CT Registry ID#7065 Page 1 Summary ID# 7065 Clinical Study Summary: Study B4Z-MC-LYBU A Randomized, Double-Blind Comparison of Atomoxetine Hydrochloride Augmented with Either Extended-Release Methylphenidate Hydrochloride (Concerta ) or Placebo in Children with Attention- Deficit/Hyperactivity Disorder (ADHD) Who Have Not Responded to Stimulant Mono Therapy Date summary approved by Lilly: 13 July 2006 Brief Summary of Results Study B4Z-MC-LYBU was a 10-week study in children aged 6-12 years with ADHD, and retrospectively identified in other well-documented clinical trials as non-responsive to stimulant therapy (nonremitter). The primary objective of the study was to assess the safety of up to 1.4 mg/kg/day of atomoxetine plus placebo administered once daily (QD), compared with up to 1.4 mg/kg/day of atomoxetine plus up to 1.1 mg/kg/day of Concerta administered QD, in stimulant nonremitter patients exposed to acute treatment with atomoxetine. Safety was measured by categorical changes in blood pressure or pulse. Secondary objectives were to assess the safety of atomoxetine+placebo compared with atomoxetine+concerta as measured by electrocardiograms (ECGs), clinical laboratory tests, and adverse events (AEs); and to compare efficacy as measured by the Attention- Deficit/ Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator- Administered and Scored (ADHDRS-IV-Parent:Inv), Weekly Parent Ratings of Evening and Morning Behavior-Revised (WPREMB-Revised), Life Participation Scale-Parent Version (LPS-P), Conners Parent Rating Scale-Revised: Short Form (CPRS-R:S), and the Conners Global Index-Teacher Version (Conners GI-T).
CT Registry ID#7065 Page 2 Study LYBU consisted of two study periods: Study Period I, the screening and washout phase (5-28 days); and Study Period II, the double-blind treatment phase. During Study Period IIa (4 weeks), eligible patients were titrated to a target dose of up to 1.4 mg/kg/day atomoxetine+placebo. During Study Period IIb (6 weeks), patients who had a marked response (remitter group) in Study Period IIa continued atomoxetine+placebo, but patients who did not have a marked response were randomized to receive up to 1.4 mg/kg/day atomoxetine+placebo (atomoxetine+placebo treatment group) or up to 1.1 mg/kg/day Concerta (atomoxetine+concerta treatment group). Enrollment was stopped due to lower than expected enrollment rates (25 patients; 50 patients were planned). Results of the study were as follows: In Study Period IIb, 3 patients from the atomoxetine+concerta treatment group, 1 patient from the atomoxetine+placebo treatment group, and 1 patient from the remitter group had one or more categorical changes in vital signs. There were no statistically significant differences across randomized groups in categorical changes in vital signs. There were no statistically significant changes in vital signs or weight across treatment groups in either study period. Statistically significant decreases from baseline in body mass index (p=.014) and orthostatic diastolic blood pressure (p=.006) were noted at LOCF endpoint in the atomoxetine+concerta treatment group, and increases in standing systolic blood pressure (p=.036) in the remitter group. In Study Period IIa, statistically significant decreases from baseline to LOCF endpoint (p<.001) were noted for ADHDRS-IV-Parent:Inv, Total, Inattention, and Hyperactivity-Impulsivity Subscale scores; CGI-ADHD-S; WPREMB-Revised- Parent, total score; and CPRS-R:S, total score. In Study Period IIa, a statistically significant increase from baseline to endpoint (LOCF) was noted for LPS-P (p<.001). In Study Period IIb, there were no statistically significant differences across randomized groups among the secondary objective measures. Within the atomoxetine+placebo treatment group, statistically significant decreases from baseline to LOCF endpoint were noted for CGI-ADHD-S (p=.011) and ADHDRS-IV-Parent:Inv, Inattention (p=.031) Subscale scores. No patients died or experienced serious adverse events (SAEs) during this study.
