Summary ID#2552. Clinical Study Summary: Study B4Z-MC-LYAF (Final Report, Study Period III Visit Group II Study Period IV)

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1 CT Registry ID# 2552 Page 1 Summary ID#2552 Clinical Study Summary: Study B4Z-MC-LYAF (Final Report, Study Period III Visit Group II Study Period IV) Relapse Prevention after 10-Week and 52-Week Treatment with Tomoxetine Hydrochloride in Children with Attention-Deficit/Hyperactivity Disorder Date summary approved by Lilly: 14 June 2007 Brief Summary of Results The results for Study Periods I, II, and III Visit Group I (10-week, acute treatment plus 9- month, double-blind, placebo-controlled treatment) are reported in a separate CTR summary (CT Registry ID#2552, Clinical Study Summary Study B4Z-MC-LYAF [LYAF]) (9-month interim report for Study Period I through Study Period III Visit Group I). The current summary contains data for the last 2 periods of Study LYAF, in which investigators tested the hypothesis that pediatric outpatients who achieved and maintained a satisfactory response to approximately 52 weeks of treatment with atomoxetine (previously called tomoxetine hydrochloride and hereafter referred to as atomoxetine), and continued treatment with atomoxetine, would have a superior response when compared with placebo-treated patients as measured by the number of days until relapse. The results for Study Period III Visit Group II and Study Period IV are as follows: After 1 year of active atomoxetine treatment, patients who continued atomoxetine for 6 additional months (taper group) were statistically significantly less likely to relapse or to experience partial symptom return compared with patients who discontinued active treatment and switched to placebo (nontaper group). The p- value from the Wilcoxon test for qualified patients was not statistically significant (p=.055), but the p-value for all randomized patients was (p=.008).

2 CT Registry ID# 2552 Page 2 At the end of Study Period III Visit Group II, all randomized patients who were treated with atomoxetine showed statistically significantly less symptom worsening than patients on placebo as assessed by: the Attention- Deficit/Hyperactivity Disorder Rating Scale (ADHDRS-IV-Parent:Inv) Total Score and Subscale Score (p<.001 for Total Score and Hyperactivity-Impulsivity Subscale, p=.002 for Inattentive Subscale), Clinical Global Impressions-Attention Deficit/Hyperactivity Disorder Severity (CGI-ADHD-S) Scale (p=.005), Conners Parent Rating Scale-Revised: Short Form (CPRS-R:S) Scale (Hyperactivity Subscale p=.018; Cognitive Problems/Inattention Subscale p=.050), and the Conners Teacher Rating Scale-Revised: Short Form (CTRS R:S) Scale (Attention-Deficit/Hyperactivity Disorder [ADHD] Index p<.001, Hyperactivity Subscale p=.027). There were no statistically significant differences among treatment groups in any of the patient characteristics examined at baseline (for example, gender, age, and ADHD subtype) for patients randomized in Study Period III Visit Group II. There were no deaths in Study LYAF. During this reporting period, 1 atomoxetine patient discontinued due to an adverse event (AE), ST segment depression, and 1 placebo patient discontinued due to depression. A total of 7 serious adverse events (SAEs) were reported by 5 placebo patients during this portion of the study. Of these, 1 SAE, incomplete right bundle branch block (RBBB), was classified as possibly related to the study drug (the patient was on atomoxetine therapy at RBBB onset, but was randomized to placebo group at Visit 22 and discontinued while on placebo). There were no statistically significant differences between all randomized patient treatment groups in the incidence of treatment-emergent abnormal laboratory values during Study Period III Visit Group II. There were statistically significant differences between the 2 treatment groups for mean change in weight (p<.001), pulse (p<.001), and temperature (p=.038) when analyzed for all randomized patients during Study Period III Visit Group II. Statistically significant differences between atomoxetine and placebo were found for heart rate (p<.001), RR interval (p<.001), PR interval (p=.014), QT interval (p<.001), and Bazett corrected QT interval (QTcB) (p=.003), but not for Fridericia corrected QT (QTcF), when analyzed for all randomized patients during Study Period III Visit Group II. There was a statistically significant difference (p=.029) between atomoxetine taper and nontaper groups for mean diastolic blood pressure when analyzed for all randomized patients during Study Period IV (discontinuation phase). On 14 January 2005, the Food and Drug Administration (FDA) requested Eli Lilly and Company (Lilly) to undertake a comprehensive reexamination of the

