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

Transcription

1 CT Registry ID#8226 Page 1 Summary ID# Clinical Study Summary: Study B4Z-MC-LYCL Guiding Dose Increases in Patients Incompletely Responsive to Usual Doses of Atomoxetine by Determining Plasma Atomoxetine Concentrations: A Randomized, Double-Blind Study Date summary approved by Lilly: 29 March 2006

2 CT Registry ID#8226 Page 2 Brief Summary of Results Study B4Z-MC-LYCL (LYCL) was a multicenter, double-blind, randomized trial of increased-dose versus continued same-dose atomoxetine in patients who failed to respond optimally to an initial course of atomoxetine at usual doses and whose plasmaatomoxetine levels were below a specified threshold. The primary objective of this study was to test the hypothesis that patients treated with atomoxetine hydrochloride (hereafter referred to as atomoxetine) at doses of approximately 1.2 mg/kg/day as a single daily dose who have suboptimal clinical responses and peak plasma-atomoxetine levels no higher than 800 ng/ml would benefit from a dose increase to approximately 2.4 mg/kg/day compared to patients continued on a dose of approximately 1.2 mg/kg/day. It was found that: There was no statistically significant difference in symptom improvement between the randomized higher-dose and target-dose groups in the primary efficacy analysis of the Attention Deficit/Hyperactivity Disorder Rating Scale-IV- Parent Version:Investigator Administered and Scored (ADHDRS-IV-Parent:Inv). Secondary efficacy measures demonstrated that: There was no statistically significant difference in symptom improvement in the higher-dose group compared with the target-dose group on the ADHDRS-IV- Parent:Inv subscales and Clinical Global Impressions Attention- Deficit/Hyperactivity Disorder Severity scale (CGI-ADHD-S). Patients who had peak plasma levels that were 800 ng/ml after acute, open-label treatment were statistically significantly more likely to meet the response criterion than patients with peak plasma levels 800 ng/ml. There were no statistically significant differences between the randomized higherand lower-dose groups with respect to treatment-emergent adverse events (TEAEs) and mean changes in vital signs, weight, or electrocardiogram (ECG) values during double-blind treatment. Mean concentrations of atomoxetine for extensive metabolizer (EM) patients increased with increases in dose.

3 CT Registry ID#8226 Page 3 Title of Study: Clinical Study Synopsis: Guiding Dose Increases in Patients Incompletely Responsive to Usual Doses of Atomoxetine by Determining Plasma Atomoxetine Concentrations: A Randomized, Double-Blind Study Investigator(s): This multicenter study included 18 principal investigators. Study Center(s): This study was conducted at 18 study centers in the United States and Canada. Length of Study: 23 months Phase of Development: 4 Date first patient enrolled: 29 July 2003 Date last patient completed: 15 June 2005 Objectives: The primary objective of this study was to test the hypothesis that patients treated with atomoxetine at doses of approximately 1.2 mg/kg/day as a single daily dose who have suboptimal clinical responses and peak plasma-atomoxetine levels no higher than 800 ng/ml would benefit from a dose increase to approximately 2.4 mg/kg/day compared to patients continued on a dose of approximately 1.2 mg/kg/day. This objective was assessed by mean reduction in the total score of the Attention Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version:Investigator Administered and Scored (ADHDRS-IV-Parent:Inv). The secondary objectives of the study are as follows: to assess the relationship between plasma-atomoxetine concentration levels and Attention- Deficit/Hyperactivity Disorder (ADHD) symptom response, as measured by the ADHDRS-IV- Parent:Inv Total Score to compare the efficacy of atomoxetine given at a dose of up to 2.4 mg/kg/day with atomoxetine given at a dose of 1.2 mg/kg/day in reducing residual ADHD symptoms, as measured by the mean change in ratings on the Clinical Global Impressions Attention-Deficit/Hyperactivity Disorder Severity scale (CGI-ADHD-S) to assess the safety and tolerability of atomoxetine at doses up to 2.4 mg/kg/day compared to the standard dose of 1.2 mg/kg/day in patients with peak plasma-atomoxetine concentration levels no higher than 800 ng/ml at usual doses, as assessed by adverse events (AEs) elicited during open-ended questioning. Study Design: Study B4Z-MC-LYCL (LYCL) was a multicenter, double-blind, randomized study of increased-dose versus continued same-dose atomoxetine in patients who failed to respond optimally to an initial course of atomoxetine at usual doses and whose plasma-atomoxetine levels were below a specified threshold (see Figure LYCL.1). Study Period I was a 3- to 28-day screening and medication washout period. During Study Period II, approximately 6 weeks, patients received open-label treatment with atomoxetine titrated up to a target dose of approximately 1.2 mg/kg/day, after which response and plasmaatomoxetine levels were measured. During Study Period III, approximately 4 weeks, patients with plasmaatomoxetine concentration levels no higher than 800 ng/ml who failed to achieve adequate ADHD symptom reduction were randomized to continued treatment with either atomoxetine at a dosage of approximately 1.2 mg/kg/day (target-dose group) or atomoxetine increased to approximately 1.8 to 2.4 mg/kg/day (higher-dose group). Patients (nonrandomized responders) who achieved adequate ADHD symptom reduction during Study Period II continued to receive atomoxetine at a dosage of approximately 1.2 mg/kg/day. Nonresponders who had peak plasma-atomoxetine concentrations >800 ng/ml completed the study at Visit 4 after approximately 6 weeks. An addendum to the protocol provided an optional, openlabel treatment extension (Study Period IV) for patients enrolled in the study at Canadian sites. This extension permitted Canadian patients to continue receiving open-label treatment until atomoxetine became commercially available in Canada.