CT Registry ID#7065 Page 3 Title of Study: A Randomized, Double-Blind Comparison of Atomoxetine Hydrochloride Augmented with Either Extended-Release Methylphenidate Hydrochloride (Concerta ) or Placebo in Children with Attention-Deficit/Hyperactivity Disorder (ADHD) Who Have Not Responded to Stimulant Mono Therapy Investigator(s): This multicenter study included 5 principal investigators. Study Center(s): This study was conducted at 5 study centers in 1 country. Length of Study: 14 months Phase of Development: 3 Date first patient enrolled: 06 January 2004 Date last patient completed: 10 March 2005 Objectives: The primary objective was to assess the safety of up to 1.4 mg/kg/day of atomoxetine plus placebo administered QD, compared with up to 1.4 mg/kg/day of atomoxetine plus up to 1.1 mg/kg/day of Concerta administered QD, in children (aged 6 to 12 years) with ADHD who were retrospectively identified as stimulant nonremitters and who were exposed to acute treatment with atomoxetine. Safety was measured by categorical changes in blood pressure or pulse. Secondary objectives were to assess the safety of atomoxetine+placebo compared with atomoxetine+concerta as measured by ECGs, clinical laboratory tests, and AEs; and to compare efficacy as measured by the ADHDRS-IV-Parent:Inv, WPREMB-Revised, LPS-P, Clinical Global Impressions-Attention-Deficit/Hyperactivity Disorder-Severity and -Improvement (CGI-ADHD-S and CGI-ADHD-I) scales, CPRS-R:S, and the Conners GI-T. Study Design: Study LYBU was a multicenter, Phase 3, randomized, parallel, double-blind pilot study of atomoxetine+ either Concerta or placebo in children aged 6 through 12 years who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV ) criteria for ADHD and who were previously identified as stimulant nonremitters. Following a screening and washout period (Study Period I; 5-28 days), eligible patients were titrated to a target dose of up to 1.4 mg/kg/day atomoxetine+placebo (Study Period IIa). Patients who had a marked response after 4 weeks (remitter group; defined as clinical remission of their symptoms, as measured by a CGI-ADHD-S score of 1 or 2) continued atomoxetine+placebo for an additional 6 weeks (Study Period IIb). Patients who did not have a marked response after 4 weeks (nonremitter group) were randomized to receive up to 1.4 mg/kg/day atomoxetine+ either placebo (atomoxetine+placebo treatment group) or up to 1.1 mg/kg/day Concerta (atomoxetine+concerta treatment group) during Study Period IIb. Number of Patients: Planned: Up to 85 patients entered with approximately 50 nonremitting patients randomized (25 to atomoxetine+placebo and 25 to atomoxetine+concerta). Screened: 30 patients. Study Period IIa: Enrolled: 25 patients (enrollment was stopped due to lower-than-expected enrollment rates). Study Period IIb: Remitters: 4 patients. Nonremitters: 17 patients (randomized: 9 to atomoxetine+concerta, 8 to atomoxetine+placebo). Completed: Remitters: 4 patients. Nonremitters: 13 patients (7 atomoxetine+concerta, 6 atomoxetine+placebo). Diagnosis and Main Criteria for Inclusion: Male and female children aged 6 through 12 years who met DSM-IV criteria for ADHD as confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children Present and Lifetime, Behavioral Disorders Supplement (K-SADS-PL). Patients had a severity rating at least 1.5 standard deviations (SD) above their age and gender norms on the ADHDRS-IV-Parent:Inv, as well as a CGI-ADHD-S score 4 (at Visit 1 and Visit 2). Patients met criteria for a stimulant nonremitter (for example, the patient did not demonstrate clinically significant improvement during a well-documented clinical trial with adequate therapy in approximately the 12 months prior to study enrollment, such that in the clinical opinion of the treating physician a change in therapy was indicated).
CT Registry ID#7065 Page 4 Study Drug, Dose, and Mode of Administration: Atomoxetine up to 1.4 mg/kg/day (exact dose could vary slightly to correspond to available capsule strengths, but was not to exceed 1.8 mg/kg/day), given orally QD. The exact dose was based on the patient s weight. Atomoxetine was provided as 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, and 40 mg capsules. Reference Therapy, Dose, and Mode of Administration: Concerta up to 1.1 mg/kg/day, given orally QD. The exact dose was based on the patient s weight but was not to exceed 54 mg/day. Concerta was provided as 18 mg capsules. Placebo capsules, identical in appearance to atomoxetine or Concerta, given orally QD. Duration of Treatment: Study Period IIa (Visit 2 until Visit 5) was approximately 4 weeks; Study Period IIb (Visit 5 through Visit 8) was approximately 6 weeks. Variables: Efficacy: ADHDRS-IV-Parent:Inv, Total and subscale scores; WPREMB-Revised, total score; Life Participation Scale, total score; CGI-ADHD-S score; CGI-ADHD-Improvement (CGI-ADHD-I) score; CPRS-R:S, total score; and Conners GI-T, total score. Safety: AEs, vital sign measurements, laboratory test results, and ECGs. Evaluation Methods: Statistical: Analyses were performed on an intent-to-treat basis, unless otherwise specified. Safety analyses included data from all patients who took at least one dose of Study Period II medication. All tests of hypotheses were considered statistically significant if the two-sided p-value was less than 0.05, unless otherwise stated. No adjustments for multiple comparisons were made. An LOCF endpoint approach was used to impute missing post-baseline data. For Study Period IIa, baseline was defined as the last measurement obtained on, or prior to Visit 2 (start of Study Period IIa); and endpoint as the last