summary id# 9684 clinical study summary: study b4z-ca-s012...

CT Registry ID# 9684 Page 1

Atomoxetine Copyright © 2007 Eli Lilly and Company. All rights reserved.

Summary ID# 9684

Clinical Study Summary: Study B4Z-CA-S012

A 3-Month, Open-Label Study of Atomoxetine in Children with Attention-Deficit/Hyperactivity Disorder;

Symptomatic and Functional Outcomes

Date summary approved by Lilly: 03 June 2007

Brief Summary of Results

This Phase 4, multicenter, single-arm, open-label study was designed to examine the change in efficacy measures, functional outcomes, and health-related quality of life measures in children aged 6 – 11 years with Attention-Deficit/Hyperactivity Disorder (ADHD) treated with open-label, flexible doses of atomoxetine for approximately 3 months.

• A total of 212 patients were enrolled in this study (stimulant-naïve, n=116; non-stimulant-naïve, n=96). Of these, 150 (70.8%) completed the study.

• The correlation in change from baseline to 3 months between the Attention Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-Parent:Inv) total score and the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) overall score was 0.403 (p



• At 3 months, the mean change from baseline in ADHDRS-IV-Parent:Inv total score was -23.0 (95% CI: -25.0, -21.1; p



Objectives: Primary Objective: The primary objective of this study was to assess the correlation of change from baseline to approximately 3 months in the core symptoms of ADHD as measured by the Attention Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored, total score, (ADHDRS-IV-Parent:Inv) with change from baseline in functional outcome as assessed by the average score of the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) in children with ADHD, treated with open-label flexible doses of atomoxetine. Secondary Objectives: The secondary objectives of the study were as follows: 1. To assess the relationships of change from baseline to approximately 1, 2, and 3 months, or endpoint in

the core symptoms of ADHD with the changes in functional outcomes, as assessed by the WFIRS-P, and QoL, as assessed by the Child Health and Illness Profile – Child Edition – Parent Rated (CHIP –CE) in the total sample and in the subgroups of stimulant-naïve and non-stimulant-naïve patients.

2. To explore the time course of changes in ADHD symptomatology, functional outcomes, and QoL over the approximately 3 months of atomoxetine treatment in the total sample, the subgroups of stimulant-naïve and non-stimulant-naïve patients, and the diagnostic subtypes of ADHD.

3. To assess the efficacy of open-label flexible doses of atomoxetine after approximately 1, 2, and 3 months, or endpoint as measured by the change from baseline in the ADHDRS-IV-Parent:Inv (total score) and the Clinical Global Impression-ADHD-Severity (CGI-ADHD-S), in the total sample and in the subgroups of stimulant-naïve and non-stimulant-naïve patients.

4. To explore the impact of data collection time points on efficacy, quality of life, and functional outcome in four groups: 1) both baseline and endpoint collected during school year, 2) baseline during school year and endpoint during summer vacation, 3) baseline during summer vacation and endpoint during the school year, and 4) both baseline and endpoint collected during summer vacations.

5. To use the data collected in this study to examine the WFIRS-P questionnaire’s psychometric properties including internal consistency, convergent validity, and responsiveness to change.

Study Design: This was a Phase 4, multicenter, single-arm, open-label study of atomoxetine in outpatients aged 6 – 11 years diagnosed with ADHD. This study was conducted over a 3-month period, and consisted of two study periods: a screening and washout period (approximately 7 days), and an open-label, atomoxetine treatment period (approximately 91 days). Number of Patients: Planned: 200 Entered: 212 Completed: 150 Diagnosis and Main Criteria for Inclusion: Male and female outpatients weighing at least 20 kg and aged 6 – 11 years meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for ADHD (any subtype), and who met a symptom severity threshold of at least 1.5 standard deviations above the age and gender norm of the ADHDRS-IV-Parent:Inv total score were enrolled in this study. Study Drug, Dose, and Mode of Administration: Atomoxetine hydrochloride 0.5 – 1.2 mg/day, given orally once daily (or twice daily, if the patient experienced tolerability issues). Atomoxetine was prescribed based on the weight and titration schedule as recommended by the approved product label in Canada. Flexible doses between the recommended dose range of the study drug were permitted if judged appropriate by the investigator, based on tolerability and response to the medication. Comparator, Dose, and Mode of Administration: Not applicable Duration of Treatment: 3 months