3 CT Registry ID# 2552 Page 3 coding of AEs, reasons for discontinuation, and patients with hospitalizations in Study LYAF. That post hoc analysis is presented separately in this document; it was not integrated into any of the analyses done prior to unblinding. Title of Study: Relapse Prevention after 10-Week and 52-Week Treatment with Tomoxetine Hydrochloride in Children with Attention-Deficit/Hyperactivity Disorder Investigator(s): This multicenter study included 33 principal investigators. Study Center(s): This study was conducted at 33 study centers in 14 countries. Length of Study: 2 years 5 months Phase of Development: 2/3 Date of first patient enrolled: 28 November 2000 Date of last patient completed: 03 June 2003 Objectives: Primary: The primary objective of Study LYAF was to test the hypothesis that pediatric outpatients who achieved a satisfactory initial response to acute (approximately 10 weeks) treatment with atomoxetine hydrochloride continued treatment with atomoxetine would have a superior response when compared with placebo-treated patients as measured by the number of days until relapse. Since atomoxetine proved to be superior to placebo in the above analysis (as shown in this study s interim study report, the summary of which appears in CT Registry Synopsis ID#2552, Clinical Study Summary Study LYAF (9- Month Interim Report for Study Periods I through Study Period III Visit Group I), the following hypothesis was also tested: among pediatric outpatients who achieve and maintain a satisfactory response to approximately 52 weeks of treatment with atomoxetine, continued treatment with atomoxetine would be superior to placebo as measured by the number of days until relapse. Secondary: Secondary objectives of the study were to assess: the long-term safety of atomoxetine; the effects of atomoxetine on measures of cognitive and neuropsychological function during long-term treatment; teacher evaluations of the effects of atomoxetine on symptoms associated with impaired performance at school; and health outcomes during long-term treatment with atomoxetine. Methodology: Double-blind, randomized, placebo-controlled, relapse-prevention study (see Figure 1 for illustration of study design). Number of Patients: Planned: 500 patients Enrolled: 604 patients Randomized in Study Period III Visit Group I: 416 (292 atomoxetine, 124 placebo) Randomized in Study Period III Visit Group II: 81 atomoxetine, 82 placebo; 46 continuing on placebo (not randomized) Randomized Study Period IV: 34 atomoxetine tapered discontinuation, 31 atomoxetine nontapered discontinuation; 91 continuing on placebo (not randomized) Completed: 33 atomoxetine tapered discontinuation, 31 atomoxetine nontapered discontinuation; 90 continuing on placebo Diagnosis and Main Criteria for Inclusion: Patients 6 through 15 years of age (inclusive) at Visit 1, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV ) diagnostic criteria for ADHD. Each patient s score from the ADHDRS-IV-Parent:Inv was at least 1.5 standard deviations above the age/gender norm for their diagnostic subtype. Test Product/Study Drug, Dose, and Mode of Administration: : 0.5 mg/kg/day to 1.8 mg/kg/day, given twice daily; atomoxetine capsules, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, and 40 mg. Reference Therapy/Comparator, Dose, and Mode of Administration: Placebo, given twice daily. Duration of Treatment: Maximum of 78 weeks treatment.

4 CT Registry ID# 2552 Page 4 Variables: Criteria for Evaluation Efficacy: Days to relapse, relapse rate, ADHDRS-IV-Parent:Inv Total Score, Inattention Subscale Scores and Hyperactivity-Impulsivity Subscale Score; CGI-ADHD-S Score; CPRS-R:S Oppositional Subscale Score, Cognitive Problems/Inattention Subscale Score, Hyperactivity Subscale Score, and ADHD Index; CTRS-R:S Oppositional Subscale Score, Cognitive Problems/Inattention Subscale Score, Hyperactivity Subscale Score, and ADHD Index; Children s Depression Inventory Total Score; Children s Depression Rating Scale-Revised Total Score; Multidimensional Anxiety Scale for Children Total Score, Physical Symptoms Scale, Harm Avoidance Scale, Social Anxiety Scale, and Separation/Panic Scale Score; Stroop Color Word Test interference Score; Dual Verbal Working Memory Task Score; Trail Making Test (A and B) Scores; Mazes Subtest Score, Block Design Score, Wechsler Intelligence Scale for Children Third Edition Working Memory Arithmetic and Digit Span Test Scores, Picture Arrangement Score, Similarities, and Vocabulary Score; and the CGI-Efficacy Index Score. Safety: Treatment-emergent adverse events (TEAEs), vital signs, height and weight, laboratory analytes, and electrocardiograms (ECGs). Health Outcomes: Physical and psychosocial well-being using the Child Health Questionnaire (CHQ). Evaluation Methods: Statistical Methods: The primary efficacy variable was days to relapse and was analyzed using Kaplan-Meier analysis; Wilcoxon test was used to assess the treatment difference in the distribution. Secondary analysis using primary efficacy variable included log-rank test and proportional hazard analyses. Secondary efficacy measures and safety measures: Changes from baseline to endpoint values were computed for each vital sign, continuous laboratory measures, and continuous ECG parameters by treatment group. Last-observation-carried-forward (LOCF) approach was used to handle missing data. For continuous variables, treatment effect was assessed by analysis of variance (ANOVA) model. Within-treatment-group changes were assessed using Wilcoxon signed rank test. Mean standard deviation and 2-sided 95% confidence intervals were also calculated for selected measures. The percentage of patients meeting categorical criteria was also computed for abnormal labs, vital signs, and ECG intervals by treatment group. For categorical variables, Fisher s Exact test was used to assess treatment effect.

5 CT Registry ID# 2552 Page 5 Study Design Figure 1 shows the study design for Study LYAF. Study Period I was used for screening. Study Period II comprised 10 weeks of acute open-label treatment with atomoxetine 0.5 mg/kg titrated up to 1.2 mg/kg. Patients who tolerated doses up to 0.8 mg/kg/day and met response criteria at the end of Study Period II were randomized at Visit 11 into the double-blind, placebo-controlled Study Period III Visit Group I. Patients randomized to atomoxetine were rerandomized (at Visit 22, after approximately 1 year of blinded therapy) into Study Period III Visit Group II, to placebo or atomoxetine, which they continued at the same dose that they received at the end of Study Period III Visit Group I. In Study Period IV, which consisted of 2 visits, patients who completed all Study Period III visits were randomized to a double-blind, placebo-controlled, dose-reduction period, during which study drug was either abruptly discontinued, or tapered and discontinued. Study period III Visit Group I = Visits 11 to 22; Study period III Visit Group II = Visits 22 to 28. Figure 1. Illustration of study design for Study B4Z-MC-LYAF. Results: Patient Demographics Table 1 summarizes demographic characteristics for randomized patients in Study Period III Visit Group II (visits from the second randomization to the end of Study Period III). Of the 163 randomized patients, 89.6% were male, and 96.3% were Caucasian. The mean age for patients randomized in Study Period III Visit Group II (at study entry) was years (range of 6.07 years to 15.4 years). Other baseline characteristics included:

