CT Registry ID#6934 Page 1 Summary ID# 6934 Clinical Study Summary: Study B4Z-MC-LYBR Title of Study: A Randomized, Double-Blind Comparison, Safety and Efficacy Trial of Atomoxetine Hydrochloride and Methylphenidate Hydrochloride in Pediatric Outpatients with DSM-IV Attention- Deficit/Hyperactivity Disorder Date summary approved by Lilly: 10 August 2005 Brief Summary of Results Data from this randomized, double-blind study comparing atomoxetine and methylphenidate in 330 pediatric outpatients diagnosed with Attention- Deficit/Hyperactivity Disorder (ADHD) showed that: After an acute treatment period of approximately 8 weeks, 77.4% of subjects treated with atomoxetine responded to treatment, compared with 81.5% of those on methylphenidate. The results of the primary efficacy analysis demonstrated that atomoxetine is noninferior to methylphenidate in the improvement of ADHD symptoms based on criteria defined a priori. Response was defined as a reduction of 40% or greater from baseline to endpoint in the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version:Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv) scale total score. Repeated-measures and last-observation-carried-forward (LOCF) mean change analyses using an analysis of covariance (ANCOVA) model show that both atomoxetine and methylphenidate were associated with statistically significant improvements in ADHD symptoms, including inattention and hyperactivity/impulsivity. Scores for both treatment groups were comparable throughout the acute treatment period. There were no differences based on gender, age, ADHD subtype, prior stimulant medication use, or the presence of comorbid oppositional defiant disorder.
CT Registry ID#6934 Page 2 Atomoxetine was associated with a statistically significantly greater rate of treatment-emergent adverse events (TEAEs) than methylphenidate. Anorexia, nausea, somnolence, dizziness, and vomiting were statistically significantly more likely to be reported in atomoxetine-treated subjects than in those treated with methylphenidate. Subjects treated with atomoxetine also were statistically significantly more likely to experience weight loss. There were no deaths reported during the study. One serious adverse event, a focal motor convulsion, was reported for a subject randomized to atomoxetine.
CT Registry ID#6934 Page 3 Title of Study: A Randomized, Double-Blind Comparison, Safety and Efficacy Trial of Atomoxetine Hydrochloride and Methylphenidate Hydrochloride in Pediatric Outpatients with DSM-IV Attention- Deficit/Hyperactivity Disorder Investigator(s): This multicenter study included 13 principal investigators. Study Center(s): This study was conducted at 13 study centers in 3 countries. Length of Study: Approximately 9 months Phase of Development: 3 Date first subject enrolled: 06 January 2004 Date last subject completed: 17 October 2004 Objectives: The primary objective of this study was to test the hypothesis that atomoxetine is noninferior to methylphenidate in improving Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms following a double-blind treatment period of approximately 8 weeks. Assessment was based on a comparison of response rates derived from the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv) scale. Secondary objectives included a comparison of the tolerability of atomoxetine and methylphenidate as assessed by treatment-emergent adverse events, and an assessment of the comparability of the efficacy of atomoxetine and methylphenidate based on the Conners Parent Rating Scale-Revised: Short Form (CPRS-R:S) and the Clinical Global Impressions-Attention-Deficit/Hyperactivity Disorder-Severity (CGI-ADHD-S) scale. Study Design: Study B4Z-MC-LYBR (LYBR) was a multicountry, multicenter, randomized, double-blind study comparing atomoxetine and methylphenidate in 330 pediatric outpatients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth EditionTM (DSM-IVTM) diagnostic criteria for ADHD. The trial comprised three study periods and included an initial randomization of all subjects to acute treatment. After an initial screening period, eligible subjects were randomized in a double-blind fashion to receive atomoxetine or methylphenidate for approximately 8 weeks. Study drug dosage was adjusted by the physician based on an assessment of response and tolerability. This phase was followed by a discontinuation phase of approximately 1 week during which physicians assessed each subject s safety and tolerability after study drug discontinuation. Number of Subjects: Planned: Approximately 330 pediatric outpatients (165 subjects per treatment group) Randomized: 164 atomoxetine, 166 methylphenidate Completed: 138 atomoxetine, 152 methylphenidate Diagnosis and Main Criteria for Inclusion: Subjects 6 through 16 years of age at Visit 1 who met DSM- IV diagnostic criteria for ADHD (any subtype) as determined by a physician investigator