SYNOPSIS. Publications No publications at the time of writing this report.

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1 Drug product: TOPROL-XL Drug substance(s): Metoprolol succinate Study code: D4020C00033 (307A) Date: 8 February 2006 SYNOPSIS Dose Ranging, Safety and Tolerability of TOPROL-XL (metoprolol succinate) Extended-release Tablets (metoprolol CR/XL) in Hypertensive Pediatric Subjects: A Multicenter, Double-blind, Placebo-controlled, Randomized, Parallel-group Study International co-ordinating investigator Bonita E. Falkner, M.D. Professor of Medicine and Pediatrics Thomas Jefferson University 833 Chestnut Street, Suite 700 Philadelphia, PA USA Study center(s) This study was initiated at 36 centers in the United States and 1 center in the Dominican Republic. Seven of the 36 centers in the United States were shipped drug but did not enroll any patients. Publications No publications at the time of writing this report. Study dates Phase of development First patient enrolled 30 May 2002 Therapeutic exploratory (II) Last patient completed 09 June 2004 Objectives The purpose of this study was to evaluate the [efficacy], dose range, safety, and tolerability of TOPROL-XL in hypertensive pediatric patients. The primary evaluation of the dose range [ie, efficacy] was based on the change in sitting systolic blood pressure (SBP) from baseline to the end of treatment. It was hypothesized that there would be a positive [ie, statistically significant, nonzero] slope to the dose-response line representing placebo-corrected changes in sitting SBP as a function of target dose ratio.

2 Study design This was a multicenter, international, double-blind, placebo-controlled, randomized, parallelgroup study. The study included a screening visit, a 1- to 2-week single-blind, placebo run-in period during which all previous antihypertensive medications were discontinued, and a 4-week double-blind treatment period. At the end of the placebo run-in period, eligible patients with blood pressure (BP) measurements in the qualifying range were randomized in a 1:2:1:2 ratio to receive once daily, oral doses of placebo, TOPROL-XL 0.2 mg/kg, TOPROL-XL 1.0 mg/kg, or TOPROL-XL 2.0 mg/kg. TOPROL-XL doses of 12.5, 25, 37.5, 50, 75, 100, 150, or 200 mg were used to approximate the target doses. At the end of the 4-week double-blind treatment period, patients were offered the opportunity to enter the openlabel extension of this study to examine the pharmacokinetic profile and long-term safety of TOPROL-XL. This study was conducted in response to a Written Request from the Food and Drug Administration (FDA) to investigate TOPROL-XL in a pediatric population with hypertension. The study utilized the FDA-approved Type A design. Target patient population and sample size Consented male and female patients, 6 to 16 years of age inclusive, with newly diagnosed and untreated hypertension or previously diagnosed and currently treated hypertension, were eligible for participation in this study. Patients with secondary hypertension, SBP greater than 20 mmhg or DBP greater than 10 mmhg above the 95 th percentile using height-adjusted charts for age and gender, a heart rate <55 bpm at randomization, other clinically significant medical conditions, or contraindications to beta-blocker therapy were ineligible for study participation. In order to be randomized to double-blind study medication, mean sitting SBP or diastolic blood pressure (DBP) measurements were to be above the 95 th percentile for height-adjusted charts of age and gender. Based on statistical considerations, a total of 144 hypertensive patients were planned to be randomized in this study. Investigational product and comparator(s): dosage, mode of administration, and batch numbers TOPROL-XL (metoprolol CR/XL), 25 mg or 50 mg tablets, administered orally once daily, batch numbers H , H , H or placebo matching TOPROL-XL 25 mg or 50 mg, administered orally once daily, batch numbers H , H , H The 25-mg tablet was scored and able to be split to meet targeted TOPROL-XL dose levels of 12.5 mg and 37.5 mg. Single-blind placebo tablet, administered orally once daily, batch number H and H Duration of treatment 4 weeks. Patients in the placebo and TOPROL-XL 0.2 mg/kg groups received the target dose for 4 weeks, while patients in the TOPROL-XL 1.0 mg/kg and 2.0 mg/kg groups had their dose uptitrated (based on weight) to the target dose over the first 1 to 2 weeks of double-blind treatment. 2