6 CT Registry ID# 2552 Page % had no prior stimulant exposure, 74.2% met criteria for the combined ADHD subtype, with 20.9% classified as predominantly inattentive and 4.9% as hyperactive-impulsive, and 7.4% were determined to be poor cytochrome P450 2D6 (CYP2D6) metabolizer (PM) patients. There were no statistically significant differences between treatment groups in any of the patient characteristics examined at baseline. Table 1. Patient Demographics Comparison of Treatment Groups at Baseline All Randomized Patients in Double-Blind Continuation Therapy Phase Study Period III Visit Group II TMX_TMX TMX_PLA Total p-value Variable (N=81) (N=82) (N=163) Sex: No. (%) No. Patients a Female 9 (11.1) 8 (9.8) 17 (10.4) Male 72 (88.9) 74 (90.2) 146 (89.6) Origin: No. (%) No. Patients a African Descent 2 (2.5) 1 (1.2) 3 (1.8) Western Asian 1 (1.2) 0 1 (0.6) Caucasian 78 (96.3) 79 (96.3) 157 (96.3) Other 0 2 (2.4) 2 (1.2) Age: yrs. No. Patients b Mean Median Standard Dev Minimum Maximum Population: ALL Randomized Patients in SPIII VG2 Initial Visit ONLY a Frequencies are analyzed using a Chi-Square test. b Means are analyzed using a Type III Sum of Squares analysis of variance (ANOVA): PROC GLM model=investigator and treatment. Abbreviations: Dev = deviation; No. = number; PLA = placebo; TMX = atomoxetine; yrs. = years. Table 2 summarizes demographic characteristics for all patients in Study Period IV. There were no statistically significant differences among treatment groups in any of the patient characteristics examined at baseline.

7 CT Registry ID# 2552 Page 7 Table 2. Patient Demographics Comparison of Treatment Groups at Baseline All Patients Entered Study Period IV TMX_TAP TMX_NTAP PLACEBO Total p-value Variable (N=34) (N=31) (N=92) (N=157) Sex: No. (%) No. Patients a Female 4 (11.8) 2 (6.5) 5 (5.4) 11 (7.0) Male 30 (88.2) 29 (93.5) 87 (94.6) 146 (93.0) Origin: No. (%) No. Patients a African Descent 2 (5.9) (1.3) Western Asian 1 (2.9) (0.6) Caucasian 31 (91.2) 31 (100) 90 (97.8) 152 (96.8) Other (2.2) 2 (1.3) Age: yrs. No. Patients b Mean Median Standard Dev Minimum Maximum Population: All Patients in Study Period IV Initial Visit ONLY a Frequencies are analyzed using a Chi-Square test. b Means are analyzed using a Type III Sum of Squares analysis of variance (ANOVA): PROC GLM model=investigator and treatment. Abbreviations: Dev = deviation; N/No. = number; NTAP = nontapered; PLA = placebo; TAP = tapered; TMX = atomoxetine; yrs = years. Patient Disposition Figure 2 shows an overview of patient disposition for Study Period III Visit Group II and Study Period IV. A total of 209 patients entered Study Period III Visit Group II. Four patients actually discontinued in Study Period III Visit Group I, but were entered into Study Period III Visit Group II inappropriately. At Visit 22, the 163 patients who received atomoxetine treatment in Study Period III Visit Group I were rerandomized to continued atomoxetine treatment (n=81) or to placebo treatment (n=82). The continuing placebo-treated patients (n=46) remained on placebo treatment throughout the study. Sixty-five atomoxetine-atomoxetine treated patients (80.2%), 54 atomoxetine-placebo treated patients (65.9%), and 37 placebo-placebo treated patients (80.4%) completed Study Period III Visit Group II. Study Period IV was a randomized, double-blind, placebo-controlled, tapering, and discontinuation of study drug phase. Patients who received atomoxetine treatment during Study Period III Visit Group II were randomized to placebo treatment by either an abrupt discontinuation of study drug (nontapered discontinuation, n=31) or to a gradual discontinuation of study drug (tapered discontinuation, n=34). Patients who received placebo treatment during Study Period III Visit Group II remained on placebo treatment

8 CT Registry ID# 2552 Page 8 throughout Study Period IV (n=91). A total of 154 patients (98.7%) successfully completed the discontinuation phase (Study Period IV). N = 209* Study Period III Visit Group I Completers N = 163 -treated Continuing Patients Randomly Assigned to Study Period III VGII N = 46 Placebo-treated Continuing Patients Assigned to Study Period III VGII N = 81 N = 82 Placebo N = 16 Discontinued Reasons: adverse event (1) lost to follow up (3) patient moved (1) personal conflict (3) MD decision (1) protocol violation (2) relapse per protocol (5) N = 65 Study Period III Complete N = 34 N = 31 Study Period IV Study Period IV Tapered Non-Tapered Discontinuation Discontinuation N = 28 Discontinued Reasons: adverse event (1) sat. response, p (1) sat. response, p & MD (4) lost to follow up (2) personal conflict (2) sponsor decision (1) MD decision (3) relapse per protocol (14) N = 54 Study Period III Complete N = 37 Study Period III Complete N = 91 Study Period IV Placebo Discontinuation N = 9 Discontinued Reasons: sat. response, p.p. (2) lost to follow up (1) personal conflict (2) MD decision (1) protocol violation (1) relapse per protocol (2) N = 1 N = 33 N = 31 N = 0 Discontinued Study Period IV Study Period IV Discontinued Reason: clinical relapse (1) Complete Complete N = 90 N = 1** Study Period IV Discontinued Reason: Complete MD decision (1) Abbreviations: MD = physician; N = number of patients; p = patient; sat. = satisfactory. * Four patients discontinued in Study Period III Visit Group I but were randomized into Study Period III Visit Group II. ** One patient was randomized into Study Period IV but actually discontinued in Study Period III Visit Group II due to physician decision. Figure 2. Patient disposition for Study Period III Visit Group II and Study Period IV. Table 3 shows the number of patients with data at each visit of Study Period III Visit Group II and Study Period IV, and the number of patients from each treatment group who completed the study.

