Summary ID# Clinical Study Summary: Study B4Z-US-LYBH

Transcription

1 CT Registry ID# 5671 Page 1 Summary ID# 5671 Clinical Study Summary: Study B4Z-US-LYBH Placebo-Controlled Study of the Effects of Atomoxetine Hydrochloride on Bladder Control in Children with Nocturnal Enuresis Date summary approved by Lilly: 30 November 2006 Brief Summary of Results This study was a randomized, double-blind, placebo-controlled comparison study of outpatients aged 6 through 14 with nocturnal enuresis with an open-label extension. Atomoxetine-treated patients reported an increase from 1.51 to 2.98 dry nights per week compared with placebo patients who reported an increase from 1.01 to 1.61 dry nights per week (p=.01). Fifteen of the atomoxetine-treated subjects had an increase of at least 2 dry nights per week compared with only 6 of the placebo-treated subjects (p=.042). Results of a repeated measures analysis indicated that atomoxetine produced significantly greater efficacy compared with placebo overall and specifically at Visits 5, 6, and 8. During the discontinuation/no drug period, patients who were previously treated with atomoxetine reported a decrease of 0.8 dry nights per week, while patients who were previously treated with placebo reported a slight increase of.06 nights per week (p=.01). Patients who continued into the open-label extension period increased their number of dry nights per week after the re-initiation of treatment and this increase continued over time (p<.001). There were no deaths reported in this study. Of the two reported serious adverse events (SAEs) for this study, one (dehydration) occurred in a placebo-treated patient, the other (asthma not otherwise specified [NOS]) occurred in an atomoxetine-treated patient. There were no significant differences in treatment-emergent adverse events (TEAEs) or reasons for study discontinuation during the acute period between placebo and patients treated with atomoxetine.

2 CT Registry ID# 5671 Page 2 Atomoxetine-treated subjects had a statistically significant increase in mean standing pulse and mean supine pulse compared with placebo-treated subjects (p<.001 for both measures). Supine pulse increased 8.39 bpm from baseline, while standing pulse increased bpm from baseline. There were no significant differences between treatments in blood pressure. During the open-label extension period, subjects had a statistically significant increase in supine pulse. Atomoxetine-treated subjects had a decrease during the acute period in weight of.45 kg compared to an increase of 1.08 kg for placebo (p<.001). During the open-label extension period, subjects had significant increases in height and weight (2.64 cm and 1.65 kg, p<.001 for each). Atomoxetine-treated subjects had a statistically significant increase in heart rate and the expected related decreases in PR interval, RR, and QT intervals compared with placebotreated subjects. None of the subjects had increased corrected QT values. During the open-label extension period, subjects had a significant decrease from baseline in RR interval; they also had a significant increase from baseline in the QRS interval. None of the changes in electrocardiogram (ECG) were considered clinically significant. There were statistically significant change score differences between atomoxetine and placebo for some laboratory values, but they were small relative to baseline.

3 CT Registry ID# 5671 Page 3 Title of Study: Placebo-Controlled Study of the Effects of Atomoxetine Hydrochloride on Bladder Control in Children with Nocturnal Enuresis Investigator(s): This multicenter study included 7 principal investigators. Study Center(s): This study was conducted at 7 study centers in 1 country. Length of Study: 8 months Phase of Development: 3b Date of first patient enrolled: 03 December 2001 Date of last patient completed: 05 August 2002 Objectives: The primary objective of this study was to compare the efficacy of atomoxetine to placebo for treating nocturnal enuresis in a sample of pediatric subjects who met DSM IV criteria for nocturnal enuresis. Efficacy was determined by a comparison of the mean number of dry nights per week using an intent-to-treat analysis of the primary outcome measure, the Dry Night Log-Parent Report (DNL-PR) for atomoxetine-treated and placebo-treated subjects. Secondary objectives: To compare the safety and tolerability of atomoxetine with placebo in a population who meet DSM-IV criteria for nocturnal enuresis. To compare the improvement in patient-reported outcomes (quality of life) between atomoxetine and placebo as assessed by the Child Health Questionnaire PF50 (CHQ-PF50). To assess the safety and tolerability of rapid-dose titration of atomoxetine to the fixed-treatment dose. To compare the improvement on the Parent Distress Scale (PADS) between atomoxetine- and placebo-treated subjects. To evaluate, during the open-label extension period, the efficacy of atomoxetine in treating nocturnal enuresis, as determined by a comparison of the mean number of dry nights per week using an intent-to-treat analysis of the primary outcome measure, the Dry Night Log-Parent (DNL-PR) for atomoxetine-treated subjects. To assess the safety and tolerability of dose titration of atomoxetine to the fixed-treatment dose, assess and track the dosing range of atomoxetine on a BID dosing regimen, and to assess the maintenance of benefits of treatment during the flexible-dosing, open-label extension. Study Design: A randomized, double-blind, placebo-controlled comparison study of outpatients aged 6 through 18 years with nocturnal enuresis with an open-label extension. Number of Patients: Planned: Approximately 80 pediatric subjects. Randomized: 44 atomoxetine, 43 placebo Completed double-blind period: 35 atomoxetine, 34 placebo Diagnosis and Main Criteria for Inclusion: Patients were at least 6 years old but less than 18 years old at Visit 1. Patients met the DSM-IV diagnostic criteria for nocturnal enuresis. The diagnosis of nocturnal enuresis was confirmed during the screening visit by administration of the Voiding History- National Kidney Foundation questionnaire (VH-NKF). Test Product, Dose, and Mode of Administration: Atomoxetine 0.5 mg/kg/day, given for three days, 1.0 mg/kg/day for three days and all subsequent days at 1.5 mg/kg/day, all doses were divided and given orally twice a day. Mean final dose for the double-blind treatment period: 1.42 mg/kg. Reference Therapy, Dose, and Mode of Administration: Placebo was administered orally BID. Duration of Treatment: Twelve weeks double-blind treatment, followed by a 9 to 18 day drug discontinuation period, then a 9 to 18 day period of no study drug, followed by an open-label extension period for up to 15 months.