3 Criteria for evaluation (main variables) Efficacy and pharmacokinetics Primary variable: Sitting SBP determined at trough at Visit 7 (Week 4). The primary measure of effect was the placebo-corrected change from baseline to the end of treatment (Week 4, Visit 7). The following secondary variables were evaluated in this study: Placebo-corrected change from baseline to end of treatment in trough sitting DBP Change from baseline at each postbaseline visit for trough sitting SBP and DBP, and trough standing SBP and DBP Percentage of responders at Week 4, defined as trough sitting SBP and DBP less than the 95 th percentile Pharmacokinetic endpoints: Plasma metoprolol concentration at trough at Visit 7 (Week 4) Safety Number and percentage of patients with adverse events (AEs; all and treatment-emergent), changes from baseline in clinical laboratory tests, heart rate, body weight, and electrocardiographic (ECG) parameters, and the incidence of clinically significant abnormal laboratory values and physical examination findings Statistical methods The primary analysis used an intention-to-treat (ITT) population which included all patients who received at least 1 dose of study medication and had baseline and at least 1 postbaseline measurement. For this analysis, missing data were imputed using a last observation carried forward (LOCF) approach. A simple linear regression analysis was performed on the placebo-corrected change from baseline to Week 4/LOCF in sitting SBP and sitting DBP with dose ratio as the explanatory variable. Given TOPROL-XL doses of 0.2, 1.0, and 2.0 mg/kg, the dose ratio of 1:5:10 was considered a continuous variable for analysis. The slope of the regression line was tested to see if it differed from zero using an F-test at a 0.05 significance level. A supportive analysis using individuals actual weight-adjusted doses (mg/kg) as an explanatory variable was also performed. The placebo correction for placebo-corrected changes from baseline to Week 4/ LOCF in sitting SBP and sitting DBP was performed by subtracting the mean change from baseline for the placebo group from the individual patient changes in the other treatment groups. 3

4 An analysis of variance (ANOVA) was performed with treatment group as the main factor for the changes from baseline to each postbaseline visit in sitting SBP and DBP. This ANOVA model was used to construct pairwise comparisons of each active treatment versus placebo and the active treatment groups combined versus placebo. The percentage of responders at Week 4 was summarized by frequency counts, percentages, and 95% confidence intervals (CI) for each treatment group. Subgroup analyses were also performed on the changes from baseline at Week 4 in sitting SBP and DBP, and the influence of heart rate and baseline body mass index (BMI) on the mean changes from baseline to Week 4/LOCF in sitting SBP and DBP were examined using linear regressions. Trough plasma concentrations of metoprolol were summarized descriptively and the lower limit of quantitation (LLQ) was 1 ng/ml. Safety data were summarized using the safety population, defined as all patients who received at least 1 dose of study medication and were not lost to follow-up. No statistical analyses were performed on the safety data in this study. Patient population A total of 204 patients were enrolled into this study and entered the placebo run-in period at 29 centers located in the United States and 1 center in the Dominican Republic. A total of 144 patients were randomized at 28 centers to receive double-blind treatment with placebo (n=24), TOPROL-XL 0.2 mg/kg (n=47), TOPROL-XL 1.0 mg/kg (n=23), or TOPROL-XL 2.0 mg/kg (n=50). Despite randomization to a treatment group, 2 patients were excluded from all efficacy and safety analysis populations, including 1 patient who never received study drug (TOPROL-XL 2.0 mg/kg) and 1 patient who had no data after starting study drug (TOPROL-XL 0.2 mg/kg). The proportion of patients who discontinued study drug for any reason was comparable in the 3 TOPROL-XL groups (4% to 6%) and lower than that in the placebo group (17%). The 4 treatment groups were generally well-matched with respect to demographic and baseline characteristics. Patients included in the ITT population had a mean age of 12.5 years (range, 6 to 16 years), were predominantly male (70%), nonblack (74%), and were equally distributed into Tanner Stage 3 or >3 (n=70 for each). Approximately three-quarters of the patients were overweight as evidenced by a BMI >95 th percentile adjusted for age and gender. Most patients (89%) had systolic hypertension (isolated or in combination with diastolic hypertension), and 79% of patients had been diagnosed with hypertension within the preceding 2 years. Two patients included in the ITT population (1 each in the TOPROL-XL 0.2 and 1.0 mg/kg groups) entered the double-blind period without protocol-specified hypertension (ie, SBP and DBP measurements were below the 95 th percentile adjusted for height, age, and gender following the placebo run-in period). Approximately three-quarters of patients (77%) had not received treatment for their hypertension within the month preceding the screening visit. At baseline, mean sitting SBP and sitting DBP were comparable for the 4