Variables: Efficacy: Core ADHD symptoms and efficacy were assessed by the ADHDRS-IV-Parent:Inv. Efficacy was also measured by the CGI-ADHD-S. Health-related quality of life was assessed by the CHIP-CE. Functional outcomes were measured by the WFIRS-P, and the Global Assessment of Functioning (GAF). WFIRS-P is a parent-completed questionnaire that measures the impact of ADHD on their child’s functioning in 6 domains: Home; School; Self-concept; Social; Activities of Daily Living; and Risk Taking. Safety: Assessment of adverse events and vital signs. Evaluation Methods: Statistical: For the primary analysis, endpoint was defined as measurement obtained at Visit 7 (3 months). For all secondary analyses, unless otherwise specified, endpoint was defined as the last post-baseline measurement obtained in Study Period II (i.e., on or before Visit 7). Any change to the endpoint analyses was performed using both the completer population as defined above, and the last observation carried forward (LOCF) approach. Baseline was defined as the measurement obtained on Visit 2. The primary outcome for this study was the Pearson’s correlation between the change from baseline to 3 months of the ADHDRS-IV-Parent:Inv and that of WFIRS-P. In subgroup analyses, within group differences were performed using a paired t-test. Between group differences were analyzed using ANOVA. Changes from baseline between groups were analyzed using ANCOVA, with pooled sites and baseline as covariates. Investigative sites with 5 or fewer enrolled patients were to be pooled with other small investigative sites by region. The effect size between the stimulant naïve and non stimulant naïve groups was calculated, by taking the difference in the mean change from baseline between the two groups and dividing it by the average standard deviation of the two samples. All tests of hypotheses were tested at a two-sided alpha level of 0.05. All patients who had taken at least one dose of study drug were included in the safety analysis. Since the power of the study was on the primary endpoint and not on individual subgroups, it was planned that the sample size of each subgroup would be assessed before statistical comparisons were conducted. Sample size calculation: No previous data for a similar objective were available. A conservative estimate of a correlation of 0.3 was assumed, between the change from baseline to 3 months in the total scores of ADHDRS-IV-Parent:Inv and that of the WFIRS-P. In order to have 90% power at a two-sided significance level of 0.05, a sample of 113 patients completing the study was required. Assuming a 40% drop out rate, about 200 patients were planned for enrollment.

Results:

Patient Demographics

Table 1 summarizes the baseline demographic characteristics of all patients who were enrolled in this study.



Table 1. Baseline Demographics All Enrolled Patients

Variable Stimulant-Naïve (N=116)

Non-Stimulant-Naïve (N=96)

Total (N=212)

Age (years) N 116 96 212 Mean (SD) 8.2 (1.55) 8.9 (1.57) 8.5 (1.59) Median (Min – Max) 8.0 (6 - 11) 9.0 (6 - 11) 8.0 (6 - 11)

Ethnic Origin [n (%)] Caucasian 109 (94.0) 84 (87.5) 193 (91.0) African 3 (2.6) 6 (6.3) 9 (4.2) Hispanic 0 (0.0) 2 (2.1) 2 (0.9) Native American/Inuit 0 (0.0) 1 (1.0) 1(0.5) East Asian 4 (3.4) 2 (2.1) 6 (2.8) Western Asian 0 (0.0) 1 (1.0) 1 (0.5)

Gender [n (%)] Male 90 (77.6) 67 (69.8) 157 (74.1) Female 26 (22.4) 29 (30.2) 55 (25.9)

Abbreviations: Max = maximum; Min = minimum; N = total number of patients; n = number of patients; SD = standard deviation.

Of the 212 enrolled patients, 116 (54.7%) were stimulant-naïve with the remainder (n=96, 45.3%) non-stimulant-naïve. The majority of patients were diagnosed with ADHD combined subtype (n=166, 78.3%), while 20.3% (n=43) and 1.4% (n=3) of patients were diagnosed with ADHD Inattentive subtype and Hyperactive/Impulsive subtype, respectively.

Patient Disposition

A total of 212 patients were enrolled in this study. A total of 206 patients received at least one dose of study drug. Of these, 150 (70.8%) completed the study. The reasons for discontinuation are summarized in Table 2.



Table 2. Patient Disposition All Enrolled Patients

Abbreviations: N = number of patients.