s clinical assessment. Diagnosis was confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL) semi-structured interview. Criteria included a severity rating 25 for boys or 22 for girls, or a rating >12 for a specific subtype on the ADHDRS-IV-Parent:Inv score, and a CGI-ADHD-S score 4 at both Visit 1 and Visit 2. Test Product, Dose, and Mode of Administration:, 0.8 mg/kg/day to 1.8 mg/kg/day, given once daily as oral capsules (in dosage strengths of 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, and 40 mg). Reference Therapy, Dose, and Mode of Administration: Methylphenidate hydrochloride, 0.2 mg/kg/day up to 0.6 mg/kg/day, given twice daily as oral capsules (in dosage strengths of 5 mg and 10 mg). [To maintain blinding, subjects in the atomoxetine treatment group also received placebo once daily.] Duration of Treatment: 8 weeks of acute treatment: Atomoxetine Frequency: Once daily for 8 weeks Methylphenidate Frequency: Twice daily for 8 weeks
CT Registry ID#6934 Page 4 Variables: Efficacy: Improvement of ADHD symptoms by comparing the percentage of responders derived from the ADHDRS-IV-Parent:Inv Total score. Secondary efficacy variables included ADHDRS-IV-Parent:Inv Total and subscale scores; subscores of the CPRS-R:S scale; and the CGI-ADHD-S Score. Safety: Assessment of adverse events (AEs), including serious adverse events (SAEs); vital signs; height and weight; routine laboratory tests; and electrocardiograms (ECGs). Evaluation Methods: Statistical: As the primary efficacy analysis, a one-sided 95% exact confidence interval on the difference in percentage of responders (atomoxetine minus methylphenidate) was constructed to test noninferiority between atomoxetine and methylphenidate. Response was defined as a reduction of at least 40% from baseline at endpoint on the ADHDRS-IV-Parent:Inv Total score. Noninferiority was declared if the onesided 95% lower confidence limit was greater than -18%. Treatment effects over time were evaluated using repeated measures analysis based on the restricted maximum likelihood method, assuming an unstructured covariance matrix. A Satterthwaite approximation was used for the denominator degrees of freedom in the t-test. Totals and subtotals of the efficacy rating scale were also analyzed by calculating the change from baseline to last-observation-carried-forward (LOCF) endpoint using analysis of covariance (ANCOVA). The sample size provided approximately 95% power to declare overall noninferiority of atomoxetine to methylphenidate under the assumption that the 2 treatment groups would have equal response rates of 62%. In particular, the sample size of 240 subjects from one country provided approximately 90% power to declare noninferiority of atomoxetine to methylphenidate under the same assumption. Results: Subject Demographics Table LYBR.1 presents a summary of subject demographics for this study. Of the 330 subjects who were randomized to treatment, 270 (81.8%) were male, 302 (91.5%) were Asian, and 250 (75.8%) had no prior stimulant exposure. Demographics and other characteristics were comparable for the two treatment groups, although the mean age of subjects in the methylphenidate group was statistically significantly higher than that of the atomoxetine group (methylphenidate 9.91 years, atomoxetine 9.40 years, p=.035). Overall mean age was 9.65 years (range of 6.22 years to 16.68 years). At baseline, 59.4% of the randomized subjects met the criteria for the combined ADHD subtype on the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version:Behavioral Disorders Supplement (K- SADS-PL:Behavioral), and 37.6% were classified as predominantly inattentive.
Table LYBR.1. Summary of Demographics and Other Subject Characteristics All Randomized Subjects Atomoxetine Methylphenidate TOTAL VARIABLE (N=164) (N=166) (N=330) P-value ---------------------------------------------------------------------------------------------------------------- AGE No. of Subjects 164 166 330.035** Mean 9.40 9.91 9.65 Median 9.04 9.49 9.24 Standard Deviation 2.04 2.32 2.19 Minimum 6.26 6.22 6.22 Maximum 15.35 16.68 16.68 AGE < 12 YR 142 (86.6) 131 (78.9) 273 (82.7).080* AGE >= 12 YR 22 (13.4) 35 (21.1) 57 (17.3) GENDER No. of Subjects 164 166 330.669* Female 28 (17.1) 32 (19.3) 60 (18.2) Male 136 (82.9) 134 (80.7) 270 (81.8) ---------------------------------------------------------------------------------------------------------------- *FREQUENCIES ARE ANALYZED USING A FISHER'S EXACT TEST **MEANS ANALYZED USING TYPE III SUM OF SQUARES ANALYSIS OF VARIANCE(ANOVA) (continued) CT Registry ID#6934 Page 5