9 CT Registry ID# 2552 Page 9 Table 3. Patient Disposition by Visit, All Entered Patients Study Period III Visit Group II and Study Period IV Study Period Visit Number of Patients SPIII VGI Completers 22 ATX n=163 SPIII VGII ATX-ATX ATX-PBO Randomization 81 (100%) 82 (100%) SPIII VGII PBO n=46 PBO 46 (100%) (97.5) 81 (98.8) 45 (97.8) (93.8) 74 (90.2) 43 (93.5) (90.1) 66 (80.5) 40 (87.0) (87.7) 59 (72.0) 39 (84.8) (85.2) 57 (69.5) 38 (82.6) (81.5) 56 (68.3) 38 (82.6) (80.2) 54 (65.9) 37 (80.4) SPIV Tapered Nontapered 28 Randomization SPIV Protocol Complete Abbreviations: ATX = atomoxetine; PBO = placebo; SPIII VGI = Study Period III Visit Group I; SPIII VGII = Study Period III Visit Group II; SPIV = Study Period IV; Tapered = tapered study drug discontinuation; Nontapered = abrupt study drug discontinuation. Discontinuation of Patients Discontinuation from Study Period III Visit Group II Table 4 shows the percentage of randomized patients who discontinued from Study Period III Visit Group II by their primary reason for discontinuation. A total of 163 patients who received atomoxetine treatment in Study Period III Visit Group I were randomized in Study Period III Visit Group II to either continued atomoxetine treatment (atomoxetine-atomoxetine, n=81) or to placebo (atomoxetine-placebo, n=82) (NOTE: the total of 163 patients includes 3 patients who were inappropriately randomized into this study period after being discontinued from the study. These patients are not shown in the data tables). Study Period III Visit Group II was completed by 119 randomized patients (74.4%). Statistically significantly more atomoxetine-treated patients than placebo-treated patients completed Study Period III Visit Group II (atomoxetineatomoxetine: 82.3%; atomoxetine-placebo: 66.7%; p=.030). The most common reason for discontinuation was due to relapse per the protocol definition, which was reported by 19 patients (11.9%). Statistically significantly more placebo-treated patients than atomoxetine-treated patients relapsed during this study period (atomoxetine-atomoxetine n=5; atomoxetine-placebo n=14; p=.049). Two randomized patients (1.3%) discontinued from Study Period III Visit Group II due to AEs.

10 CT Registry ID# 2552 Page 10 Table 4. Summary of Primary Reasons for Study Discontinuation Comparison of Treatment Groups All Randomized Patients Study Period III Visit Group II TMX_TMX TMX_PLA Total p-value* (N=79) (N=81) (N=160) Primary Reason for Discontinuation n (%) n (%) n (%) Adverse event 1 (1.3) 1 (1.2) 2 (1.3) 1.00 Satisfactory response, patient 0 1 (1.2) 1 (0.6) perception Satisfactory response, patient and 0 4 (4.9) 4 (2.5).120 physician perception Unable to contact patient (lost to 3 (3.8) 2 (2.5) 5 (3.1).680 follow-up) Patient moved 1 (1.3) 0 1 (0.6) Personal conflict or other patient 3 (3.8) 2 (2.5) 5 (3.1).680 decision Sponsor's decision 0 1 (1.2) 1 (0.6) Physician decision 0 2 (2.5) 2 (1.3).497 Protocol Violation 1 (1.3) 0 1 (0.6) Relapse per protocol definition 5 (6.3) 14 (17.3) 19 (11.9).049 Study Period III completed 65 (82.3) 54 (66.7) 119 (74.4).030 Population: ALL Randomized Patients in SPIII VG2 Subjects in SP3VG2: Visits Frequencies are analyzed using a Fisher's Exact test. Abbreviations: N = total sample size; n = number of patients who discontinued; PLA = placebo; TMX = atomoxetine. Discontinuation from Study Period IV Table 5 shows the percentage of all randomized patients who discontinued from Study Period IV by their primary reason for discontinuation by treatment. A total of 64 patients (98.5%) completed Study Period IV. One patient was randomized into Study Period IV, but actually discontinued in Study Period III Visit Group II due to physician decision. One patient from the atomoxetine-atomoxetine tapered treatment group discontinued in Study Period IV due to clinical relapse.

11 CT Registry ID# 2552 Page 11 Table 5. Summary of Primary Reasons for Study Discontinuation Comparison of Treatment Groups All Randomized Patients Study Period IV TMX_TAP TMX_NTAP Total p-value* (N=34) (N=31) (N=65) Primary Reason for Discontinuation n (%) n (%) n (%) Protocol completed 33 (97.1) 31 (100) 64 (98.5) 1.00 Clinical relapse 1 (2.9) 0 1 (1.5) Population: Randomized Patients in Study Period IV Subjects in SP4: Visits Frequencies are analyzed using a Fisher's Exact test. Abbreviations: N = total sample size; n = number of patients who discontinued; NTAP = nontapered; TAP = TAPERED; TMX = atomoxetine. Note: Relapse as defined by investigator. Primary Efficacy Measures The protocol defined relapse as follows: During Study Period III, if at 2 consecutive visits a patient s CGI-ADHD-S score increases by 2 or more categories from their score at the end of Study Period II (Visit 10) and their ADHDRS-IV-Parent:Inv total score returns to 90% or more of their Study Period II baseline score, the patient will be considered to be a relapser and must be discontinued from the study. If a patient shows evidence of a return of symptoms at 1 visit that meets the severity criteria described above, and because of worsening symptoms is unwilling to remain in the study, or does not return for a second visit, the patient will also be considered to have relapsed. Figure 3 contains the results from the survival analysis based on protocol-defined relapse for all randomized patients. The Kaplan-Meier plot s vertical axis shows the proportion of patients not relapsing, and the horizontal axis shows time (days on therapy). Based on the Kaplan-Meier estimates, for all randomized patients, the mean time to relapse in days (and standard error) for patients on atomoxetine was days (0.71), compared with days (3.09) for patients on placebo (Table 6). The analysis using all randomized patients showed that patients on atomoxetine treatment were statistically significantly less likely to relapse than patients assigned to placebo as assessed by the Wilcoxon test (p=.008). Figure 4 contains the results from the survival analysis based on protocol-defined relapse for qualified patients only. Treatment differences in the distribution were assessed using the Wilcoxon test (p=.055). In qualified patients, based on Kaplan-Meier estimates, time to relapse in days (and standard error) for patients on atomoxetine was days (1.11), compared with days (3.42) for patients on placebo (Table 7).