5 4 treatment groups and ranged from to mmhg and 76.3 mmhg to 81.4 mmhg, respectively. Efficacy results Data from 140 patients were analyzed for efficacy in the ITT population including 23 patients in the placebo group and 45, 23, and 49 patients in the TOPROL-XL 0.2, 1.0, and 2.0 mg/kg groups, respectively. The primary reason for exclusion from the ITT population was no baseline or no postbaseline BP data. The estimated slope (± standard error) of the placebo-corrected change from baseline in sitting SBP at Week 4/LOCF was 0.11 (±0.19) mmhg per unit increase in dose ratio (p=0.5731), indicating a nonsignificant dose response relationship for TOPROL-XL across doses of 0.2, 1.0, and 2.0 mg/kg. The actual mean changes for each treatment group, as well as the placebo-corrected mean changes for the 3 TOPROL-XL groups and the dose-response line are shown Figure S1. For sitting DBP, the slope of the placebo-corrected change from baseline was (± 0.20) mmhg per unit increase in dose ratio (p=0.0155), indicating a significant dose response relationship. Figure S1 Mean changes (actual and placebo-corrected) from baseline to Week 4/LOCF for sitting SBP (ITT population) 0 Mean changes with SE Placebo 0.2 mg/kg 1.0 mg/kg 2.0 mg/kg (n=23) (n=45) (n=23) (n=49) Placebo-corrected mean changes and dose-response line 0.2 mg/kg 1.0 mg/kg 2.0 mg/kg (n=45) (n=23) (n=49) mmhg Note: For each treatment group, the standard error (SE) was calculated using the following formula: standard deviation square root of n. 5