Table LYBR.1. Summary of Demographics and Other Subject Characteristics All Randomized Subjects (Continued) Atomoxetine Methylphenidate TOTAL VARIABLE (N=164) (N=166) (N=330) P-value ------------------------------------------------------------------------------------------- ORIGIN No. of Subjects 164 166 330 1.00* East/Southeast Asia 150 (91.5) 152 (91.6) 302 (91.5) Hispanic 14 (8.5) 14 (8.4) 28 (8.5) HEIGHT No. of Subjects 150 159 309.261** Mean 136.71 138.49 137.63 Median 134.00 136.00 135.00 Standard Deviation 13.60 14.18 13.91 Minimum 115.00 111.00 111.00 Maximum 174.00 177.00 177.00 WEIGHT No. of Subjects 153 161 314.093** Mean 33.45 35.38 34.44 Median 31.00 32.50 31.75 Standard Deviation 9.68 10.55 10.16 Minimum 20.00 20.20 20.00 Maximum 60.00 60.00 60.00 ---------------------------------------------------------------------------------------------------------------- *FREQUENCIES ARE ANALYZED USING A FISHER'S EXACT TEST **MEANS ANALYZED USING TYPE III SUM OF SQUARES ANALYSIS OF VARIANCE(ANOVA) (continued) CT Registry ID#6934 Page 6
Table LYBR.1. Summary of Demographics and Other Subject Characteristics All Randomized Subjects (Continued) Atomoxetine Methylphenidate TOTAL VARIABLE (N=164) (N=166) (N=330) P-value ------------------------------------------------------------------------------------------- CY2D6 Phenotype Extn Slow No. of Subjects 161 162 323.574* ERROR 2 (1.2) 1 (0.6) 3 (0.9) EXTN 157 (97.5) 160 (98.8) 317 (98.1) SLOW 2 (1.2) 1 (0.6) 3 (0.9) DSM-IV ADHD Subtype No. of Subjects 164 166 330.645* Hyperactive 4 (2.4) 6 (3.6) 10 (3.0) Inattentive 59 (36.0) 65 (39.2) 124 (37.6) Combined 101 (61.6) 95 (57.2) 196 (59.4) Previous Stimulant Use No. of Subjects 164 166 330.701* No 126 (76.8) 124 (74.7) 250 (75.8) Yes 38 (23.2) 42 (25.3) 80 (24.2) ---------------------------------------------------------------------------------------------------------------- *FREQUENCIES ARE ANALYZED USING A FISHER'S EXACT TEST **MEANS ANALYZED USING TYPE III SUM OF SQUARES ANALYSIS OF VARIANCE(ANOVA) (continued) CT Registry ID#6934 Page 7
Table LYBR.1. Summary of Demographics and Other Subject Characteristics All Randomized Subjects (Continued) Atomoxetine Methylphenidate TOTAL VARIABLE (N=164) (N=166) (N=330) P-value ------------------------------------------------------------------------------------------- Family Hist ADHD-Mother No. of Subjects 163 166 329.750* No 159 (97.5) 159 (95.8) 318 (96.7) Unknown 0 (0.0) 1 (0.6) 1 (0.3) Yes 4 (2.5) 6 (3.6) 10 (3.0) Family Hist ADHD-Father No. of Subjects 163 166 329.741* No 145 (89.0) 145 (87.3) 290 (88.1) Unknown 3 (1.8) 2 (1.2) 5 (1.5) Yes 15 (9.2) 19 (11.4) 34 (10.3) Family Hist ADHD-Grandp No. of Subjects 163 166 329 1.00 No 149 (91.4) 150 (90.4) 299 (90.9) Unknown 12 (7.4) 13 (7.8) 25 (7.6) Yes 2 (1.2) 3 (1.8) 5 (1.5) ---------------------------------------------------------------------------------------------------------------- *FREQUENCIES ARE ANALYZED USING A FISHER'S EXACT TEST **MEANS ANALYZED USING TYPE III SUM OF SQUARES ANALYSIS OF VARIANCE(ANOVA) (continued) CT Registry ID#6934 Page 8
Table LYBR.1. Summary of Demographics and Other Subject Characteristics All Randomized Subjects (Concluded) Atomoxetine Methylphenidate TOTAL VARIABLE (N=164) (N=166) (N=330) P-value ------------------------------------------------------------------------------------------- Family Hist ADHD-Sib No. of Subjects 163 166 329.805* No 45 (27.6) 51 (30.7) 96 (29.2) Not Applicable 108 (66.3) 104 (62.7) 212 (64.4) Unknown 2 (1.2) 1 (0.6) 3 (0.9) Yes 8 (4.9) 10 (6.0) 18 (5.5) ---------------------------------------------------------------------------------------------------------------- *FREQUENCIES ARE ANALYZED USING A FISHER'S EXACT TEST **MEANS ANALYZED USING TYPE III SUM OF SQUARES ANALYSIS OF VARIANCE(ANOVA) CT Registry ID#6934 Page 9
CT Registry ID#6934 Page 10 Subject Disposition A total of 361 subjects entered the study at Visit 1, and 330 were assigned to treatment (164 atomoxetine, 166 methylphenidate). Of the 330 subjects randomized, 290 (87.9%) completed acute treatment. The methylphenidate treatment group had a statistically significantly higher (p=.044) completion rate than the atomoxetine group (91.6% versus 84.1%). Statistically significantly more (p=.011) atomoxetine-treated subjects discontinued due to adverse events compared with methylphenidate-treated subjects (11% versus 3.6%). An analysis of study discontinuation by visit showed that half of the discontinuations due to adverse events in the atomoxetine group happened early, particularly during the first two visits of the double-blind treatment period. Figure LYBR.1 presents a summary of subject disposition for the screening/washout and double-blind treatment periods. N = 361 Subjects Entered N = 330 Subjects Randomized N = 31 Screen Failures Protocol entry criteria not met 11 Other 20 N = 164 Atomoxetine N = 166 Methylphenidate N = 26 Discontinuations N = 138 Completed Adverse event 18 Protocol violation 5 Personal conflict/ other subject decision 3 N = 152 Completed N = 14 Discontinuations Adverse event 6 Protocol violation 4 Personal conflict/ other subject decision 2 Subject moved 1 Lost to followup 1 Figure LYBR.1. Subject disposition.