Primary Outcome Measure

As shown in Table 3, the correlation in change from baseline to 3 months (Day 91, study completers) between ADHDRS-IV-Parent:Inv total score and WFIRS-P overall score was 0.403 (95% CI: 0.259 - 0.529; p



Table 3. Correlation in Change from Baseline Between ADHDRS-IV-Parent:Inv (Total Score) and WFIRS-P (Overall) All Enrolled Patients

Abbreviations: ADHDRS-IV-Parent:Inv = Attention Deficit/Hyperactivity Disorder Rating Scale-IV-

Parent Version: Investigator Administered and Scored; CI = confidence interval; CORR = Pearson’s correlation coefficient; LOCF = last observation carried forward; N = number of patients; WFIRS-P = Weiss Functional Impairment Rating Scale-Parent Report.

[1] The p-value is under the null hypothesis of zero correlation.

Table 4. Correlation in Change from Baseline Between ADHDRS-IV-Parent:Inv (Total Score) and WFIRS-P (Overall) All Enrolled Patients by Prior Stimulant Use

Visit

35 63 91 LOCF Abbreviations: ADHDRS-IV-Parent:Inv = Attention Deficit/Hyperactivity Disorder Rating Scale-IV-

Parent Version: Investigator Administered and Scored; CI = confidence interval; CORR = Pearson’s correlation coefficient; LOCF = last observation carried forward; N = total number of patients (column 2); N = number of patients (column 3); WFIRS-P = Weiss Functional Impairment Rating Scale-Parent Report.




Table 5. Correlation in Change from Baseline Between ADHDRS-IV-Parent:Inv Subscale Scores and CHIP-CE (Domains) All Enrolled Patients.

Visit CHIP-CE Domain

35 Satisfaction

Comfort Resilience Risks

Avoidance

Achievement

63 Satisfaction Comfort Resilience Risks

Avoidance

Achievement

91 Satisfaction Comfort Resilience Risks

Avoidance

Achievement

LOCF Satisfaction Comfort Resilience Risks

Avoidance

Achievement Abbreviations: ADHDRS-IV-Parent:Inv = Attention Deficit/Hyperactivity Disorder Rating Scale-IV-

Parent Version: Investigator Administered and Scored; CHIP-CE = Child Health and Illness Profile – Child Edition – Parent Rated; CI = confidence interval; CORR = Pearson’s correlation coefficient; LOCF = last observation carried forward; N = number of patients.




Table 6. Correlation in Change from Baseline Between ADHDRS-IV-Parent:Inv (Subscale Scores) and CHIP-CE (Domains) by Visit. All Enrolled Patients by Prior Stimulant Use

CHIP-CE Domain

Visit

Satisfaction 35

63

91

LOCF

Comfort 35

63

91

LOCF

Resilience 35

63

91

LOCF

(continued)



Table 6. Correlation in Change from Baseline Between ADHDRS-IV-Parent:Inv (Subscale Scores) and CHIP-CE (Domains). All Enrolled Patients by Prior Stimulant Use (concluded)

CHIP-CE Domain

Visit

Risks Avoidance

35

63

91

LOCF

Achievement 35

63

91

LOCF

Abbreviations: ADHDRS-IV-Parent:Inv = Attention Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored;

CHIP-CE = Child Health and Illness Profile – Child Edition – Parent Rated; CI = confidence interval; CORR = Pearson’s correlation coefficient; LOCF = last observation carried forward; N = total number of patients (column 3); N = number of patients (columns 4 and 9).




2) Changes in ADHDRS-IV-Parent:Inv, WFIRS-P, and CHIP-CE Over Time

The change from baseline in ADHDRS-IV-Parent:Inv total score over time for the total patient sample is presented in Table 7. No statistically significant differences were found between the stimulant-naïve and non-stimulant-naïve patient subgroups (p >.05).

The change from baseline in WFIRS-P overall score over time for the total patient sample is presented in Table 8. The was a statistically significant difference between the stimulant-naïve and non-stimulant-naïve patient subgroups in the “Learning and School” domain at LOCF endpoint [mean change: -0.63 (stimulant-naïve), -0.44 (non-stimulant-naïve); p=.048].

The change from baseline in CHIP-CE domain and subdomain scores over time for the total patient sample is presented in Table 9. These data are presented by stimulant-naïve and non-stimulant-naïve patient subgroups in Table 10.

The ADHD diagnostic subgroup analyses were deemed statistically inappropriate because of the disproportionate number of patients diagnosed with the different ADHD subtypes [Combined: 78.3% (n=166); Inattentive: 20.3% (n=43); Hyperactive/Impulsive: 1.4% (n=3)].



