Summary ID# Clinical Study Summary: Study B4Z-MC-LYAX

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1 CT Registry ID#5004 Page 1 Summary ID# 5004 Clinical Study Summary: Study B4Z-MC-LYAX A Randomized, Double-Blind, Placebo-Controlled Study of Hydrochloride in Adolescents with Attention-Deficit/Hyperactivity Disorder and Comorbid Depressive Disorder Date summary approved by Lilly: 26 July 2006 Brief Summary of Results The primary objective of Study B4Z-MC-LYAX was to assess the efficacy of atomoxetine hydrochloride (hereafter referred to as atomoxetine) given orally at doses of up to 1.8 mg/kg/day for approximately 9 weeks compared to placebo in reducing signs and symptoms of depression in adolescent patients with Attention-Deficit/Hyperactivity Disorder (ADHD), and comorbid depression, as measured by the Child Depression Rating Scale Revised (CDRS-R) and the ADHD Rating Scale IV Parent Version: Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv). The results were as follows: There were no statistically significant differences observed between the atomoxetine-treated and placebo-treated groups based on the CDRS-R repeated measures analysis or the CDRS-R total score with mean change analysis for Study Period II. Statistically significant improvement in symptoms of ADHD were demonstrated in the atomoxetine-treated group in the repeated measures analyses for: ADHDRS-IV-Parent:Inv total scores (p<.001), total T-scores (p<.001), inattention subscale scores (p.004), and the hyperactivity-impulsivity subscale scores (p.002). In addition, the mean change analyses of: the ADHDRS-IV-Parent:Inv total score, total T-score, inattention subscale score, and the hyperactivityimpulsivity subscale score for demonstrated statistically significant (p<.001) changes in the atomoxetine treatment groups.

2 CT Registry ID#5004 Page 2 was declared noninferior to placebo in reducing scores on the CDRS-R and, therefore, did not worsen depression when compared with placebo. There were no patient deaths in Study LYAX. One patient (placebo treatment group) experienced the serious adverse events (SAEs) of worsening major depression and acute psychotic features. During, 2 patients discontinued the Study LYAX due to an adverse event (AE); 1 due to nausea (atomoxetine treatment group), and 1 due to an AE prior to taking study drug (placebo treatment group). During I, 2 patients discontinued due to somnolence, and 1 patient discontinued due to upper abdominal pain. One patient also discontinued due to lethargy the day of randomization to atomoxetine. During Study Period IV, 1 patient discontinued due to anorexia. Of the treatment-emergent adverse events (TEAEs) that occurred with 5% incidence in, nausea (22.2%) and decreased appetite (12.5%) occurred at a statistically significantly greater incidence (p 0.05) in patients treated with atomoxetine than those of placebo. The most frequently occurring TEAEs with 5% incidence for patients in Study Periods III/IV were: nausea (22.5%), headache (17.5%), fatigue (15%), decreased appetite (14.2%), abdominal pain upper (11.7%), weight decrease (11.7%), and unexpected therapeutic drug effect (10.8%). In, statistically significant (p<.05) treatment differences in mean change scores were observed in the atomoxetine treatment group for: monocytes, ALT/SGPT, GGT, BUN, cholesterol, uric acid, creatinine, and platelet count. In, the mean change and the categorical analyses of vitals including: height, weight, blood pressure (diastolic and systolic), and temperature, indicated no statistically significant differences in the mean changes in the atomoxetine treatment group with the exception of weight (p<.001). In, the mean change analysis of electrocardiogram (ECG) variables showed a statistically significant decrease in: RR interval values (p<.001), decrease in QT interval values (p=.006), increase in heart rate (p<.001), prolongation of QTcB (p=.045), and decrease of PR values(p=.002) for the mean change in the atomoxetine treatment group when compared to the placebo treatment group when using QTcB. There was not a statistically significant difference when using data corrections or Fridericia correction.