12 Table 6. Time-to-Relapse Based on Kaplan-Meier Estimates (Relapse per Protocol) All Randomized Patients Study Period III Visit Group II Relapse Placebo Total Fishers Exact N n(%) N n(%) N n(%) p-value Relapse 82 10(12.2%) 81 2(2.5%) (7.4%) Placebo Difference between Days to N at Prop. N at Prop. and Placebo Relapse Risk Nonrelapse SE Risk Nonrelapse SE Diff ( LCI, UCI ) ( 0.000, ) ( 0.000, ) ( 0.000, ) ( , ) ( , ) ( 0.010, ) ( 0.039, ) ( 0.049, ) ( 0.049, ) ( 0.049, ) ( 0.040, ) ( 0.040, ) ( 0.017, ) ( 0.017, ) ( 0.017, ) (.,. ) (.,. ) (.,. ) Log-Rank p-value = TIME(DAYS) TO EVENT/CENSOR MEAN(SE) : (0.71) Placebo: (3.09) Abbreviations: LCI = Lower limit of Confidence Interval; N = total number in sample; n = sample subset; Prop. = proportion; SE = Standard Error; UCI = Upper limit of Confidence Interval. Relapse Definition: Relapse per protocol definition within study period III visit Group II CT Registry ID# 2552 Page 12

13 Table 7. Time-to-Relapse by Visit Based on Kaplan-Meier Estimates (Relapse per Protocol) Qualified Patients Only Study Period III Visit Group II Relapse Placebo Total Fishers Exact N n(%) N n(%) N n(%) p-value Relapse 54 7(13%) 48 2(4.2%) 102 9(8.8%) Placebo Difference between Days to N at Prop. N at Prop. and Placebo Relapse Risk Nonrelapse SE Risk Nonrelapse SE Diff ( LCI, UCI ) ( 0.000, ) ( 0.000, ) ( 0.000, ) ( 0.000, ) ( 0.000, ) ( , ) ( 0.018, ) ( 0.032, ) ( 0.032, ) ( 0.032, ) ( 0.015, ) ( 0.015, ) ( , ) ( , ) ( , ) (.,. ) (.,. ) (.,. ) Log-Rank p-value = TIME(DAYS) TO EVENT/CENSOR MEAN(SE) : (1.11) Placebo: (3.42) Relapse Definition: Relapse per protocol definition within study period III visit Group II Abbreviations: N = total number in sample; n = sample subset; Prop. = proportion; SE = Standard Error LCI = Lower limit of Confidence Interval; UCI = Upper limit of Confidence Interval CT Registry ID# 2552 Page 13

14 CT Registry ID# 2552 Page 14 Figure 3. Relapse rates among treatment groups based on protocol-defined relapse for all randomized patients.

15 CT Registry ID# 2552 Page 15 Figure 4. Relapse rates among treatment groups based on protocol defined relapse for qualified patients. Secondary Efficacy Measures Study Period III Visit Group II Secondary objectives of the study were to assess the long-term safety of atomoxetine, the effects of atomoxetine on measures of cognitive and neuropsychological function during long-term treatment, teacher evaluations of the effects of atomoxetine on symptoms associated with impaired performance at school, and health outcomes during long-term treatment with atomoxetine. Results were as follows: Postrandomization mean ADHDRS-IV-Parent:Inv Total Scores, Total T-Score and 2 subscale scores showed statistically significantly greater worsening in the placebo treatment group than in the atomoxetine treatment group (p=.002 for the Inattentive Subscale and p<.001 for all other variables) (see Table 8).

16 CT Registry ID# 2552 Page 16 Statistically significant differences between treatment groups were also noted in the CGI-ADHD-S Score (p=.005) (see Table 8). There was a statistically significant difference between treatment groups when patients showed an unchanged or worse therapeutic effect without experiencing any side effects (atomoxetine: 5 [6.41%], placebo: 15 [18.52%]; p=.03) for the Clinical Global Impressions-Attention-Deficit/Hyperactivity Disorder-Efficacy Index (CGI-ADHD-EI) Rating Scale. There was no statistically significant difference between the atomoxetine group and the placebo group as measured by patient frequency in any of the other 15 categories of CGI-ADHD-EI Rating Scales. The placebo treatment group showed statistically significantly greater worsening compared with the atomoxetine treatment group on the CPRS-R:S Cognitive Subscale (p=.050) and Hyperactive Subscale (p=.018). There was no statistically significant difference between the 2 treatment groups on the ADHD Index Score (p=.054), or on the Oppositional Subscale (p=.575) (see Table 9). There was a statistically significant difference between the 2 treatment groups on the CTRS-R:S ADHD Index Subscale (p<.001) and the Hyperactive Subscale (p=.027). The placebo treatment group showed symptom worsening while the atomoxetine treatment group showed symptom improvement. There was no statistically significant difference between the 2 treatment groups on the Cognitive Subscale, (p=.056) and on the Oppositional Subscale (p=.195) (see Table 10). The differences between treatment groups for the Children s Depression Inventory (CDI), Children s Depression Rating Scale-Revised (CDRS-R) and Multidimensional Anxiety Scale for Children (MASC) were not statistically significant for any of the measurements (see Table 11). There was a statistically significant difference between the 2 treatment groups on the Wechsler Intelligence scale (WISC) IQ (p=.038) and WISC Vocabulary Scaled Score (p=.049). No statistically significant differences were found between the treatment groups on the other WISC Scales, or on the Cognitive Measurement Dual Verbal Working Memory Task (DUAL-VWM), Stroop Color and Word Test (Stroop), Trail Making Part A (Trails A), and Trail Making Part B (Trails B). Tables 12 and 13 present the summaries of efficacy scores for a subset of efficacy measures, which includes all patients in Study Period III Visit Group II by visit.