4 CT Registry ID#8226 Page 4 Number of Patients: Planned: 350 patients to be entered, 300 patients to be enrolled, and 120 patients to be randomized. Study Period I (Screening): 418 entered, 378 completed (40 screen failures). Study Period II (Open-Label): 378 patients enrolled (292 completed). Study Period III (Double-Blind): Randomized Higher-Dose Group: 63 (57 completed). Randomized Target-Dose Group: 62 (54 completed). Nonrandomized US Responders: 99 (93 completed). Nonrandomized Canadian Patients* (Nonresponders and Responders): 62 (58 completed) Study Period IV (Open-Label, Canadian Extension): 65 (n=44 completed) *Patients at sites in the US and Canada were to be randomized to treatment using an Interactive Voice Response System (IVRS). Due to a process error, none of the Canadian patients were randomized. Nonrandomized Canadian Patients, whether nonresponders or responders, continued at their Study Period II dose. Diagnosis and Main Criteria for Inclusion: Patients were males or females aged 6 through 16 years at Visit 1. For inclusion, patients had to have met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criterion for ADHD and scored at least 1.5 standard deviations above the age and gender norm at both Visits 1 and 2 for their diagnostic subtype using published norms (DuPaul et al. 1998) for the ADHDRS-IV-Parent:Inv. Patients must have had an electrocardiogram (ECG) performed at Visit 1. Test Product, Dose, and Mode of Administration: Open-Label: Atomoxetine, titrated to a target dose of approximately 1.2 mg/kg/day given orally once daily using 2.5-, 5-, 10-, 25-, and 40-mg capsules. Double-Blind: Randomized Higher-Dose Group: Atomoxetine, at a dose of approximately 1.8 mg/kg/day or, if significant residual ADHD symptoms remained, a maximum dose of approximately 2.4 mg/kg/day, given orally once or twice daily using 2.5-, 5-, 10-, 20-, 25-, and 40-mg capsules. Randomized Target-Dose Group: Atomoxetine, at a target dose of approximately 1.2 mg/kg/day or, if the dose was not tolerated, a dose of approximately 0.8 mg/kg/day, given orally once or twice daily using 2.5-, 5-, 10-, 20-, 25-, and 40-mg capsules. Nonrandomized Responders: Atomoxetine, at approximately 1.2 mg/kg/day, given orally once or twice daily using 2.5-, 5-, 10-, 20-, 25-, and 40-mg capsules. Open-Label Canadian Extension: Atomoxetine, at a dose of approximately 0.8 to 1.8 mg/kg/day, given orally once or twice daily using 2.5-, 5-, 10-, 25-, and 40-mg capsules. Duration of Treatment: Open-Label: Approximately 6 weeks. Double-Blind: Approximately 4 weeks. Open-Label Canadian Extension: Up to approximately 23 months. Variables: Efficacy: Variables included the total score of the 18-item ADHDRS-IV-Parent:Inv and its subscale scores (Inattention and Hyperactivity-Impulsivity), and the secondary measure of CGI-ADHD-S. Safety: AEs, vital signs, weight, laboratory tests, and ECGs. Pharmacokinetic: Plasma concentrations of atomoxetine were determined from single blood samples obtained at Visit 3 and at the end of Study Period III (Visit 5 or Visit 6).

