Summary ID# Clinical Study Summary: Study B4Z-SB-LYDD

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1 CT Registry ID# 9496 Page 1 Summary ID# 9496 Clinical Study Summary: Study B4Z-SB-LYDD An Open-label Study on Effectiveness and Tolerability of as Perceived by Patients, Parents, and Physicians in Children with Attention- Deficit/Hyperactivity Disorder in Germany Date summary approved by Lilly: 08 February 2007 Brief Summary of Results The primary objective of this study was to compare the perception of general effectiveness and tolerability of atomoxetine between children with Attention- Deficit/Hyperactivity Disorder (ADHD), their parents/primary caregivers, and their physicians, as measured by the newly devised Global Impression of Perceived Difficulties (GIPD) instrument. The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv) Scale and Clinical Global Impression (CGI) Scales were also used to assess the baseline severity of ADHD and to evaluate the effectiveness of atomoxetine. The effect of atomoxetine on evening and morning behavior was assessed with the Weekly Ratings of Evening and Morning Behavior - Revised - Investigator Rated (WREMB-R-Inv) evening and morning scores, and Items 1 (morning) and 4 (evening) of the newly devised GIPD instrument. The O Brien Sleep Questionnaire (OBSQ) was used to assess sleep quality. The results of this open-label study (Screening and Washout [Study Period I], 8-week Treatment Period [Study Period II], followed by a 16-week Extension Period [Study Period III]) were as follows: Patients gave the lowest ratings for ADHD-related difficulties, parents higher ratings, and physicians the highest ratings. The mean baseline ratings for the GIPD total score differed statistically significantly as shown by non-overlapping 95% confidence intervals (CIs): patients

2 CT Registry ID# 9496 Page ±5.8 (95% CI: 12.6;14.1); parents 19.4±5.9 (95% CI: 18.7;20.1); physicians 21.1±5.7 (95% CI: 20.4;21.8). The mean scores per rater group for the GIPD total score decreased statistically significantly from baseline to Week 8, and decreases were maintained at Week 24. This improvement was smallest for the patients rating, greater for the parents rating, and greatest for the physicians rating. The mean decrease from baseline to Week 8 for the physician-rated score of -6.5±7.9 (95% CI: -7.4;-5.5) was statistically significantly greater than the corresponding mean change for the patient-rated score of -2.8±6.5 (95% CI: -3.6;-2.0) and the mean change for the parent-rated score of -4.6±7.6 (95% CI: -5.6;-3.7). There was a higher degree of agreement between the mean parent- and physician-rated scores than between the mean patient- and parent- or patient- and physician-rated scores (Cohen s kappa [95% CI]: parentphysician 0.50 [0.44;0.57]; patient-parent 0.12 [0.07;0.17]; patientphysician 0.11 [0.08;0.15]). All effectiveness scores used, including the ADHDRS-IV-Parent:Inv, CGI-S-ADHD, and WREMB-R-Inv scores, improved consistently and statistically significantly (non-overlapping 95% CIs) from baseline to Week 8. Improvements were maintained at Week 24. Evening and morning behavior of ADHD patients both improved consistently during the study, as shown by statistically significant decreases (non-overlapping 95% CIs) in the mean WREMB-R-Inv evening (e.g., from 14.7±5.1 to 8.5±6.0 at Week 8) and morning subscores (e.g., from 4.5±2.5 to 2.5±2.4 at Week 8). All changes from baseline to Week 24 were also statistically significant. Corresponding statistically significant decreases (non-overlapping 95% CIs were found for the ADHD-related morning and evening difficulties (GIPD Items 1 and 4) at Week 8 and Week 24 as perceived by patients, parents, and physicians. For 21 of 23 different sleep-related items assessed in the OBSQ, the proportion of patients affected by the problem decreased from baseline to Week 8. No patients died during the study, and no serious adverse events were rated as possibly related to study drug. Adverse events possibly related to study drug were reported in 47.7% of patients overall, with fatigue (19.8%), nausea (13.4%), headache (8.0%), upper abdominal pain (7.3%), decreased appetite (5.7%), and anorexia (5.3%) reported most frequently. Treatment-emergent adverse events led to atomoxetine discontinuation in 12 (4.6%) patients.