17 Table 8. ADHDRS-IV-Parent:Inv and CGI-ADHD-S Change from Baseline to Endpoint All Randomized Patients Study Period III Visit Group II Within Between Variable / -- Baseline Endpoint Change Group Group Treatment Group N Mean SD Mean SD Mean SD LSMean(a) p-value(b) p-value(a) ADHDRS-PI Total Score Placebo <.001 < _ Treatment LSMean Difference(95%CI) = 6.00(2.76, 9.24) ADHDRS-PI Total T-score Placebo <.001 < _ Treatment LSMean Difference(95%CI) = 6.31(2.95, 9.67) ADHDRS-PI Hyp/Imp Subscale Placebo <.001 < _ Treatment LSMean Difference(95%CI) = 3.11(1.37, 4.85) ADHDRS-PI Inatt. Subscale Placebo < _ Treatment LSMean Difference(95%CI) = 2.89(1.09, 4.68) CGI ADHD Severity Placebo < _ Treatment LSMean Difference(95%CI) = 0.56(0.17, 0.95) (a) LSMeans and Between Groups p-value are from ANOVA model with terms for Treatment and Investigator. (b) Within Groups p-values obtained from Wilcoxons Signed-rank Test for mean change from baseline to endpoint. Population: All randomized patients with at least one baseline and postbaseline measurement. Baseline visits: 1-22, Endpoint visits: CT Registry ID# 2552 Page 17

18 Table 9. CPRS-R:S Change from Baseline to Endpoint All Randomized Patients Study Period III Visit Group II Within Between Variable / -- Baseline Endpoint Change Group Group Treatment Group N Mean SD Mean SD Mean SD LSMean(a) p-value(b) p-value(a) CPRS ADHD Index Placebo < _ Treatment LSMean Difference(95%CI) = 2.18(-0.04, 4.41) CPRS Oppositional Score Placebo _ Treatment LSMean Difference(95%CI) = 0.34(-0.86, 1.55) CPRS Cognitive Problems Placebo < _ Treatment LSMean Difference(95%CI) = 1.37(0.00, 2.73) CPRS Hyperactive Score Placebo < _ Treatment LSMean Difference(95%CI) = 1.38(0.24, 2.51) (a) LSMeans and Between Groups p-value are from ANOVA model with terms for Treatment and Investigator. (b) Within Groups p-values obtained from Wilcoxons Signed-rank Test for mean change from baseline to endpoint. Population: All randomized patients with at least one baseline and postbaseline measurement. Baseline visits: 1-22, Endpoint visits: CT Registry ID# 2552 Page 18

19 Table 10. CTRS-R:S Change from Baseline to Endpoint All Randomized Patients Study Period III Visit Group II Within Between Variable / -- Baseline Endpoint Change Group Group Treatment Group N Mean SD Mean SD Mean SD LSMean(a) p-value(b) p-value(a) CTRS ADHD Index Subscale Placebo < _ Treatment LSMean Difference(95%CI) = 6.08(2.85, 9.30) CTRS Cognitive Problems Subscale Placebo _ Treatment LSMean Difference(95%CI) = 1.24(-0.03, 2.51) CTRS Hyperactive Subscale Placebo _ Treatment LSMean Difference(95%CI) = 2.31(0.27, 4.34) CTRS Oppositional Subscale Placebo _ Treatment LSMean Difference(95%CI) = 0.87(-0.46, 2.20) (a) LSMeans and Between Groups p-value are from ANOVA model with terms for Treatment and Investigator. (b) Within Groups p-values obtained from Wilcoxons Signed-rank Test for mean change from baseline to endpoint. Population: All randomized patients with at least one baseline and postbaseline measurement. Baseline visits: 1-22, Endpoint visits: CT Registry ID# 2552 Page 19

20 CT Registry ID# 2552 Page 20 Study Period IV During the discontinuation phase, there were no statistically significant differences between treatment groups (tapered atomoxetine discontinuation versus nontapered discontinuation) on any of the following scales (that is, ADHDRS-IV- Parent:Inv Total Score, Total T-Scores, Subscale Scores, and CGI-ADHD-S Scores) (see Table 14). During the discontinuation phase (2 weeks), no tapered discontinuation patients relapsed, and 1 nontapered discontinuation patient relapsed (p=.4769) based on the protocol definition of relapse (see Table 15). This differs from the investigator s clinical judgment of relapse as the reason for disposition (shown in Table 5).

21 Table 11. CDI, CDRS-R, MASC Change from Baseline to Endpoint All Randomized Patients Study Period III Visit Group II Within Between Variable / -- Baseline Endpoint Change Group Group Treatment Group N Mean SD Mean SD Mean SD LSMean(a) p-value(b) p-value(a) MASC Total Score Placebo _ Treatment LSMean Difference(95%CI) = 1.01(-2.39, 4.41) MASC Physical Symptoms Score Placebo _ Treatment LSMean Difference(95%CI) = 0.40(-0.97, 1.77) MASC Harm Avoidance Score Placebo _ Treatment LSMean Difference(95%CI) = -0.66(-1.91, 0.59) MASC Social Anxiety Score Placebo _ Treatment LSMean Difference(95%CI) = 1.37(-0.11, 2.86) MASC Separation Score Placebo _ Treatment LSMean Difference(95%CI) = -0.08(-1.12, 0.97) (continued) CT Registry ID# 2552 Page 21

