Jeffrey Blumer, MD, PhD, Department of Pediatrics, Pediatric Pharmacology and Pediatric Administration, Case Western Reserve University, Rainbow Babies and Children’s Hospital, 11100 Euclid Avenue, Cleveland, OH 44106 E-mail: email@example.com
Hypertension is a significant health concern in the pediatric population. Children with hypertension may not manifest any overt signs; however, target organ damage similar to that seen in adults has been reported widely.1–5 Prevention of target organ damage is preferable, and in children with persistent hypertension despite aggressive nonpharmacologic therapy, antihypertensive agents are recommended.6,7 In patients with end-organ damage at the time of presentation, drug treatment to lower blood pressure (BP) is indicated.6–8
The safe and effective use of antihypertensive agents in children and adolescents has emerged as an important unmet medical need recognized by primary care physicians who treat these patients, academic subspecialists to whom these patients are referred frequently, and the US Food and Drug Administration (FDA) that has issued a number of written requests calling for study of marketed agents in this vulnerable patient population.6,9 The resulting studies have yielded mixed results. While all have shown some effect on either systolic or diastolic BP compared with placebo or baseline measurements, when evaluation is limited to marketed agents using the same experimental design, some have been shown to meet regulatory requirements for effectiveness while others have not.10 At the heart of this ambiguity are issues of incorrect dosing and, often, an inability to demonstrate clearly an exposure-response relationship. For these reasons, each agent with the potential for use in pediatric patients must be studied in this target population to ensure that effectiveness and safety can be demonstrated.
The angiotensin-converting enzyme (ACE) inhibitors have been among those most extensively evaluated in children and adolescents.11,12 Angiotensin II (A-II) receptor inhibition is perceived to have a physiologic advantage over inhibition of the converting enzyme alone since the latter does not inhibit tissue and serum enzymes that convert A-I to A-II, thus circumventing the ACE inhibitor–induced blockade of the renin-angiotensin-aldosterone system.13–15 Blocking the receptor mitigates the effects of A-II–induced vasoconstriction and aldosterone-dependent and aldosterone-independent sodium reabsorption.16
This study was designed to evaluate the efficacy and safety of valsartan, an angiotensin receptor blocker (ARB), in hypertensive children and adolescents using a randomized, dose-ranging, controlled-withdrawal design. The drug has recently been reported to be safe and effective in children aged 1 to 5 years with no negative effects on growth and development.17 In this trial, the age range is extended to patients aged 6 to 16 years.
Children with documented hypertension were studied in a prospective 4-week, double-blind, randomized, multicenter study followed by a 52-week, open-label phase conducted at 55 centers in 9 countries (see Appendix for a list of the principal investigators). The study was conducted in response to a written request from the FDA.
Children aged 6 to 16 years old with a mean sitting systolic BP (SSBP) ≥95th percentile for age, sex, and height were eligible for participation in the study.7,18 Children who had not previously received antihypertensive therapy or, in the opinion of their treating physician, could be withdrawn from antihypertensive therapy, were considered for inclusion in the study. Potential patients who met the age and BP criteria were excluded if any of the following were present: severe hypertension (BP ≥5% above the 99th percentile); hypertensive neurologic injury; estimated creatinine clearance of <40 mL/min/1.73 m2; severe arrhythmias; coarctation of the aorta; bilateral renal artery stenosis (unilateral for children with a single kidney); pregnancy or lactation; human immunodeficiency virus or hepatitis; clinically significant gastrointestinal or hepato-biliary disease; pertinent electrolyte disorders and other significant systemic diseases; prior adverse reaction to an ARB; or concurrent treatment with antipsychotics, tricyclic antidepressants, monoamine oxidase inhibitors, lithium, anticonvulsants, or drugs known to have a significant effect on BP. Children who had functioning renal allografts for more than 1 year and who met the other entry criteria were permitted to enroll. As per FDA requirements, the intended demographic profile for the study was that ≥50% of the patients must be aged between 6 and 11 years and 40% to 60% must be black.