3 CT Registry ID# 9496 Page 3 Title of Study: An Open-label Study on Effectiveness and Tolerability of as Perceived by Patients, Parents, and Physicians in Children with Attention-Deficit/Hyperactivity Disorder in Germany Investigator(s): This multicenter study included 58 principal investigators (1 investigator recruited patients at 2 different sites). Study Center(s): This study was conducted at 59 study centers in one country. Length of Study: 1 year and 4 months Phase of Development: 3 Date first patient entered: 28 October 2004 Date first patient enrolled: 02 November 2004 Date last patient completed: 24 February 2006 Objectives: The primary objective of this study was to compare the perception of general effectiveness and tolerability of atomoxetine between children with ADHD, their parents/primary caregivers, and their physicians, based on scores on the newly devised GIPD Scale at baseline, Week 8, and Week 24. Secondary objectives : To assess differences in the perception of ADHD severity (ADHD-related difficulties as assessed by the GIPD Scale) between rater groups at baseline and over the course of atomoxetine treatment. To assess the effectiveness of atomoxetine in the treatment of children as measured by the ADHDRS-IV-Parent:Inv. To assess the effectiveness of atomoxetine in the treatment of children as measured by the Clinical Global Impression-Severity-ADHD (CGI-S-ADHD) and Clinical Global Impression-Improvement- ADHD (CGI-I-ADHD). To assess the effect of atomoxetine on evening and morning behavior of children as measured by the WREMB-R-Inv. To assess sleep characteristics of children treated with atomoxetine as measured by the OBSQ. To assess the tolerability of atomoxetine in the treatment of children as assessed by treatmentemergent adverse events (TEAEs) elicited by open-ended questioning. To assess solicited tolerability parameters as rated by the patients, their parents/primary caregivers and physicians, measured by the Pediatric Adverse Events Rating Scale (PAERS). To assess parameters reflecting attitudes towards ADHD and representing common clinical practice in Germany (e.g., pretreatment, concomitant treatment, treatment by pediatricians or child and adolescent psychiatrists, family setting) and their impact on effectiveness and tolerability of atomoxetine (not included in Statistical Analysis Plan, to be reported separately). To assess specific safety and sleep parameters as measured by the PAERS and the OBSQ in subgroups (i.e., type of pretreatment) of patients at screening (not included in Statistical Analysis Plan, to be reported separately). To evaluate effectiveness and tolerability of atomoxetine in the treatment of children and adolescents (accomplished by a pooled analysis of data from the studies B4Z-SB-LYDD [children] and B4Z-SB-LYDE [adolescents; CT#7233]). Study Design: Single-arm, open-label, phase 3, multicenter study to evaluate the effectiveness and tolerability of atomoxetine (once daily, target dose 1.2 mg/kg/day), as perceived by patients, parents, and physicians, and its impact on quality of sleep in children with ADHD treated as outpatients in Germany (aged 6 11 years). After an initial Screening and Washout Period (Study Period I), there was an 8-week Treatment Period (Study Period II), followed by a 16-week Extension Period (Study Period III). At the end of Study Period II, the physician decided whether the patient was to be continued into Study Period III. Number of Patients: Planned: 257 Screened: 265 Enrolled: 262 Completed: 149