3 CT Registry ID#5004 Page 3 Title of Study: A Randomized, Double-Blind, Placebo-Controlled Study of Hydrochloride in Adolescents with Attention-Deficit/Hyperactivity Disorder and Comorbid Depressive Disorder Investigator(s): This multicenter study included 18 principal investigator(s). Study Center(s): This study was conducted at 16 study centers in one country. Two study centers had 2 co-principal investigators, making the total investigators 18. Length of Study: Approximately 2 years Phase of Development: 3 First patient enrolled (assigned to therapy): 08 July 2002 Date of early study termination: 13 November 2003 Last patient completed: 26 May 2004 Objectives: The primary objective of Study LYAX was to assess efficacy of atomoxetine given orally at doses up to 1.8 mg/kg/day for approximately 9 weeks compared with placebo in reducing signs and symptoms of depression in adolescent patients with ADHD and comorbid depression as measured by the CDRS-R and the ADHDRS-IV-Parent:Inv. The secondary objectives are: To test the hypothesis that atomoxetine does not worsen depressive symptoms in adolescents with depression by testing whether atomoxetine is noninferior to placebo in reducing scores on the CDRS-R. To test the hypothesis that atomoxetine is superior to placebo in improving psychosocial functioning in adolescents with ADHD and depression as assessed by parental reports of change in the CHQ- PF50. To test the hypothesis that atomoxetine is superior to placebo in reducing the signs and symptoms of depression as assessed by the MADRS. To test the hypothesis that atomoxetine is superior to placebo in reducing the symptoms of depression as assessed by patient self-report using the RADS. To test the hypothesis that atomoxetine is superior to placebo in improving psychosocial functioning as assessed by patient self-report using the CHQ-CF87. To test the hypothesis that atomoxetine will improve overall outcomes (considering both ADHD and depressive symptoms) in patients with ADHD as measured by the CGI-S and the CGI I when compared to patients receiving placebo. To test the hypothesis that atomoxetine does not induce manic switching as assessed by the YMRS. To assess the safety and tolerability of atomoxetine at total daily doses up to 1.8 mg/kg/day. Study Design: Study LYAX is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of atomoxetine in approximately 240 adolescent outpatients with ADHD and comorbid depressive disorder. Study LYAX incorporated 4 Study Periods including an initial (up to 2-week) evaluation period followed by a 1-week, single-blind, placebo-administration period (Period I); a double-blind, acute treatment period of up to 9 weeks, with either atomoxetine or placebo (Period II); and 2 open-label treatment phases of up to 9 months total of extended treatment with atomoxetine (Periods III and IV). All patients, including those from the placebo group, had the opportunity to receive atomoxetine during the study extension periods. Number of Patients: Planned: 240 (120 atomoxetine, 120 placebo) patients : 142 (72 atomoxetine, 70 placebo) patients were randomized into, 120 (59 atomoxetine, 61 placebo) completed. I: 120 patients entered I, 40 completed I Study Period IV: 20 patients entered Study Period IV, 2 completed Study Period IV.

4 CT Registry ID#5004 Page 4 Main Criteria for Inclusion: The child or adolescent was at least 12 years of age, but had not reached their 18th birthday prior to Visit 1,and had to meet DSM-IV criteria for ADHD and major depression. The presence of ADHD and major depression must be confirmed by the K-SADS-PL. The patient s ADHD had to be diagnosed by a physician or psychologist prior to the age of 12. There also must have been some period after the age of 7, of at least 6 months, during which some symptoms of ADHD were present and the patient was not depressed. In addition, to be eligible for randomization at Visit 4, the following criteria must have been met. At Visits 2, 3, and 4, patients must have an ADHDRS-IV- Parent:Inv score at least 1.5 standard deviations above age and gender norms for at least 1 of the 3 following scores: the inattention subscale score, the hyperactivity subscale score or the total scale score, and the attentional symptoms are not, in the investigator s judgment, better accounted for by the affective disorder than by an ADHD spectrum disorder. Additionally, at Visits 1, 2, 3, and 4, patients had to have a CDRS-R score of at least 40. Study Drug, Dose, and Mode of Administration:, up to 1.8 mg/kg/day, given once daily, in, or as an evenly or unevenly divided doses taken twice daily in Study Periods III and IV; as 2.5, 5, 10, 20, 25, and 40 mg capsules. Reference Therapy, Dose, and Mode of Administration: Placebo capsules used for the single-blind, placebo lead-in during Study Period I and the double-blind dosing in were identical in appearance to atomoxetine capsules. However, during Study Periods III/IV, the study drug was supplied in bottles. Duration of Treatment: One-week, single-blind, placebo lead-in, with 9 weeks double-blind treatment, and up to 9 months open-label therapy with atomoxetine. Variables: Efficacy: Primary efficacy variables were the CDRS-R and ADHDRS-IV-Parent:Inv. The secondary efficacy measures were: MADRS, RADS, CGI-S, CGI-I, and Y-MRS. Safety: AEs, laboratory data, vital signs, and ECG. Health Outcomes: CHQ-PF50 and CHQ-CF87.