5 CT Registry ID#8226 Page 5 Evaluation Methods: Statistical: During open-label treatment, summary statistics (sample size, mean, standard deviation, minimum, median, maximum scores, and percentages) were computed for efficacy and safety variables. Within-treatment-group changes were assessed using Wilcoxon s signed-rank test. The primary efficacy analysis used analysis of covariance (ANCOVA), with terms for baseline ADHDRS-IV-Parent:Inv Total score, treatment, and investigator included in the model. Baseline was defined as the last measurement obtained on or prior to Visit 4, and endpoint as the last measurement obtained after Visit 4 but on or before Visit 6. The last-observation-carried-forward (LOCF) approach was used to handle missing observations. Changes from baseline to endpoint for vital signs, continuous laboratory values, and ECG parameters were summarized by treatment group, and treatment differences for randomized patients were assessed with analysis of variance (ANOVA) on the ranked data. Categorical safety variables were analyzed by Fisher s exact test. Patients were assigned to treatment based on ADHD symptom response; the definition of response was detailed in a separate document provided to Institutional Review Boards (IRBs). Throughout the study, investigators and patients remained blinded to this information. Following open-label treatment, incomplete response (nonresponder) was defined as an ADHDRS-IV-Parent:Inv total T-score at Visit 4 at least one standard deviation (SD) above age and gender norms, a value indicating the continuing presence of greater ADHD symptoms than in the normal population. Pharmacokinetic: Observed plasma concentration data were summarized using a descriptive analysis, and were displayed graphically. No formal pharmacokinetic analysis was performed; however, there were subgroup analyses based on genotype, responder status, and categorical plasma levels ( 800 ng/ml versus >800 ng/ml). Results: Patient Demographics Patients who enrolled in the open-label phase of Study LYCL were predominately Caucasian (81.1%), male (73.9%), with a mean age of 10.9 (SD=2.5; range 6.0 to 16.8 years), and with the Combined ADHD subtype (65.7%). The majority (92.8%) had the extensive metabolizer (EM) genotype for cytochrome P450 2D6 (CYP2D6). During double-blind treatment, the randomized treatment groups were not statistically significantly different with respect to racial origin, sex, age, ADHD subtype, CYP2D6 genotype, and all other characteristics that were measured. Patient Disposition A total of 378 patients were enrolled in the approximately 6-week, acute, open-label phase of this study. Two hundred ninety-two patients (77.2%) completed the open-label phase and were enrolled into the double-blind treatment phase. Among the most frequent reasons for discontinuation during open-label treatment were AE (22; 5.8%), lack of efficacy (19; 5.0%), entry criteria for Study Period III not met (15; 4.0%), and lost to follow-up (14; 3.7%). Thirteen out of the 15 patients who did not meet entry criteria for Study Period III were discontinued from the study at Visit 4 due to the combination of a plasma concentration level greater than 800 ng/ml and a failure to meet the blinded response criteria.

6 CT Registry ID#8226 Page 6 Of the 292 patients who continued into the double-blind treatment phase, 125 met the criteria for randomization (plasma concentration levels 800 ng/ml and inadequate ADHD symptom reduction) and were randomized to receive either higher-dose atomoxetine (n=63) or continue with target-dose atomoxetine (n=62). Six of the randomized higher-dose patients and 8 of the randomized target-dose patients discontinued during double-blind treatment. Three patients in the target-dose group discontinued due to personal conflict and all other categories for both higher- and targetdose patients were not experienced by more than 2 patients. When reasons for study discontinuation were compared for these two randomized groups, there were no statistically significant differences. A total of 161 patients were not randomized, 99 US patients who met the criteria for response and 62 Canadian patients (responders and nonresponders [inadvertently not randomized due to an IVRS programming error]). Study completion rates were high for the double-blind treatment phase, as follows: randomized higher-dose group (90.5%), randomized target-dose group (87.1%), nonrandomized US responders (93.9%), and nonrandomized Canadian patients group (93.5%). Sixty-five Canadian patients were enrolled in the open-label Canadian extension (Study Period IV). Six of these patients were patients who skipped directly from open-label treatment (Study Period II). Forty-four Canadian patients completed this study period (67.7%). See Figure LYCL.1 for the study disposition.

7 CT Registry ID#8226 Page 7 Study Period I Entered N=418 Study Period II Open-Label ATX Enrolled n=378 Screening Failures N=40 Reason: Entry criteria not met (26) Patient/caregiver decision (5) Unable to contact (5) Other (4) Discontinued n=86 Reason: Adverse event (22) Lack of efficacy (19) Other a (45) Completed Study Period II n=292 (77.2%) Study Period III Double-Blind Treatment Entered n=292 Canadian Patients Permitted to Skip to Study Period IV n=6 b Nonrandomized Group n=161 Randomized Group n=125 Canadian Patients (Responders/Nonresponders) c n=62 US Patients (Responders) n=99 Randomized Higher Dose ATX ( mg/kg/day) n=63 Randomized Target Dose ATX (1.2 mg/kg/day) n=62 Discontinued n=4 Reason: Adverse event (1) Protocol viol (2) d Lack of efficacy (1) Discontinued n=6 Reason: Adverse event (4) Personal conflict (1) Unable to contact (1) Discontinued n=6 Reason: Adverse event (1) Protocol viol (2) Lack of efficacy (1) Lost to follow-up (1) Phys decision (1) Discontinued n=8 Reason: Patient moved (1) Protocol viol (2) Lack of efficacy (1) Unable to contact (1) Personal conflict (3) Completed n=58 (93.5%) Completed n=93 (93.9%) Completed n=57 (90.5%) Completed n=54 (87.1%) Discontinued After Completing n=1 Study Period IV Open-Label Canadian Extension Enrolled n=65 Discontinued n=21 Completed Reason: n=44 (67.7%) Adverse event (8) Lack of efficacy (5) Personal conflict (2) Physician/Sponsor decision (2) Lost to follow-up (4) Abbreviations and footnotes appear on next page. Figure LYCL.1. Study disposition.