measurement obtained after Visit 2 but on, or before Visit 5 (the time of randomization). For Study Period IIb, baseline was defined as the last measurement obtained on, or prior to Visit 5; and endpoint as the last measurement obtained after Visit 5 but on, or before Visit 8 (final visit). Safety Analyses: Study Period IIa: The incidences of treatment-emergent adverse events (TEAEs) and SAEs were tabulated for all treated patients. Changes from baseline to endpoint values were summarized for vital signs, laboratory measures, and ECG parameters. Within-treatment group changes were assessed using a Wilcoxon s signed-rank test for laboratory parameters and a paired t-test for vital signs and ECG intervals. Categorical analyses of vital signs and ECG intervals were summarized. Study Period IIb: The primary analysis was a Fisher s exact test of the proportion of patients experiencing one or more categorical changes in vital signs. Criteria for categorical changes were: for diastolic and systolic blood pressure, an increase of at least 5 mmhg to above the 95th percentile based on age, gender, and height-adjusted National Institute of Health norms and; for pulse, an increase of at least 25 bpm to a value of at least 110 bpm. The incidences of TEAEs and SAEs were tabulated for all remitter patients and for randomized patients by treatment group. Treatment group differences were analyzed using Fisher s exact test. Changes from baseline to endpoint values were summarized for vital signs, laboratory measures, and ECG parameters. Within-treatment group changes were assessed using a Wilcoxon signedrank test for laboratory parameters and a paired t-test for vital signs and ECG intervals. Categorical analyses of vital signs and ECG intervals were summarized. Treatment comparisons were assessed using an analysis of covariance (ANCOVA). Efficacy Analyses: Study Period IIa: For CGI-ADHD-I scores, mean values at endpoint were provided and proportions in each category were summarized. For other efficacy variables, changes from baseline to endpoint were summarized for all treated patients. A paired t-test was used to assess whether mean changes from baseline to endpoint were statistically significant.
CT Registry ID#7065 Page 5 Efficacy Analyses (concluded): Study Period IIb: For CGI-ADHD-I scores, mean values at endpoint were provided and proportions in each category were summarized. For other efficacy variables, changes from baseline to endpoint were summarized for all remitter patients and for randomized patients by treatment group. Changes from baseline to endpoint were analyzed using an ANCOVA model with treatment and investigator as factors and baseline as a covariate. A paired t-test test was used to assess whether mean changes within treatment groups from baseline to endpoint were statistically significant. Results: Patient Demographics Table LYBU.1 summarizes baseline characteristics for enrolled patients. Enrollment rates were lower than expected; therefore, enrollment was closed after 25 patients had enrolled in Study Period IIa. Of these patients, 24 received double-blind treatment with atomoxetine+placebo. Most treated patients were Caucasian (83.3%), male (83.3%), and met the criteria for the combined ADHD subtype (79.2%). The mean (SD) age was 9.6 (1.8) years. Except for Life Participation Scale-Parent-rated (LPS-P) total score, randomized groups were comparable across demographic and baseline characteristics. The least square mean LPS-P total score in the atomoxetine+concerta treatment group was 21.5 at baseline compared with 28.4 in the atomoxetine+placebo treatment group (p=.015).
CT Registry ID#7065 Page 6 Table LYBU.1. Summary of Patient Characteristics at Enrolled Patients Receiving Treatment Study Period IIa Study Period IIbb Characteristic Atomoxetinea (N=24) Remitters (N=4) Atx+Cnc (N=9) Atx+Pla (N=8) Age, years: mean (SD) 9.6 (1.8) 10.5 (1.3) 10 (1.9) 9 (1.9) Sex: n (%) Male 20 (83.3) 4 (100.0) 8 (88.9) 6 (75.0) Female 4 (16.7) 0 (0.0) 1 (11.1) 2 (25.0) Race Origin: n (%) Caucasian 20 (83.3) 2 (50.0) 8 (88.9) 7 (87.5) African descent 2 (8.3) 1 (25.0) 0 (0.0) 1 (12.5) Other 2 (8.3) 1 (25.0) 1 (11.1) 0 (0.0) ADHD Subtype: n (%) Combined 20 (83.3) 3 (75.0) 7 (77.8) 7 (87.5) Inattentive 4 (16.7) 1 (25.0) 2 (22.2) 1 (12.5) Hyperactive 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) CYP2D6 Phenotype: n (%) Extensive 21 (87.5) 4 (100.0) 8 (88.9) 8 (100.0) Poor 3 (12.5) 0 (0.0) 1 (11.1) 0 (0.0) LPS-P: LS Mean N/A N/A 21.5 28.4 Abbreviations: ADHD = Attention-Deficit/Hyperactivity Disorder; Atx = atomoxetine; Cnc = Concerta; CYP2D6 = cytochrome P450 2D6; LPS-P = Life Participation Scale-Parent Rated Total Score; LS = least square; N = number of enrolled patients; n = number of patients with specific characteristic; N/A = not applicable; Pla = placebo; SD = standard deviation. a One enrolled patient did not receive treatment. b Three patients discontinued during Study Period IIa and did not get randomized into Study Period IIb: two patients due to adverse events and one patient due to lack of efficacy. Patient Disposition A total of 30 patients entered the screening phase (Figure LYBU.1). Of the 25 patients who enrolled in Phase IIa of the study, 24 patients received double-blind treatment with atomoxetine+placebo. Twenty-one patients continued into Study Period IIb: 4 patients met the double-blind criteria for remission (remitters) and continued double-blind treatment with atomoxetine+placebo; 17 patients were nonremitters and were randomized to acute, double-blind treatment with either atomoxetine+concerta (9 patients) or atomoxetine+placebo (8 patients).
