Summary ID# Clinical Study Summary: Study B4Z-MC-LYBX

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1 CT Registry ID#7068 Page 1 Summary ID# 7068 Clinical Study Summary: Study B4Z-MC-LYBX A Randomized, Double-Blind Comparison of Hydrochloride and Placebo in Child and Adolescent Outpatients with Attention- Deficit/Hyperactivity Disorder and Comorbid Oppositional Defiant Disorder Date summary approved by Lilly: 17 September 2008

2 CT Registry ID#7068 Page 2 Title of Study: A Randomized, Double-Blind Comparison of Hydrochloride and Placebo in Child and Adolescent Outpatients with Attention-Deficit/Hyperactivity Disorder and Comorbid Oppositional Defiant Disorder Investigator(s): This multicenter study included 17 principal investigators. Study Center(s): This study was conducted at 17 study centers in the European Union and Australia. Length of Study: Phase of Development: 3 Date of first patient entered: (acute phase: 22 December 2003; 06 April 2004 for the open-label phase) Date of last patient completed: (acute phase: 02 June 2005; 16 November 2007 for the open-label phase) Objectives: Primary: The primary objective of this study was to test the hypothesis that atomoxetine hydrochloride (hereafter referred to as atomoxetine [ATX]), given once daily at a dose of 1.2 mg/kg/day for approximately 8 weeks, is superior to placebo in the treatment of children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and comorbid oppositional defiant disorder (ODD). Symptom change was measured by mean reduction in ODD symptoms on the investigator-rated ODD subscale score of the Swanson, Nolan, and Pelham Rating Scale-Revised (SNAP-IV). Secondary: To test the hypothesis that ATX given once daily at a dose of 1.2 mg/kg/day is superior to placebo in reducing symptoms of ADHD as measured by mean change in the investigator-rated ADHD subscale score of the SNAP-IV. To compare the efficacy of ATX given at a dose of 2.4 mg/kg/day with ATX given at a dose of 1.2 mg/kg/day in reducing symptoms of ODD (in patients with peak plasma ATX concentrations of <800 ng/ml during once-daily dosing), as measured by mean change in ratings on the ODD subscale of the SNAP-IV. To compare the efficacy of ATX given at a dose of 2.4 mg/kg/day with ATX given at a dose of 1.2 mg/kg/day in reducing symptoms of ADHD (in patients with peak plasma ATX concentrations of <800 ng/ml during once-daily dosing), as measured by mean change in ratings on the ADHD subscale of the SNAP-IV. To test the hypothesis that ATX is superior to placebo in reducing symptoms of ADHD and ODD, as measured by mean change in ratings on the Clinical Global Impressions-Severity (CGI-S). To test the hypothesis that ATX is superior to placebo in improving psychosocial functioning, as measured by the total score on the ADHD Impact Module (AIM). To investigate the role of environmental stress, as measured by the Social Readjustment Rating Scale (SRRS), in the exacerbation of ODD symptoms. To assess the safety and tolerability of ATX compared with placebo, as assessed by adverse events (AEs) elicited during open-ended questioning. The purpose of the open-label phase (Study Periods IV to VI) of Study B4Z-MC-LYBX (hereafter referred to as Study LYBX) was to assess long-term safety and tolerability in children and adolescent patients who had completed the earlier acute phase (Study Periods I to III). Also assessed were selected primary and secondary efficacy and health outcome measures collected during the acute phase (Study Periods I to III). Study Design: Study LYBX was a multicenter, randomized, double-blind, placebo-controlled, parallel group comparison of outpatients with ADHD and comorbid ODD. Patients were aged 6 to 12 years. This study consisted of 6 study periods: Study Period I: Screening, assessment, and washout. Study Period II; Primary Objective Placebo-Controlled Phase: This phase consisted of randomized, double-blind, placebo-controlled, acute treatment; it was an approximately 8-week treatment comparison of ATX 1.2 mg/kg/day or placebo in a 2:1 ratio and administered once daily or optional twice daily.