CT Registry ID#6934 Page 11 Primary Efficacy Measure Table LYBR.2 summarizes results of the primary efficacy analysis, which examined noninferiority between atomoxetine and methylphenidate by comparing the response rates for the atomoxetine and methylphenidate treatment groups on the ADHDRS-IV- Parent:Inv Total score. The analysis included randomized subjects with a baseline and at least one postbaseline ADHDRS-IV-Parent:Inv Total score who had no more than one visit during which the subject was noncompliant. Because the lower bound of the 1-sided 95% exact confidence interval (-11.7%) on the difference in response rates (atomoxetine minus methylphenidate) was greater than the pre-specified noninferiority margin ( 18%), these results met the primary efficacy objective and supported the hypothesis that atomoxetine was noninferior to methylphenidate in this study. The results from a similar analysis for the intent-to-treat population were consistent with the data shown in Table LYBR.2 (lower bound of the 1-sided 95% exact confidence interval was -12.8%, p=0.282). Table LYBR.2. Atomoxetine versus Methylphenidate Response Rates: >40% Reduction from Baseline Based on ADHDRS-IV-Parent:Inv Total Score Compliant Subjects* Responders * 95% Confidence Interval Therapy N N % For ATX%-MPH% Atomoxetine 159 123 77.4 1-sided: (-11.7, --) 2-sided: (-13.2, 4.9) p-value**: 0.405 Methylphenidate 157 128 81.5 Abbreviations: ATX = atomoxetine; MPH = methylphenidate. * Subjects who had no more than one non-compliant visit. ** P-value is based on Fisher s exact test. Secondary Efficacy Measures Secondary efficacy analyses (of the intent-to-treat population) were conducted using the ADHDRS-IV-Parent:Inv Total and subscale scores (Inattention, Hyperactivity/Impulsivity), as well as the Clinical Global Impressions-Attention- Deficit/Hyperactivity Disorder-Severity (CGI-ADHD-S) scale and Conners Parent Rating Scale-Revised:Short Form (CPRS-R:S) subscales. These analyses included the following approaches: Repeated measures analysis with independent effects for country, investigator (nested within country), treatment, visit, baseline total score, and treatment-by-visit interaction in the model.
CT Registry ID#6934 Page 12 Mean change from baseline to last observation carried forward (LOCF) endpoint with independent effects for country, investigator (nested within country), treatment, and baseline total score in the analysis of covariance (ANCOVA) model. In all of the secondary efficacy analyses, both treatment groups were associated with statistically significant improvements in ADHD symptoms. Repeated measures analyses comparing the two treatments on the ADHDRS-IV-Parent:Inv Inattention Subscale, ADHDRS-IV-Parent:Inv Hyperactivity-Impulsivity Subscale, and CGI-ADHD-S scale all showed statistically significant improvement for both groups, starting at Visit 3. The improvement noted throughout acute (double-blind) treatment was comparable for the two groups. There were no statistically significant differences between groups at any visit. Table LYBR.3 presents results for one of the secondary efficacy analyses, showing the least squares means of change from baseline for each treatment group and the treatment comparisons at each postbaseline visit for ADHDRS-IV-Parent:Inv Total scores. The data show that subjects in both treatment groups experienced statistically significant reductions (p<.001) in baseline scores at each visit, indicating improvement in their ADHD symptoms (atomoxetine mean change from baseline ranged from 8.17 at Visit 3 to 21.66 at Visit 8; methylphenidate mean change ranged from 6.50 at Visit 3 to 21.85 at Visit 8). The improvement observed throughout the double-blind treatment period was comparable for the two treatment groups, although subjects in the atomoxetine group experienced a statistically significantly greater reduction (p=.018) from baseline at Visit 3.
Table LYBR.3. Repeated Measures Analysis of ADHDRS-IV-Parent:Inv Total Score Change from Baseline All Randomized Subjects --------Atomoxetine------------------ --------Methylphenidate-------- ------------- DIFFERENCE------------ VISIT LS MEAN SE P-VAL A LS MEAN SE P-VAL A LS MEAN SE P-VAL B ------------------------------------------------------------------------------------------------------------------------ 3-8.17 0.60 <.001-6.50 0.60 <.001 1.67 0.70.018 4-12.41 0.65 <.001-11.74 0.64 <.001 0.67 0.78.392 5-15.61 0.67 <.001-15.36 0.66 <.001 0.25 0.81.757 6-17.46 0.72 <.001-16.72 0.71 <.001 0.74 0.90.410 7-20.16 0.72 <.001-20.04 0.70 <.001 0.11 0.88.899 8-21.66 0.74 <.001-21.85 0.72 <.001-0.19 0.92.833 GEOCODE 3.32 0.0375 INVP(GEOCODE) 4.94 <.0001 TRTMNT 0.66 0.4159 VISIT 163.38 <.0001 BASELINE 58.83 <.0001 TRTMNT*VISIT 1.26 0.2818 ---------------------------------------------------------------------------------------------------------------- MODEL: CHANGE = COUNTRY CODE,VISIT,IMPUTED BASELINE SCORE,POOLED INVESTIGATOR NUMBER(COUNTRY CODE), TREATMENT,INTERACTION OF VISIT BY TREATMENT COVARIANCE STRUCTURE = UNSTRUCTURED, VISITS: 3-8 A P-VALUES ARE FROM TESTS FOR A NONZERO LEAST SQUARES MEAN AT THE GIVEN VISIT B P-VALUES ARE FROM TESTS FOR A TREATMENT DIFFERENCE IN LEAST SQUARES MEAN AT THE GIVEN VISIT C P-VALUES ARE FROM F-TESTS FOR A NONZERO COEFFICIENT ESTIMATE CT Registry ID#6934 Page 13
CT Registry ID#6934 Page 14 Table LYBR.4 summarizes one of the mean change analyses, showing the mean change from baseline to LOCF endpoint in ADHDRS-IV-Parent:Inv Total and subscale scores (Inattention and Hyperactivity-Impulsivity). Total and subscale scores showed statistically significant changes (p<.001) from baseline to endpoint during double-blind treatment for both groups. There were no statistically significant differences between treatment groups.