4 CT Registry ID# 9496 Page 4 Diagnosis and Main Criteria for Inclusion: ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV ) criteria, confirmed by the German instrument Diagnose-Checkliste Hyperkinetische Störungen (Diagnostic checklist for hyperkinetic disorders) routinely used for ADHD diagnosis in Germany. Patients had to be children aged between 6 and 11 years. They had to be of normal intelligence (likely to achieve an IQ test score of 70). Patients were to be excluded if they had any significantly abnormal laboratory findings, any acute or unstable medical conditions, cardiovascular diseases, history of seizure disorder, bipolar disorder, psychosis or pervasive developmental disorder, any medical condition that would markedly increase sympathetic nervous system activity, or were likely to need psychotropic medication other than the study drug. Test Product, Dose, and Mode of Administration: capsules. Recommended dosing according to German Summary of Product Characteristics (SmPC): initial dose approx. 0.5 mg/kg/day for 7 days, titrated to a target of approx. 1.2 mg/kg/day for the remainder of Study Period II. During Study Period II, dose reductions to a minimum of 0.5 mg/kg were allowed for safety reasons only. During Study Period III, the investigator was allowed to titrate the dose between 0.5 and 1.2 mg/kg/day according to clinical effectiveness and tolerability. Duration of Treatment: An 8-week treatment period (Study Period II) was followed by a 16-week Extension Period (Study Period III). Variables: Effectiveness: Primary - comparison of the perception of general effectiveness and tolerability (ADHDrelated difficulties) of atomoxetine between patients, parents, and their physicians at baseline, and after 8 and 24 weeks of treatment based on the GIPD Scale completed by all rater groups at each visit. Secondary - application of the ADHDRS-IV-Parent:Inv Scale, CGI-S-ADHD Scale, CGI-I-ADHD Scale, WREMB-R-Inv Scale, and the OBSQ to observe effectiveness, compare ratings, and assess sleep quality. Safety: Standard adverse event reporting, laboratory safety investigations, and application of the Pediatric Adverse Events Rating Scale (PAERS). Evaluation Methods: Statistical: Analyses of effectiveness parameters were based on the full analysis set. Different imputation rules for missing values were applied, including last observation carried forward (LOCF) and observed cases (OC) approaches. For all instruments used, the scores at each visit and the respective changes from baseline were presented using descriptive statistics. In addition, exploratory 95% confidence intervals (CIs) were calculated. For the primary analysis, the agreement between patient, parent, and physician GIPD ratings was assessed using Cohen s kappa. Subgroup analyses by gender and by type of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis were provided.

5 CT Registry ID# 9496 Page 5 Results: Patient Demographics Of the 262 patients enrolled, 213 (81.3%) patients were boys and 49 (18.7%) were girls. Table 1 shows the DSM-IV diagnostic subtypes of ADHD by gender. Table 1. Diagnostic Subtypes According to DSM-IV by Gender Full Analysis Set DSM-IV ADHD diagnosis Number (%) of patients Female N=49 (100%) Male N=213 (100%) Total N=262 (100%) Combined type 26 (53.1) 171 (80.3) 197 (75.2) Predominantly inattentive type 18 (36.7) 33 (15.5) 51 (19.5) Predominantly hyperactive-impulsive type 2 (4.1) 4 (1.9) 6 (2.3) ADHD not otherwise specified 3 (6.1) 5 (2.3) 8 (3.1) Abbreviations: ADHD=Attention-Deficit/Hyperactivity Disorder; DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ; N = total number of patients. Combined type ADHD was the most frequent DSM-IV diagnosis (197, 75.2%), followed by predominantly inattentive type ADHD (51, 19.5%). There were very small numbers (6 [2.3%] and 8 [3.1%], respectively) of predominantly hyperactive-impulsive type patients and patients in whom the ADHD subtype was not otherwise specified (not further reported). The proportion of combined type ADHD patients was 80.3% in boys (171/213) and 53.1% in girls (26/49). The proportion of predominantly inattentive type ADHD patients was 36.7% in girls (18/49) and 15.5% in boys (33/213). The patients mean age (±SD) at baseline was 9.3±1.5 years. Symptoms of ADHD first occurred at a mean age of 3.8±1.9 years, and ADHD was first diagnosed at a mean age of 7.1±1.8 years. A mean interval of 3.2±1.9 years had elapsed between the first occurrence of ADHD symptoms and the first diagnosis of ADHD. Details on age characteristics by gender and DSM-IV diagnostic subtypes can be found in Table 2 and Table 3, respectively.