3 CT Registry ID#7068 Page 3 Study Period III; Dose-Comparison Phase: This phase consisted of a randomized, double-blind, acute dose comparison of ATX-treated patients who did not achieve a peak plasma concentration of at least 800 ng/ml and who did not demonstrate adequate ODD symptom reduction during Study Period II. These patients were re-randomized in a 1:1 ratio to either a higher dose (ATX 2.4 mg/kg/day) or the same dose (ATX 1.2 mg/kg/day) of continued ATX treatment for approximately 4 weeks. All other Study Period II completers were eligible to continue into Study Period III and were not re-randomized. Study Period II ATX remitter patients continued at ATX 1.2 mg/kg/day and Study Period II placebo patients were titrated to ATX 1.2 mg/kg/day. The open-label phase consisted of Study Period IV (Visits 7 to 13) and Study Periods V to VI (Visits 14 to 25). These extension phases allowed eligible patients to receive continued ATX treatment for up to 4 years duration. Number of Patients: Planned: Approximately 220 patients Entered: 257 Enrolled/Randomized: 226 Study Period II: acute, double-blind, placebo-controlled Randomized: 2:1; 226 patients (156 ATX, 70 placebo) Completed: 197 patients (132 ATX, 65 placebo) Study Period III: Total patients entered: 197 Total patients completed: 179 All patients who entered Study Period III were in one of the following 3 ATX treatment groups: Group 1: Patients who were nonremitters and who had an ATX peak plasma concentration of less than 800 ng/ml in Study Period II were re-randomized 1:1 to a higher dose of ATX treatment (ATX 2.4 mg/kg/day) or the same dose administered in Study Period II (ATX 1.2 mg/kg/day). Patients entered: 92 (46 high dose, ATX 2.4 mg/kg/day; 46 low dose, ATX 1.2 mg/kg/day) Patients completed: 82 (41 high dose; 41 low dose) Group 2: Patients who were remitters or who had an ATX peak plasma concentration of at least 800 ng/ml in Study Period II remained at their ATX treatment dose (ATX 1.2 mg/kg/day). Patients entered: 40 Patients completed: 38 Group 3: Patients who were treated with placebo in Study Period II were titrated to an ATX dose (ATX 1.2 mg/kg/day). Patients entered: 65 Patients completed: 59 Entered Open-Label Phase (Study Period IV): 173 patients Completed Study Period IV: 102 patients Completed Study Period V: 52 patients Completed Study Period VI: 17 patients Diagnosis and Main Criteria for Inclusion: Patients who were at least 6 years of age and not more than 12 years of age at Visit 1, and met the disease diagnostic criteria for ADHD and comorbid ODD as determined by a physician investigator s clinical assessment using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), the K-SADS-PL, the SNAP-IV ADHD subscale score, the CGI-S score, and the SNAP-IV ODD subscale score. Patients who completed the acute phase of the study were given the option to enter the open-label extension phase of the study. Test Product/Study Drug, Dose, and Mode of Administration: The dose administered was ATX 1.2 mg/kg/day given orally once daily. Patients randomly assigned to a higher dose during the dose comparison phase were administered ATX 2.4 mg/kg/day orally as a once-daily or twice-daily dose. The doses of ATX were administered as hydrochloride salt with doses expressed as ATX free base in capsules

4 CT Registry ID#7068 Page 4 supplied in blister cards. The dose was weight-based and was given once daily or twice daily as a divided dose (equally or unequally) in the morning and late afternoon/evening. During the open-label phase, the maximum dose was not to exceed ATX 1.4.mg/kg/day but could have been increased to a maximum of ATX 1.8 mg/kg/day, provided the total daily dose did not exceed ATX 150 mg. Doses could be adjusted at any time during the open-label phase based on weight and tolerability. Reference Therapy, Dose, and Mode of Administration: Placebo was administered during Study Period II only and was identical in appearance to ATX. Duration of Treatment: Study Period II: Approximately 8 weeks Study Period III: Approximately 4 weeks Open-label phase (Study Periods IV to VI): 1 to 3.25 years Variables: Efficacy: Primary: SNAP-IV ODD subscale total score (8 items) Secondary: SNAP-IV subscale scores of 18 ADHD items (including inattention and hyperactivity/impulsivity, and 8 ODD items), as well as CGI-S (ADHD/ODD), Clinical Global Impressions-Improvement (CGI-I [ADHD/ODD]), Connors Global Index-Parent Version (CGI-P), and the SRRS Safety: Treatment-emergent adverse events (TEAEs), vital signs, height, weight, laboratory analyses, and electrocardiograms (ECGs) Pharmacokinetic: Peak plasma ATX concentration Health Outcomes: AIM Evaluation Methods: Statistical: The primary efficacy analysis was a mixed-effects model repeated measures (MMRM) analysis of the SNAP-IV ODD subscale score. The independent effects in the model were investigator, treatment, visit, baseline SNAP-IV ODD subscale score, and treatment-by-visit interaction. Secondary analyses using analysis of covariance (ANCOVA) on the last observation carried forward (LOCF) change from baseline to endpoint were conducted on secondary efficacy variables. Study Period II baseline was defined as Visit 1 or Visit 2, and endpoint was defined as the final visit or Visit 5. Study Period III baseline was defined as Visit 5, and endpoint was defined as the final visit with nonmissing data. Separate analyses were conducted, one using Visits 1 and 2 as baseline and another using Visit 7 as baseline (for the open-label phase). If more than 1 item of an efficacy subscale was missing, the score for the subscale was considered missing. If a single item of a subscale was missing, the mean score of all other items in the subscale was imputed as the score for the missing item when computing totals (imputed data). The frequency of serious adverse events (SAEs), discontinuations due to TEAEs, overall rate of TEAEs, categorical changes in abnormal laboratory analytes, and changes in QT intervals were computed. Changes in vital signs from baseline to endpoint were compared using the Wilcoxon signed-rank test. Bioanalytical: Plasma samples were assayed for ATX concentration using a validated Atmospheric Pressure Chemical Ionization (APCI) Liquid Chromatography/Mass Spectrometry/Mass Spectrometry (LC/MS/MS) analytical method. Pharmacokinetic: ATX concentration data were summarized by treatment, response category, and/or CYP2D6 status.

5 CT Registry ID#7068 Page 5 Summary: Patient Demographics and Baseline Illness Characteristics Of the 257 patients entering Study Period I, 31 patients did not meet inclusion criteria; therefore, 226 patients were enrolled in the Study Period II treatment phase. Patients were randomly assigned to treatment with either ATX (n=156) or placebo (n=70). Of the total enrolled patients, the mean age was 9.6 years, the majority (n=211, 93.4%) were male, and 69.0% had prior stimulant exposure. There were no statistically significant differences between treatment groups for any parameter except weight (p=.024); the placebo group weighed more at baseline. All patients had a present diagnosis of ADHD/ODD as per the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL). The other common present comorbid disorders noted were behavior conduct disorder current (12.0%), followed by anxiety (2.2%). Overall, 30.1% of ATX-treated patients and 27.1% of placebo-treated patients had at least 1 historical disorder. For the open-label phase (Study Periods IV to VI), the mean age was 9.65 years. Most of the patients were Caucasian males (n=165, 95.4%), and had combined hyperactive and inattentive ADHD (n=144, 83.2%). The majority of patients (n=119, 68.8%) had previously used stimulants prior to treatment with ATX. Severity of Illness For both Study Period II and Study Period III, baseline score symptom severity of ADHD and ODD did not show a statistically significant difference between any treatment groups. Patient Disposition Study Period II: Of the 257 patients who entered the study, 226 were randomized (156 ATX, 70 placebo). In all, 197 patients completed Study Period II, in which the primary objective was evaluated as ADHD and comorbid ODD symptom improvement in patients treated with 1.2 mg/kg/day ATX versus patients treated with placebo. Study Period III: Of the 156 patients randomly assigned to ATX treatment in Study Period II, 132 (84.6%) patients continued into Study Period III. Of the 70 patients randomly assigned to placebo treatment in Study Period II, 65 (92.9%) patients continued into Study Period III. Open-label phase: A total of 173 patients received at least 1 dose of ATX 1.2 mg/kg/day. A total of 102 patients completed Study Period IV, 52 patients completed Study Period V, and 17 patients completed Study Period VI.