Table 7. Visit-wise Mean Score and Change from Baseline in ADHDRS-IV-Parent-Inv (Total and Subscales) All Patients Enrolled

Abbreviations: ADHDRS-IV-Parent:Inv = Attention Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored; CI

= confidence interval; LOCF = last observation carried forward; Max = maximum; Min = minimum; N = number of patients; SD = standard deviation. [1] The p-value is based on paired t-test.



Table 8. Visit-wise Mean Score and Change from Baseline in WFIRS-P (Overall and Subscales) All Patients Enrolled

(continued)



Table 8. Visit-wise Mean Score and Change from Baseline in WFIRS-P (Overall and Subscales) All Patients Enrolled (concluded)

Abbreviations: CI = confidence interval; LOCF = last observation carried forward; Max = maximum; Min = minimum; N = number of patients; SD = standard

deviation; WFIRS-P = Weiss Functional Impairment Rating Scale-Parent Report. [1] The p-value is based on paired t-test.



Table 9. Visit-wise Mean Score and Change from Baseline in CHIP-CE (Domains) All Patients Enrolled

Abbreviations: CHIP-CE = Child Health and Illness Profile – Child Edition – Parent Rated; CI = confidence interval; LOCF = last observation carried forward; Max = maximum; Min = minimum; N = number of patients; SD = standard deviation. [1] The p-value is based on paired t-test.



Table 10. Visit-wise Change from Baseline in CHIP-CE (Domains) All Patients Enrolled by Prior Stimulant Use

CHIP-CE Domain Visit

Satisfaction 35

63

91

LOCF

Comfort 35

63

91

LOCF

Resilience 35

63

91

LOCF

Risks Avoidance 35

63

91

LOCF

(continued)



Table 10. Visit-wise Change from Baseline in CHIP-CE (Domains) All Patients Enrolled by Prior Stimulant Use (concluded)

CHIP-CE Domain Visit

Achievement 35

63

91

LOCF

Abbreviations: ANCOVA = analysis of covariance; CHIP-CE = Child Health and Illness Profile – Child Edition – Parent Rated; CI = confidence interval; LOCF

= last observation carried forward; Max = maximum; Min = minimum; N = total number of patients (column 4); N = number of patients (column 5); SD = standard deviation.

[1] The p-value within group is based on paired t-test. [2] The p-value between groups is based on ANCOVA using pooled sites and baseline as covariates. [3] The effect size is calculated by taking the difference in the mean change from baseline between the two groups and dividing it by the average standard

deviation of the two samples.



3) Efficacy: Change in ADHDRS-IV-Parent:Inv Total Score and CGI-ADHD-S Score

The change from baseline in ADHDRS-IV-Parent:Inv total score at 1, 2, and 3 months (study completers) and LOCF endpoint for the total patient sample is presented in Table 7. No statistically significant differences were found between the stimulant-naïve and non-stimulant-naïve patient subgroups.

The change from baseline in CGI-ADHD-S score at 1, 2, and 3 months (study completers) and LOCF endpoint for the total patient sample is presented in Table 11. There was a statistically significant difference between the stimulant-naïve and non-stimulant-naïve patient subgroups at Day 35 [mean change: -1.8 (stimulant-naïve), -1.4 (non-stimulant-naïve); p=.027].

Table 11. Change in CGI-ADHD-S Score from Baseline Over Time All Patients Enrolled

Abbreviations: CGI-ADHD-S = Clinical Global Impressions – ADHD- Severity; CI = confidence interval; Max = maximum; Min = minimum; N = number of patients; SD = standard deviation.

[1] The p-value is based on paired t-test.

4) Impact of Data Collection Time Points on Efficacy, Functional Outcome, and QoL

The impact of data collection time points subgroup analyses were deemed statistically inappropriate because of the disproportionate number of patients in the subgroup with both baseline and endpoint occurring during the school year. At 3 months, the numbers in the four patient subgroups were: 1) both baseline and endpoint occurring during the school year (n=97); 2) baseline during the school year and endpoint during summer vacation (n=32); 3) baseline during summer vacation and endpoint during the school year (n=13); 4) both baseline and endpoint occurring during summer vacation (n=0). For eight patients it was unknown whether the endpoints occurred during the school year or summer vacation.

5) Evaluation of Psychometric Properties of the WFIRS-P

Internal consistency: The Cronbach’s coefficient alpha on WFIRS-P variables within the same domain are presented in Table 12.