Table LYBR.4. ADHDRS-IV-Parent:Inv Total and Subscale Scores Mean Change from Baseline to Endpoint All Randomized Subjects Within Between Variable Baseline Endpoint Change Group Group ---------------------------------------------------------- ------------ ------------ Treatment N Mean SD Mean SD Mean SD p-value (a) p-value (b) TOTAL SCORE Atomoxetine 162 38.63 7.61 17.57 9.12-21.06 10.33 <.001 0.155 Methylphenidate 164 37.40 7.64 15.84 8.90-21.57 9.56 <.001 _ 95% Confidence Interval for Treatment Difference:(-0.49, 3.08) INATTENTIVE SUBSCALE Atomoxetine 162 21.75 3.53 10.42 4.76-11.33 5.67 <.001 0.054 Methylphenidate 164 21.40 3.77 9.37 4.90-12.02 5.40 <.001 _ 95% Confidence Interval for Treatment Difference:(-0.02, 1.97) HYP/IMP SUBSCALE Atomoxetine 162 16.88 5.56 7.15 5.02-9.73 5.84 <.001 0.432 Methylphenidate 164 16.01 5.60 6.46 4.85-9.54 5.48 <.001 _ 95% Confidence Interval for Treatment Difference:(-0.56, 1.30) (a): P-value is from paired t-test. (b): P-value is based on an ANCOVA on change from baseline scores with terms for baseline, treatment, country, investigator(nested within country). CT Registry ID#6934 Page 15
CT Registry ID#6934 Page 16 Table LYBR.5 summarizes the mean change from baseline to LOCF endpoint in the CGI-ADHD-S score. Higher scores indicate greater severity. Baseline mean for both therapies was 5.30, which indicates markedly ill to severely ill. At endpoint, the mean score in the atomoxetine treatment group was 2.97, indicating severity had lessened to mildly ill, while 2.80 was the endpoint mean in the methylphenidate treatment group. The results of this analysis show that both atomoxetine and methylphenidate were associated with statistically significant mean change on this scale.
Table LYBR.5. CGI-ADHD-S Mean Change from Baseline to Endpoint All Randomized Subjects Within Between Variable Baseline Endpoint Change Group Group ---------------------------------------------------------- ------------ ------------ Treatment N Mean SD Mean SD Mean SD p-value (a) p-value (b) Atomoxetine 162 5.30 0.81 2.97 1.21-2.33 1.39 <.001 0.154 Methylphenidate 164 5.30 0.85 2.80 1.16-2.50 1.33 <.001 _ 95% Confidence Interval for Treatment Difference:(-0.07, 0.42) (a): P-value is from paired t-test. (b): P-value is based on an ANCOVA on change from baseline scores with terms for baseline, treatment, country, investigator(nested within country). CT Registry ID#6934 Page 17
CT Registry ID#6934 Page 18 Table LYBR.6 summarizes the mean change from baseline to endpoint on the CPRS-R:S ADHD Index, Cognitive Problems/Inattention, Hyperactivity, and Oppositional subscale scores. Higher scores indicate more frequent display of symptoms. Both atomoxetine and methylphenidate demonstrated statistically significant improvement (p<.001) on each of the subscales. There were no statistically significant differences between the two treatment groups on any of the subscales.