6 CT Registry ID#7068 Page 6 Patient Discontinuation Study Period II (n=226): The most frequent reasons for discontinuation in this study period were protocol violation (n=8; 3.5%) and adverse event (n=6; 2.6%). No statistically significant differences were observed between treatment groups for reasons of discontinuation during Study Period II. Study Period III (n=197): The most frequent reasons for discontinuation in this study period were lack of efficacy as perceived by the patient and physician (n=10; 5.1%), unable to contact patient/caregiver (n=3; 1.5%), and adverse event (n=3; 1.5%). No statistically significant differences were observed between treatment groups regarding reasons for discontinuation during Study Period III. Open-label phase (n=173): The most frequent reasons for discontinuation in this study period were lack of efficacy as perceived by the patient and physician (n=33; 19.1%), and lack of efficacy as perceived by the patient (n=19; 11.0%). Efficacy (Acute Phase: Study Periods II and III) The primary efficacy analysis was performed during Study Period II only. Additionally, there was a comparison between the ATX and placebo treatment groups at the final week of Study Period II (Visit 5). Baseline was defined as scores obtained for Visit 1 or Visit 2. Study Period III was included to evaluate the effectiveness of an increased ATX dose of up to 2.4 mg/kg/day for patients who had not reached ATX plasma level concentrations of at least 800 ng/ml or who did not demonstrate symptom improvement at the 1.2 mg/kg/day ATX dose administered during Study Period II. All patients who completed Study Period II were allowed to continue into Study Period III. Primary efficacy Study Period II: Results of the MMRM analysis of the SNAP-IV ODD subscale score demonstrated that overall treatment effect of ATX was statistically significantly greater than that of placebo (p=.01). Looking at each visit using MMRM analysis of leastsquares mean (LS Mean) demonstrated statistically significantly greater ODD symptom improvement on the SNAP-IV ODD subscale score in the ATX treatment group compared to the placebo treatment group at Visit 3 (p=.003) and Visit 4 (p=.043), but not at Visit 5 (p=.209). Secondary Efficacy Derived from SNAP-IV ODD and ADHD Subscale Scores Study Period II: The mean change from baseline to LOCF in SNAP-IV ODD subscale scores did not demonstrate statistical significance between placebo and ATX treatment groups. A statistically significantly greater ADHD symptom improvement was observed in ATX-treated patients compared to placebo-treated patients in mean change from baseline to LOCF for all SNAP-IV ADHD subscale scores, including combined subtype (p<.001), inattentive subtype (p<.001), and hyperactive/impulsive subtype (p=.003).