8 CT Registry ID#8226 Page 8 Abbreviations: ATX = atomoxetine; n = number of patients; phys = physician; protocol viol = protocol violation. a The term other includes reasons for discontinuation, such as: physician decision, unable to contact/loss to follow-up, personal conflict, or other patient/caregiver decisions. b At the end of Study Period II, 6 Canadian patients who met criteria in an addendum to the protocol were permitted to skip Study Period III and enroll in Study Period IV. c Due to a process error, Canadian patients were not randomized; all (responders or nonresponders) continued to receive atomoxetine 1.2 mg/kg/day during Study Period III. d Two Canadian patients were coded as having discontinued Study Period III due to a "protocol violation". These patients completed Study Period III at Visit 5, instead of Visit 6 (the protocol-defined last visit in Study Period III), then enrolled in the open-label Canadian extension. Figure LYCL.1. Study disposition (concluded). Primary Efficacy Endpoint The primary objective of this study was to test the hypothesis that patients with inadequate clinical response and peak plasma-atomoxetine levels 800 ng/ml treated with atomoxetine 1.2 mg/kg/day would benefit from an increased atomoxetine dose up to 2.4 mg/kg/day (higher-dose group) compared with patients who continued receiving atomoxetine 1.2 mg/kg/day (target-dose group). This hypothesis was not met, as the analysis did not demonstrate a statistically significant difference between treatment groups (higher-dose versus target-dose). Despite the randomization error that occurred in this study, the primary analysis was adequately powered (82%; 2-sided, 0.05 level) to detect a treatment difference of 6 points on the primary efficacy analysis. Table LYCL.1 summarizes the primary efficacy analysis of the ADHDRS-IV-Parent:Inv total score. Table LYCL.1. Primary Efficacy Analysis of the ADHDRS-IV-Parent:Inv Total Score Treatment Group n Baseline Mean (SD) Endpoint Mean (SD) Change p-value Target-Dose Group (9.17) (11.94) Higher-Dose Group (8.22) (11.00) Abbreviations: n = number of patients; SD = standard deviation. Secondary Efficacy Endpoints The secondary objectives of the study were as follows: to assess the relationship between plasma-atomoxetine concentration levels and ADHD symptom response, as measured by the ADHDRS-IV- Parent:Inv Total Score.

9 CT Registry ID#8226 Page 9 to compare the efficacy of atomoxetine given at a dose of up to 2.4 mg/kg/day with atomoxetine 1.2 mg/kg/day in reducing residual ADHD symptoms, as measured by the mean change in ratings on the Clinical Global Impressions Attention-Deficit/Hyperactivity Disorder Severity scale (CGI-ADHD-S). to assess the safety and tolerability of atomoxetine at doses up to 2.4 mg/kg/day compared to a standard dose of 1.2 mg/kg/day in patients with peak plasma-atomoxetine concentration levels no higher than 800 ng/ml at usual doses, as assessed by AEs elicited during open-ended questioning. Table LYCL.2 summarizes the analysis for mean change from baseline to endpoint during open-label treatment for the ADHDRS-IV-Parent:Inv total and subscales and the CGI-ADHD-S score. A statistically significant within-treatment-group reduction (improvement) in mean scores was demonstrated for each scale. Table LYCL.2. Mean Change from Baseline to Endpoint Open-Label Treatment ADHDRS-IV-Parent:Inv and CGI-ADHD-S Scores na Baseline Mean (SD) Endpoint Mean (SD) Change Within-Group p-value ADHDRS Total Score (8.92) (12.14) <.001 ADHDRS Total T-Score (10.34) (12.64) <.001 ADHDRS Hyp/Imp Subscale (6.96) (7.02) <.001 ADHDRS Inatt. Subscale (3.95) (6.42) <.001 CGI-ADHD-S Score (0.79) 3.59 (1.12) <.001 Abbreviations: ADHDRS-IV-Parent:Inv = Attention Deficit/Hyperactivity Disorder Rating Scale-IV- Parent Version:Investigator Administered and Scored; CGI-ADHD-S = Clinical Global Impressions Attention-Deficit/Hyperactivity Disorder Severity; Hyp/Imp = hyperactivity/impulsivity; Inatt = inattention; n = number of patients; SD = standard deviation. a Randomized patients with a baseline and a postbaseline visit. During open-label treatment, patients had blood drawn to determine their peak plasmaatomoxetine concentrations at Visit 3. The percentage of patients who met the ADHD symptom-response criterion (ADHDRS-IV-Parent:Inv total T-score at least one standard deviation above age and gender norms) was computed by plasma-atomoxetine concentration level ( 800 or >800 ng/ml) and is shown in Table LYCL 3. Patients who had peak plasma levels that were >800 ng/ml after acute, open-label treatment were statistically significantly associated with response than patients with peak plasma levels 800 ng/ml.