Table LYBR.6. CPRS-R:S Mean Change from Baseline to Endpoint All Randomized Subjects Within Between Variable Baseline Endpoint Change Group Group ---------------------------------------------------------- ------------ ------------ Treatment N Mean SD Mean SD Mean SD p-value (a) p-value (b) CPRS ADHD Index Atomoxetine 157 26.55 6.13 15.43 6.61-11.12 7.71 <.001 0.952 Methylphenidate 162 26.30 5.42 15.32 6.76-10.98 7.77 <.001 _ 95% Confidence Interval for Treatment Difference:(-1.34, 1.42) CPRS Cognitive Problems Atomoxetine 157 13.67 3.58 7.86 4.01-5.81 4.24 <.001 0.455 Methylphenidate 162 13.46 3.57 7.45 4.04-6.01 4.67 <.001 _ 95% Confidence Interval for Treatment Difference:(-0.51, 1.14) CPRS Hyperactive Score Atomoxetine 157 10.84 4.49 4.97 4.02-5.87 4.81 <.001 0.190 Methylphenidate 162 10.02 4.20 5.15 3.88-4.87 4.26 <.001 _ 95% Confidence Interval for Treatment Difference:(-1.25, 0.25) CPRS Oppositional Score Atomoxetine 157 9.90 3.92 6.89 3.62-3.01 3.93 <.001 0.084 Methylphenidate 162 9.58 3.98 6.19 3.61-3.40 4.13 <.001 _ 95% Confidence Interval for Treatment Difference:(-0.08, 1.32) (a): P-value is from paired t-test. (b): P-value is based on an ANCOVA on change from baseline scores with terms for baseline, treatment, country, investigator(nested within country). CT Registry ID#6934 Page 19
CT Registry ID#6934 Page 20 Safety The analysis of adverse events in this study included the 330 enrolled subjects who took at least 1 dose of study drug. Subjects who received study medication (randomized subjects) were assumed to have taken at least 1 dose unless it was documented otherwise. For inclusion into the analysis of clinical laboratory values, vital signs, and ECG data, subjects also must have had a baseline and at least 1 postbaseline measurement. There were no deaths reported in this study. A serious adverse event was reported for a 6-year-old male subject assigned to atomoxetine treatment; the subject discontinued from the study due to a focal motor convulsion. This event was considered by the investigator to be possibly related to study medication or procedures. Anorexia, nausea, somnolence, dizziness, and vomiting were reported statistically significantly more often among atomoxetine-treated subjects than in methylphenidate-treated subjects. Most TEAEs for the two groups (88.6%) were reported to be mild or moderate in severity. Table LYBR.7 contains a summary of TEAEs reported in 5% of randomized subjects who had taken at least one dose of study drug.
Table LYBR.7. Summary of Treatment-Emergent Adverse Events with 5% Incidence Randomized Subjects Who Took at Least One Dose of Study Drug ATOMOX Methyl. TOTAL Fisher's (N=164) (N=166) (N=330) Exact Preferred Term n (%) n (%) n (%) p-value ------------------------------------------------------------------------------------------------------- SUBJECTS WITH >=1 TESS 142 (86.6) 112 (67.5) 254 (77.0) <.001 SUBJECTS WITH NO TESS 22 (13.4) 54 (32.5) 76 (23.0) <.001 Anorexia 61 (37.2) 42 (25.3) 103 (31.2).024 Decreased appetite 46 (28.0) 32 (19.3) 78 (23.6).070 Nausea 33 (20.1) 17 (10.2) 50 (15.2).014 Somnolence 43 (26.2) 6 (3.6) 49 (14.8) <.001 Headache 25 (15.2) 16 (9.6) 41 (12.4).135 Dizziness 25 (15.2) 12 (7.2) 37 (11.2).024 Abdominal pain 15 (9.1) 15 (9.0) 30 (9.1) 1.00 Pyrexia 11 (6.7) 17 (10.2) 28 (8.5).324 Vomiting 19 (11.6) 6 (3.6) 25 (7.6).007 Cough 11 (6.7) 10 (6.0) 21 (6.4).825 Upper respiratory tract infection 9 (5.5) 11 (6.6) 20 (6.1).818 Fatigue 13 (7.9) 5 (3.0) 18 (5.5).055 Irritability 7 (4.3) 10 (6.0) 17 (5.2).620 Rhinorrhoea 7 (4.3) 10 (6.0) 17 (5.2).620 Insomnia 5 (3.0) 9 (5.4) 14 (4.2).414 ---------------------------------------------------------------------------------------------------------------------- CT Registry ID#6934 Page 21
CT Registry ID#6934 Page 22 Eighteen (11%) subjects in the atomoxetine group and 6 (3.6%) in the methylphenidate group discontinued due to adverse events. This difference was statistically significant (p=.011). The most frequently reported AEs that led to study discontinuation for subjects in both treatment groups were anorexia (5 subjects atomoxetine, 1 subject methylphenidate), decreased appetite (2 atomoxetine, 2 methylphenidate), nausea (2 atomoxetine, 1 methylphenidate), and abdominal pain (2 atomoxetine). Table LYBR.8 presents a summary of the number and percent of subjects who discontinued from the study due to AEs.