CT Registry ID#7065 Page 7 5 patients failed screening 30 patients screened 25 patients enrolled (Study Period IIa) 21 patients continued to Study Period IIb Discontinued n=4 Adverse event: vomiting (1) dilated pupils (1) Lack of efficacy (1) Physician decision (1; did not receive study drug) Remitters: 4 patients treated with ATX+placebo Nonremitters: 17 patients randomized to treatment ATX+placebo 8 patients treated ATX+Concerta 9 patients treated Discontinued n=2 Adverse event of intermittent irritability (1) Lack of efficacy (1) Discontinued n=2 Adverse event of atrial ectopy (1) Protocol violation (1) 4 patients completed treatment 6 patients completed treatment 7 patients completed treatment Figure LYBU.1. Primary Objective Patient disposition. The primary objective of this study was to assess the safety of up to 1.4 mg/kg/day of atomoxetine and placebo administered QD, compared to 1.4 mg/kg/day of atomoxetine and 1.1 mg/kg/day of Concerta administered QD. Safety was measured by categorical changes in blood pressure or pulse. In Study Period IIb, 3 patients in the atomoxetine+concerta treatment group had one or more categorical changes in vital signs (diastolic blood pressure in 1 patient; systolic blood pressure in 1 patient; and both diastolic blood pressure and pulse in 1 patient). In addition, 1 patient from the atomoxetine+placebo treatment group had a categorical change in pulse; and 1 patient in the remitter group had a categorical change in diastolic blood pressure. There were no significant differences across randomized treatment groups in categorical changes in vital signs. Table LYBU.2 presents a summary of patients with one or more categorical changes in vital signs within Study Period IIb.
CT Registry ID#7065 Page 8 Table LYBU.2. Patients With Categorical Changes in Vital Signs Study Period IIb Treatment Group Diastolic BPa n (%) Systolic BPa n (%) Pulseb n (%) Remitters 1 (25.0) - - (N=4) Atomoxetine + Concerta 2 (22.2)c 1 (11.1) 1 (11.1) (N=9) Atomoxetine + Placebo (N=8) - - 1 (12.5) Abbreviations: BP = blood pressure, bpm = beats per minute. a Blood pressure categorical change: 5 mmhg increase and above 95th percentile. b Pulse categorical change: 25 bpm increase to 110 bpm. c One patient had a categorical change in both diastolic BP and pulse.
CT Registry ID#7065 Page 9 Secondary Objectives The secondary objectives of this study were as follows: To assess the safety, as measured by ECGs, of 1.4 mg/kg/day of atomoxetine and placebo administered QD as compared to 1.4 mg/kg/day of atomoxetine and 1.1 mg/kg/day of Concerta administered QD To assess the safety, as measured by clinical laboratory tests, of 1.4 mg/kg/day of atomoxetine and placebo administered QD as compared to 1.4 mg/kg/day of atomoxetine and 1.1 mg/kg/day of Concerta administered QD To assess the tolerability, as measured by spontaneously reported AEs, of 1.4 mg/kg/day of atomoxetine and placebo administered QD as compared to 1.4 mg/kg/day of atomoxetine and 1.1 mg/kg/day of Concerta administered QD To compare the efficacy of 1.4 mg/kg/day of atomoxetine and placebo administered QD as compared to 1.4 mg/kg/day of atomoxetine and 1.1 mg/kg/day of Concerta administered QD as measured by the ADHDRS-IV-Parent:Inv, the WPREMB-Revised, the LPS-P, the CPRS-R:S, and the Conners GI-T. In Study Period IIa, statistically significant decreases from baseline to LOCF endpoint (p<.001) were noted for ADHDRS-IV-Parent:Inv, Total, Inattention, and Hyperactivity-Impulsivity Subscale scores; CGI-ADHD-S; WPREMB-Revised, total score; and CPRS-R:S, total score. A statistically significant increase was noted for LPS-P (p<0.001). Mean changes from baseline at LOCF endpoint are summarized below (Table LYBU.3). In Study Period IIb, statistically significant decreases from baseline were noted at LOCF endpoint for CGI-ADHD-S (p=.011) and ADHDRS-IV-Parent:Inv, Inattention (p=.031) scores in the atomoxetine+placebo treatment group. No statistically significant changes from baseline either within or across randomized treatment groups were noted for any other efficacy parameter. Mean changes from baseline are summarized below (Table LYBU.4).