7 CT Registry ID#7068 Page 7 Study Period III: Patients who had been non-remitters in Study Period II demonstrated no statistically significant differences on any of the Imputed subscale scores between treatment groups treated with 1.2 mg/kg/day ATX or treated with 2.4 mg/kg/day ATX. Response Response was defined as a reduction of 1 standard deviation (SD) on the SNAP-IV ODD subscale and an improvement of 1 point on the ADHD/ODD score of the CGI-S. Remission was defined as a score <9 on the SNAP-IV ODD subscale and a score of 1 or 2 on the ADHD/ODD score of the Clinical Global Impressions-Improvement (CGI-I). Study Period II: A statistically significantly greater percentage of ATX-treated patients met the protocol-defined criteria for both response (p=.011) and remission (p=.041) in ODD symptom improvement compared to placebo-treated patients. Study period III: Results did not demonstrate a statistically significant difference in the percentage of responders (p=.266) or in the percentage of remitters (p=.485) in patients treated with 1.2 mg/kg/day ATX or in patients treated with 2.4 mg/kg/day ATX. Clinical Global Impressions Severity (ADHD and ODD) Study Period II: Results of the CGI-S scale demonstrated a statistically significantly greater mean score reduction from baseline to LOCF endpoint (p=.013) in the severity of ADHD with comorbid ODD symptoms in ATX-treated patients compared to placebotreated patients. Study Period III: No statistically significant differences were observed in mean change from baseline to LOCF endpoint scores between patients treated with 1.2 mg/kg/day ATX or patients treated with 2.4 mg/kg/day ATX (p=.464). Clinical Global Impressions Improvement (ADHD and ODD) Study Period II: Patients treated with ATX were assessed by the clinician as having statistically significantly symptom improvement compared to placebo-treated patients (p=.037). Conners Global Index-Parent Study Period II: The CGI-P total score and the Restless/Impulsive subscore demonstrated a statistically significant mean score reduction from baseline to endpoint (p=.002 and p<.001, respectively) in the ATX treatment group compared to the placebo treatment group. Study Period III: No statistically significant differences were observed on the CGI-P total score, Emotional Liability subscore or the Restless/Impulsive subscore, between the group treated with 1.2 mg/kg/day ATX and the group treated with 2.4 mg/kg/day ATX.

8 CT Registry ID#7068 Page 8 Social Readjustment Rating Scale Study Period II: No statistically significant difference was observed between ATXtreated patients and placebo-treated patients in the mean change from baseline to LOCF endpoint on the SRRS (p=.636). Study Period III: The within-group mean reduction from baseline to LOCF endpoint SRRS scores for the 2.4 mg/kg/day ATX treatment group was statistically significant (p=.010), but the between-group comparison with the 1.2 mg/kg/day ATX treatment group was not statistically significant (p=.072). Health Outcome Attention-Deficit/Hyperactivity Disorder Impact Module Study Period II: A statistically significant improvement (score increase) in mean change from baseline to LOCF endpoint was demonstrated in the ATX treatment group compared to patients in the placebo-treatment group on both summary subscale scores, the Child Scale (p=.002) and the Parent-Home Scale (p=.018). No statistically significant difference between treatment groups was observed on the single-item Child Self-Control subscale score; however, there was no decrease in mean change from baseline to endpoint score observed in either group. Study Period III: The mean change from baseline to LOCF endpoint for the AIM summary scores (Child Scale and Parent-Home Scale) and the single-item Child Self- Control subscale score for Study Period III did not demonstrate a statistically significant difference between patients treated with 1.2 mg/kg/day or 2.4 mg/kg/day ATX. Efficacy (Open-Label Phase) For the LOCF analysis of mean change from baseline (Visit 7) to endpoint of the SNAP-IV subscale scores for patients who took at least 1 dose of ATX during the openlabel phase, some minor fluctuation of scores (increase or decrease) was observed in the SNAP-IV ODD and ADHD subscales. However, there was a statistically significant decrease (improvement) in the ATX group (p=.019) and in the all-treatments-combined group (p=.013) for the Hyperactivity/Impulsivity subscale scores. For the LOCF analysis of mean change of scores from baseline (Visit 7) to endpoint for other efficacy and health outcome measures for patients who took at least 1 dose of ATX during the open-label phase, there were no statistically significant changes observed for any measure other than the SRRS (p<.001), which demonstrated a worsening (increase) in score compared to Visit 7.