Table LYBR.8. Summary of Discontinuations Due to Adverse Events Randomized Subjects Who Took at Least One Dose of Study Drug Atomoxetine Methylphenidate TOTAL (N=164) (N=166) (N=330) FISHERS EXACT n (%) n (%) n (%) P-VALUE Preferred Term --------------------------------------------------------------------------------------------------------------- SUBJECTS DISCONTINUED 18(11.0%) 6(3.6%) 24(7.3%) 0.011 Anorexia 5(3.0%) 1(0.6%) 6(1.8%) 0.120 Decreased appetite 2(1.2%) 2(1.2%) 4(1.2%) 1.000 Nausea 2(1.2%) 1(0.6%) 3(0.9%) 0.622 Abdominal pain 2(1.2%) 0(0.0%) 2(0.6%) 0.246 Chest pain 1(0.6%) 0(0.0%) 1(0.3%) 0.497 Constipation 1(0.6%) 0(0.0%) 1(0.3%) 0.497 Dermatitis medicamentosa 1(0.6%) 0(0.0%) 1(0.3%) 0.497 Dizziness 0(0.0%) 1(0.6%) 1(0.3%) 1.000 Palpitations 0(0.0%) 1(0.6%) 1(0.3%) 1.000 Rash 1(0.6%) 0(0.0%) 1(0.3%) 0.497 Simple partial seizures 1(0.6%) 0(0.0%) 1(0.3%) 0.497 Somnolence 1(0.6%) 0(0.0%) 1(0.3%) 0.497 Varicella 1(0.6%) 0(0.0%) 1(0.3%) 0.497 --------------------------------------------------------------------------------------------------------------- CT Registry ID#6934 Page 23
CT Registry ID#6934 Page 24 Change from baseline to endpoint was computed for each analyte and treatment group differences were assessed using ANOVA with country, investigator (nested within country), and treatment as independent effects in the model. Table LYBR.9 summarizes the mean change from baseline to endpoint by treatment group for analytes for which there were statistically significant changes during doubleblind treatment. Statistically significant treatment differences in mean change scores were observed for alkaline phosphatase (ALP) and creatine phosphokinase.
Table LYBR.9. Summary of Statistically Significant Laboratory Data Mean Change from Baseline to Endpoint - Ranked Randomized Subjects Who Took at Least One Dose of Study Drug Laboratory Group: Clinical Chemistry Change to Lab Lab ----Baseline---- ----Endpoint---- --P-value -- Test Unit Therapy N Mean STD Mean STD Therapy* -------------------------------------------------------------------------------------------------------------------- ALKALINE PHOSPHATASE %URL ATOMOX 142 77.77 22.09-6.35 10.67 <.001 Methyl. 154 77.23 20.74-2.39 10.59 CREATINE PHOSPHOKINASE %URL ATOMOX 142 79.67 38.90-7.90 39.66.041 Methyl. 154 83.61 50.20 7.90 151.16 --------------------------------------------------------------------------------------------------------------- Alkaline phosphatase and creatine phosphokinase were normalized. N = Total number of Subjects in each treatment group having the variable in both baseline and postbaseline visits. * Type III Sums of Squares from an ANOVA on the ranks: model=country, Pooled Investigator(nested within Country) and Therapy. CT Registry ID#6934 Page 25
CT Registry ID#6934 Page 26 Table LYBR.10 presents the percentage of subjects who had laboratory values that were normal at baseline, but were found to be statistically significantly abnormal (above or below the normal range) at endpoint. Statistically significantly more atomoxetine-treated subjects had high levels of calcium or abnormal urinalysis-protein than methylphenidatetreated subjects. Statistically significantly more methylphenidate-treated subjects had high laboratory values for alkaline phosphatase, high uric acid values, or low values for urinalysis-specific gravity tests.
Table LYBR.10. Summary of Laboratory Data Frequency of Subjects with Abnormal Laboratory Values after Baseline Randomized Subjects Who Took at Least One Dose of Study Drug ------ATOMOX ------- ------Methyl. ------- Lab Test Direction N n Percent N n Percent P-value* --------------------------------------------------------------------------------------------------------- ALKALINE PHOSPHATASE High 125 0 0.0 134 9 6.7.004 Low 145 0 0.0 155 0 0.0 CALCIUM High 133 19 14.3 145 8 5.5.015 Low 144 1 0.7 155 0 0.0.482 URIC ACID High 136 6 4.4 139 16 11.5.044 Low 145 1 0.7 155 1 0.6 1.00 UA-PROTEIN Abnormal 125 28 22.4 133 13 9.8.006 UA-SPECIFIC GRAVITY High 146 0 0.0 155 0 0.0 Low 138 0 0.0 153 6 3.9.031 --------------------------------------------------------------------------------------------------------------- * Frequencies are analyzed using Fisher's Exact test. N = number of at risk subjects with a baseline and postbaseline measurement. n = number of at risk subjects with the specific lab result (e.g. High). CT Registry ID#6934 Page 27
CT Registry ID#6934 Page 28 Table LYBR.11 shows mean change comparisons between the two treatment groups in terms of vital signs and weight, calculated from baseline to endpoint. Subjects in the atomoxetine group experienced a statistically significant (p<.001) average weight loss of 1.2 kg compared to weight loss of 0.42 kg in the methylphenidate group during doubleblind treatment. No other vital sign measure was statistically significantly different between groups.