22 Table 11. CDI, CDRS-R, MASC Change from Baseline to Endpoint All Randomized Patients Study Period III Visit Group II (Concluded) Within Between Variable / -- Baseline Endpoint Change Group Group Treatment Group N Mean SD Mean SD Mean SD LSMean(a) p-value(b) p-value(a) MASC Anxiety Disorders Index Placebo _ Treatment LSMean Difference(95%CI) = 0.86(-0.26, 1.99) CDI Total Score Placebo _ Treatment LSMean Difference(95%CI) = 0.37(-1.35, 2.09) CDRS Total Score Placebo _ Treatment LSMean Difference(95%CI) = 0.17(-1.43, 1.76) (a) LSMeans and Between Groups p-value are from ANOVA model with terms for Treatment and Investigator. (b) Within Groups p-values obtained from Wilcoxons Signed-rank Test for mean change from baseline to endpoint. Population: All randomized patients with at least one baseline and postbaseline measurement. Baseline visits: 1-22, Endpoint visits: Abbreviations: ANOVA = analysis of variance; CDI = Children s Depression Inventory; CI = confidence interval; LSMean = least-squares mean; MASC = Multidimensional Anxiety Scale for Children; N = number of patients; SD = standard deviation. CT Registry ID# 2552 Page 22

23 Table 12. WISC Change from Baseline to Endpoint All Randomized Patients Study Period III Visit Group II Within Between Variable / -- Baseline Endpoint Change Group Group Treatment Group N Mean SD Mean SD Mean SD LSMean(a) p-value(b) p-value(a) WISC Block Design Scaled Score Placebo _ Treatment LSMean Difference(95%CI) = -0.37(-1.24, 0.49) WISC IQ Placebo _ Treatment LSMean Difference(95%CI) = -3.41(-6.63, -0.19) WISC Pic Arrangement Scaled Score Placebo _ Treatment LSMean Difference(95%CI) = -0.22(-1.63, 1.19) WISC Similarities Scaled Score Placebo _ Treatment LSMean Difference(95%CI) = -0.36(-1.30, 0.59) WISC Vocabulary Scaled Score Placebo _ Treatment LSMean Difference(95%CI) = -0.77(-1.53, -0.00) (continued) CT Registry ID# 2552 Page 23

24 Table 12. WISC Change from Baseline to Endpoint All Randomized Patients Study Period III Visit Group II (Concluded) Within Between Variable / -- Baseline Endpoint Change Group Group Treatment Group N Mean SD Mean SD Mean SD LSMean(a) p-value(b) p-value(a) WISC Arithmetic Scaled Score Placebo _ Treatment LSMean Difference(95%CI) = 0.48(-0.49, 1.46) WISC Mazes Scaled Score Placebo _ Treatment LSMean Difference(95%CI) = -0.39(-1.77, 0.99) WISC Mazes Total Subset Score Placebo _ Treatment LSMean Difference(95%CI) = -0.81(-2.48, 0.86) WISC Digital Span (Total) Scaled Score Placebo _ Treatment LSMean Difference(95%CI) = -0.30(-1.29, 0.69) (a) LSMeans and Between Groups p-value are from ANOVA model with terms for Treatment and Investigator. (b) Within Groups p-values obtained from Wilcoxon Signed-rank Test for mean change from baseline to endpoint. Population: All randomized patient with at least one baseline and postbaseline measurement. Baseline visits: 1-22, Endpoint visits: Abbreviations: CI = confidence interval; LSMean = least-squares mean; N = number of patients; SD = standard deviation; WISC = Wechsler Intelligence scale. CT Registry ID# 2552 Page 24

25 Table 13. Cognitive Measurement DUAL-VWM, Stroop, Trails A, and Trails B Change from Baseline to Endpoint All Randomized Patients Study Period III Visit Group II Within Between Variable / -- Baseline Endpoint Change Group Group Treatment Group N Mean SD Mean SD Mean SD LSMean(a) p-value(b) p-value(a) Stroop CW test Interference T Score Placebo _ Treatment LSMean Difference(95%CI) = 0.23(-2.69, 3.15) Dual Working Memory Total Score Placebo _ Treatment LSMean Difference(95%CI) = -0.36(-1.06, 0.33) Trail Making Trials A Time Placebo _ Treatment LSMean Difference(95%CI) = 1.44(-1.13, 4.01) Trail Making Trials B Time Placebo _ Treatment LSMean Difference(95%CI) = -1.53(-7.51, 4.45) (a) LSMeans and Between Groups p-value are from ANOVA model with terms for Treatment and Investigator. (b) Within Groups p-values obtained from Wilcoxons Signed-rank Test for mean change from baseline to endpoint. Population: All randomized patient with at least one baseline and postbaseline measurement. Baseline visits: 1-22, Endpoint visits: Abbreviations: CI = confidence interval; CW = color-word; LSMean = least-squares mean; N = number of patients; SD = standard deviation. CT Registry ID# 2552 Page 25

26 Table 14. ADHDRS-IV-Parent:Inv and CGI-ADHD-S Change from Baseline to Endpoint Study Period IV Variable / -- Baseline Endpoint Change Group Group Treatment Group N Mean SD Mean SD Mean SD LSMean(a) p-value(b) p-value(a) ADHDRS-PI Total Score - No Tape Taper _ Treatment LSMean Difference(95%CI) = 2.92(-3.13, 8.97) ADHDRS-PI Total T-score - No Tape Taper _ Treatment LSMean Difference(95%CI) = 2.64(-3.56, 8.84) ADHDRS-PI Hyp/Imp Subscale - No Tape Taper _ Treatment LSMean Difference(95%CI) = 1.15(-1.79, 4.08) ADHDRS-PI Inatt. Subscale - No Tape Taper _ Treatment LSMean Difference(95%CI) = 1.77(-1.74, 5.28) CGI ADHD Severity - No Tape Taper _ Treatment LSMean Difference(95%CI) = 0.35(-0.29, 0.98) (a) LSMeans and Between Groups p-value are from ANOVA model with terms for Treatment and Investigator. (b) Within Groups p-values obtained from Wilcoxons Signed-rank Test for mean change from baseline to endpoint. Population: All randomized patients with at least one baseline and postbaseline measurement. Baseline visits: 1-28, Endpoint visits: Abbreviations: ADHD = Attention-Deficit/Hyperactivity disorder; ADHDRS-PI = Attention-Deficit/Hyperactivity Disorder Rating Scale; Inatt. = inattention; LSMean = least-squares mean; N = number of patients; SD = standard deviation. CT Registry ID# 2552 Page 26