4 CT Registry ID# 5671 Page 4 Variables: Efficacy: The primary efficacy measure was the number of dry nights per week with data recorded on the Dry Night Log-Parent Report (DNL-PR). The secondary efficacy measure was the Parent Distress Scale (PADS) which assessed the impact of the child s enuresis on the parent via a 100 mm Visual Analog Scale. Safety: Safety measures included TEAEs, vital signs, height and weight, laboratory analytes, pregnancy tests at screening, and ECGs. Health Outcomes: Physical and psychosocial well being was assessed using the Child Health Questionnaire Parent Form 50 (CHQ-PF50). Evaluation Methods: Data were analyzed separately for Study Period II (acute double-blind), Study Period III/IV (discontinuation/washout), and Study Period V (open-label extension). A fixed-effects ANOVA model with terms for treatment and investigator was used to assess whether there was a treatment difference in mean number of dry nights per week, a two-sided significance level of.05 was assumed. Each subject s number of dry nights per week was defined as the product of 7 and the ratio of dry nights to total number of nights recorded during the study period visit window, provided that no more than 30% of the possible nights were missing from that interval. All postbaseline DNL-PR and PADS scores during the acute period were analyzed using a restricted maximum likelihood (REML) based mixed effects model, repeated measures technique. This analysis included the fixed categorical effects of treatment, investigator, visit, and treatment-by-visit interaction as well as the continuous, fixed covariate of baseline score and a random subject effect. Four different covariance structures were considered to model the within-subject variance: unstructured, heterogeneous toeplitz, heterogeneous autoregressive of order 1, and heterogeneous compound symmetric. The covariance structure that produced the largest Akaike s Information Criteria score was selected for each analysis. These analyses compared atomoxetine and placebo at each postbaseline visit using a contrast from the repeated measures mixed effects model. During the open-label extension period, DNL-PR postbaseline scores were analyzed with a repeated measures model that included only investigator and visit. Parent Distress Scale and CHQ change from baseline was analyzed during the acute period and drug washout period using a fixed-effects analysis of variance (ANOVA) model with terms for treatment and investigator. For analyses of data during the drug washout period, treatment groups were defined as the treatment to which patients were randomized at Visit 2. Fisher s Exact test was used to test for a treatment difference in incidence of response (increase from baseline to endpoint of 2 or more dry nights per week). Changes from baseline in labs, vitals, and ECGs were analyzed using a one-way ANOVA model with a term for treatment during the acute period and within group changes (for acute and open-label period) were assessed using Wilcoxon s Signed rank test. Incidence of TEAEs and treatment-emergent abnormal labs were compared across treatments during the acute period using Fisher s Exact test.

5 CT Registry ID# 5671 Page 5 I Washout/ Sreening V1-V2: 9-18 Days (14 Days Suggested) II III Double - Blind, Placebo Discontinuation Controlled - Treatment Phase 7-15 weeks V2-V Days (14 Days Suggested) IV No Study Drug V Flexible-dosing Open-Label Treatment V 10- V13: 9-18 days (14 Days suggested) V13-V17: Days (45 Days suggested) V17-V20: Days (90 Days suggested) I N=80 randomized Visit Week No medication Atomoxetine (N=40) Atomoxetine Placebo (N=40) Figure LYBH.1. Study design. Patient Demographics There were 95 patients entered in this study of which 8 were not randomized, 44 were randomized to Atomoxetine, and 43 to placebo. The patient population was approximately 26% female and 74% male. The median age of patients in this study was 9.4 years. The majority of the patients (approximately 86%) were Caucasian. See Table LYBH.1 below.

6 CT Registry ID# 5671 Page 6 Table LYBH.1. Patient Demographics Not Rand ATOMOX Placebo Total Variable (N=8) (N=44) (N=43) (N=95) Sex: No. (%) No. Patients Female 2 (25.0) 11 (25.0) 12 (27.9) 25 (26.3) Male 6 (75.0) 33 (75.0) 31 (72.1) 70 (73.7) Origin: No. (%) No. Patients African Descent 2 (25.0) 2 (4.5) 1 (2.3) 5 (5.3) Caucasian 4 (50.0) 38 (86.4) 40 (93.0) 82 (86.3) Hispanic 2 (25.0) 3 (6.8) 1 (2.3) 6 (6.3) Other 0 1 (2.3) 1 (2.3) 2 (2.1) Age: yrs No. Patients Mean Median Standard Dev Minimum Maximum Height (cm) at Visit 1 No. Patients Mean Median Standard Dev Minimum Maximum Unspecified Weight (kg) at Visit 1 No. Patients Mean Median Standard Dev Minimum Maximum CYP2D6 Status No. Patients EXTN 5 (100) 42 (95.5) 41 (95.3) 88 (95.7) SLOW 0 2 (4.5) 2 (4.7) 4 (4.3) Unspecified

7 CT Registry ID# 5671 Page 7 Patient Disposition Eighteen patients discontinued during the treatment phase (Study Period II); three for adverse events. Three-fourths of the randomized patients (75%) entered the open-label extension period. See Tables LYBH.2 and LYBH.3 below for summary of patient disposition for Study Periods I-V. Table LYBH.2. Summary Report of Patient Disposition by Visit Study Period I-II N N N N N N N N ADVERSE EVENT DEATH LACK OF EFFICACY, PATIENT AND PHYSICIAN PERCEPTION LACK OF EFFICACY, PATIENT PERCEPTION LACK OF EFFICACY, PHYSICIAN PERCEPTION LOST TO FOLLOW-UP NONCOMPLIANCE PATIENT CONFLICT OR OTHER PATIENT DECISION PHYSICIAN DECISION PROTOCOL COMPLETE PROTOCOL VIOLATION SATISFACTORY RESPONSE, PATIENT AND PHYSICIAN PERCEPTION SATISFACTORY RESPONSE, PATIENT PERCEPTION SATISFACTORY RESPONSE, PHYSICIAN PERCEPTION SPONSOR DECISION STUDY PERIOD I COMPLETED STUDY PERIOD II COMPLETED NOT RANDOMIZED Entry criteria not met TOTAL PATIENTS DISPOSITION AT EACH VISIT POPULATION: ALL OF THE PATIENTS ENROLLED IN STUDY PERIODS I-II ARE INCLUDED