CT Registry ID#7065 Page 10 Table LYBU.3. Secondary Objective Study Period IIa Mean Change from to LOCF Endpoint Enrolled Patients Parameter, Mean (SD) Atomoxetine (N=24)a p-valueb ADHDRS-IV-Parent:Inv, total ADHDRS-IV-Parent:Inv, Inattention ADHDRS-IV-Parent:Inv, Hyperactivity-Impulsivity WPREMB-Revised, total LPS-P, total CGI-ADHD-S CPRS-R:S, total Conners GI-T, total 44.9 (6.6) -17.8 (9.2) <0.001 23.4 (3.3) -8.0 (5.8) <0.001 21.5 (5.4) -9.8 (5.9) <0.001 21.4 (6.3) -6.7 (6.5) <0.001 25.4 (7.9) 8.2 (7.9) <0.001 5.3 (0.7) -1.5 (0.9) <0.001 59.5 (13.4) -17.1 (11.0) <0.001 17.4 (6.8) (n=14) -0.5 (4.1) 0.653 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, Conners GI-T = Conners Global Index-Teacher, CPRS-R:S = Conners' Parent Rating Scale-Revised: Short Form, LPS-P = Life Participation Scale- Parent Version, WPREMB-Revised-Parent = Weekly Parent Ratings of Evening and Morning Behavior-Revised a Treatment included double-blind atomoxetine+placebo. b Within-treatment group changes were assessed using a paired t-test. : last measurement obtained on or prior to Visit 2. Endpoint: last measurement after Visit 2 but on, or before Visit 5 (time of randomization).
CT Registry ID#7065 Page 11 Table LYBU.4. Secondary Objective Study Period IIb Mean Change from to LOCF Endpoint Enrolled Patients Parameter, Mean (SD) ADHDRS-IV-Parent:Inv, total p-valuea ADHDRS-IV- Parent:Inv, Inattention p-valuea ADHDRS-IV- Parent:Inv, Hyperactivity-Impulsivity p-valuea WPREMB-Revised-Parent, total p-valuea LPS-P, total p-valuea CGI-ADHD-S p-valuea CGI-ADHD-I CPRS-R:S, total p-valuea Conners GI-T, total p-valuea Atomoxetine+Concerta (N=9) 28.7 (12.1) -3.3 (20.9) 0.645 18.1 (5.8) -4.0 (10.0) 0.265 10.6 (7.9) 0.7 (11.5) 0.866 15.4 (7.7) 1.9 (9.4) 0.562 31.2 (10.3) 3.3 (15.7) 0.541 4.1 (1.1) -0.7 (1.8) 0.299 2.78 (0.83) 0.11 (1.54) 40.9 (19.4) -4.7 (24.5) 0.584 13.7 (5.9) (n=6) -1.3 (1.4) (n=6) 0.062 Atomoxetine+Placebo (N=8) 31.9 (10.9) -4.3 (5.2) 0.053 16.3 (5.1) -1.8 (1.8) 0.031 15.6 (6.5) -2.5 (4.2) 0.140 17.4 (6.9) -2.1 (4.8) 0.253 35.4 (6.6) -1.3 (9.0) 0.707 4.3 (1.2) -0.6 (0.5) 0.011 p-valueb 0.909 0.662 0.657 0.419 0.601 0.953 3.5 (0.93) -0.63 (1.30) 0.433 45.6 (18.3) -2.9 (5.6) 0.187 0.771 17.4 (6.4) (n=7) -0.2 (2.7) (n=5) 0.339 0.876 (Abbreviations and footnotes continues)
CT Registry ID#7065 Page 12 Table LYBU.4. Secondary Objective Study Period IIb Mean Change from to LOCF Endpoint Enrolled Patients (concluded) Abbreviations: ADHDRS-IV-Parent:Inv = Attention-Deficit/Hyperactivity Disorder Rating Scale-IV- Parent Version: Investigator-Administered and Scored, CGI-ADHD-I = Clinical Global Impressions- Attention-Deficit/Hyperactivity Disorder-Improvement, CGI-ADHD-S = Clinical Global Impressions- Attention-Deficit/Hyperactivity Disorder-Severity, Conners GI-T = Conners Global Index-Teacher, CPRS-R:S = Conners' Parent Rating Scale-Revised: Short Form, LOCF = last observation carried forward, LPS-P = Life Participation Scale-Parent Version, N = number of patients, SD = standard deviation, WPREMB-Revised-Parent = Weekly Parent Ratings of Evening and Morning Behavior- Revised. a Within-treatment group changes were assessed using a paired t-test. b Treatment comparisons were assessed using an ANCOVA. : last measurement obtained on or prior to Visit 5. Endpoint: last measurement after Visit 5 but on, or before Visit 8 (final visit). Safety There were no deaths or SAEs in this study. Table LYBU.5 lists the treatment-emergent adverse events that occurred in 2% of patients. Treatment-emergent adverse events (TEAEs) were reported by 16 of the 24 patients treated in Study Period IIa. Events reported by 14 of the 16 patients were considered possibly related to study drug. The most frequently reported events were vomiting (5 patients); headache (4 patients); decreased appetite, nausea, pyrexia, and somnolence (each in 3 patients); and irritability and rash (each in 2 patients). One TEAE (headache) was considered severe. Two patients discontinued due to AEs (mydriasis/dilated pupils and vomiting). In Study Period IIb, TEAEs were reported for 2 of 4 patients in the remitter group, 5 of 9 patients in the atomoxetine+concerta treatment group, and 6 of 8 patients in the atomoxetine+placebo treatment group. Of the 13 patients randomized across all three treatment groups, 9 patients had events that were considered possibly related to study drug. Adverse events reported by more than 1 patient included nausea, vomiting, and initial insomnia (each in 3 patients); and headache and rhinitis (each in 2 patients). There were no significant differences in the incidence of TEAEs across the randomized groups. Only one TEAE (irritability in an atomoxetine+placebo patient) was considered severe. Two patients discontinued due to an AE: 1 patient due to intermittent irritability (atomoxetine+placebo treatment group), and 1 patient due to atrial ectopy (atomoxetine+concerta treatment group).
CT Registry ID#7065 Page 13 Table LYBU.5. Summary of Treatment-Emergent Adverse Events Incidence Greater than or Equal to 2 Percent All Study Periods, Enrolled Patients Study Period IIa (N=24) Atx + Pla (N=24) n (%) Atx + Pla Remitters (N=4) n (%) Study Period IIb (N=21) Atx + Cnc Atx + Pla Nonremitters Nonremitters (N=9) (N=8) n (%) n (%) Total SPIIb (N=21) n (%) MedDRA Preferred Terma Patients with no 8 (33.3) 2 (50.0) 4 (44.4) 3 (37.5) 9 (42.9) TEAE Patients with 1 16 (66.7) 2 (50.0) 5 (55.6) 5 (62.5) 12 (57.1) TEAE Vomiting 5 (20.8) 1 (25.0) 1 (11.1) 1 (12.5) 3 (14.3) Headache 4 (16.7) b 1 (11.1) 1 (12.5) 2 (9.5) Nausea 3 (12.5) 1 (12.5) 1 (4.8) Pyrexia 3 (12.5) Decreased appetite 3 (12.5) - - - - Somnolence 3 (12.5) Irritability 2 (8.3) 1 (12.5)c 1 (4.8) Rash 2 (8.3) 1 (11.1) 1 (4.8) Mydriasis 1 (4.2) Diarrhoea 1 (4.2) Fatigue 1 (4.2) Therapeutic response unexpected 1 (4.2) Influenza 1 (4.2) Hand fracture 1 (4.2) Blood pressure increased 1 (4.2) Dizziness 1 (4.2) Initial insomnia 1 (4.2) 1 (11.1) 2 (25.0) 3 (14.3) Mood altered 1 (4.2) Rhinorrhoea 1 (4.2) Rhinitis 1 (25.0) 1 (12.5) 2 (9.5) Supraventricular 1 (11.1) 1 (4.8) extrasystoles Stomach 1 (11.1) 1 (4.8) discomfort Toothache 1 (11.1) 1 (4.8) Abdominal pain, 1 (4.8) upper 1 (12.5) (abbreviations and footnotes continues)
CT Registry ID#7065 Page 14 Table LYBU.5. Summary of Treatment-Emergent Adverse Events Incidence Greater than or Equal to 2 Percent All Study Periods Enrolled Patients (concluded) Abbreviations: Atx = atomoxetine, Cnc = Concerta, N = number of patients who took at least one dose of study drug, n = number of patients with treatment-emergent adverse event, Pla = placebo, TEAE = treatment-emergent adverse event. a Based on MedDRA coding dictionary version 8.0. b Reported as severe by 1 patient. c Reported as severe by 1 patient. Note: Study Period IIa: defined as Visits 1-2, and endpoint as Visits 3-5. Study Period IIb: defined as Visit 5, and endpoint as Visits 6-8. Laboratory Values No ECG changes were statistically significant in either Study Period IIa or IIb. In Study Period IIa, statistically significant laboratory changes were seen in non-fasting glucose (p=.022) and alkaline phosphate (p<.001). In Study Period IIb, statistically significant laboratory changes were seen only in the atomoxetine+concerta treatment group. These laboratory changes included: alkaline phosphate (p=.004), GGT (p=.016), leukocyte count (p=.016), and neutrophils (p=.039). However, none of the changes in ECGs or laboratory analytes in either Study Period IIa or Study Period IIb were considered by study physician review to be clinically meaningful. No patient discontinued from the study due to an abnormal lab value. Table LYBU.6 presents a summary of ECG results.