9 CT Registry ID#7068 Page 9 The ODD remitters were defined as those patients who had a score of <9 on the SNAP-IV ODD subscale and a score of 1 or 2 on the CGI-I. Of the 173 patients who entered the open-label phase, 38 (22%) patients were remitters. This percentage is higher than that observed in Study Period III, during which 3 (6.5%) patients in the ATX 1.2 mg/kg/day group and 6 (13%) patients in the ATX 2.4 mg/kg/day group were remitters. Pharmacokinetics A blood sample for the measurement of plasma ATX was collected for all patients at both Visit 3 (Study Period II; placebo and ATX 1.2 mg/kg/day doses) and Visit 7 (Study Period III; ATX 1.2 mg/kg/day and ATX 2.4 mg/kg/day doses). Samples were intended to capture peak ATX plasma concentration and were to be drawn between 30 and 90 minutes postdose. The samples collected at Visit 3 served to determine eligibility for double-blinded re-randomization into Study Period III. Overall, mean concentrations in nonremitters (both nonresponders and responders) and remitters were comparable after the initial dosing with ATX 1.2 mg/kg/day. As expected at Visit 7, concentrations were higher in the ATX 2.4 mg/kg/day group compared with the ATX 1.2 mg/kg/day group. Safety Extent of Exposure Study Period II: The mean final prescribed dose and mean maximum prescribed dose were ATX 1.14 mg/kg/day and ATX 1.17 mg/kg/day, respectively, and the mean of the total days on therapy was similar between treatment groups (ATX, 79 days; placebo, 84 days). Study Period III: The mean of the total days on therapy (87 days) was the same for ATX 1.2 mg/kg/day (low dose) and ATX 2.4 mg/kg/day (high dose) of ATX treatment groups. Open-label phase: The mean final prescribed daily dose was ATX 1.33 mg/kg and the mean daily maximum dose was ATX 1.64 mg/kg. The mean duration of therapy was days. Adverse Events Deaths and Serious Adverse Events No deaths were reported during any period of the study. Study Period II: One placebo-treated patient experienced the SAE of self-injurious ideation. Three ATX-treated patients experienced the following SAEs: 1 report each of obsessive compulsive disorder, tic, and fatigue. Study Period III: One patient (1.2 mg/kg/day of ATX) experienced aggression reported as an SAE.

10 CT Registry ID#7068 Page 10 Open-label phase: A total of 15 (8.7%) patients experienced 1 or more SAEs. The most frequently-reported SAEs were appendicitis (n=3, 1.7%) and oppositional defiant disorder (n=2, 1.2%). Patient Discontinuation due to Adverse Events Study Period II: Of the 156 ATX-treated patients, 6 (3.8%) patients discontinued due to an adverse event (AE; 1 report each of upper abdominal pain, aggression, fatigue, headache, irritability, and nausea). No placebo-treated patients discontinued due to an AE. Study Period III: A total of 3 (1.5%) of the 197 patients enrolled in Study Period III who took at least 1 dose of study drug discontinued the study due to an AE. One patient (ATX 1.2 mg/kg/day) discontinued due to rash, and 2 patients (ATX 2.4 mg/kg/day) discontinued due to an AE (1 report each of tic and elevated AST). Open-label phase: Of the 173 patients who took at least 1 dose of study medication, 13 (7.5%) patients discontinued due to an AE. Those AEs were oppositional defiant disorder (n=2, 1.2%), weight decreased (n=2, 1.2%), abdominal pain upper, anxiety, blood bilirubin increased, disturbance in attention, electrocardiogram QT corrected interval prolonged, hepatic enzyme increased, somnolence, syncope, and vomiting (n=1 in each, 0.6%). Treatment-Emergent Adverse Events Study Period II: Of the 226 randomized patients who took at least 1 dose of study drug, 126 (80.8%) ATX-treated patients and 43 (61.4%) placebo-treated patients reported at least 1 TEAE. The most commonly reported TEAEs (reported in 10% of patients) for ATX-treated patients were headache (n=54, 34.6%), decreased appetite (n=38, 24.4%; p<.001 versus placebo), nausea (n=32, 20.5%; p=.033 versus placebo), fatigue (n=27, 17.3%; p=.021 versus placebo), vomiting (n=19, 12.2%), abdominal pain upper (n=19, 12.2%), and nasopharyngitis (n=17, 10.9%). The most commonly reported AE in placebo-treated patients was headache in 18 patients (25.7%). Study Period III: Of the 197 patients who entered this study period, 83 (55.0%) patients treated with ATX 1.2 mg/kg/day (low dose) and 27 (58.7%) patients treated with ATX 2.4 mg/kg/day (high dose) reported at least 1 TEAE. No statistically significant differences between low- or high-dose ATX treatment groups were seen for any AE in 5% of patients. The most common AE (reported in 10% of patients) was fatigue (low dose, 18 patients [11.9%]; high dose, 4 patients [8.7%]). One of the 10 female patients in the low-dose group reported a hot flush. Open-label phase: Of the 173 patients who entered this phase, 150 (86.7%) patients experienced 1 or more TEAEs. The most frequently reported TEAEs (>10%) were headache (n=112, 64.7%), nasopharyngitis (n=52, 30.1%), vomiting (n=41, 23.7%), nausea (n=31, 17.9%), cough (n=27, 15.6%), upper abdominal pain (n=-25, 14.5%), diarrhea (n=20, 11.6%), and fatigue (n=19, 11.0%).