8 CT Registry ID# 5671 Page 8 Table LYBH.3. Summary Report of Patient Disposition by Visit Study Period III-V N N N N N N N N N N ADVERSE EVENT DEATH LACK OF EFFICACY, PATIENT AND PHYSICIAN PERCEPTION LACK OF EFFICACY, PATIENT PERCEPTION LACK OF EFFICACY, PHYSICIAN PERCEPTION LOST TO FOLLOW-UP NONCOMPLIANCE PATIENT CONFLICT OR OTHER PATIENT DECISION PHYSICIAN DECISION PROTOCOL COMPLETE PROTOCOL VIOLATION SATISFACTORY RESPONSE, PATIENT AND PHYSICIAN PERCEPTION SATISFACTORY RESPONSE, PATIENT PERCEPTION SATISFACTORY RESPONSE, PHYSICIAN PERCEPTION SPONSOR DECISION STUDY PERIOD III COMPLETED STUDY PERIOD IV COMPLETED STUDY PERIOD V COMPLETED TOTAL PATIENTS DISPOSITION AT EACH VISIT POPULATION: ALL OF THE PATIENTS ENROLLED IN STUDY PERIODS III-V ARE INCLUDED

9 CT Registry ID# 5671 Page 9 Primary Efficacy Measures Results of a repeated measures analysis of the DNL-PR of Study Period II, shown in Table LYBH.4a, indicated that atomoxetine produced significantly greater efficacy compared with placebo overall and specifically at Visits 5, 6, and 8. Atomoxetine-treated patients reported an increase from 1.51 to 2.98 dry nights per week compared with placebo patients who reported an increase from 1.01 to 1.61 dry nights per week (p=.01) (see Table LYBH.4b).

10 Table LYBH.4a. Dry Night Log-Parent Report: Average Dry Nights Per Week Repeated Measures Summary Table Study Period II Atomoxetine Placebo Treatment Difference Visit LS Mean SE p-val a LS Mean SE p-val a LS Mean SE p-val b < < < < < < < < < < < < % Confidence Interval on Change from Baseline to Visit 8 ( -0.16, 1.03 ) ( 0.99, 2.16 ) Summary of Model Parameters F-Value P-Value c Baseline <.001 Treatment Visit Investigator Treatment*Visit Results based on a mixed model with visit, baseline, treatment,investigator, treatment by visit interaction using an unstructured covariance matrix to model correlations within patient across visits. 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 means at the given visit. c) P-values are from F-tests for a nonzero coefficient estimate. CT Registry ID# 5671 Page 10

11 Table LYBH.4b. Dry Night Log-Parent Report: Average Dry Nights per Week Mean Change From Baseline to Endpoint Study Period II BASELINE ENDPOINT CHANGE P-VALUE(A) P-VALUE(B) TREATMENT GROUP N MEAN SD MEAN SD MEAN SD AVG DRY NIGHTS PER WEEK TMX < PLA % CONFIDENCE INTERVAL: (-1.54, -0.22) A) P-VALUE IS FROM WILCOXON SIGNED-RANK TEST. B) BETWEEN TREATMENT GROUP P-VALUES ARE FROM BASELINE TO ENDPOINT SCORES USING LEAST SQUARES MEANS FROM AN ANCOVA MODEL WITH TERMS FOR INVESTIGATOR, TREATMENT AS COVARIATE TMX = Atomoxetine CT Registry ID# 5671 Page 11

12 CT Registry ID# 5671 Page 12 Table LYBH.5 shows that 15 of the atomoxetine-treated subjects had an increase of at least 2 dry nights per week compared with only 6 placebo-treated subjects (p=.042). Table LYBH.5. Efficacy Response Rates ATOMOX Placebo Total p-value Variable (N=44) (N=43) (N=87) Increase of >=2 dry nights per week No. Patients * No 27 (64.3) 35 (85.4) 62 (74.7) Yes 15 (35.7) 6 (14.6) 21 (25.3) One patient was excluded from this analysis due to Dry Night Log non-compliance * Frequencies are analyzed using a Fishers-Exact test. During the discontinuation/no drug period (Study Period III/IV), patients who were previously treated with atomoxetine reported a decrease of 0.8 dry nights per week, while patients who were previously treated with placebo reported an increase of.06 nights per week (p=.01) (Table LYBH.6).

13 Table LYBH.6. Dry Night Log-Parent Report: Average Dry Nights Per Week Mean Change From Baseline to Endpoint Study Period III/IV BASELINE ENDPOINT CHANGE P-VALUE(A) P-VALUE(B) TREATMENT GROUP N MEAN SD MEAN SD MEAN SD AVG DRY NIGHTS PER WEEK TMX < PLA % CONFIDENCE INTERVAL: (0.20, 1.37 ) A) P-VALUES ARE FROM THE WILCOXON SIGNED-RANK TEST B) BETWEEN TREATMENT GROUP P-VALUES ARE FROM BASELINE TO ENDPOINT (LOCF) SCORES USING A FIXED EFFECT ANOVA MODEL WITH TERMS FOR TREATMENT AND INVESTIGATOR POPULATION: ALL OF THE PATIENTS ENROLLED IN STUDY PERIOD III/IV ARE INCLUDED CT Registry ID# 5671 Page 13

14 CT Registry ID# 5671 Page 14 Table LYBH.7 shows that the patients who continued into the open-label extension period increased their number of dry nights per week after the reinitiation of treatment and this increase continued over time (p<.001).