The study design is shown in Figure 1. Before randomization, all eligible patients underwent a placebo-controlled washout period lasting up to 7 days. At the end of the washout period, patients entered phase 1, a double-blind, dose-response phase in which they were randomly assigned to low-, medium-, or high-dose valsartan using a 2:1:2 randomization scheme. Patients completing phase 1 entered a placebo-controlled withdrawal phase (phase 2). In phase 2, patients were randomly assigned in a 1:1 ratio to either continue on the same dose of valsartan that they had received in phase 1 or to receive placebo. Phases 1 and 2 were each 2 weeks in duration. Patients who completed phase 2 or who discontinued from the study due to uncontrolled hypertension (>95th percentile) were given the option of continuing in a 52-week, open-label extension phase that assessed long-term safety.
During phase 1, children were treated with valsartan 10 mg (low dose), 40 mg (medium dose), or 80 mg (high dose) if their body weight was <35 kg at baseline, whereas children weighing ≥35 kg were treated with valsartan 20 mg (low dose), 80 mg (medium dose), or 160 mg (high dose). During the 52-week open-label extension, all patients initially received valsartan 40 mg daily. For those whose mean trough SSBP remained ≥95th percentile, the valsartan dose was increased in a stepwise fashion from 40 mg to 80 mg to 160 mg at 2-week intervals. Hydrochlorothiazide 12.5 mg daily was added if BP remained ≥95th percentile following 2 weeks’ treatment with valsartan 160 mg.
Assessments and Outcome Measurements
Three individual measurements of BP were taken in the sitting position according to accepted standards at each study visit.7 The mean of the 3 measurements was used for analysis. All measurements were made at trough, 24 hours after the previous dose of valsartan or placebo. Mean SSBP and mean sitting diastolic BP (SDBP) were the primary and secondary outcome measures, respectively. In both phases 1 and 2, a responder was defined as a patient achieving an SSBP <95th percentile for age, sex, and height, a cut-off derived from the definition of hypertension in the Fourth Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents7 (average SBP or DBP ≥95th percentile for sex, age, and height on at least 3 occasions). Each patient was provided with an oscillometric monitoring device to measure their home BP. Home BP measurements were used for monitoring safety only, these measurements were not used in the analysis.
The entire study lasted a total of 56 weeks. Patients were seen 6 times during the double-blind phase and had an additional 6 visits during the open-label portion of the study. Safety assessments were performed at each visit, including vital signs, physical examinations, developmental assessments, laboratory tests, pregnancy testing, and electrocardiography (ECG). Developmental evaluation included a neurocognitive evaluation covering attention, processing speed, working memory, cognitive flexibility, memory, and motor speed. Standard laboratory evaluations were performed at a central location. ECG results were interpreted by the investigators for diagnostic purposes and centrally for data analysis. Adverse events (AEs) were reported according to their duration, severity, possible relationship to the study drug, and outcome.
This study was conducted according to Good Clinical Practice standards established by the International Conference on Harmonization. The study protocol and informed consent were reviewed by the institutional review board or ethics committee at each site. Informed consent and, where applicable, assent were obtained from all participants and their parents or legal guardians according to local standards.
For phase 1, the slope of the dose-response curve for the change from baseline in mean SSBP was analyzed using an analysis of covariance (ANCOVA) model, with region strata, race strata, and weight strata as factors, and centered baseline SSBP and dose ratio as covariates. All pair-wise comparisons for the changes from baseline were made based on ANCOVA models, with treatment, region strata, race strata, and weight strata as factors, and centered baseline SSBP as the covariate. For phase 2, the change from end of phase 1 in mean SSBP was analyzed using an ANCOVA model with treatment (pooled valsartan group and pooled placebo group), region strata, race strata, and weight strata as factors, and centered visit 4 SSBP as the covariate. All pair-wise treatment comparisons by dose level for the changes from end of phase 1 were made based on ANCOVA models, with treatment (3 dose levels and 3 placebo groups), region strata, race strata, and weight strata as factors, and centered visit 4 SSBP as the covariate. Descriptive statistics were employed in the open-label phase. No other statistical analyses were conducted.
Both intent-to-treat and per-protocol analyses were conducted. Unless specifically stated, data presented are from the intent-to-treat analysis. All statistical tests were conducted against a 2-sided alternative hypothesis unless otherwise stated. The level of significance accepted was .05 for all analyses.