5 CT Registry ID#5004 Page 5 Evaluation Methods: Statistical: Efficacy analyses were conducted on the full analysis set. Safety analyses were conducted using all data from all randomized patients taking at least 1 dose of the study drug. For questionnaires such as the ADHDRS-IV-Parent:Inv, if more than 1 item of a subscale was missing, then the score for that subscale was also considered missing. All tests of treatment effects were conducted at a two-sided alpha level of 0.05 unless otherwise stated. The primary efficacy analysis for the CDRS-R total score and the ADHDRS-IV-Parent:Inv total score was the treatment group comparison of Visit 9 values based on contrasts from a repeated measures analysis for the postbaseline scores (Visit 5 through Visit 9) during. To assess the overall robustness of the primary analyses, the CDRS-R total score and the ADHDRS-IV-Parent:Inv total score were also analyzed based on treatment comparisons of change from baseline-to-endpoint scores during computed on a last observation carried forward (LOCF) basis. Treatment differences in change scores were assessed using an analysis of covariance (ANCOVA). In addition, the ADHDRS-IV-Parent:Inv inattention subscale, hyperactivity-impulsivity subscale, and T-score were analyzed from a repeated measures analysis and a baseline-to-endpoint change was computed on a LOCF basis. The secondary efficacy endpoints including: MADRS, RADS, CGI-S, CGI-I, and Y-MRS and health outcomes (CHQ-PF50 and CHQ-CF87) were analyzed based on treatment comparisons of change from baseline-to-endpoint scores during and were computed on a LOCF basis. Treatment differences in change scores were assessed using ANCOVA. Treatment differences in percentages of TEAEs collected by discussion were assessed using the Fisher s exact test. Baseline-to-endpoint changes for laboratory data, vital signs (including height and weight), and ECG intervals were computed. Treatment differences were assessed using ANOVA. Within-group changes were assessed with paired t-tests or the Wilcoxon signed-rank test. Treatment differences in treatment-emergent out-of-range laboratory values were assessed in a similar fashion as TEAEs. Categorical analyses of changes in ECG intervals and vital signs were also performed. Patient Demographics The majority of enrolled patients were male (73.2%), Caucasian (82.4%), and had previously used stimulants (81.0%). Most of these patients were also extensive metabolizers (EMs) based on their CYP2D6 genotype. The median age was 14.3 years. The age range was 12.0 to 17.9 years. Most patients were diagnosed with either ADHD inattention subtype (57%) or ADHD combined subtype (43%). See Table LYAX.1 for baseline demographics.

6 CT Registry ID#5004 Page 6 Table LYAX.1. Variable Baseline Demographics ATOMOX (N=72) PLACEBO (N=70) TOTAL (N=142) p-value Sex: No. (%) No. Patients * Female 20 (27.8) 18 (25.7) 38 (26.8) Male 52 (72.2) 52 (74.3) 104 (73.2) Origin: No. (%) No. Patients * African Descent 6 (8.3) 11 (15.7) 17 (12.0) Caucasian 64 (88.9) 53 (75.7) 117 (82.4) East/Southeast A 0 1 (1.4) 1 (0.7) Hispanic 2 (2.8) 3 (4.3) 5 (3.5) Other 0 2 (2.9) 2 (1.4) Age: yrs. No. Patients ** Mean Median Standard Dev Height: cm No. Patients ** Mean Median Standard Dev Weight: kg No. Patients ** Mean Median Standard Dev DSM-IV ADHD Subtype No. Patients * INATTV 39 (54.2) 42 (60.0) 81 (57.0) MIXED 33 (45.8) 28 (40.0) 61 (43.0) Prior Stimulant Exposure No. Patients * N 15 (20.8) 12 (17.1) 27 (19.0) Y 57 (79.2) 58 (82.9) 115 (81.0) CYP2D6 No. Patients * EXTN 67 (95.7) 64 (92.8) 131 (94.2) SLOW 3 (4.3) 5 (7.2) 8 (5.8) Unspecified * Frequencies are analyzed using a Fishers-Exact test. ** Means are analyzed using a Type III Sum of Squares analysis of variance (ANOVA): PROC GLM model=treatment.

7 CT Registry ID#5004 Page 7 Patient Disposition Figure LYAX.1 outlines the reasons for study drug discontinuations during each Study Period. Study LYAX had originally planned to enroll approximately 240 patients in ; however, enrollment was slower than anticipated, and the study was stopped early on 13 November 2003 after enrolling 142 patients. One hundred twentynine patients entered Study Period I; 142 patients were randomized in (72 to atomoxetine, 70 to placebo); 120 patients enrolled in I; 20 patients enrolled in Study Period IV; 2 patients completed Study Period IV. Of the patients who discontinued due to AEs in, 1 atomoxetine-treated patient discontinued due to nausea. One patient in the placebo treatment group discontinued due to insomnia, in addition to cold, influenza, and nausea symptoms, and had discontinued Study LYAX before beginning treatment. In addition, 1 patient in the placebo treatment group discontinued due to a lack of efficacy, which was coded as patient and physician perception. The investigator described the lack of efficacy as a worsening in symptoms of depression. The most common reasons for discontinuation were found to be similar between treatment groups. In Study Periods III/IV, 5 patients discontinued atomoxetine due to AEs: 2 patients discontinued due to somnolence, 1 patient discontinued due to abdominal pain upper, and 1 patient discontinued due to anorexia. In addition, 1 patient discontinued due to lethargy the day of randomization to atomoxetine.

8 CT Registry ID#5004 Page 8 Abbreviations: LOE, P+PP = lack of efficacy, patient and physician perception; LOE, PP = lack of efficacy, patient perception; LtF = lost to follow-up; PC/OPD = personal conflict/other patient decision; PEC = protocol entry criteria; UCP = unable to contact patient. Figure LYAX.1. Patient disposition.