6 CT Registry ID# 9496 Page 6 Table 2. Age of Patients at Baseline, First Occurrence of ADHD Symptoms and First Diagnosis of ADHD, and Time Difference between First Occurrence and Diagnosis by Gender, Full Analysis Set Variable (years) Female N=49 Male N=213 Total N=262 Age at baseline Median Mean ± standard deviation 9.7± ± ±1.5 95% confidence interval [9.2;10.1] [9.1;9.5] [9.2;9.5] Age at first occurrence Median Mean ± standard deviation 3.8 ± ± ± % confidence interval [3.2;4.4] [3.6;4.1] [3.6;4.1] Age at first diagnosis Median Mean ± standard deviation 7.6 ± ± ± % confidence interval [7.1;8.0] [6.7;7.2] [6.8;7.3] Time difference Median Mean ± standard deviation 3.8 ± ± ± % confidence interval [3.1;4.4] [2.8;3.3] [3.0;3.5] Abbreviations: ADHD=Attention-Deficit/Hyperactivity Disorder; N = total number of patients. Table 3. Age of Patients at Baseline, First Occurrence of ADHD Symptoms and First Diagnosis of ADHD, and Time Difference between First Occurrence and Diagnosis by DSM-IV Diagnosis, Full Analysis Set Variable (years) Combined type ADHD N=197 Predominantly inattentive type ADHD N=51 Age at baseline Median Mean ± standard deviation 9.2 ± ± % confidence interval [9.0;9.4] [9.5;10.2] Age at first occurrence Median Mean ± standard deviation 3.6 ± ± % confidence interval [3.3;3.8] [4.4;5.4] Age at first diagnosis Median Mean ± standard deviation 6.8 ± ± % confidence interval [6.5;7.0] [7.6;8.5] Time difference Median Mean ± standard deviation 3.2 ± ± % confidence interval [2.9;3.5] [2.6;3.7] Abbreviations: ADHD=Attention-Deficit/Hyperactivity Disorder; DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ; N = total number of patients.

7 CT Registry ID# 9496 Page 7 Overall, 212 (80.9%) patients had had previous treatment for ADHD (boys 173, 81.2%; girls 39, 79.6%). A total of 164 (83.2%) patients with combined type ADHD and 36 (70.6%) patients with predominantly inattentive type ADHD had been treated previously for ADHD. Overall, 173 (66.0%) patients were given any concomitant therapy, most frequently pharmacological therapy. Concomitant medications used in more than 5% of all patients included paracetamol (37; 14.1%), ambroxol (32; 12.2%), xylometazoline (25; 9.5%), ibuprofen (23; 8.8%), acetylcysteine (14; 5.3%), and Hedera helix (14; 5.3%). The mean daily prescribed dose of atomoxetine remained in the same range of 1.16 mg/kg/day after the first week of up-titration, up to the final prescription at Week 16 (for the last visit interval, i.e., Weeks 17 24). The mean final prescribed dose at Week 16 was 1.16±0.19 mg/kg/day. A total of 18 (6.9%) patients were noncompliant with respect to medication at some time during the study. Patient Disposition Of the 262 patients enrolled, 191 (72.9%) patients continued into Study Period III and 149 (56.9%) completed treatment at Week 24. Figure 1 summarizes patient disposition, including the reasons for discontinuation.

8 CT Registry ID# 9496 Page 8 Screened in Study Period I (N=265) Discontinued during Study Period II (N=46, 17.6%) Reasons: Lack of efficacy 22 Parent/caregiver decision 10 Adverse event 6 Protocol violation 5 Patient decision 2 Entry criterion not met 1 Enrolled and started Study Period II (N=262, 100%) Completed Study Period II (N=216, 82.4%) Completed Study Period II, not continued into Period III (N=25, 9.5%) Continued treatment in Study Period III (N=191, 72.9%) Discontinued during Study Period III (N=42, 16.0%) Reasons: Lack of efficacy 20 Parent/caregiver decision 13 Adverse event 6 Protocol violation 1 Physician decision 1 Entry criterion not met 1 Completed treatment at Week 24 (N=149, 56.9%) Abbreviation: N = total number of patients. Note: At the end of the Study Period II (Visit 7), it was decided whether the patient should continue into the Extension Period (Study Period III). This decision was at the investigator s discretion, based on the effectiveness and tolerability of treatment as well as parents and patients wishes. Figure 1. Patient disposition and reasons for discontinuation. For 25 (9.5%) patients who completed Study Period II, the physician decided they should not continue into Study Period III. In addition, 46 (17.6%) patients were withdrawn during Study Period II, 42 (16.0%) patients were withdrawn during Study Period III. The main reason for withdrawal was lack of efficacy, for 42 (16.0%) patients overall,