Patient Characteristics and Demographics
Demographic characteristics for patients enrolled in the study are shown in Table I. Baseline characteristics were similar across the 3 groups. By design, children aged 6 to 11 and 12 to 16 years were equally represented in the study population. Approximately one half (50.6%) of randomized patients were prepubertal or had immature secondary sexual characteristics (Tanner stage <3) and 49.4% were in more advanced stages of pubertal development (Tanner stage ≥3). Black patients made up 48.7% of the randomized patient population, and 46.0% of patients were Caucasian. A diagnosis of diabetes was present in 8 (3.1%) patients (3 Caucasian, 4 black, and 1 of “other” race). Of those enrolled, 37.9% had at least 1 abnormality that was renal or urinary in nature (most commonly nephrotic syndrome [5.0%], reflux nephropathy [6.1%], chronic renal failure [7.7%], and vesicoureteric reflux [5.7%]); 8.0% had a history of renal transplant; and 54% had a body mass index that was ≥95th percentile for sex and age. Overall, 151 patients (57.9%) had been treated with at least 1 antihypertensive drug before being enrolled in the study.
Table I. Baseline Patient Characteristics by Treatment (Low-, Medium- and High-Dose Valsartan [Randomized Population]) in Children Aged 6 to 16 Years
Low Dose (n=103)
Medium Dose (n=53)
High Dose (n=105)
Abbreviations: SD, standard deviation. aScale of the stages of pubertal maturation: one denotes prepuberty and 5 indicates presence of mature/adult-like secondary sexual characteristics. bWeight-adjusted dose at baseline is calculated by individual dose/weight (mg/kg).
Age, mean (SD), y
Age group, No. (%), y
Sex, No. (%)
Race strata, No., (%)
Region strata, No. (%)
Weight, mean (SD), kg
Weight group, No. (%), kg
Tanner stage,a No. (%)
Weight-adjusted dose, mean (SD), mg/kgb
Phase 1: Dose Response
A total of 261 children and adolescents were randomized in phase 1. Two patients did not take study medication following randomization. Sixteen patients (6.1%) did not complete phase 1: 3 patients were removed from the study due to protocol violations, 4 patients were dropped because of a perceived lack of therapeutic effect, 4 patients withdrew consent, 2 patients withdrew because of AEs, 2 patients were dropped due to administrative problems, and 1 patient was lost to follow-up.
Patients in phase 1 of the study received daily doses of valsartan ranging from 0.1 mg/kg to 4.6 mg/kg (10-160 mg absolute dose range). The mean weight-adjusted doses administered in the low-, medium-, and high-dose groups were 0.4 mg/kg, 1.3 mg/kg, and 2.7 mg/kg, respectively. As shown in Table II, administration of valsartan resulted in significant reductions from baseline in mean SSBP and SDBP at all 3 doses. Larger doses resulted in greater reductions in mean SSBP and SDBP (Figure 2). The changes from baseline in mean SSBP in phase 1 were −7.9 mm Hg, −9.6 mm Hg, and −11.5 mm Hg for the low-, medium-, and high-dose groups, respectively. Corresponding changes in mean SDBP were −4.6 mm Hg, −5.8 mm Hg, and −7.4 mm Hg, respectively. Regression modeling of the dose-response curve revealed a slope estimate of −0.43 mm Hg per unit increase in dose ratio (dose ratio=1:4:8 for low-, medium-, and high-dose valsartan, respectively).
Table II. Changes From Baseline to End of Phase 1 in MSSBP and MSDBP According to Valsartan Treatment Group in Children Aged 6 to 16 Years
Low Dose (n=102)
Medium Dose (n=52)
High Dose (n=105)
Abbreviations: CI, confidence interval; MSDBP, mean sitting diastolic blood pressure; MSSBP, mean sitting systolic blood pressure; SD, standard deviation. aP values and 95% CIs are based on the paired t test of the null hypothesis of no change from baseline within each treatment group. aStatistical significance at the .05 level.
Blood pressure, mean (SD), mm Hg
End of phase 1
Change from baseline to end of phase 1
Mean (SD), mm Hg
−9.98 to −5.89
−12.16 to −7.08
−13.66 to −9.34
−6.75 to −2.44
−8.26 to −3.33
−9.19 to −5.51
Subgroup analyses (Figure 3) demonstrated that the effect of valsartan was consistent across the following important demographic subgroups: weight (<35, ≥35 kg), sex (male, female), age (6–11 years, 12–16 years), Tanner stage (<3, ≥3), race (black, nonblack), and region (United States, non–United States). Slightly steeper slopes were observed for patients weighing <35 kg, females, and black patients; however, these were not statistically significant.