9 CT Registry ID#5004 Page 9 Results Primary Efficacy Measures The primary objective of Study LYAX was to assess the efficacy of atomoxetine given orally at doses of up to 1.8 mg/kg/day for approximately 9 weeks compared to placebo in reducing signs and symptoms of depression in adolescent patients with ADHD and comorbid depression, as measured by the CDRS-R and the ADHDRS-IV-Parent:Inv. Analysis of CDRS-R There were no statistically significant differences between the atomoxetine-treated and placebo-treated groups in mean improvement of depression symptoms at any visit observed on the repeated measures analysis for the postbaseline CDRS-R total scores (Visit 5 through Visit 9) (Table LYAX.2) or the CDRS-R total score with mean change from baseline-to-endpoint analysis for (Table LYAX.3). Table LYAX.2. CDRS-R Total Score Repeated Measures Analysis Randomized Patients Treatment Visit N LSMean SE Placebo Placebo Placebo Placebo Placebo N = Number of randomized subjects with non-missing data at the specified visit. Model CDRS Total Score = Pooled investigator TRT VISIT CYP2D6 BASELINE trt*visit. Baseline Visit 1-4, Endpoint Visit 5-9. Pairwise P-Value

10 Table LYAX.3. CDRS-R Total Score Mean Change from Baseline to Endpoint All Randomized Patients Baseline Change 95%CI Study Period Treatment N Mean SD Mean* SD Lower Upper% p-value* II Placebo Population: Randomized patients with a baseline and a postbaseline visit. **p-value is from a t-test on differences in mean changes from baseline to endpoint scores using terms for baseline, pooled investigator, CYP2D6 status and treatment. ***95% CI:2-sided confidence interval of LSmean difference in change score between atomoxetine and placebo. CT Registry ID#5004 Page 10

11 CT Registry ID#5004 Page 11 Analysis of ADHDRS-IV-Parent:Inv Improvement (p<.001) in symptoms of ADHD were demonstrated at each visit in the atomoxetine-treated group compared with the placebo-treated group in the repeated measures analysis for the postbaseline ADHDRS-IV-Parent:Inv total scores (Visit 5 through Visit 9). The least squares means for the placebo-treated group changed very little at each visit (Table LYAX.4). In addition, statistically significant improvement in the ADHDRS-IV-Parent:Inv total T-scores (p<.001), inattention subscale scores (p.004), and the hyperactivity-impulsivity subscale scores (p.002) was also demonstrated at each visit in the atomoxetine-treated group compared with the placebotreated group in the repeated measures analysis (Table LYAX.5). The mean change from baseline-to-locf endpoint analysis of the ADHDRS-IV- Parent:Inv total score, total T-score, inattention subscale score, and the hyperactivityimpulsivity subscale score for demonstrated statistically significant (p<.001) change scores in the atomoxetine treatment group compared with the placebo treatment group (Table LYAX.6), which demonstrates ADHD symptom improvement that is consistent with the primary analysis (repeated measures) results observed on the ADHDRS-IV-Parent:Inv total score. Table LYAX.4. ADHDRS-IV-Parent:Inv Total Score Repeated Measures Analysis Randomized Patients Treatment Visit N LSMean SE Pairwise P- Value Placebo <.001 Placebo <.001 Placebo <.001 Placebo <.001 Placebo <.001 N = Number of randomized subjects with non-missing data at the specified visit. Model ADHSRS-INV Total Score = Pooled investigator TRT VISIT CYP2D6 BASELINE trt*visit. Baseline Visit 1-4, Endpoint Visit 5-9.

12 CT Registry ID#5004 Page 12 Table LYAX.5. ADHDRS-IV-Parent:Inv Subscales and Total Tscore Repeated Measures Analysis Randomized Patients Treatment Visit N LSMean SE Pairwise P-Value ADHDRS-INV Total Tscore Placebo <.001 Placebo <.001 Placebo <.001 Placebo <.001 Placebo <.001 ADHDRS-INV HYP/IMP Score Treatment Visit N LSMean SE Pairwise P-Value Placebo Placebo <.001 Placebo <.001 Placebo Placebo <.001 ADHDRS-INV Inatten Score Treatment Visit N LSMean SE Pairwise P-Value Placebo Placebo <.001 Placebo Placebo Placebo <.001 N = Number of randomized subjects with non-missing data at the specified visit. Model ADHDRS -INV Total Tscore,inatten score, and HYP/IMP score=pooled investigator TRT VISIT CYP2D6 BASELINE trt*visit Baseline Visit 1-4, Endpoint Visit 5-9

13 Table LYAX.6. ADHDRS-IV-Parent:Inv Total and Subscores Mean Change from Baseline to Endpoint Baseline Change 95%CI Treatment N Mean SD Mean* SD Lower Upper% p-value* ADHDRS -INV Total Score ADHDRS -INV Total T- Score ADHDRS -INV HYP/IMP Score ADHDRS-INV Inatten Score <.001 Placebo <.001 Placebo <.001 Placebo <.001 Placebo Population: Randomized patients with a baseline and a postbaseline visit. **p-value is from a t-test on differences in mean changes from baseline to endpoint scores using terms for baseline,pooled investigator, CYP2D6 status and treatment. ***95% CI:2-sided confidence interval of LSmean CT Registry ID#5004 Page 13