15 Table LYBH.7. Repeated Measures Summary Table for Dry Night Log (Average Dry Nights per Week) Study Period V VISIT LSMEAN SE P-VAL (A) P-VAL (B) < RESULTS BASED ON A MIXED MODEL WITH VISIT, BASELINE, CYP2D6GEN,INVESTIGATOR USING AN UNSTRUCTURED COVARIANCE MATRIX TO MODEL CORRELATIONS WITHIN PATIENT ACROSS VISITS A) P-VALUES ARE FROM TESTS FOR A NONZERO LEAST SQUARES MEAN AT THE GIVEN VISIT B) P-VALUE IS FROM F-TEST FOR A NONZERO COEFFICIENT ESTIMATE FOR THE VISIT TERM BASED ON THE MODEL DESCRIBED ABOVE POPULATION: ALL PATIENTS WHO ENTERED IN THE OPEN LABEL EXTENSION TREATMENT PERIOD ARE INCLUDED CT Registry ID# 5671 Page 15

16 CT Registry ID# 5671 Page 16 Table LYBH.8 shows that no statistically significant treatment differences in change from baseline were detected on the PADS during the acute period.

17 Table LYBH.8. Parent Distress Scale Mean Change From Baseline to Endpoint Study Period II BASELINE ENDPOINT CHANGE P-VALUE(A) P-VALUE(B) TREATMENT GROUP N MEAN SD MEAN SD MEAN SD PADS SCORE FOR ENURESIS TMX < PLA % CONFIDENCE INTERVAL: (-6.29, 19.36) A) P-VALUE IS FROM WILCOXON SIGNED-RANK TEST. B) BETWEEN TREATMENT GROUP P-VALUES ARE FROM BASELINE TO ENDPOINT (LOCF) SCORES USING LEAST SQUARES MEANS FROM AN ANCOVA MODEL WITH TERMS FOR INVESTIGATOR, TREATMENT AS COVARIATE CT Registry ID# 5671 Page 17

18 CT Registry ID# 5671 Page 18 Table LYBH.9 shows that there were no statistically significant differences between treatment groups in mean change from baseline in Parent Distress Scale scores during drug discontinuation. Parent Distress Scale scores worsened for both treatment groups during the drug discontinuation; however, there was not a statistically significant difference between the original randomization groups.

19 Table LYBH.9. Parent Distress Scale Mean Change From Baseline To LOCF Endpoint Study Period III/IV BASELINE ENDPOINT CHANGE P-VALUE(A) P-VALUE(B) TREATMENT GROUP N MEAN SD MEAN SD MEAN SD PADS SCORE FOR ENURESIS TMX PLA % CONFIDENCE INTERVAL: (-10.53, 11.94) A) P-VALUES ARE FROM THE WILCOXON SIGNED-RANK TEST. B) BETWEEN TREATMENT GROUP P-VALUES ARE FROM BASELINE TO ENDPOINT (LOCF) SCORES USING A FIXED EFFECT ANOVA MODEL WITH TERMS FOR TREATMENT AND INVESTIGATOR POPULATION: ALL OF THE PATIENTS ENROLLED IN STUDY PERIOD III/IV ARE INCLUDED TMX = Atomoxetine CT Registry ID# 5671 Page 19

20 CT Registry ID# 5671 Page 20 Safety There were no deaths reported in this study. Of the two reported SAEs for this study (see Table LYBH.10), one (dehydration) occurred in a placebo-treated patient. The other (asthma NOS) occurred in an atomoxetine-treated patient.

21 Table LYBH.10. Listing of Patients who died or had SAEs Days from Event Therapy Start of Event Duration Inv Pat Group Therapy Resolved? (days) Preferred Term Name J Placebo 49 Yes 2 Dehydration 7 P ATOMOX 129 Yes 2 Asthma NOS Visits 1-8 CT Registry ID# 5671 Page 21

22 CT Registry ID# 5671 Page 22 There were no statistically significant differences in TEAEs (Table LYBH.11) or reasons for study discontinuation (LYBH.12) during the acute period between placebo-treated and atomoxetine-treated patients. Table LYBH.13 gives a summary of TEAEs during the open-label extension period. Table LYBH.11. Summary of Treatment-Emergent Adverse Events that Occurred in 5% of Patients All Randomized Patients with 1 Dose of Study Drug ATOMOX Placebo Total p-value* (N=44) (N=43) (N=87) Preferred Term n (%) n (%) n (%) - PATIENTS WITH >= 1 TESS 29 (65.9) 25 (58.1) 54 (62.1).512 PATIENTS WITH NO TESS 15 (34.1) 18 (41.9) 33 (37.9).512 Headache NOS 9 (20.5) 4 (9.3) 13 (14.9).229 Nausea 4 (9.1) 3 (7.0) 7 (8.0) 1.00 Appetite decreased NOS 3 (6.8) 2 (4.7) 5 (5.7) 1.00 Gastroenteritis viral NOS 3 (6.8) 1 (2.3) 4 (4.6).616 Gastroenteritis NOS 3 (6.8) 1 (2.3) 4 (4.6).616 Heart rate increased 3 (6.8) 0 3 (3.4).241 Insomnia 3 (6.8) 0 3 (3.4).241 Irritability 3 (6.8) 1 (2.3) 4 (4.6).616 Pyrexia 3 (6.8) 2 (4.7) 5 (5.7) 1.00 Vomiting NOS 3 (6.8) 3 (7.0) 6 (6.9) 1.00 Abdominal pain upper 1 (2.3) 3 (7.0) 4 (4.6).360 Diarrhoea NOS 1 (2.3) 3 (7.0) 4 (4.6).360 Nasopharyngitis 0 3 (7.0) 3 (3.4).116 Upper respiratory tract infection NOS 0 4 (9.3) 4 (4.6).055 Baseline: Visits 1-2, Endpoint: Visits 3-8 Frequencies are analyzed using a Fisher's Exact test.