27 Table 15. Summary of Relapse Rate Relapse per Protocol Randomized Patients Study Period IV Relapse ATX-No Taper ATX-Taper Total Fishers Exact N n(%) N n(%) N n(%) p-value Relapse 31 1(3.2%) 34 0(0%) 65 1(1.5%) Relapse per protocol definition within study Period IV Note: Relapse as defined by protocol. CT Registry ID# 2552 Page 27

28 CT Registry ID# 2552 Page 28 Safety Adverse Events Analysis per Protocol In Study Period III Visit Group II, 2 TEAEs had >5% incidence rate (headache [n=15, 9.4%] and nasopharyngitis [n=13, 8.1%]). There were no statistically significant differences between the treatment groups (see Table 16).

29 CT Registry ID# 2552 Page 29 Table 16. Summary of Treatment-Emergent Adverse Events ( 5%) by System Organ Class Using MedDRA Preferred Terms All Randomized Patients Study Period III Visit Group II TMX_TMX TMX_PLA Total p-value* (N=79) (N=81) (N=160) Preferred Term n (%) n (%) n (%) PATIENTS WITH >= 1 TESS 42 (53.2) 47 (58.0) 89 (55.6).633 PATIENTS WITH NO TESS 37 (46.8) 34 (42.0) 71 (44.4).633 Headache 8 (10.1) 7 (8.6) 15 (9.4).792 Nasopharyngitis 6 (7.6) 7 (8.6) 13 (8.1) 1.00 Population: ALL Randomized Patients in SPIII VG2 Baseline: Visit 22, Endpoint: Visits Abbreviations: N = number of patients; n = number of patients in subgroup; PLA = placebo; TESS = treatment-emergent signs and symptoms; TMX = tomoxetine. In Study Period IV, 1 class of TEAEs had more than a 5% incidence in either treatment group (mood swings: atomoxetine taper n=2 [5.9%]; atomoxetine nontaper n=0 [0.0%]) (see Table 17). Table 17. Summary of Treatment-Emergent Adverse Events ( 5%) by System Organ Class Using MedDRA Preferred Terms All Randomized Patients Study Period IV TMX_TAP TMX_NTAP Total p-value* (N=34) (N=31) (N=65) Preferred Term n (%) n (%) n (%) PATIENTS WITH >= 1 TESS 8 (23.5) 9 (29.0) 17 (26.2).778 PATIENTS WITH NO TESS 26 (76.5) 22 (71.0) 48 (73.8).778 Mood swings 2 (5.9) 0 2 (3.1) Population: Randomized Patients in Study Period IV Baseline: Visit 28, Endpoint: Visits Frequencies are analyzed using a Fisher s Exact test. Abbreviations: N = number of patients; n = number of patients in subgroup; NTAP = nontaper ; TAP = taper; TESS = treatment-emergent signs and symptoms; TMX = tomoxetine. A total of 7 SAEs were reported by 5 patients (placebo group) during Study Periods III and IV. Of these, 1 SAE was classified as possibly related to study drug. This patient experienced the SAE of incomplete RBBB, which began after 365 days of atomoxetine therapy; the patient was randomized to placebo group at Visit 22 after the onset of this SAE. The patient was discontinued from the study 9 days after Visit 22, 374 days after first receiving study drug. Fourteen days after the SAE was discovered at Visit 22 the patient recovered and an ECG confirmed the disappearance of the incomplete RBBB. See Table 18 for a listing of all patients who experienced an SAE.

30 CT Registry ID# 2552 Page 30 Table 18. Obs VISIT TRTP3VG1 TRTP3VG2 TRTSP4 Listing of Serious Adverse Events All Patients Visit 23 Through Visit 30 ACTTERM 1 23 TMX PLA INCOMPLETE RIGHT BUNDLE BRANCH BLOCK 2 28 PLA OPLA PLA INJURY IN ARM CAUSED BY DOG BITE 3 28 PLA OPLA PLA INFECTION IN LEFT ARM 4 28 PLA OPLA PLA MOTOR ACCIDENT 5 29 PLA OPLA PLA MOTOR ACCIDENT 6 24 PLA OPLA PLA SINOVITIS 7 23 TMX PLA DEPRESSIVE ILLNESS Obs SEREVNT STDRGRLX 1 Y YES 2 Y NO 3 Y NO 4 Y NO 5 Y NO 6 Y NO 7 Y NO trtp3vg1=treatment in SPIII VG1, actterm=actual event term, trtp3vg2=treatment in SPIII VG2, trtsp4=treatment in SP4, serevnt=event serious flag, stdrgrlx=possible related to drug flag Abbreviations: OPLA = ; PLA = placebo; SP = study period; TMX = tomoxetine; VG = visit group. Post Hoc Analysis of Hospitalization After Unblinding per FDA Request On 14 January 2005, the FDA asked Lilly to verify that study sites did not inappropriately hospitalize patients during the trial. In response, Lilly has thoroughly investigated the hospitalizations that occurred at any site during Study LYAF that were not previously reported as SAEs in the LYAF clinical study reports. Through this process, 5 hospitalizations for 5 patients were identified during Study Period III Visit Group II and Study Period IV. This study was conducted in Europe under several socialized medical systems. Hospitalizations are permitted in some countries and even encouraged for better observation of the patient by the investigator. Additionally, in some countries, hospitalizations also occur for a number of social reasons, such as the need for brief boarding of the patient, or to separate the patient from an undesirable family situation. Of the 5 hospitalizations identified in the post hoc review, 3 were considered observational, 1 was considered social, and 1 was categorized as an SAE. Hospitalizations Occurring in Study LYAF Table 19 presents a listing of all 5 hospitalizations that occurred during Study Period III Visit Group II and Study Period IV.