14 CT Registry ID#5004 Page 14 Secondary Efficacy Measures Noninferiority Analysis Using the CDRS-R A noninferiority comparison between atomoxetine and placebo was computed using the least squares means from the CDRS-R total score to construct a 95% confidence interval for the difference between treatments (calculated as atomoxetine placebo) in mean change from baseline total score. In agreement with the repeated measures analysis, no significant difference between atomoxetine and placebo was observed, and the lower 95% confidence limit for the difference, which was set a priori, was 2.5. was declared noninferior to placebo in reducing scores on the CDRS-R and, therefore, did not worsen depression compared with placebo. Mean Change from Baseline to LOCF for Secondary Endpoints The analyses of: CHQ-PF50, MADRS, RADS, CHQ-CF87, CGI-S, CGI-I, and the YMRS were presented using the mean change from baseline-to-locf endpoint for Study Period II. CGI-S and CGI-I scores were also presented using the percentage of responders analysis. A responder was defined as having an endpoint score of a 1 or 2 on the CGI-S or CGI-I scale. There were no statistically significant changes between atomoxetine and placebo treatment groups in the mean change from baseline in: Improving psychosocial functioning as measured by the CHQ-PF50 subscales (i.e., psychosocial summary score, mental health, role-emotion/behave, and selfesteem) or physical functioning subscale scores (Table LYAX.7). Improving the signs and symptoms of depression as measured by the MADRS and RADS scores (Table LYAX.8). Improving psychosocial functioning as measured by the CHF-CH87 subscales (i.e., mental health, role-emotion, role-behavior, and self-esteem) or physical functioning subscale scores (Table LYAX.9). Improving the overall outcomes of both ADHD and depressive symptoms as measured by the CGI-S scale (Table LYAX.10). Preventing the induction of manic switching as measured by the YMRS mean scores (Table LYAX.11). Results of the mean change in CGI-I score analysis demonstrated statistically significant improvement (p=.003) in the mean change from baseline in the atomoxetine treatment group compared with placebo group in improving the overall outcomes of both ADHD and depressive symptoms (Table LYAX.12). The responders analysis for the CGI-S and the CGI-I demonstrated that the atomoxetine group was significantly higher (p<.001) than the placebo treatment group using the CGI-I scale (Table LYAX.13).

15 Table LYAX.7. CHQ-PF50 Subscales Mean Change from Baseline to LOCF Endpoint All Randomized Patients Baseline Change 95%CI Treatment N Mean SD Mean* SD Lower Upper% p-value* Mental Health Placebo Psychosocial Summary Score Placebo Role-Emotion/Behave Placebo Self-Esteem Placebo Physical Functioning Placebo Population: Randomized patients with a baseline and a postbaseline visit. **p-value is from a t-test on differences in mean changes from baseline to endpoint scores using terms for baseline, pooled investigator, CYP2D6 status and treatment. ***95% CI:2-sided confidence interval of LSmean difference in change score between atomoxetine and placebo. Baseline Visit 1-4, Endpoint Visit 5-9 CT Registry ID#5004 Page 15

16 Table LYAX.8. MADRS and RADS Total Scores Mean Change from Baseline to LOCF Endpoint All Randomized Patients Baseline Change 95%CI Treatment N Mean SD Mean* SD Lower Upper% p-value* MADRS Total Score Placebo RADS Total Score Placebo Population: Randomized patients with a baseline and a postbaseline visit. **p-value is from a t-test on differences in mean changes from baseline to endpoint scores using terms for baseline, pooled investigator, CYP2D6 status and treatment. ***95% CI:2-sided confidence interval of LSmean difference in change score between atomoxetine and placebo. Baseline Visits 1-4, Endpoint Visits 5-9 CT Registry ID#5004 Page 16

17 Table LYAX.9. CHF-CH87 Subscales Mean Change from Baseline to LOCF Endpoint All Randomized Patients Baseline Change 95%CI Treatment N Mean SD Mean* SD Lower Upper% p-value* Mental Health Placebo Role-Behavior Placebo Role Emotion Placebo Self Esteem Placebo Physical Functioning Placebo Population: Randomized patients with a baseline and a postbaseline visit. **p-value is from a t-test on differences in mean changes from baseline to endpoint scores using terms for baseline, pooled investigator, CYP2D6 status and treatment. ***95% CI:2-sided confidence interval of LSmean difference in change score between atomoxetine and placebo. Baseline Visit 1-4, Endpoint Visit 5-9 CT Registry ID#5004 Page 17