Convergent validity: The correlation between WFIRS-P and the Global Assessment of Functioning (GAF) score at each visit are presented in Table 13 (WFIRS-P: overall) and



Table 14 (WFIRS-P: domains). The correlation on change from baseline are presented in Table 15 (WFIRS-P: overall) and Table 16 (WFIRS-P: domains).

Discriminant analysis: The change in WFIRS-P (overall and domains) by change in ADHDRS-IV-Parent:Inv (total), ADHDRS-IV-Parent:Inv (Inattention), and ADHDRS-IV-Parent:Inv (Hyperactive/Impulsive) by visit are presented in Table 17, Table 18, and Table 19, respectively.

The change in WFIRS-P (overall and domains) by change in CGI-ADHD-S by visit is presented in Table 20 (improvement: CGI-ADHD-S score reduction by at least 1 point) and Table 21 (improvement: CGI-ADHD-S score reduction by at least 2 points).

Table 12. Cronbach's Coefficient Alpha on WFIRS-P All Patients Enrolled

Abbreviations: LOCF = last observation carried forward; N = number of patients; WFIRS-P = Weiss

Functional Impairment Rating Scale-Parent Report. Note: Some standardized Cronbach’s coefficients could not be calculated due to missing scores.



Table 13. Correlation in Scores between GAF and WFIRS-P (Overall) All Patients Enrolled by Visit

Abbreviations: CI = confidence interval; CORR = Pearson’s correlation coefficient; GAF = Global

Assessment of Functioning; LOCF = last observation carried forward; N = number of patients; WFIRS-P = Weiss Functional Impairment Rating Scale-Parent Report.


Table 14. Correlation in Raw Scores between GAF and WFIRS-P (Domains) by Visit All Patients Enrolled






Table 15. Correlation in Change from Baseline between GAF and WFIRS-P (Overall) by Visit All Patients Enrolled




Table 16. Correlation in Change from Baseline between GAF and WFIRS-P (Domains) by Visit All Patients Enrolled






Table 17. Change in WFIRS-P (Overall and Domains) by Change in ADHDRS-IV-Parent:Inv (Total) by Visit All Patients Enrolled

(continued)



Table 17. Change in WFIRS-P (Overall and Domains) by Change in ADHDRS-IV-Parent:Inv (Total) by Visit All Patients Enrolled (continued)

(continued)



Table 17. Change in WFIRS-P (Overall and Domains) by Change in ADHDRS-IV-Parent:Inv (Total) by Visit All Patients Enrolled (concluded)


LOCF = last observation carried forward; N = total number of patients (column 3); N = number of patients (column 4); SD = standard deviation; WFIRS-P = Weiss Functional Impairment Rating Scale-Parent Report.

[1] Change in ADHDRS-IV-Parent:Inv: Improved = when percent change ≤-25%; No Change = when percent change is >-25% and ≤0%;.Worsened = when percent change is >0%.

[2] The p-value within group is based on paired t-test. [3] The p-value between groups is based on ANCOVA using pooled sites and baseline as covariates.



Table 18. Change in WFIRS-P (Overall and Domains) by Change in ADHDRS-IV-Parent:Inv (Inattention) by Visit All Patients Enrolled

(continued)



Table 18. Change in WFIRS-P (Overall and Domains) by Change in ADHDRS-IV-Parent:Inv (Inattention) by Visit All Patients Enrolled (continued)

(continued)




(continued)



Table 18. Change in WFIRS-P (Overall and Domains) by Change in ADHDRS-IV-Parent:Inv (Inattention) by Visit All Patients Enrolled (concluded)







Table 19. Change in WFIRS-P (Overall and Domains) by Change in ADHDRS-IV-Parent:Inv (Hyperactive/Impulsive) by Visit All Patients Enrolled

(continued)



Table 19. Change in WFIRS-P (Overall and Domains) by Change in ADHDRS-IV-Parent:Inv (Hyperactive/Impulsive) by Visit All Patients Enrolled (continued)

(continued)




(continued)



Table 19. Change in WFIRS-P (Overall and Domains) by Change in ADHDRS-IV-Parent:Inv (Hyperactive/Impulsive) by Visit All Patients Enrolled (concluded)







Table 20. Change in WFIRS-P (Overall and Domains) by Change in CGI-ADHD-S (First Set) by Visit All Patients Enrolled

(continued)



Table 20. Change in WFIRS-P (Overall and Domains) by Change in CGI-ADHD-S (First Set) by Visit All Patients Enrolled (continued)

(continued)




(continued)



Table 20. Change in WFIRS-P (Overall and Domains) by Change in CGI-ADHD-S (First Set) by Visit All Patients Enrolled (concluded)

Abbreviations: CGI-ADHD-S = Clinical Global Impressions – ADHD – Severity; GRP = group; LOCF = last observation carried forward; N = total number of

patients (column 3); N = number of patients (column 4); SD = standard deviation; WFIRS-P = Weiss Functional Impairment Rating Scale-Parent Report. [1] Change in CGI-S (first set): Group 1 = reduction of at least 1 point; Group 2 = no change; Group 3 = worsened. [2] The p-value within group is based on paired t-test. [3] The p-value between groups is based on ANCOVA using pooled sites and baseline as covariates.