11 CT Registry ID#7068 Page 11 Clinical Laboratory Evaluation Study Period II: Statistically significant between-group changes from baseline to LOCF endpoint were observed in alkaline phosphatase (p=.002), creatine phosphokinase (p=.008), total protein (p=.040), erythrocyte count (p=.031), and uric acid (p<.001). The ATX-treated patients showed a mean decrease in alkaline phosphatase and uric acid. Both ATX- and placebo-treated patients showed a mean increase in creatine phosphokinase and erythrocyte count. The ATX-treated patients showed a mean increase in total protein, whereas a decrease in total protein was observed in placebo-treated patients. Study Period III: No statistically significant differences were observed between treatment groups (low- or high-dose ATX treatment) in the change to LOCF endpoint for any laboratory analyte. Open-label phase: Increased levels above the normal range (observed in 5% of patients) were creatinine (n=23, 18.1%), platelet count (n=12, 10.7%), calcium (n=13, 10.6%), urine specific gravity (n=11, 8.4%), eosinophils (n=8, 7.2%), and creatinine phosphokinase (n=7, 5.4%). The number of patients with levels of creatinine elevated above normal ranges in the open-label phase was relatively large compared to Study Period II (5 [3.6%] patients in the ATX 1.2 mg/kg/day group, and 3 [4.7%] patients in the placebo group) and Study Period III (8 [6.0%] patients in the ATX 1.2 mg/kg/day group, and 3 [6.7%] patients in the ATX 2.4 mg/kg/day group). The only decrease in laboratory analytes that occurred at a frequency of 5% was observed in the leukocyte count (n=8, 7%). Vital Signs Study Period II: A statistically significant difference was observed in the ATX treatment group compared to the placebo-treated group in the percentage of patients who met the criterion for increases in diastolic blood pressure (p=.042). No patient discontinued due to an increase in diastolic blood pressure or due to weight loss concerns. A statistically significant (p<.001) number of ATX-treated patients showed a decrease (at least 3.5%) in weight compared to placebo-treated patients. Study Period III: No statistically significant differences in mean change from baseline to LOCF endpoint were observed for any vital sign or weight between the low-dose and high-dose ATX treatment groups. Open-label phase: There was a statistically significant increase (p<.001) in height and weight from baseline to endpoint in this phase; this was not unexpected in the patient population studied. There were no statistically significant changes observed in other vital signs from baseline to endpoint.

12 CT Registry ID#7068 Page 12 Electrocardiogram Study Period II: Statistically significant differences were observed between the ATXtreatment group compared to the placebo treatment group in mean change from baseline to LOCF endpoint for ECG parameters, with a statistically significant increase in ECG heart rate (8.19 bpm, p<.001), and decreases in RR interval ( msec, p<.001), QT interval ( msec, p<.001), and QT interval corrected by both Fridericia (-3.78 msec, p<.001) and Data correction (-1.50 msec, p=.015) methods. Study Period III: No statistically significant differences were observed between ATX low-dose and high-dose treatment groups in mean change from baseline to LOCF endpoint for the ECG parameters. Open-label phase: No patient demonstrated a postbaseline QT interval increase 60 msec or had an endpoint QT interval value 500 msec, whether corrected by the Fridericia, Bazett, or Data methods. Additionally, no increases from normal to prolonged QT intervals were observed.