18 CT Registry ID#5004 Page 18 Table LYAX.10. CGI Severity Mean Change from Baseline to LOCF Endpoint All Randomized Patients Baseline Change 95%CI Treatment N Mean SD Mean* SD Lower Upper% p-value* Placebo Population: Randomized patients with a baseline and a postbaseline visit. **p-value is from a t-test on differences in mean changes from baseline to endpoint scores using terms for baseline, pooled investigator, CYP2D6 status and treatment. ***95% CI:2-sided confidence interval of LSmean difference in change score between atomoxetine and placebo. Baseline Visits 1-4, Endpoint Visits 5-9 Table LYAX.11. YMRS Total Score Mean Change from Baseline to Endpoint For All Randomized Patients with Baseline and Postbaseline Visit Baseline Change 95%CI Treatment N Mean SD Mean* SD Lower Upper% p-value* Placebo Population: Randomized patients with a baseline and a postbaseline visit. **p-value is from a t-test on differences in mean changes from baseline to endpoint scores using terms for baseline,pooled investigator, CYP2D6 status and treatment. ***95% CI:2-sided confidence interval of LSmean difference in change score between atomoxetine and placebo. Baseline Visit 1-4, Endpoint Visit 5-9

19 CT Registry ID#5004 Page 19 Table LYAX.12. CGI Improvement Mean Change from Baseline to Endpoint All Randomized Patients Baseline Change 95%CI Treatment N Mean SD Mean* SD Lower Upper% p-value* Placebo Population: Randomized patients with a baseline and a postbaseline visit. **p-value is from a t-test on differences in mean changes from baseline to endpoint scores using terms for baseline, pooled investigator, CYP2D6 status and treatment. ***95% CI:2-sided confidence interval of LSmean difference in change score between atomoxetine and placebo. Baseline Visits 1-4, Endpoint Visits 5-9 Table LYAX.13. Treatment CGI-I and CGI-S Percentage of Responders CGI Severity N n % p- value* CGI Improvement N n % p-value* Placebo 67 7 (10.4) (17.9) (18.8) (47.8) <.001 Responder is defined as having a endpoint score of 1 or 2 on the CGI-ADHD-Severity and CGI-ADHD- Improvement scale. *p-values for between treatment differences vs. Placebo were found using Fisher's Exact test. Baseline Visit 1-4, Endpoint Visit 5-9

20 CT Registry ID#5004 Page 20 Safety Adverse Events There were no patient deaths in Study LYAX. One patient who had been randomized to placebo experienced SAEs of worsening major depression and acute psychotic features. During, 1 of 72 patients in the atomoxetine treatment group discontinued due to moderate nausea, which began on the day the patient began atomoxetine administration. It was noted that this patient also started taking the concomitant medication pseudoephedrine/naproxen on the same day. One patient who was assigned to the placebo treatment group discontinued Study LYAX due to an AE prior to taking study drug. During I, 2 patients discontinued due to somnolence, and 1 patient discontinued due to upper abdominal pain. One patient discontinued due to lethargy the day of randomization to atomoxetine. During Study Period IV, 1 patient discontinued due to anorexia. Table LYAX.14 summarizes the most frequently reported TEAEs that occurred during, with 5% incidence.. Of these TEAEs, the occurrence of nausea (22.2%) and decreased appetite (12.5%) was significantly greater (p 0.05) in patients treated with atomoxetine than those of placebo. TEAEs with 5% incidence for all enrolled patients in Study Periods III/IV are also reported (Table LYAX.15). The most frequently occurring TEAEs were: nausea (22.5%), headache (17.5%), fatigue (15%), decreased appetite (14.2%), abdominal pain upper (11.7%), weight decrease (11.7%), and unexpected therapeutic drug effect (10.8%).

21 CT Registry ID#5004 Page 21 Table LYAX.14. Summary of Treatment-Emergent Adverse Events with 5% Incidence Using MedDRA Preferred Terms All Enrolled Patients Who Took at Least One Dose of Study Drug ATOMOX(N=72) PLACEBO(N=69 Total(N=141) p- ) Value Preferred Term n (%) n (%) n (%) PATIENTS WITH >= 1 TESS 51 (70.8) 49 (71.0) 100 (70.9) 1.00 PATIENTS WITH NO TESS 21 (29.2) 20 (29.0) 41 (29.1) 1.00 Headache 12 (16.7) 7 (10.1) 19 (13.5).326 Nausea 16 (22.2) 3 (4.3) 19 (13.5).002 Vomiting 9 (12.5) 6 (8.7) 15 (10.6).588 Fatigue 9 (12.5) 3 (4.3) 12 (8.5).130 Abdominal pain upper 6 (8.3) 5 (7.2) 11 (7.8) 1.00 Dizziness 9 (12.5) 2 (2.9) 11 (7.8).056 Decreased appetite 9 (12.5) 0 9 (6.4).003 Diarrhoea 1 (1.4) 6 (8.7) 7 (5.0).059 Influenza 3 (4.2) 4 (5.8) 7 (5.0).715 Pyrexia 2 (2.8) 5 (7.2) 7 (5.0).268 Weight decreased 6 (8.3) 1 (1.4) 7 (5.0).116 Irritability 4 (5.6) 1 (1.4) 5 (3.5).367 Weight increased 1 (1.4) 4 (5.8) 5 (3.5).202 Population: Enrolled patients who took at least 1 dose of study drug. Baseline: Visits 1-4, Endpoint: Visits 5-9 * Frequencies are analyzed using a Fisher's Exact test. Table LYAX.15. Summary of Treatment-Emergent Adverse Events with 5% Incidence Using MedDRA Preferred Terms All Enrolled Patients Who Took at Least One Dose of Study Drug I/IV Preferred Term n ATOMOX (N=120) (%) PATIENTS WITH >= 1 TESS 101 (84.2) PATIENTS WITH NO TESS 19 (15.8) Nausea 27 (22.5) Headache 21 (17.5) Fatigue 18 (15.0) Decreased appetite 17 (14.2) Abdominal pain upper 14 (11.7) Weight decreased 14 (11.7) Unexpected therapeutic drug effect 13 (10.8) Vomiting 9 (7.5) Dizziness 8 (6.7) Irritability 8 (6.7) Somnolence 8 (6.7) Influenza 6 (5.0) Insomnia 6 (5.0) Nasopharyngitis 6 (5.0) Upper respiratory tract infection 6 (5.0) Weight increased 6 (5.0) Population: Enrolled patients who took at least 1 dose of study drug. Baseline: Visits 1-4, Endpoint: Visits 10-1