10 CT Registry ID#8226 Page 10 Table LYCL.3. Response Rates Response n (%) ATX 800 ng/ml ATX >800 ng/ml Yes 132 (40.0%) 109 (37.3%) 23 (60.5%) No 198 (60.0%) 183 (62.7%) 15 (39.5%) Abbreviations: ATX = atomoxetine; n = number of patients. In the open-label treatment phase, peak plasma-atomoxetine concentration values were correlated with change in the ADHDRS-IV-Parent:Inv total T-score. The Pearson correlation coefficient (r = -0.12; p=.027) demonstrated a statistically significant negative correlation between these values (plasma concentration and change score). Table LYCL.4 summarizes the analysis of mean change from baseline to endpoint during double-blind treatment. There were no statistically significant differences between randomized treatment groups on mean ADHDRS-IV-Parent:Inv total T-score and subscale scores and CGI-ADHD-S score. Table LYCL.4. Mean Change from Baseline to Endpoint Scales n Baseline Mean (SD) Endpoint Mean (SD) Change Between Group- Value ADHDRS Hyp/Imp Subscale Higher-Dose Group (6.01) (6.57) Target-Dose Group (6.63) (7.22) ADHDRS Inatt. Subscale Higher-Dose Group (4.46) (6.05) Target-Dose Group (4.82) (6.48) ADHDRS Total T-Score Higher-Dose Group (8.56) (12.31) Target-Dose Group (9.42) (13.86) CGI-ADHD-Severity Higher-Dose Group (0.81) 3.34 (1.19) Target-Dose Group (0.92) 3.66 (1.13) Abbreviations: ADHDRS = Attention Deficit/Hyperactivity Disorder Rating Scale; CGI-ADHD- S = Clinical Global Impressions Attention-Deficit/Hyperactivity Disorder Severity; Hyp/Imp = hyperactivity/impulsivity; Inatt = inattention; n = number of patients; SD = standard deviation. During double-blind treatment, blood was drawn at Visit 6 to determine the peak plasmaatomoxetine concentration level. The Pearson correlation coefficient for the randomized target- and higher-dose groups (r = 0.04 and r = -0.10, respectively) demonstrated no statistically significant correlation between these values (plasma concentration and change score).

11 CT Registry ID#8226 Page 11 Safety The mean final prescribed dose during double-blind treatment was 1.13 mg/kg in the randomized target-dose group and 2.10 mg/kg in the randomized higher-dose group. Adverse Events One of the objectives of the study was to assess the safety and tolerability of atomoxetine by comparing AEs in the randomized higher-dose group with those in the randomized target-dose group. There were no deaths during this study. One patient reported the serious adverse event (SAE) of gastroenteritis viral during open-label treatment, determined by the investigator to be unrelated to study drug. One patient reported the SAE of hepatitis during the open-label Canadian extension, which was considered possibly related to study drug by the investigator. Table LYCL.5 through Table LYCL.9 summarize the reasons for discontinuations by study period. A total of 36 patients who took at least one dose of study drug discontinued due to an AE during the study. By study period, discontinuation due to AE included: 5.9% (22 out of 376) of patients during open-label treatment; 0.8% (1 out of 125) of randomized and 3.1% (5 out of 161) of nonrandomized patients during double-blind treatment (Tables LYCL 7 and 8 combined); and 12.3% (8 out of 65) of patients during the open-label Canadian extension. Table LYCL.5. Summary of Discontinuations Open-Label Treatment TMX (N=376) Preferred Term n (%) PATIENTS DISCONTINUED 22 (5.9) Nausea 4 (1.1) Abdominal pain upper 2 (0.5) Dysgeusia 2 (0.5) Somnolence 2 (0.5) Vomiting 2 (0.5) Abdominal pain 1 (0.3) Alopecia 1 (0.3) Dyspnoea 1 (0.3) Fatigue 1 (0.3) Gastroenteritis viral 1 (0.3) Irritability 1 (0.3) Orthostatic hypotension 1 (0.3) Palpitations 1 (0.3) Suicidal ideation 1 (0.3) Tachycardia 1 (0.3) Abbreviations: TMX = atomoxetine; n = number of patients.

