change within Subgroup Measure Subgroup N Mean SD Mean SD p-value(a) p-value(b) PR Interval PM Patients EM Patients <.001 QRS Interval PM Patients EM Patients QT Interval PM Patients < EM Patients <.001 QTcB PM Patients EM Patients <.001 QTcF PM Patients EM Patients QTcD PM Patients EM Patients Heart Rate PM Patients < EM Patients <.001 Abbreviations: EM = extensive metabolizer; PM = poor metabolizer; QTcB = QT interval Bazett correction; QTcD = QT interval data correction; QTcF = QT interval Fridericia correction. (a) Within group p-values are based on Wilcoxon's Signed Rank Test. (b) Subgroup p-values comparing PMs and EMs are based on an ANOVA on change from baseline scores with terms for treatment and subgroup. Population: Phenotypic PMs and EMs. CT Registry ID#4668 Page 19

20 CT Registry ID#4668 Page 20 Table LYAQ.13. Mean Change in QTcD During Atomoxetine Treatment in Different Groups B4Z-MC-LYAQ Group Mean QTcD in msec (SD) p-value All Patients administered atomoxetine and either fluoxetine or placebo Atomoxetine + Placebo (n=41) (12.7) p<.001 Atomoxetine + Fluoxetine (n=125) (12.5) EM and PM Patients co-administered fluoxetine and atomoxetine Fluoxetine+Atomoxetine; Phenotypic EM Patients (n=76) Fluoxetine+Atomoxetine; Phenotypic PM Patients (n=49a) 5.63 (11.97) p= (13.25) a Only PM patients converted genotypic EM status by fluoxetine Abbreviations: EM=extensive metabolizer; n = number of patients; PM=poor metabolizer; QTcD=data-corrected QT interval; SD = standard deviation.

21 CT Registry ID#4668 Page Change from Baseline QTcD (msec) Atomoxetine Plasma Concentration (ng/ml) Fitted line is a least square line from a regression model with effects for baseline and plasma concentration Figure LYAQ.1. Change from data-corrected QT (QTcD) interval by plasma atomoxetine concentration, patients taking fluoxetine and atomoxetine.

22 CT Registry ID#4668 Page 22 Normalized Plasma Concentration (ng/ml) Mean-2SD Genotypic EM Genotypic PM Time (hours) Plasma concentrations were normalized to a 1.2 mg/kg/day dose. Mean - 2SD was based on data from genotypic PM adult subjects from previous studies. Figure LYAQ.2. Peak atomoxetine plasma concentration data, for patients who received atomoxetine plus fluoxetine.

23 CT Registry ID#4668 Page Mean-2SD Genotypic EM Genotypic PM Normalized Plasma Concentration (ng/ml) Time (hours) Plasma concentrations were normalized to a 1.2 mg/kg/day dose. Mean - 2SD was based on data from genotypic PM adult subjects from previous studies. Figure LYAQ.3. Peak atomoxetine plasma concentration data, for patients who received atomoxetine only.

24 Table LYAQ.14. Summary of Correlation between Atomoxetine Plasma Concentration (Peak and Trough) and ECG Measurements at Visit 8 Patients who Received Atomoxetine Plus Fluoxetine Visit A B Sample Sample Correlation p-value* Time Size(n) Coefficient between A & B 8/9 Atomoxetine Change of QTcB Peak plasma Change of QTcD Concentration Change of QTcF Change of QTcB Trough Change in QTcD Change in QTcF Abbreviations: n=number of patients with a baseline and at least one postbaseline measurement; QTcB = QT Interval Bazett Correction; QTcD = QT Interval Data Correction; QTcF = QT Interval Fridericia Correction. Baseline: Visit 1-4, Endpoint: Visit 5-9. * p-value is the significance probability of the correlation and is calculated based on a test for nonzero Pearson Correlation Coefficient. CT Registry ID#4668 Page 24

25 Table LYAQ.15. Summary of Correlation between Atomoxetine Plasma Concentration (Peak and Trough) and ECG Measurements at Visit 8 Patients who Received Atomoxetine Only Visit A B Sample Sample Correlation p-value* Time Size(n) Coefficient between A & B 8/9 Atomoxetine Change of QTcB Peak plasma Change of QTcD Concentration Change of QTcF Change of QTcB Trough Change in QTcD Change in QTcF Abbreviations: n=number of patients with a baseline and at least one postbaseline measurement; QTcB = QT Interval Bazett Correction; QTcD = QT Interval Data Correction; QTcF = QT Interval Fridericia Correction. Baseline: Visit 1-4, Endpoint: Visit 5-9. * p-value is the significance probability of the correlation and is calculated based on a test for nonzero Pearson Correlation Coefficient. CT Registry ID#4668 Page 25