9 CT Registry ID# 9496 Page 9 followed by patient/caregiver decision for 23 (8.8%), and treatment-emergent adverse events for 12 (4.6%) patients overall. Primary Effectiveness Measure The primary objective of this study was to compare the perception of general effectiveness and tolerability (ADHD-related difficulties) of atomoxetine between patients, their parents/primary caregivers, and their physicians. The GIPD Scale was used to assess ADHD-related difficulties, and was completed by all three rater groups. The degree of agreement between the mean scores was also assessed using Cohen s kappa. The primary assessment timepoints were baseline, Week 8, and Week 24. Table 4 shows details of the GIPD Total Score, the GIPD Score Item 1 (ADHD-related difficulties in the morning), and GIPD Score Item 4 (ADHD-related difficulties in the evening). Table 4. GIPD Scores at Baseline, Week 8, and Week 24 Full Analysis Set (LOCF) Patient Parenta Physician Timepoint N Mean ± 95% CI N Mean ± 95% CI N Mean ± 95% CI SD SD SD GIPD Total Score (Sum of Items 1-5) BL ± ; ± ; ± ;21.8 Wk ± ; ± ; ± ;15.6 Wk ± ; ± ; ± ;16.9 GIPD Score Item 1 (ADHD-related difficulties in the morning) BL ± ; ± ; ± ;4.0 Wk ± ; ± ; ± ;2.7 Wk ± ; ± ; ± ;3.0 GIPD Score Item 4 (ADHD-related difficulties in the evening) BL ± ; ± ; ± ;4.5 Wk ± ; ± ; ± ;3.1 Wk ± ; ± ; ± ;3.3 a LOCF-BR for parent-rated scores, i.e., LOCF for all ratings made by the same parent. Abbreviations: ADHD=Attention-Deficit/Hyperactivity Disorder; BL=Baseline; CI=Confidence interval; GIPD=Global Impression of Perceived Difficulties; LOCF=Last observation carried forward; LOCF- BR=Last observation carried forward, baseline rater; N = total number of patients; SD=standard deviation; Wk=Week. At baseline, the mean patient-rated total score (±SD) was the lowest at 13.4±5.8, the parent-rated score was intermediate at 19.4±5.9, and the physician-rated score was highest at 21.1±5.7. All three ratings for the total score differed statistically significantly at baseline (non-overlapping 95% CIs), but the parent- and physician-rated scores did not differ statistically significantly at Week 8 or Week 24. All scores improved statistically significantly up to Week 8; this improvement was maintained at Week 24 (Table 4).

10 CT Registry ID# 9496 Page 10 Patients gave similar ratings for their ADHD-related difficulties in the morning and evening, whereas parents and physicians gave higher ratings for the evening problems than for the morning problems (Table 4). However, all 3 ratings improved statistically significantly from baseline to Week 8 (non-overlapping 95% CIs), and the improvement was maintained at Week 24. Further, parents and physicians gave statistically significantly higher ratings for ADHDrelated difficulties in combined type ADHD patients than in predominantly inattentive type ADHD patients (e.g., GIPD total score, physician-rated at baseline: combined type ADHD 22.4±5.4; 95% CI [21.7;23.2]; predominantly inattentive type 17.3±4.4; 95% CI [16.8;18.5]). Analysis of agreement between rater groups for GIPD scores: The agreement was highest between parent- and physician-rated scores (kappa for agreement at baseline [95% CI]: 0.50 [0.44;0.57]) and low between patient- and parent- (0.12 [0.07;0.17]) and patient- and physician-rated (0.11 [0.08;0.15]) scores. Table 5 shows details of the degree of agreement between each rater group at baseline, Week 8, and Week 24 for the GIPD Total Score, GIPD Item 1 (Morning) Score, and GIPD Item 4 (Evening) Score. Table 5. Agreement Between Each Rater Group at Baseline, Week 8 and Week 24 for GIPD Total Score, GIPD Item 1 (Morning) Score and GIPD Item 4 (Evening) Score, Weighted Kappa Statistics, Full Analysis Set Kappa statistic, 95% Confidence interval Timepoint Patient Parent Patient Physician Parent Physician N Ka 95% CI N Ka 95% CI N Ka 95% CI GIPD Total Score Baseline ; ; ;0.57 Week ; ; ;0.74 Week ; ; ;0.73 GIPD Score Item 1 (ADHD-related difficulties in the morning) Baseline ; ; ;0.62 Week ; ; ;0.66 Week ; ; ;0.71 GIPD Score Item 4 (ADHD-related difficulties in the evening) Baseline ; ; ;0.55 Week ; ; ;0.71 Week ; ; ;0.72 a K: weighted Kappa coefficient; analysis based on OC data for patient- and physician-ratings, and OC-BR for parents. Abbreviations: ADHD=Attention-Deficit/Hyperactivity Disorder; CI=confidence interval; GIPD=Global Impression of Perceived Difficulties; N = total number of patients; OC=last observed value within a visit interval was taken for this visit interval; OC-BR=values not rated by the baseline rater were deleted and then the last value from the baseline rater within a visit interval was chosen, if present, otherwise the value was dropped.