Table 21. Change in WFIRS-P (Overall and Domains) by Change in CGI-ADHD-S (Second Set) by Visit All Patients Enrolled

(continued)



Table 21. Change in WFIRS-P (Overall and Domains) by Change in CGI-ADHD-S (Second Set) by Visit All Patients Enrolled (continued)

(continued)




(continued)



Table 21. Change in WFIRS-P (Overall and Domains) by Change in CGI-ADHD-S (Second Set) by Visit All Patients Enrolled (concluded)

Abbreviations: CGI-ADHD-S = Clinical Global Impressions – ADHD – Severity; GRP = group; LOCF = last observation carried forward; N = total number of

patients (column 3); N = number of patients (column 4); SD = standard deviation; WFIRS-P = Weiss Functional Impairment Rating Scale-Parent Report. [1] Change in CGI-S (second set): Group 1 = reduction of at least 2 points; Group 2 = no change or reduction of 1 point; Group 3 = worsened. [2] The p-value within group is based on paired t-test. [3] The p-value between groups is based on ANCOVA using pooled sites and baseline as covariates.



Safety

No deaths occurred during this study. Three serious adverse events were reported during this study, as follows: 1) one patient with “suicidal ideation/suicidal thoughts” which was reported by the investigator as not related to study drug. This event did not lead to study discontinuation. 2) one patient with “aggressive hostile behaviour” which was reported by the investigator as related to study drug. This event did not lead to study discontinuation. 3) one patient with “depression/suicidal ideation” which was reported by the investigator as related to study drug. This event did lead to study discontinuation.

A total of 14/206 patients (6.6%) discontinued due to at least one adverse event. A total of 175 patients (84.95%) reported 853 treatment-emergent adverse events (TEAEs) during this study. The most commonly reported TEAEs (occurring in ≥5% of patients) are summarized in Table 22.

Table 22. TEAEs Occurring In ≥5% Of Patients MedDRA Preferred Term (Version 8.0) Patients Who Received At Least One Dose of Study Drug

TEAEa

MedDRA Preferred Term Number of Patients [n (%)]

(N=206) Total number of patients experiencing TEAE(s) 175 (84.95)

Headache 48 (23.30) Decreased appetite 32 (15.53) Nausea 30 (14.56) Abdominal pain upper 30 (14.56) Cough 28 (13.59) Vomiting 26 (12.62) Pharyngolaryngeal pain 25 (12.14) Therapeutic response unexpected 23 (11.17) Aggression 23 (11.17) Pyrexia 22 (10.68) Abdominal pain 22 (10.68) Fatigue 20 (9.71) Nasopharyngitis 18 (8.74) Emotional disorder 15 (7.28) Irritability 14 (6.80) Diarrhoea 14 (6.80) Mood altered 13 (6.31) Somnolence 12 (5.83) Negativism 11 (5.34)

Abbreviations: TEAE = treatment emergent adverse event; MedDRA = Medical Dictionary for Regulatory Activities; N = total number of patients; n = number of patients.

a This table contains adverse events that occurred on and after the first dose. Multiple occurrences of an adverse event within a patient are counted only once.



Vital Signs, Height, and Weight

Change in vital signs, height and weight from baseline to endpoint are summarized in Table 23.



Table 23. Change in Vital Signs, Height and Weight from Baseline to Study Discontinuation by Age Group All Patients Who Received At Least One Dose of Study Drug

(continued)



Table 23. Change in Vital Signs, Height and Weight from Baseline to Study Discontinuation by Age Group All Patients Who Received At Least One Dose of Study Drug (concluded)

Abbreviations: BMI = body mass index; bpm = beats per minute; N = total number of patients (column 1); N = number of patients (column 4); SD = standard

deviation. [1] The p-value within group is based on paired t-test.

summary id# 9684 clinical study summary: study b4z-ca-s012...

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