12 CT Registry ID#8226 Page 12 Table LYCL.6. Summary of Discontinuations Randomized Population TMX1_2 TMX1_82 Total p-value* (N=62) (N=63) (N=125) Preferred Term n (%) n (%) n (%) PATIENTS DISCONTINUED 0 1 (1.6) 1 (0.8) 1.00 Accidental overdose 0 1 (1.6) 1 (0.8) Abbreviations: TMX1_2 = atomoxetine lower dose group; TMX1_82 = atomoxetine higher dose group. Table LYCL.7. Summary of Discontinuations Nonrandomized US Population RESTX1.2 (N = 99) Primary Reason for Discontinuation n ( % ) Adverse Event 4( 4.0) Personal conflict or other patient/caregiver decision 1( 1.0) Protocol completed 93(93.9) Unable to contact patient/caregiver 1( 1.0) Abbreviations: RESTX1.2 = atomoxetine. Table LYCL.8. Reason for Discont.: Adverse event RESTX1_2 (N=62) Preferred Term n (%) PATIENTS DISCONTINUED 1 (1.6) Anger 1 (1.6) Abbreviations: RESTX1_2 = atomoxetine. Summary of Discontinuations Nonrandomized Canadian Population Table LYCL.9. Summary of Discontinuations Open-Label Canadian Extension RESTX1_2 Primary Reason for Discontinuation (N = 65) Adv. evt. 8(12.3) Lack of efficacy, pat/cargivr & phys per 2( 3.1) Lack of efficacy, patient/caregiver perc 3( 4.6) Personal conflict or other pat/carg dec 2( 3.1) Physician decision 1( 1.5) Protocol completed 44(67.7) Sponsor's decision 1( 1.5) Unable to contact patient/caregiver 4( 6.2) Abbreviations: RESTX1-2 = atomoxetine.

13 CT Registry ID#8226 Page 13 Treatment-emergent adverse events (TEAEs) were summarized by study period and treatment group. Table LYCL.10 summarizes TEAEs by study period using MedDRA 7.0 and 8.0 preferred terms. During open-label treatment, the most commonly reported TEAEs (>10%) were fatigue (17.0%), decreased appetite (15.4%), nausea (15.2%), somnolence (12.2%), and headache (11.2%). The most commonly reported TEAE in the randomized higher-dose group was vomiting (9.5%); in the randomized target-dose group, it was headache (9.7%). Overall, there was a statistically higher proportion of TEAEs in the higher-dose group (41.3%) than in the target-dose group (22.6%; p=.035). Among nonrandomized US responders, the most common TEAE reported was vomiting (4.0%); in nonrandomized Canadian patients, it was headache (6.5%). During the open-label Canadian extension, the most commonly reported TEAEs reported were headache (21.5%), fatigue (18.5%), nausea (18.5%), vomiting (16.9%), and decreased appetite (13.8%).

14 CT Registry ID#8226 Page 14 Table LYCL.10. Treatment-Emergent Adverse Events with Greater than 4% Incidence Preferred Term n (%) Open-Label treatment Fatigue 64 (17.0%) Decreased appetite 58 (15.4%) Nausea 57 (15.2%) Somnolence 46 (12.2%) Headache 42 (11.2%) Abdominal pain upper 32 (8.5%) Vomiting 31 (8.2%) Dizziness 20 (5.3%) Pyrexia 16 (4.3%) Upper respiratory tract 15 (4.0%) infection Randomized Treatment Higher-Dose Group Vomiting 6 (9.5%) Headache 3 (4.8%) Abdominal pain upper 3 (4.8%) Nausea 3 (4.8%) Upper respiratory tract 3 (4.8%) infection Somnolence 3 (4.8%) Cough 3 (4.8%) Target-Dose Group Headache 6 (9.7%) Abdominal pain upper 3 (4.8%) Nonrandomized US responders Vomiting 4 (4.0%) Nonrandomized Canadian patients Headache 4 (6.5%) Abdominal pain 3 (4.8%) Decreased appetite 3 (4.8%) Canadian patients in openlabel extension Headache 14 (21.5%) Fatigue 12 (18.5%) Nausea 12 (18.5%) Vomiting 11 (16.9%) Decreased appetite 9 (13.8%) Abdominal pain 7 (10.8%) Pharyngolaryngeal pain 7 (10.8%)