11 CT Registry ID# 9496 Page 11 Changes in GIPD scores over time: Changes in GIPD scores over time are presented in Figures 2 4 (observed cases, vertical bars indicate 95% CIs). Mean GIPD total scores decreased statistically significantly (non-overlapping 95% CIs) in all three rater groups from baseline to Week 8. The smallest improvements were given by patients, greater improvements by parents, and the greatest improvement by physicians (LOCF/LOCFbaseline rater (BR), mean changes in GIPD total scores: patients, LOCF, -2.8±6.5; parents, LOCF-BR, -4.6±7.6; physicians, LOCF, -6.5±7.9). The improvements were maintained at Week 24 (Figure 2). Morning and evening problems also decreased statistically significantly from baseline to Week 8 in all three rater groups. Again, this improvement was maintained at Week 24 (Figures 3 and 4). Score Total 25 N= N= N=198 N=259 N=196 N=149 N= N=199 N= Mean physician rating 95% CIs physician rating Week Mean parents rating 95% CIs parents rating Mean patient rating 95% CIs patient rating Figure 2. GIPD mean total scores over time for the full analysis set; OC analysis.

12 CT Registry ID# 9496 Page 12 Score 1 4 N=261 N=261 3 N=260 2 N=201 N= Mean physician rating 95% CIs physician rating Week Mean parents rating 95% CIs parents rating Mean patient rating 95% CIs patient rating Figure 3. GIPD mean scores for Item 1 (morning) over time for the full analysis set; OC analysis. Score 4 5 N=261 4 N=261 3 N=201 N=149 N= Mean physician rating 95% CIs physician rating Week Mean parents rating 95% CIs parents rating Mean patient rating 95% CIs patient rating Figure 4. GIPD mean scores for Item 4 (evening) over time for the full analysis set; OC analysis. Abbreviations in Figures 2 4: CI=confidence interval; GIPD=Global Impression of Perceived Difficulties; N= total number of patients; OC=observed cases, last observed value within a visit interval was taken for this visit interval.

13 CT Registry ID# 9496 Page 13 Secondary Effectiveness Measures The ADHDRS-IV-Parent:Inv, CGI-S-ADHD, and WREMB-R-Inv evening and morning scores all improved statistically significantly and consistently from baseline to Week 8 (non-overlapping 95% CIs, Table 6). The improvements were maintained at Week 24. On the CGI-S-ADHD Scale, the proportion of patients rated as at least markedly ill decreased from 218 (83.5%) at baseline to 96 (36.6%) at Week 8 and 115 (43.9%) at Week 24. In terms of CGI-I-ADHD, 126 (48.1%) patients were rated as much or very much improved at Week 8, compared with 112 (42.7%) at Week 24. With all instruments, combined type ADHD patients had higher ratings than predominantly inattentive type ADHD patients at baseline, Week 8 and Week 24, but statistically significant improvements from baseline to Week 8 were found in both subgroups (Table 6). In terms of CGI-I-ADHD, 47.7% of combined type and 52.9% of predominantly inattentive type ADHD patients were rated as much or very much improved at Week 8 (41.7% and 52.9% at Week 24).