22 CT Registry ID#5004 Page 22 Laboratory Data Laboratory tests, including chemistry, hematology, and urinalysis, were analyzed for all patients enrolled in using the mean change from baseline-to-endpoint analysis. Statistically significant (p<.05) treatment differences in mean change scores were observed for: monocytes, ALT/SGPT, GGT, BUN, cholesterol, uric acid, creatinine, and platelet count (Table LYAX.16). Table LYAX.17 summarizes the frequency of patients with abnormal laboratory values after baseline in. The data indicate that there were no statistically significant abnormal laboratory values reported in the atomoxetine treatment group compared to placebo. Uric acid (p=.013) and alkaline phosphatase levels (p=.004) were significantly abnormally higher in the placebo treatment group compared to the atomoxetine treatment group. The mean change from baseline to endpoint for laboratory analytes and the frequency of abnormal laboratory values were recorded for Study Periods III/IV. However, the statistical significance of these data were not evaluated.

23 CT Registry ID#5004 Page 23 Table LYAX.16. Lab Test Summary of Laboratory (SI) Data Mean Change from Baseline to Endpoint/Significant Analytes All Enrolled Patients Who Took at Least One Dose of Study Drug Lab Baseline Change to Endpoint Unit Therapy n Mean SD Mean SD p-values Therapy Model MONOS GI/L ATOMOX FULL1 PLACEBO ALT U/L ATOMOX <.001 FULL1 PLACEBO GGT U/L ATOMOX <.001 FULL1 PLACEBO BUN mmol/l ATOMOX FULL1 PLACEBO UR AC umol/l ATOMOX FULL1 PLACEBO CHOL mmol/l ATOMOX FULL1 PLACEBO CREAT umol/l ATOMOX FULL1 PLACEBO PLTCT GI/L ATOMOX FULL1 PLACEBO FULL1 - Type III Sums of Squares from an analysis of variance (ANOVA) on the ranks: PROC GLM model=treatment. Least-squares mean option in PROC GLM from the ANOVA on the ranks using the mean square for error. ABBREV: MONOS=monocytes, ALT=ALT/SGPT, GGT=GGT (GGPT/SGGT/YGGT), BUN=urea nitrogen, UR AC=uric acid, CHOL=cholesterol, CREAT=creatinine, PLTCT=platelet count

24 CT Registry ID#5004 Page 24 Table LYAX.17. Lab Test Summary of Laboratory (SI) Data Frequency of Patients with Abnormal Laboratory Values after Baseline (with TESS Option) All Enrolled Patients Who Took at Least One Dose of Study Drug Incidence ATOMOX (1) (Total=72) PLACEBO(2) (Total=69) Group N n (%) N n (%) p-value * Overall HEMATOCRIT LOW 51 2 (3.9) 53 4 (7.5).678 ERYTH COUNT LOW 53 2 (3.8) 56 1 (1.8).611 EOSINOPHLIS HIGH 56 1 (1.8) 56 4 (7.1).364 MCV LOW 56 2 (3.6) 48 4 (8.3).411 PLT COUNT HIGH (3.8).496 UA-SPC GRAV LOW 53 2 (3.8) 58 3 (5.2) 1.00 HIGH 53 5 (9.4) 58 3 (5.2).476 CPK HIGH 55 3 (5.5) 56 6 (10.7).489 ALK PHOS HIGH (14.9).004 CALCIUM HIGH 45 7 (15.6) 47 6 (12.8).771 INORG PHOS HIGH 54 2 (3.7) 53 1 (1.9) 1.00 ALBUMIN HIGH 47 8 (17.0) 51 5 (9.8).376 URIC ACID HIGH (12.7).013 CHOLESTEROL LOW 52 3 (5.8) 47 2 (4.3) 1.00 HIGH (5.7).243 CREATININE HIGH 56 4 (7.1) 54 2 (3.7).679 BILI, TOTAL HIGH 56 2 (3.6) 57 2 (3.5) 1.00 Population: Enrolled patients who took at least 1 dose of study drug. Baseline: Visits 1-4, Endpoint: Visits 5-9 * Frequencies are analyzed using a Fisher's Exact test. Note: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). Abbrev: ERYTH=erythrocyte, MCV=mean cell volume, PLT=platelet, UA SPC GRAV=urinalysis specific gravity, CPK= creatine phosphokinase, ALK PHOS=alkaline phosphatase, INORG PHOS=inorganic phosphate, BILI=bilrubin.