23 CT Registry ID# 5671 Page 23 Table LYBH.12. Reasons for Discontinuation ATOMOX Placebo p-value* (N=44) (N=43) Reason for Discontinuation n (%) n (%) Study Period II Completed 35 (79.5) 34 (79.1) 1.00 Adverse Event 2 (4.5) 1 (2.3) 1.00 Lack of efficacy, patient perception 2 (4.5) 1 (2.3) 1.00 Lack of efficacy, pat and MD perception 0 1 (2.3).494 Unable to contact pat(lost to follow-up) 3 (6.8) 2 (4.7) 1.00 Personal conflict or other pat decision 1 (2.3) 3 (7.0).360 Noncompliance 1 (2.3) 1 (2.3) 1.00 Study Period II: Visits 3-8

24 CT Registry ID# 5671 Page 24 Table LYBH.13. Summary Report of Treatment-Emergent Adverse Events; Open-Label Extension Period: B4Z-US-LYBH - TESS: BY DESCENDING FREQUENCY N N % PATIENT >= 1 TESS % Upper respiratory tract infection NOS % Nasopharyngitis % Nausea % Vomiting NOS % Headache % Abdominal pain upper % Pyrexia % Appetite decreased NOS % Cough % Ear infection NOS % Gastroenteritis viral NOS % Influenza like illness % - TESS: BY DESCENDING FREQUENCY N N % Micturition urgency % Pharyngitis streptococcal % Pharyngolaryngeal pain % Rash NOS % Sinusitis NOS % Unexpected therapeutic drug effect % Upper respiratory tract infection viral NOS % Aggression % Asthma NOS % Contusion % Dizziness % Heart rate increased % (continued)

25 CT Registry ID# 5671 Page 25 Table LYBH.13. Summary Report of Treatment-Emergent Adverse Events; Open-Label Extension Period: B4Z-US-LYBH (continued) Influenza % Nasal congestion % Pain in extremity % Pollakiuria % Post procedural pain % Toothache % Abdominal pain NOS % Accidental overdose % Anorexia % Anxiety % Appetite increased NOS % Arthralgia % Attention deficit/hyperactivity disorder % - TESS: BY DESCENDING FREQUENCY N N % Back pain % Cerebellar syndrome % Chest pain % Conjunctivitis % Constipation % Dehydration % Disturbance in attention % Dysuria % Ear piercing % Epistaxis % Excoriation % Fatigue % Feeling cold % (continued)

26 CT Registry ID# 5671 Page 26 Table LYBH.13. Summary Report of Treatment-Emergent Adverse Events; Open-Label Extension Period: B4Z-US-LYBH (concluded) Insomnia % Intention tremor % Irritability % Mood swings % Mouth injury % Multiple allergies % Oral pain % Orthodontic procedure % Otitis media NOS % Pain exacerbated % Pain in jaw % Pruritus % Psychomotor hyperactivity % - TESS: BY DESCENDING FREQUENCY N N % Rash erythematous % Rash generalised % Rash macular % Rhinorrhoea % Scab % Sinus headache % Social avoidant behaviour % Somnolence % Sweating increased % Tearfulness % Ventricular hypertrophy % Weight increased % - POPULATION: ALL OF PATIENTS WHO ENROLLED IN THE OPEN LABEL EXTENSION PERIOD AND TOOK AT LEAST ONE DOSE OF STUDY DRUG ARE INCLUDED

27 CT Registry ID# 5671 Page 27 Table LYBH.14 shows that atomoxetine-treated subjects had a statistically significant increase in heart rate and the expected related decreases in PR interval, RR, and QT intervals compared with placebo-treated subjects during the acute period. Table LYBH.14 Summary of Change from Baseline to Endpoint for ECG Parameters All Randomized Patients with 1 Dose of Study Drug Change to --Baseline --Endpoint-- p-values Variables Therapy Analyzed Therapy n Mean SD Mean SD (Int*1) HR ATOMOX Placebo (.822) PR ATOMOX Placebo (.296) QRS ATOMOX Placebo (.327) QT ATOMOX Placebo (.445) QTCD ATOMOX Placebo (.022) QTCF ATOMOX Placebo (.022) QTCR ATOMOX Placebo (.019) RR ATOMOX Placebo (.865) Protocol B4Z-US-LYBH Final Report Atomoxetine vs Placebo on Bladder Control in Children with Nocturnal Enuresis Research Project Code: B4Z Baseline: Visits 1-2, Endpoint: Visits 3-8 Note: n = Total number of patients in each treatment group having the variable in both baseline and postbaseline visits. Note: Models: RDUC1 - *1 Type III Sums of Squares from an analysis of variance (ANOVA): PROC GLM model=investigator and treatment for the overall p-value and model=investigator, treatment, and interaction for the interaction p-value. Least-squares mean option in PROC GLM from the ANOVA using the mean square for error. Note: Each investigator has at least one patient in each treatment group. Legend of Variable Abbreviations: Abbrev. Description HR ECG Heart Rate PR PR Interval QRS QRS Interval QT QT Interval QTCD QTC Data-based Correction QTCF QTC Fridericia Correction QTCR QTC RR Correction RR RR Interval

28 CT Registry ID# 5671 Page 28 None of the subjects had increased corrected QT values (Table LYBH.15).

29 Table LYBH.15. Incidence of Potentially Clinically Significant Changes in ECG - Study Period II Fisher's Exact PLA TMX PVALUE ++- N n % N n % P-value Heart Rate High % % Low % % QTCD(Data Corrected) High % % n/a QTCF(Fridericia) High % % n/a Heart rate - High:Increase of at least 20 to a value of at least Low: Decrease of at least 15 to a value of at most 60 QTCF(Fridericia) - High:Increase of at least 30 to a value of at least 435 QTCD(Data Corrected) - High:Increase of at least 30 to a value of at least 440 Patients counted as meeting criteria if criteria was met at any postbaseline visit Population: Enrolled patients who took at least one dose of study drug Population: Patient should only be in N if they do not meet criteria at baseline CT Registry ID# 5671 Page 29

30 CT Registry ID# 5671 Page 30 Table LYBH.16 shows that during the open-label extension period, subjects had a statistically significant decrease from baseline in RR interval; they also had a statistically significant increase from baseline in the QRS interval. Table LYBH.17 gives a summary of the change from baseline lab values. Table LYBH.18 lists the mean change from baseline to last-observation carried forward (LOCF) Endpoint for laboratory tests. Table LYBH.19 gives a summary of frequency of patients with treatment-emergent abnormal lab values.