Table LYBR.11. Summary of Vital Signs and Weight Mean Change from Baseline to Endpoint Randomized Subjects Who Took at Least One Dose of Study Drug Within Between Variable Baseline Endpoint Change Group Group ---------------------------------------------------------- ------------ ------------ Treatment N Mean SD Mean SD Mean SD p-value (a) p-value (b) DIASAVG Atomoxetine 162 62.31 8.22 65.63 9.00 3.33 10.08 <.001 0.646 Methylphenidate 164 63.08 8.17 65.90 8.35 2.82 9.61 <.001 _ SYSAVG Atomoxetine 162 100.11 10.35 102.15 10.71 2.04 11.08 0.020 0.927 Methylphenidate 164 101.10 9.87 103.35 10.37 2.25 10.75 0.008 _ PULSAVG Atomoxetine 162 84.56 10.52 90.40 11.26 5.84 12.77 <.001 0.174 Methylphenidate 164 83.75 11.01 87.61 12.29 3.87 12.85 <.001 _ WEIGHT Atomoxetine 162 33.63 9.72 32.43 9.44-1.20 1.40 <.001 <.001 Methylphenidate 164 35.28 10.57 34.87 10.61-0.42 1.34 <.001 _ HEIGHT Atomoxetine 151 136.81 13.62 137.72 13.50 0.91 1.13 <.001 0.285 Methylphenidate 157 138.23 13.93 139.30 13.82 1.07 1.41 <.001 _ TEMP Atomoxetine 162 36.37 0.39 36.35 0.34-0.02 0.39 0.600 0.222 Methylphenidate 164 36.38 0.34 36.42 0.34 0.04 0.37 0.202 DIASAVG=Diastolic Blood Pressure; SYSAVG=Systolic Blood Pressure; PULSAVG=Pulse; WEIGHT=Weight in KG; HEIGHT=Height in CM; TEMP=Temperature in Centigrade. (a): P-value is from paired t-test. (b): Type III Sums of Squares from an ANOVA: PROC GLM model= country, investigator(nested within country) and treatment. CT Registry ID#6934 Page 29
CT Registry ID#6934 Page 30 Table LYBR.12 summarizes the comparison of change from baseline to endpoint for heart rate and ECG intervals (RR, PR, QRS, QT, and QT corrected using Bazett s, Fridericia s, and data-corrected methods) between atomoxetine and methylphenidate. Both drugs were associated with a statistically significant increase (p<.001) in heart rate; the difference between the mean increase in heart rate for atomoxetine (8.51 bpm) and methylphenidate (4.76 bpm) also was statistically significant (p=.005). Statistically significant separation also was noted between the two treatment groups in ECG intervals (RR, QRS, PR, and QT). There were no statistically significant differences between treatment groups on QT intervals using QTcF, QTcB, and QTcD correction formulae. Analyses assessing the percentage of subjects in each treatment group who met the criteria for potentially clinically significant changes in corrected QTc interval and heart rate following baseline indicated no statistically significant differences in categorical changes in QT intervals.
Table LYBR.12. Summary of Mean Change to Endpoint for ECG Data Randomized Subjects Who Took at Least One Dose of Study Drug Within Between Variable Baseline Endpoint Change Group Group ---------------------------------------------------------- ------------ ------------ Treatment N Mean SD Mean SD Mean SD p-value (a) p-value (b) HR Atomoxetine 152 78.24 10.32 86.76 12.57 8.51 11.54 <.001 0.005 Methylphenidate 157 79.00 12.09 83.76 13.17 4.76 11.79 <.001 _ RR Atomoxetine 152 780.25 104.45 707.15 109.90-73.10 106.06 <.001 0.017 Methylphenidate 157 778.02 124.27 734.40 118.22-43.62 111.58 <.001 _ QRS Atomoxetine 152 81.97 9.43 83.66 9.80 1.68 8.06 0.011 0.009 Methylphenidate 157 82.78 10.41 82.26 10.41-0.52 6.14 0.294 _ PR Atomoxetine 152 139.81 18.45 133.92 16.43-5.89 14.01 <.001 <.001 Methylphenidate 157 136.43 19.39 135.19 19.04-1.24 10.22 0.132 _ QT Atomoxetine 152 366.20 24.86 352.47 24.00-13.72 21.51 <.001 0.029 Methylphenidate 157 365.73 28.05 357.45 25.35-8.28 22.77 <.001 _ QTCF Atomoxetine 152 398.30 14.62 396.46 13.10-1.85 12.59 0.073 0.710 Methylphenidate 157 398.42 15.27 397.12 14.28-1.31 13.57 0.229 _ QTCB Atomoxetine 152 414.93 14.52 420.02 14.97 5.09 15.52 <.001 0.191 Methylphenidate 157 415.45 15.34 418.17 16.33 2.73 16.28 0.037 _ QTCD Atomoxetine 152 404.11 13.96 404.56 12.85 0.45 12.86 0.666 0.780 Methylphenidate 157 404.37 14.46 404.39 14.10 0.02 13.75 0.985 HR=ECG Heart Rate; PR=PR Interval; QRS=QRS Interval; QT=QT Interval; QTCB=Bazett Corrected QT Interval; QTCF=Fridericia Corrected QT Interval; QTCD=Data Corrected QT Interval; RR=RR Interval. (a): P-value is from paired t-test. (b): Type III Sums of Squares from an ANOVA: PROC GLM model= country, investigator(nested within country) and treatment. CT Registry ID#6934 Page 31