15 CT Registry ID#8226 Page 15 Table LYCL.10. Treatment-Emergent Adverse Events with Greater than 4% Incidence (concluded) Preferred Term n (%) Nasopharyngitis 6 (9.2%) Upper respiratory tract 6 (9.2%) infection Irritability 6 (9.2%) Anxiety 5 (7.7%) Insomnia 5 (7.7%) Pyrexia 4 (6.2%) Dizziness 4 (6.2%) Varicella 4 (6.2%) Emotional disorder 4 (6.2%) Sinusitis 3 (4.6%) Somnolence 3 (4.6%) Depressed mood 3 (4.6%) Cough 3 (4.6%)

16 CT Registry ID#8226 Page 16 Laboratory Values, Vital Signs and ECGs Frequencies of abnormal laboratory values were compared for the randomized treatment groups (high- vs target-dose) during double-blind treatment, and one analyte was statistically significantly different. A statistically significantly greater percentage of patients in the randomized higher-dose group had an abnormal low cholesterol value at endpoint compared with patients in the randomized target-dose group (10.3% [6 out of 58] versus 0% [0 out of 49], respectively; p=.030). Table LYCL.11 presents the frequency of patients with abnormal lab values for randomized patients.

17 CT Registry ID#8226 Page 17 Table LYCL.11. Frequency of Patients with Abnormal Lab Values after Baseline Randomized Population - p-value * - TMX1_2 (1) TMX1_82(2) Incidence (Total=62) (Total=63) Group N n (%) N n (%) Overall Lab Test: CHOLESTEROL LOW (10.3).030 HIGH 43 1 (2.3) 58 4 (6.9).391 Abbreviations: TMX1_2 = atomoxetine lower dose group; TMX1_82 = atomoxetine higher dose group. Mean change from baseline to endpoint and categorical change was assessed for vital signs and weight. During open-label treatment, there were statistically significant withintreatment-group differences. There was a mean decrease in weight, 0.76 kg. Categorical changes most commonly noted (>3%) included diastolic (5.3%; 19 out of 357) and systolic blood pressure increase (3.7%; 13 out of 355) and weight decrease (26.6%, 97 out of 364). Table LYCL.12 summarizes the categorical changes in vital signs and weight for the open-label population. Table LYCL.12. Categorical Changes in Vital Signs and Weight at Endpoint Open-Label Population Abnormal Vitals Atomoxetine 1.2 N n % Vital Direction* Diastolic Blood High Pressure % Pulse High % Low % Systolic Blood High Pressure % Temperature (C) High % Low % Weight (kg) Decrease % *Criteria: Pulse - High:Increase of at least 25 to a value of at least 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 Low: Decrease of at least 1.3 to a value of at most 35.6 Weight - Decrease of at least 3.5% Blood Pressure - High:Increase of at least 5 mm to above 95% percentile During double-blind treatment, there were no statistically significant differences between treatment groups in mean change from baseline to endpoint or categorical changes for vital signs or weight. Categorical changes noted in at least 5% of patients included weight decrease (target-dose: 5.2%, 3 out of 58; higher-dose: 11.3%, 7 out of 62). The

18 CT Registry ID#8226 Page 18 mean change in weight was less than 1 kg for either randomized treatment group. Table LYCL.13 summarizes the categorical changes in vital signs and weight at endpoint for the randomized population. Table LYCL.13. Categorical Changes in Vital Signs and Weight at Endpoint Randomized Population Abnormal Vitals Atomoxetine 1.8- Fisher's Atomoxetine Exact N n % N n % P-value Vital Direction* Diastolic Blood High Pressure % % Pulse High % % n/a Low % % n/a Systolic Blood High Pressure % % Temperature (C) High % % n/a Low % % n/a Weight (kg) Decrease % % *Criteria: Pulse - High:Increase of at least 25 to a value of at least 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 Low: Decrease of at least 1.3 to a value of at most 35.6 Weight - Decrease of at least 3.5% Blood Pressure - High:Increase of at least 5 mm to above 95% percentile Abbreviations: TMX1_2 = atomoxetine lower dose group; TMX1_82 = atomoxetine higher dose group. Categorical changes noted in at least 5% of patients included diastolic blood pressure increase (5.6%, 5 out of 90) and weight decrease (6.1%; 6 out of 98) in nonrandomized US nonresponders, and diastolic increase (5.4%; 3 out of 56) and weight decrease (12.9%; 8 out of 62) in nonrandomized Canadian responders and nonresponders. Mean change in weight was less than 1 kg in either group. Tables LYCL.14 and 15 present the categorical changes in vital signs and weight for the nonrandomized US and Canadian populations.