31 Table LYBH.16. Mean Change from Baseline to LOCF Endpoint For ECGs: Open Label Extension Period BASELINE ENDPOINT CHANGE P-VALUE(A) - MEASUREMENT N MEAN SD MEAN SD MEAN SD ECG HEART RATE ECG RR INTERVAL ECG PR INTERVAL ECG QRS INTERVAL ECG QT INTERVAL FRIDERICIA QTC INTERVAL DATABASE CORRECTED QTC INTERVAL A) P-VALUES ARE FROM THE WILCOXON SIGNED-RANK TEST POPULATION: ALL OF PATIENTS WHO ENROLLED IN THE OPEN LABEL EXTENSION PERIOD AND TOOK AT LEAST ONE DOSE OF STUDY DRUG ARE INCLUDED CT Registry ID# 5671 Page 31

32 CT Registry ID# 5671 Page 32 Table LYBH.17. Summary of Change from Baseline to Endpoint for Laboratory Analytes All Randomized Patients with 1 Dose of Study Drug Change to --Baseline --Endpoint-- p-values Lab Lab Therapy Test Unit Therapy n Mean SD Mean SD (Int*1) HCT 1 ATOMOX Placebo (.004) HGB mml/l-fe ATOMOX Placebo (.008) RBC TI/L ATOMOX Placebo (.016) WBC GI/L ATOMOX Placebo (.779) BANDS GI/L ATOMOX Placebo (.520) POLYS GI/L ATOMOX Placebo (.869) LYMPHS GI/L ATOMOX Placebo (.375) MONOS GI/L ATOMOX Placebo (.664) EOSN GI/L ATOMOX Placebo (.498) BASO GI/L ATOMOX Placebo (.802) MCV fl ATOMOX Placebo (.885) PLTCT GI/L ATOMOX Placebo (.293) (continued)

33 CT Registry ID# 5671 Page 33 Table LYBH.17. Summary of Change from Baseline to Endpoint for Laboratory Analytes All Randomized Patients with 1 Dose of Study Drug (continued) Change to --Baseline --Endpoint-- p-values Lab Lab Therapy Test Unit Therapy n Mean SD Mean SD (Int*1) U-SPGR NO UNITS ATOMOX Placebo (.177) AST U/L ATOMOX Placebo (.623) ALT U/L ATOMOX Placebo (.018) CPK U/L ATOMOX Placebo (.678) ALKPH U/L ATOMOX Placebo (.804) GGT U/L ATOMOX Placebo (.784) BUN mmol/l ATOMOX Placebo (.674) CALC mmol/l ATOMOX Placebo (.216) PHOS mmol/l ATOMOX Placebo (.571) SODIUM mmol/l ATOMOX Placebo (.317) POTAS mmol/l ATOMOX Placebo (.924) CHLOR mmol/l ATOMOX Placebo (.189) TPROT g/l ATOMOX Placebo (.462) ALBUM g/l ATOMOX Placebo (.092) NFGLU mmol/l ATOMOX Placebo (.909) UR AC umol/l ATOMOX Placebo (.386) CHOL mmol/l ATOMOX Placebo (.183) (continued)

34 CT Registry ID# 5671 Page 34 Table LYBH.17. Summary of Change from Baseline to Endpoint for Laboratory Analytes All Randomized Patients with 1 Dose of Study Drug (concluded) Change to --Baseline --Endpoint-- p-values Lab Lab Therapy Test Unit Therapy n Mean SD Mean SD (Int*1) BICARB mmol/l ATOMOX Placebo (.836) CREAT umol/l ATOMOX Placebo (.020) T.BILI umol/l ATOMOX Placebo (.563) Baseline: Visits 1-2, Endpoint: Visits 3-8 Note: n = Total number of patients in each treatment group having the variable in both baseline and postbaseline visits. Note: Models: RDUC1 - *1 Type III Sums of Squares from an analysis of variance (ANOVA): PROC GLM model=investigator and treatment for the overall p-value and model=investigator, treatment, and interaction for the interaction p-value. Least-squares mean option in PROC GLM from the ANOVA using the mean square for error. Note: Each investigator has at least one patient in each treatment group. Legend of Lab Test Code Abbreviations: -- Abbrev. Description - -- HCT HGB RBC WBC BANDS POLYS LYMPHS MONOS EOSN BASO MCV PLTCT U-SPGR AST ALT CPK ALKPH GGT BUN CALC PHOS SODIUM POTAS CHLOR TPROT ALBUM NFGLU UR AC CHOL BICARB CREAT T.BILI HEMATOCRIT HEMOGLOBIN ERYTHROCYTE COUNT LEUKOCYTE COUNT BANDS NEUTROPHILS, SEGMENTED LYMPHOCYTES MONOCYTES EOSINOPHILS BASOPHILS MEAN CELL VOLUME (MCV) PLATELET COUNT UA-SPECIFIC GRAVITY AST/SGOT ALT/SGPT CREATINE PHOSPHOKINASE ALKALINE PHOSPHATASE GGT (GGPT/SGGT/YGGT) UREA NITROGEN CALCIUM INORGANIC PHOSPHORUS SODIUM POTASSIUM CHLORIDE TOTAL PROTEIN ALBUMIN GLUCOSE, NON-FASTING URIC ACID CHOLESTEROL BICARBONATE, HCO3 CREATININE BILIRUBIN, TOTAL

35 CT Registry ID# 5671 Page 35 Table LYBH.18. Mean Change From Baseline to LOCF Endpoint for Laboratory Tests Open-Label Extension Period: B4Z-US-LYBH -- WITHIN BASELINE CHANGE GROUP N MEAN STD MEAN STD P-VALUE ALBUMIN ALKALINE PHOSPHATASE ALT/SGPT AST/SGOT BANDS N/A BASOPHILS BICARBONATE, HCO BILIRUBIN, TOTAL CALCIUM CHLORIDE < CHOLESTEROL CREATINE PHOSPHOKINASE CREATININE EOSINOPHILS ERYTHROCYTE COUNT < GGT (GGPT/SGGT/YGGT) GLUCOSE, NON-FASTING HEMATOCRIT < HEMOGLOBIN < INORGANIC PHOSPHORUS LEUKOCYTE COUNT LYMPHOCYTES MEAN CELL VOLUME (MCV) MONOCYTES NEUTROPHILS, SEGMENTED (continued) POPULATION: ALL OF PATIENTS WHO ENROLLED IN THE OPEN LABEL EXTENSION PERIOD AND TOOK AT LEAST ONE DOSE OF STUDY DRUG ARE INCLUDED