25 CT Registry ID#5004 Page 25 Vitals The mean change from baseline to endpoint (Table LYAX.18) and the categorical analysis of vital signs (Table LYAX.19), including: height, weight, blood pressure (diastolic and systolic), and temperature indicated that there were no statistically significant differences in the mean changes in the atomoxetine treatment group versus the placebo group, with the exception of weight, in. The mean change in weight was statistically significant (p<.001) with a mean increase of 2.6 kg in the placebo treatment group and a mean decrease of 0.84 kg in the atomoxetine treatment group. The mean change from baseline to endpoint for vital signs and a categorical analysis of vital signs were reported for the atomoxetine treatment group in Study Periods III/IV; however, the statistical significance of the results were not analyzed. Table LYAX.18. Condensed Summary of Vital Sign Data Mean Change from Baseline to Endpoint Baseline Change to Endpoint p-values Variables Analyzed Therapy n Mean SD Mean SD Therapy DIASTOLIC ATOMOX BP PLACEBO SYSTOLIC ATOMOX BP PLACEBO HEART ATOMOX RATE PLACEBO WEIGHT ATOMOX <.001 (KG) PLACEBO HEIGHT ATOMOX (CM) PLACEBO TEMPERATURE ATOMOX (CENTIGRADE) PLACEBO Population: Enrolled patients who took at least 1 dose of study drug. Baseline: Visits 1-4, Endpoint: Visits 5-9 Note: n = Total number of patients in each treatment group having the variable in both baseline and postbaseline visits.

26 CT Registry ID#5004 Page 26 Table LYAX.19. Categorical Changes in Vital Signs and Weight at Endpoint Fisher s ATOMOX PLACEBO Vital Incidence Exact N n (%) N n (%) p-value Diastolic Bp High 68 3 (4.4) 69 1 (1.4).366 Pulse Low 71 1 (1.4) 69 1 (1.4) 1.00 Systolic Bp High 66 1 (1.5) 67 3 (4.5).619 Tempurature Low 71 1 (1.4) Weight(Kg) Decrease (28.2) 68 2 (2.9) <.001 *Criteria: Pulse: High: Increase of at least 25 to a value of at least 110; Low: Decrease of at least 20 to a value of at most 65. Temperature: High: Increase of at least 1.0 to a value of at least 37.8; Low: Decrease of at least 1.3 to a value of at most Weight: Decrease of at least 3.5% Blood Pressure: High: Increase of at least 5 mm to above 95% percentile. Patients counted as meeting criteria if criteria was met at endpoint. Patients were excluded from BP analysis if they have abnormal Blood Pressure at last baseline visit Baseline: Visit 1-4, Postbaseline: Visit 5-9 Electrocardiograms Categorical and mean change from baseline-to-endpoint analyses of ECG variables for all enrolled patients were reported for. The categorical analysis of ECG heart rate and QTc intervals using the Bazett s formula (QTcB), Fredericia s formula (QTcF), and a data-derived (QTcD) formula, showed no statistically significant differences were observed between treatment groups for any of these variables. The mean change from the baseline analysis showed a statistically significant decrease in: RR interval values (p<.001), decrease in QT interval values (p=.006), increase in heart rate (p<.001), prolongation of QTcB (p=.045), and decrease of PR values(p=.002) for the mean change in the atomoxetine treatment group compared to the placebo treatment group when corrected using the Bazett formula (Table LYAX.20). There was no statistically significant difference when using data corrections or the Fredericia correction method.

27 CT Registry ID#5004 Page 27 Table LYAX.20. Condensed Summary of ECG Data Mean Change from Baseline to Endpoint Ranked All Enrolled Patients Who Took at Least One Dose of Study Drug Baseline Change to Endpoint Variables Analyzed Therapy n Mean SD Mean SD p-values Therapy (Int*1) RR ATOMOX <.001 PLACEBO PR ATOMOX PLACEBO QRS ATOMOX PLACEBO QT ATOMOX PLACEBO QTCB ATOMOX PLACEBO QTCF ATOMOX PLACEBO QTCD ATOMOX PLACEBO HR ATOMOX <.001 PLACEBO Population: Enrolled patients who took at least 1 dose of study drug. Baseline: Visits 1-4, Endpoint: Visits 5-9 Note: n = Total number of patients in each treatment group having the variable in both baseline and postbaseline visits.