14 CT Registry ID# 9496 Page 14 Table 6. ADHDRS-IV-Parent:Inv, CGI-ADHD, and WREMB-R-Inv Scores at Baseline, Week 8 and 24 Full Analysis Set (LOCF) Total ADHD subtype Timepoint Combined Predom. inattentive N Mean ± SD 95% CI N Mean ± SD 95% CI N Mean ± SD 95% CI ADHDRS-IV-Parent:Inv Score BL ± ; ± ; ± ;28.3 Wk ± ; ± ; ± ;17.3 Wk ± ; ± ; ± ;16.7 CGI-S-ADHD Score BL ± ; ± ; ± ;4.7 Wk ± ; ± ; ± ;3.7 Wk ± ; ± ; ± ;3.7 CGI-I-ADHD Score Wk ± ; ± ; ± ;3.0 Wk ± ; ± ; ± ;3.0 WREMB-R-Inv Evening Score (8 items) BL ± ; ± ; ± ;11.9 Wk ± ; ± ; ± ;7.0 Wk ± ; ± ; ± ;7.3 WREMB-R-Inv Morning Score (3 items) BL ± ; ± ; ± ;4.1 Wk ± ; ± ; ± ;2.4 Wk ± ; ± ; ± ;2.4 Abbreviations: ADHDRS-IV-Parent:Inv=Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored; BL=Baseline; CGI-I-ADHD=Clinical Global Impression Improvement Attention Deficit/Hyperactivity Disorder; CGI-S-ADHD=Clinical Global Impression Severity Attention Deficit/Hyperactivity Disorder; CI=confidence interval; LOCF=Last observation carried forward; N = total number of patients; Predom = predominately; SD=standard deviation; Wk=Week; WREMB-R-INV=Weekly Ratings of Evening and Morning Behavior-Revised. The ADHDRS-IV-Parent:Inv mean score over time by gender is shown in Figure 5.

15 CT Registry ID# 9496 Page 15 Score Total 40 N= N=49 25 N= N= N=38 N= Week Mean female 95% CIs Mean Female Mean Male 95% CIs Male Figure 5. ADHDRS-IV-Parent:Inv mean score over time by gender for the full analysis set; OC analysis. Note: Vertical bars indicate 95% confidence intervals. Abbreviations: ADHDRS-IV-Parent:Inv=Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored; CI = confidence interval; N = total number of patients; OC=observed cases, last observed value within a visit interval was taken for this visit interval. Quality of Sleep (OBSQ): For 21 of 23 different sleep-related items assessed in the OBSQ, the proportion of patients affected by the problem decreased from baseline to Week 8. For the sleep-related problems reported most frequently at baseline, the proportion of patients affected decreased as follows: Problems with going to bed willingly: baseline, 57.6%; Week 8, 31.3%; Week 24, 35.9%; Problems with falling asleep easily: baseline, 53.4%; Week 8, 32.1%; Week 24, 40.1%; Child complains of difficulties going to sleep: baseline, 50.4%; Week 8, 20.2%; Week 24, 26.3%; Restless sleeper: baseline, 45.4%; Week 8, 24.0%; Week 24, 27.5%; Patient is easy to wake up: baseline, 44.7%; Week 8, 24.8%; Week 24, 20.6%. Increases in the proportion of patients affected were observed for two problems: sleepiness during daytime (baseline, 22.9%; Week 8, 27.5%; Week 24, 23.7%) and falls asleep watching television (baseline, 4.6%; Week 8, 9.5%; Week 24, 8.0%).

16 CT Registry ID# 9496 Page 16 Safety Treatment-emergent adverse events (TEAEs) were reported in 207/262 (79.0%) patients and were considered as possibly related to study drug in 125/262 (47.7%) patients. Table 7 shows an overview of adverse events reported during the study. Serious adverse events were reported in 3 patients, none was rated as related to study drug (1 forearm fracture; 1 fall, abdominal injury, forearm fracture and head injury; 1 appendicitis). In 12 (4.6%) patients, adverse events led to discontinuation from the study (3 nausea, 2 aggression, 2 fatigue; 1 each for: headache, psychotic disorder, sleep disorder, upper abdominal pain, suicidal ideation). Table 7. Overview of Adverse Events, Full Analysis Set Type of adverse event Number (%) of patients N=262 (100%) Deaths 0 (0) Serious adverse events 3 (1.1) Serious adverse events (possibly, probably, or definitely related 0 (0) to study drug as judged by the investigator) Discontinuations due to an adverse event 12 (4.6) Treatment-emergent adverse events (TEAEs) 207 (79.0) Adverse reactions (TEAEs possibly, probably, or definitely 125 (47.7) related to study drug as judged by the investigator) Abbreviation: N = total number of patients. Table 8 presents the TEAEs reported in at least 5% of patients. Table 8. Treatment-Emergent Adverse Events Occurring in 5% of Patients by Preferred Term, Full Analysis Set Adverse Event Number (%) of patients N=262 (100%) Fatigue 61 (23.3) Headache 48 (18.3) Nausea 47 (17.9) Vomiting 31 (11.8) Abdominal pain upper 30 (11.5) Nasopharyngitis 20 (7.6) Upper respiratory tract infection 20 (7.6) Diarrhea 18 (6.9) Cough 17 (6.5) Decreased appetite 17 (6.5) Abdominal pain 16 (6.1) Anorexia 15 (5.7) Rhinitis 15 (5.7) Abbreviation: N = total number of patients.