19 CT Registry ID#8226 Page 19 Table LYCL.14. Categorical Changes in Vital Signs and Weight at Endpoint Nonrandomized US Population Abnormal Vitals Atomoxetine Responders N n % Vital Direction* Diastolic Blood High Pressure % Pulse High % Low % Systolic Blood High Pressure % Temperature (C) High % Low % Weight (kg) Decrease % *Criteria: Pulse - High:Increase of at least 25 to a value of at least 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 Low: Decrease of at least 1.3 to a value of at most 35.6 Weight - Decrease of at least 3.5% Blood Pressure - High:Increase of at least 5 mm to above 95% percentile Table LYCL.15. Categorical Changes in Vital Signs and Weight at Endpoint Nonrandomized Canadian Population Abnormal Vitals Atomoxetine Responders N n % Vital Direction* Diastolic Blood High Pressure % Pulse High % Low % Systolic Blood High Pressure % Temperature (C) High % Low % Weight (kg) Decrease % *Criteria: Pulse - High:Increase of at least 25 to a value of at least 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 Low: Decrease of at least 1.3 to a value of at most 35.6 Weight - Decrease of at least 3.5% Blood Pressure - High:Increase of at least 5 mm to above 95% percentile

20 CT Registry ID#8226 Page 20 During the open-label Canadian extension, 4 patients met the categorical criterion for a decrease in weight. However, the mean change in weight from baseline to endpoint was a weight increase of 3.19 kg. Table LYCL.16 presents the categorical changes in vital signs and weight for the open-label Canadian extension. Table LYCL.16. Categorical Changes in Vital Signs and Weight at Endpoint Open-Label Canadian Extension Abnormal Vitals TMX_OLEX N n % Vital Direction* Diastolic BP High % PULSE High % Low % Systolic BP High % Temperature (C) High % Low % Weight (kg) Decrease % *Criteria: Pulse - High:Increase of at least 25 to a value of at least 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 Low: Decrease of at least 1.3 to a value of at most 35.6 Weight - Decrease of at least 3.5% Blood Pressure - High:Increase of at least 5 mm to above 95% percentile Abbreviations: TMX_OLEX = atomoxetine responders. Mean change in ECG intervals from baseline to endpoint were summarized by study period and analysis group. A categorical analysis of changes in QT intervals was also conducted using the Committee for Proprietary Medicinal Products (CPMP) criteria for potentially clinically significant changes in corrected QT intervals following baseline. During double-blind treatment, there were no statistically significant differences in the proportion of patients who met the CPMP criteria between the randomized treatment groups. Pharmacokinetic Outcomes Blood samples for determination of atomoxetine in plasma were to be drawn 1.0 to 1.5 hours (h) post dose, both at Visit 3 and at the end of Study Period III (Visit 6). At Visit 3, the targeted daily dose was 1.2 mg/kg for all patients. Based upon their Visit 3 plasma concentration results and ADHD symptom reduction, patients were assigned to treatment groups for Study Period III. Patients with adequate ADHD symptom reduction (responders) continued on approximately 1.2 mg/kg/day of atomoxetine into Study Period III. Patients who had peak plasma-atomoxetine concentrations >800 ng/ml and did not achieve adequate ADHD symptom reduction completed the study at Visit 4.

21 CT Registry ID#8226 Page 21 Patients with plasma-atomoxetine concentrations 800 ng/ml who failed to achieve adequate ADHD symptom reduction (nonresponders) were randomized in a double-blind 1:1 ratio to either remain at their current dose of atomoxetine (target 1.2 mg/kg/day) or be increased up to approximately 1.8 mg/kg/day at Visit 4 and then to approximately 2.4 mg/kg/day at Visit 5 if still symptomatic. Patients were then categorized as responder or nonresponder at the end of Study Period III (Visit 5 or 6). At Visit 3, 87% of patients (256/294) had concentrations 800 ng/ml. Of the patients with concentrations 800 ng/ml, 39% (99/256) achieved adequate ADHD symptom reduction while 55% (21/38) of patients having concentrations >800 ng/ml were categorized as having adequate ADHD symptom reduction. Concentrations from CYP2D6 poor metabolizer (PM) patients were generally higher than those from CYP2D6 extensive metabolizer (EM) patients. While 88% (29/33) of all concentrations for PM patients were >800 ng/ml, only 9% (40/440) of EM patients concentrations were >800 ng/ml. At Visit 3, 57% of PM patients were responders, and these observations comprised about 10% of the responder group. At Study Period 3, all PM patients were responders and were receiving 1.2 mg/kg/day; their observations comprised about 14% of the 1.2 mg/kg/day responder group. Mean concentrations for the 1.8 to 2.4 mg/kg/day groups (only EM patients) increased when compared to the mean concentrations for EM patients taking 1.2 mg/kg/day. References DuPaul GJ, Power TJ, Anastopoulos AD, Reid R (1998), ADHD Rating Scale-IV: checklists, norms, and clinical interpretations. New Your: The Guilford Press.