Table LYBU.6. Summary of Mean Change in Electrocardiogram from to Endpoint Study Periods IIa and IIb Study Period IIa a Study Period IIb b ECG Assessment Atx (n=24) p-value Remitters (n=4) Atx + Cnc (n=9) Atx + Plc (n=8) p-value c Heart rate (bpm) RR interval (msec) PR interval (msec) QRS interval (msec) QT interval (msec) Data-corrected QT interval (msec) QTcB interval (msec) QTcF interval (msec) 87.5 (13.0) -1.3 (14.7).674 89.5 (5.7) 2.0 (4.1) 699.9 (101.4) d.642 672.8 (44.2) 11.5 (117.2) e -15.8 (33.1) 133.8 (18.1) d.903 137.5 (12.6) -0.4 (16.9) e -12.0 (14.2) 80.4 (6.2) d.648 80.0 (8.2) -0.9 (9.0) e 2.5 (5.0) 350.0 (24.0) d.763 347.5 (9.6) -1.3 (20.5) e -12.5 (9.6) 403.3 (16.9) d.354 406.0 (15.9) -3.5 (17.6) e -11.0 (18.2) 420.0 (19.2) d.380 424.3 (19.0) -4.3 (22.8) e -10.8 (20.9) 395.0 (16.7) d.369 397.0 (14.6) -3.0 (15.9) e -11.3 (16.6) 84.6 (16.6) 2.2 (16.8) 738.2 (172.6) -29.8 (126.7) 132.2 (13.9) 0.0 (15.0) 77.8 (6.7) 5.6 (7.3) 353.3 (22.9) 0.0 (24.5) 400.8 (19.9) 5.3 (19.6) 415.6 (27.2) 7.0 (25.3) 393.6 (17.3) 4.2 (18.2) 87.5 (16.1) 1.0 (13.1) 704.6 (118.5) -13.5 (98.8) 131.3 (21.0) 0.0 (20.7) 81.3 (8.3) 1.3 (6.4) 353.8 (32.9) -10.0 (23.3) 406.4 (18.2) -8.6 (17.3) 422.9 (18.5) -7.9 (20.5) 398.1 (19.5) -8.9 (17.1).650.774.873.455.162.208.331.187 (continues) CT Registry ID#7065 Page 15
Table LYBU.6. Summary of Mean Change in Electrocardiogram from to Endpoint Study Periods IIa and IIb (Concluded) Study Period IIa a Study Period IIb b ECG Assessment Atx (n=24) p-value Remitters (n=4) Atx + Cnc (n=9) Atx + Plc (n=8) p-value c QTcR interval (msec) 400.4 (16.8) d -3.4 (16.9) e.341 403.0 (15.1) -11.5 (16.9) 398.0 (19.0) 5.2 (19.1) 403.4 (18.6) -8.5 (17.3).203 Abbreviations: Atx = atomoxetine, bpm = beats per minute, Cnc = Concerta, ECG = electrocardiogram; msec = milliseconds; n = number of patients with nonmissing data, Plc = placebo, PR interval = the time elapsing between the beginning of the P wave and the beginning of the next QRS complex; QRS = deflections in an electrocardiographic tracing that represent ventricular activity of the heart; QTc = corrected QT interval; QTcB = corrected QT interval using Bazett s correction; QTcF = corrected QT interval using Fridericia s correction; QTcR = corrected QT interval using Regression correction; RR = The time elapsing between two consecutive R waves; SD = standard deviation. Analyzed using paired t-test. a was last observation taken before or on Visit 2. Endpoint was last observation taken after Visit 2. b was last observation taken before or on Visit 5. Endpoint was last observation taken after Visit 5. c Analyzed using analysis of covariance with effects for treatment and investigator with baseline value as covariate. Remitters were excluded from this analysis. d n=24 e n=23 CT Registry ID#7065 Page 16