36 CT Registry ID# 5671 Page 36 Table LYBH.18. Mean Change From Baseline to LOCF Endpoint for Laboratory Tests Open-Label Extension Period: B4Z-US-LYBH (concluded) -- WITHIN BASELINE CHANGE GROUP N MEAN STD MEAN STD P-VALUE PLATELET COUNT POTASSIUM SODIUM TOTAL PROTEIN UA-SPECIFIC GRAVITY UREA NITROGEN URIC ACID POPULATION: ALL OF PATIENTS WHO ENROLLED IN THE OPEN LABEL EXTENSION PERIOD AND TOOK AT LEAST ONE DOSE OF STUDY DRUG ARE INCLUDED Table LYBH.19 presents a summary of frequency of patients with treatment-emergent abnormal lab values. Table LYBH.19. Summary of Frequency of Patients with Treatment- Emergent Abnormal Lab Values All Randomized Patients with 1 Dose of Study Drug - p-value * - ATOMOX (1) Placebo(2) Incidence (Total=44) (Total=43) Group N n (%) N n (%) Overall Lab Test: HEMATOCRIT LOW 36 4 (11.1) 35 3 (8.6) 1.00 HIGH (2.5).482 Lab Test: HEMOGLOBIN LOW HIGH Lab Test: ERYTHROCYTE COUNT LOW HIGH Lab Test: LEUKOCYTE COUNT LOW HIGH (continued)

37 CT Registry ID# 5671 Page 37 Table LYBH.19. Summary of Frequency of Patients with Treatment- Emergent Abnormal Lab Values All Randomized Patients with 1 Dose of Study Drug (continued) - p-value * - ATOMOX (1) Placebo(2) Incidence (Total=44) (Total=43) Group N n (%) N n (%) Overall Lab Test: BANDS LOW HIGH Lab Test: NEUTROPHILS, SEGMENTED LOW HIGH (5.1).223 Lab Test: LYMPHOCYTES LOW (5.1).229 HIGH Lab Test: MONOCYTES LOW HIGH Lab Test: EOSINOPHILS LOW HIGH (2.7).481 Lab Test: BASOPHILS LOW HIGH Lab Test: MEAN CELL VOLUME (MCV) LOW 37 1 (2.7) HIGH Lab Test: PLATELET COUNT LOW HIGH 36 3 (8.3) 36 1 (2.8).614 Lab Test: UA-SPECIFIC GRAVITY LOW 43 2 (4.7) 37 3 (8.1).658 HIGH 43 6 (14.0) 35 3 (8.6).504 Lab Test: AST/SGOT LOW HIGH 42 1 (2.4) (continued)

38 CT Registry ID# 5671 Page 38 Table LYBH.19. Summary of Frequency of Patients with Treatment- Emergent Abnormal Lab Values All Randomized Patients with 1 Dose of Study Drug (continued) - p-value * - ATOMOX (1) Placebo(2) Incidence (Total=44) (Total=43) Group N n (%) N n (%) Overall Lab Test: ALT/SGPT LOW 44 1 (2.3) HIGH 44 1 (2.3) 36 1 (2.8) 1.00 Lab Test: CREATINE PHOSPHOKINASE LOW HIGH 44 1 (2.3) Lab Test: ALKALINE PHOSPHATASE LOW 44 1 (2.3) HIGH (2.7).474 Lab Test: GGT (GGPT/SGGT/YGGT) LOW HIGH Lab Test: UREA NITROGEN LOW HIGH Lab Test: CALCIUM LOW HIGH 39 2 (5.1) 32 1 (3.1) 1.00 (continued)

39 CT Registry ID# 5671 Page 39 Table LYBH.19. Summary of Frequency of Patients with Treatment- Emergent Abnormal Lab Values All Randomized Patients with 1 Dose of Study Drug (continued) - p-value * - ATOMOX (1) Placebo(2) Incidence (Total=44) (Total=43) Group N n (%) N n (%) Overall Lab Test: INORGANIC PHOSPHORUS LOW HIGH 43 1 (2.3) 39 2 (5.1).602 Lab Test: SODIUM LOW HIGH Lab Test: POTASSIUM LOW HIGH Lab Test: CHLORIDE LOW HIGH Lab Test: TOTAL PROTEIN LOW HIGH Lab Test: ALBUMIN LOW HIGH 39 3 (7.7) 36 2 (5.6) 1.00 Lab Test: GLUCOSE, NON-FASTING LOW 43 1 (2.3) HIGH Lab Test: URIC ACID LOW 44 1 (2.3) HIGH (5.0).224 (continued)

40 CT Registry ID# 5671 Page 40 Table LYBH.19. Summary of Frequency of Patients with Treatment- Emergent Abnormal Lab Values All Randomized Patients with 1 Dose of Study Drug (concluded) - p-value * - ATOMOX (1) Placebo(2) Incidence (Total=44) (Total=43) Group N n (%) N n (%) Overall Lab Test: CHOLESTEROL LOW 40 2 (5.0) 36 2 (5.6) 1.00 HIGH 39 3 (7.7) 33 3 (9.1) 1.00 Lab Test: BICARBONATE, HCO3 LOW HIGH Lab Test: CREATININE LOW (2.5).476 HIGH (15.4).011 Lab Test: BILIRUBIN, TOTAL LOW HIGH 44 1 (2.3) Baseline: Visits 1-2, Endpoint: Visits 3-8 * Frequencies are analyzed using a Fisher's Exact test. Note:Total = Total number of patients in the treatment group having both baseline and endpoint visits. N = Total number of at risk patients with the lab test. n = Total number of at risk patients with the specific lab result (e.g. HIGH). Atomoxetine-treated subjects had a statistically significant increase in mean standing pulse and mean supine pulse compared with placebo-treated subjects (p<.001). Supine pulse increased 8.39 bpm from baseline, while standing pulse increased bpm from baseline. There were no statistically significant differences between treatments in blood pressure. Atomoxetine-treated subjects had an acute decrease in weight of.45 kg compared to an increase of 1.08 kg for placebo (p<.001) (see Table LYBH.20).