17 CT Registry ID# 9496 Page 17 The most common spontaneously reported TEAEs were fatigue (23.3%), headache (18.3%), nausea (17.9%), vomiting (11.8%), and upper abdominal pain (11.5%). Table 9 shows the TEAEs considered at least as possibly related to study drug by the investigator, reported in at least 3% of patients. Table 9. Treatment-Emergent Adverse Events Classified as Related To Study Drug Occurring in 3% of Patients by Preferred Term, Full Analysis Set Adverse Event Number (%) of patients N=262 (100%) Fatigue 52 (19.8) Nausea 35 (13.4) Headache 21 (8.0) Abdominal pain, upper 19 (7.3) Decreased appetite 15 (5.7) Anorexia 14 (5.3) Vomiting 12 (4.6) Hypersomnia 11 (4.2) Weight decreased 10 (3.8) Abdominal pain 9 (3.4) Abbreviation: N = total number of patients. The most common TEAEs classified as related to study drug by the investigator were fatigue (19.8%), nausea (13.4%), headache (8.0%), upper abdominal pain (7.3%), decreased appetite (5.7%), and anorexia (5.3%). Clinical laboratory measurements and changes in vital signs were unremarkable; there were no clinically relevant changes and their evaluation gave no cause for any safety concerns. PAERS: The PAERS questionnaire assesses the frequency and severity of 48 solicited events frequently observed in pediatric patient populations under treatment with psychotropic medication. Because several items represent symptoms of ADHD, the patient-, physician-, and parent-rated PAERS total scores were high at baseline and decreased over time (e.g., mean total patient-rated score: Baseline, 20.6±14.4; Week 8, 10.9±10.3; Week 24, 11.3±11.2). Pooled Analysis of Studies B4Z-SB-LYDD and B4Z-SB-LYDE Parallel to this study B4Z-SB-LYDD in children, a similarly designed study in adolescents (B4Z-SB-LYDE; CT#7233) was performed. The pooled dataset from Studies LYDD and LYDE comprised a sample of 421 patients aged 6 17 years. In the pooled sample, the mean patient-rated GIPD total score (±SD) was the lowest at 13.1±5.8, the parent-rated score was intermediate at 18.6±6.1, and the physician-rated score was highest at 20.3±5.9. All 3 ratings differed statistically significantly at baseline

18 CT Registry ID# 9496 Page 18 (non-overlapping 95% CIs), but the parent- and physician-rated scores did not differ statistically significantly at Week 8 and Week 24. The analysis of agreement by Cohen kappa statistics also showed that agreement was highest between parent- and physicianrated scores (Cohen s kappa for agreement at baseline [95% CI]: 0.52 [0.47;0.57]), and low between patient- and parent-rated scores (0.16 [0.12;0.21]) or between patient- and physician-rated scores (0.14 [0.11;0.18]). All effectiveness scores used, including the ADHDRS-IV-Parent:Inv, CGI-S-ADHD and WREMB-R-Inv scores, improved consistently and statistically significantly from baseline to Week 8. Improvements were maintained at Week 24. In the pooled sample, treatment-emergent adverse events were reported in 331/421 (76.3%) patients, which were considered as possibly related to study drug in 207/421 (49.2%) patients. The most common spontaneously reported adverse events were fatigue (25.2%, related 22.3%), headache (20.4%, related 8.6%), nausea (18.3%, related 13.5%), vomiting (12.4%, related 5.0%), and upper abdominal pain (10.0%, related 7.1%). Laboratory investigations and vital signs were clinically not relevant and gave no cause for concern.