6 Statistically significant reductions from baseline in sitting SBP and sitting DBP were observed at Week 4/LOCF in each of the TOPROL-XL treatment groups (0.2 mg/kg, p= and p=0.0184, respectively; 1.0 mg/kg; p= and p=0.0081, respectively; 2.0 mg/kg, p< for both). No significant reductions in blood pressure were observed at Week 4/ LOCF in the placebo group (p>0.050). The reductions in blood pressure at Week 4/LOCF in the TOPROL-XL 1.0 and 2.0 mg/kg treatment groups were clinically meaningful, with least square mean reductions for sitting BP of -7.65/-4.93 mmhg for 1.0 mg/kg and mmhg/ mmhg for 2.0 mg/kg. By comparison, the least square mean reductions in sitting BP at Week 4/LOCF in the placebo group were -1.86/-2.12 mmhg. Comparisons with placebo for the mean reduction in sitting SBP at Week 4/LOCF were statistically significant in favor of the combined TOPROL-XL groups (p=0.0351) and the TOPROL-XL 1.0 and 2.0 mg/kg groups (p= and p=0.0492, respectively), and in sitting DBP in favor of the TOPROL-XL 2.0 mg/kg group (p=0.0170). There was no trend suggesting that the between-group differences in mean reductions in sitting SBP and DBP at Week 4/LOCF differed as a function of age, Tanner stage, race, or type of hypertension. The results for gender, prior antihypertensive use, and baseline BMI were more variable and meaningful conclusions cannot be drawn due to the small sample size of each of these subgroups. Approximately one-half of patients in the 3 TOPROL-XL treatment groups (43% to 49%) and one-quarter of patients in the placebo group (26%), were responders at Week 4, defined as sitting SBP and DBP below the 95 th percentile (adjusted for height, age, and gender). Pharmacokinetic results Trough plasma metoprolol concentrations obtained approximately 24 hours after the last dose of TOPROL-XL averaged 4.5, 13.9, and 28.3 ng/ml in the 0.2 mg/kg (n=12), 1.0 mg/kg (n=15), and 2.0 mg/kg (n=40) groups, respectively, among patients with evaluable samples at Visit 7 whose values were above the LLQ. Safety results Overall, oral administration of TOPROL-XL to pediatric patients 6 to 16 years of age with hypertension in daily doses ranging from 12.5 mg to 200 mg for 4 weeks was safe and well tolerated (Table S1). The safety and tolerability profiles for TOPROL-XL were generally comparable to those observed for placebo. The percentage of patients experiencing at least 1 treatment-emergent AE following treatment with TOPROL-XL was generally comparable to that observed following placebo. Across all treatment groups, the most frequently reported treatment-emergent AE was headache, which was reported by 17%, 11%, 22%, and 10% of patients in the placebo, TOPROL-XL 0.2 mg/kg, TOPROL-XL 1.0 mg/kg, and TOPROL-XL 2.0 mg/kg groups, respectively. All but 1 of the reported treatment-emergent AEs were mild or moderate in severity, and few patients in any treatment group ( 10%) had drug-related treatment-emergent AEs. 6

7 Table S1 Summary of treatment-emergent AEs (safety population) TOPROL-XL treatment groups Category Placebo (N=24) 0.2 mg/kg (N=46) 1.0 mg/kg (N=23) 2.0 mg/kg (N=49) All patients (N=142) a n (%) n (%) n (%) n (%) n (%) At least 1 treatment-emergent AE a 12 (50.0) 17 (37.0) 9 (39.1) 30 (61.2) 68 (47.9) Drug-related AE 2 (8.3) 3 (6.5) 2 (8.7) 5 (10.2) 12 (8.5) Serious adverse event Discontinued treatment due to AE 1 (4.2) (0.7) Death A treatment-emergent adverse event (AE) is defined as an AE which began following the first dose of double-blind study medication. Meaningful conclusions regarding the influence of age ( 12 years, >12 years) on the incidence of treatment-emergent AEs are difficult to make because of the overall small numbers of AEs and patients and no clearly discernable pattern of distribution of these AEs between treatment groups. TOPROL-XL was not associated with clinically significant changes in clinical laboratory tests, body weight, ECG parameters, or physical examination findings. As expected, heart rate was reduced following 4 weeks of treatment with TOPROL-XL, with mean reductions of -3.7 to -6.5 bpm. Fructosamine levels were relatively unchanged from baseline at Visit 7 in all treatment groups (1% to 3% decrease) in this study, suggesting that glucose levels were not elevated following 4 weeks of treatment with TOPROL-XL in pediatric patients. Conclusion(s) The results of this study are interpretable as specified in the FDA Written Request and provide evidence that TOPROL-XL, administered once daily for up to 4 weeks at oral doses of 12.5 to 200 mg, is an effective antihypertensive agent in 6- to 16-year-olds with documented essential hypertension. Statistically significant and clinically meaningful reductions in SBP and DBP were noted for some individual and/or pooled target dose groups (0.2, 1.0, and 2.0 mg/kg), and there was a significant dose response for DBP. TOPROL-XL was well tolerated in these pediatric patients and there were no unexpected adverse drug reactions as compared to those seen in adults. Date of the report 8 February