41 CT Registry ID# 5671 Page 41 Table LYBH.20. Summary of Change from Baseline to Endpoint for Vital Signs All Randomized Patients with 1 Dose of Study Drug Change to --Baseline --Endpoint-- p-values Variables Therapy Analyzed Therapy n Mean SD Mean SD (Int*1) WEIGHTKG ATOMOX <.001 Placebo (.382) HEIGHTCM ATOMOX Placebo (.437) SYSBPST ATOMOX Placebo (.723) SYSBPSU ATOMOX Placebo (.792) DIABPST ATOMOX Placebo (.100) DIABPSU ATOMOX Placebo (.842) PULSEST ATOMOX <.001 Placebo (.999) PULSESU ATOMOX <.001 Placebo (.893) Baseline: Visits 1-2, Endpoint: Visits 3-8 Note: n = Total number of patients in each treatment group having the variable in both baseline and postbaseline visits. Note: Models: RDUC1 - *1 Type III Sums of Squares from an analysis of variance (ANOVA): PROC GLM model=investigator and treatment for the overall p-value and model=investigator, treatment, and interaction for the interaction p-value. Least-squares mean option in PROC GLM from the ANOVA using the mean square for error. Note: Each investigator has at least one patient in each treatment group. Legend of Variable Abbreviations: DIABPST Diastolic BP - Standing DIABPSU Diastolic BP - Supine HEIGHTCM Height PULSEST Pulse - Standing PULSESU Pulse - Supine SYSBPST Systolic BP - Standing SYSBPSU Systolic BP - Supine WEIGHTKG Weight As shown in Table LYBH.21, during the open-label extension period, subjects had a statistically significant increase in supine pulse, as well as statistically significant increases in height and weight (2.64 cm and 1.65 kg, p<.001 for each).

42 Table LYBH.21. Mean Change from Baseline to LOCF Endpoint for Vitals: Open Label Extension Period BASELINE ENDPOINT CHANGE P-VALUE(A) - MEASUREMENT N MEAN SD MEAN SD MEAN SD SUPINE SBP STANDING SBP SUPINE DBP STANDING DBP SUPINE PULSE STANDING PULSE ORTHOSTATIC SBP ORTHOSTATIC DBP ORTHOSTATIC PULSE WEIGHT(KG) <.001 HEIGHT(CM) <.001 A) P-VALUES ARE FROM THE WILCOXON SIGNED-RANK TEST POPULATION: ALL OF PATIENTS WHO ENROLLED IN OPEN LABEL EXTENSION PERIOD AND TOOK AT LEAST ONE DOSE OF STUDY DRUG ARE INCLUDED CT Registry ID# 5671 Page 42

43 CT Registry ID# 5671 Page 43 Health Outcomes Table LYBH.22a indicates that the only statistically significant difference on the CHQ- PF50 was a statistically significant decrease in family activities for atomoxetine compared with placebo. Table LYBH.22b shows the CHQ-PF50 scores mean change from baseline to LOCF endpoint. Table LYBH.23 gives a summary of final, maximum, and modal dose for all randomized patients that took at least one dose of study drug.

44 Table LYBH.22a. Child Health Questionnaire Parent Form Cluster Subscore Mean Change From Baseline To Endpoint Study Period II BASELINE ENDPOINT CHANGE P-VALUE A P-VALUE B TREATMENT GROUP N MEAN SD MEAN SD MEAN SD BODYILY PAIN TMX PLA % CONFIDENCE INTERVAL: (-13.60,4.44 ) BEHAVIOR TMX PLA % CONFIDENCE INTERVAL: (-4.34,9.33 ) FAMILY ACTIVITIES TMX PLA % CONFIDENCE INTERVAL: (1.04,14.25) GENERAL HEALTH TMX PLA % CONFIDENCE INTERVAL: (-9.61,1.95 ) MENTAL HEALTH TMX PLA % CONFIDENCE INTERVAL: (-4.17,6.24 ) PARENT EMOTIONAL TMX PLA % CONFIDENCE INTERVAL: (-7.34,14.19) (continued) CT Registry ID# 5671 Page 44

45 Table LYBH.22a. Child Health Questionnaire Parent Form 50: Cluster Subscore Mean Change From Baseline To Endpoint Study Period II (continued) BASELINE ENDPOINT CHANGE P-VALUE A P-VALUE B TREATMENT GROUP N MEAN SD MEAN SD MEAN SD PHYSICAL FUNCTION TMX PLA % CONFIDENCE INTERVAL: (-3.26,3.83 ) PHYSICAL SUMMARY TMX PLA % CONFIDENCE INTERVAL: (-3.58,1.52 ) PARENT TIME IMPACT TMX PLA % CONFIDENCE INTERVAL: (-4.91,12.68) PSYCHOSOCIAL SUMMARY SCORE TMX PLA % CONFIDENCE INTERVAL: (-3.08,5.06 ) ROLE EMOTIONAL/BEHAVIOR TMX PLA % CONFIDENCE INTERVAL: (-11.60,7.42 ) ROLE PHYSICAL TMX PLA % CONFIDENCE INTERVAL: (-5.63,5.47 ) (continued) CT Registry ID# 5671 Page 45

46 Table LYBH.22a. Child Health Questionnaire Parent Form Cluster Subscore Mean Change From Baseline To Endpoint Study Period II (concluded) BASELINE ENDPOINT CHANGE P-VALUE A P-VALUE B TREATMENT GROUP N MEAN SD MEAN SD MEAN SD SELF ESTEEM TMX PLA % CONFIDENCE INTERVAL: (-8.47,6.51 ) A) P-VALUE IS FROM WILCOXON SIGNED-RANK TEST. B) BETWEEN TREATMENT GROUP P-VALUES ARE FROM BASELINE TO ENDPOINT (LOCF) SCORES USING LEAST SQUARES MEANS FROM AN ANCOVA MODEL WITH INVESTIGATOR, TREATMENT AS COVARIATE CT Registry ID# 5671 Page 46