CT Registry ID#7065 Page 17 Vital Signs and Weight There were no statistically significant changes in vital signs or weight across treatment groups during either of the Study Periods. In Study Period IIb, statistically significant decreases from baseline in body mass index (p=.014) and orthostatic diastolic blood pressure (p=.006) were noted at LOCF endpoint in the atomoxetine+concerta treatment group, and increases in standing systolic blood pressure (p=.036) in the remitter group. There were no other significant changes from baseline to LOCF endpoint either within or across randomized groups in other vital sign parameters or body weight. Table LYBU.7 presents a summary of mean change in vital signs and weight from baseline to endpoint. Table LYBU.7. Summary of Mean Change in Vital Signs and Weight from to Endpoint Study Periods IIa and IIb Enrolled Patients Variable Diastolic blood pressure (mmhg); sitting Diastolic blood pressure (mmhg); standing Diastolic blood pressure (mmhg); orthstatic Systolic blood pressure (mmhg); sitting Systolic blood pressure (mmhg); standing Study Period IIa a Atx + Plc n=24 69.1 (9.7) -0.6 (12.8).825 70.0 (8.2) -1.9 (10.3).373 0.9 (4.8) -1.3 (8.4).443 106.2 (11.5) 0.5 (11.8).850 104.3 (10.3) 0.3 (11.2).886 Remitters n=4 69.0 (10.4) 0.0 (5.4) 1.000 68.5 (15.0) -1.0 (5.0).718-0.5 (9.0) -1.0 (4.8).703 104.5 (9.3) -1.5 (14.1).845 99.5 (9.6) 7.5 (4.1).036 Study Period IIb b Atx + Cnc Atx + Plc n=9 n=8 p-value c 62.7 (7.6) 7.1 (9.8).062 62.8 (8.5) 3.6 (8.4).240 0.1 (3.6) -3.6 (2.8).006 99.9 (15.0) 5.0 (10.0).171 99.2 (14.4) 3.2 (11.5).424 71.0 (9.5) -2.5 (8.7).445 71.6 (8.7) -3.1 (9.1).365 0.6 (6.5) -0.6 (3.5).629 108.8 (11.3) -5.8 (12.5).234 109.3 (13.7) -4.4 (11.7).326.502.903.062.269.681 (continues)
CT Registry ID#7065 Page 18 Table LYBU.7. Summary of Mean Change in Vital Signs and Weight from to Endpoint Study Periods IIa and IIb Enrolled Patients (concluded) Study Period IIa a Atx + Plc n=24 Remitters n=4 Study Period IIb b Atx + Cnc Atx + Plc n=9 n=8 p-value c Variable Systolic blood pressure (mmhg); orthstatic -1.9 (7.3) -5.0 (7.4) -0.7 (4.7) 0.5 (5.0).120-0.1 (7.9) 9.0 (10.1) -1.8 (5.2) 1.4 (5.2).939.174.332.480 Heart rate (bpm); sitting 92.0 (13.2) 101.5 (13.0) 85.7 (11.1) 94.0 (14.0) 0.4 (14.2) -9.5 (9.1) 5.0 (13.0) -5.5 (18.0).901.887.129.281.415 Heart rate (bpm); standing 93.8 (13.4) 105.5 (15.8) 89.7 (12.7) 93.8 (14.2) 0.9 (15.0) -6.5 (7.2) 5.0 (12.6) 1.0 (13.4).988.767.168.268.838 Heart rate (bpm); orthstatic 1.8 (10.9) 4.0 (5.7) 4.0 (3.0) -0.3 (5.4) 0.5 (12.3) 3.0 (6.2) 0.0 (4.6) 6.5 (12.1).751.844.406 1.000.172 Body Mass Index (kg/m 2 ) 17.8 (3.3) 21.4 (6.1) 17.6 (2.1) 16.4 (1.6) 0.0 (0.6) 0.5 (1.4) -0.9 (0.8) -0.2 (0.5).168.847.492.014.392 Weight (kg) 35.5 (12.2) 45.0 (17.8) 37.8 (11.9) 29.7 (6.9) 0.0 (1.3) 2.6 (4.1) -1.0 (1.9) 0.0 (0.6).189.988.288.146.956 Body Temperature ( C) 36.4 (0.7) 36.5 (0.2) 36.3 (0.5) 36.0 (0.7) -0.1 (0.5) 0.0 (0.5) -0.1 (0.4) 0.1 (0.7).882.372.929.601.677 Abbreviations: bpm = beats per minute, C = Celsius; Cnc = Concerta, kg = kilogram; n = number of patients with non-missing data, Plc = placebo, SD = standard deviation. Population: Enrolled patients with at least one baseline and endpoint observation. a was last observation taken before or on Visit 2. Endpoint was last observation taken after Visit 2. b was last observation taken before or on Visit 5. Endpoint was last observation taken after Visit 5. c Analyzed using analysis of covariance with effects for treatment and investigator with baseline value as covariate. Remitters were excluded from this analysis. d Within group changes analyzed using a paired t-test.