Phase 2: Placebo Withdrawal
A total of 245 patients completed phase 1 and entered phase 2. Thirteen patients (5.3%) were withdrawn from phase 2: two patients were removed due to protocol violations, 8 patients were dropped from the study because of a perceived lack of therapeutic effect, 1 patient withdrew consent, and 2 patients withdrew because of AEs.
Figure 4 depicts the changes in SSBP and SDBP from the end of phase 1 to the end of phase 2. At the end of phase 1, mean SSBP and SDBP were similar in the pooled valsartan and pooled placebo groups. At the end of phase 2, mean SSBP and SDBP in the pooled valsartan group increased by 1.2 mm Hg and 0.5 mm Hg, respectively, while in the pooled placebo group, corresponding increases were 3.9 mm Hg and 3.5 mm Hg, respectively. Both changes were highly significant (Table III). Significant differences were observed in both the intent-to-treat and the per-protocol analyses.
Table III. Changes From End of Phase 1 to End of Phase 2 in MSSBP and MSDBP
Abbreviations: BP, blood pressure; CI, confidence interval; MSDBP, mean sitting diastolic blood pressure; MSSBP, mean sitting systolic blood pressure; SD, standard deviation. aWithin-treatment P values and 95% CIs are based on the paired t test of the null hypothesis of no change from end of phase 1 within each treatment group. bBetween-treatment P values are from the analysis of covariance model with treatment, region strata, weight strata, and race strata as factors, and centered visit 4 systolic blood pressure as a covariate. aStatistical significance at the .05 level.
BP, mean (SD), mm Hg
End of phase 1/visit 4
End of phase 2
Change in BP from end of phase 1 to end of phase 2, mean (SD), mm Hg
−0.52 to 2.84
2.15 to 5.61
−1.05 to 1.98
1.87 to 5.23
Additional between-group comparisons were performed in patients who were re-randomized to continue receiving low-, medium-, or high-dose valsartan and those who were re-randomized to receive placebo. These between-group comparisons, based on mean changes in SSBP from the end of phase 1 to the end of phase 2, showed a statistically significant difference between the high-dose valsartan group and placebo in favor of treatment with valsartan (least-squares mean difference=−5.4 mm Hg; P=.0034). There was a numeric difference (least-squares mean difference=−3.5 mm Hg) between medium-dose valsartan and placebo, although this was not statistically significant. No difference was observed between the low-dose valsartan and placebo groups. Similar relationships were observed for mean SDBP. The subgroups (female patients, black patients, and non–US patients) with a greater BP reduction during phase 1, tended to have a more significant rebound after withdrawal to placebo in phase 2.
The mean and median durations of exposure to valsartan were both 14 days during each of the double-blind phases. Corresponding values for the open-label phase were 315 and 365 days, respectively. Headache was the most commonly observed AE, which was reported in 11.6% of patients during phase 1, 9.8% of patients during phase 2, and 33.2% of patients during the open-label phase. Headaches did not appear to be dose-dependent. All other AEs were reported in <5% of the study population during phases 1 and 2. Dizziness was reported in 7 patients during phase 1, five of whom were randomized to the high-dose valsartan group. Five patients reported dizziness during phase 2, one of whom was assigned to the placebo group. Orthostatic hypotension was reported by 1 patient in the high-dose valsartan group during phase 1, and by 1 valsartan-treated and 1 placebo-treated patient during phase 2. Diabetes was reported by 1 Caucasian female patient in the low-dose valsartan group during phase 2. Insulin was used to manage the condition until the patient was withdrawn from the study due to swelling of the left hand during open-label valsartan treatment (discontinuation was not related to diabetes). In general, during the double-blind phase, the incidence of AEs in patients treated with valsartan continuously for 4 weeks (Val/Val) was similar to that observed in patients treated with valsartan for 2 weeks followed by placebo for 2 weeks (Val/Pbo). As expected, the reported frequency of all AEs during the open-label phase was considerably higher than that in the double-blind phase. During the open-label phase, the most frequent AEs were nasopharyngitis, pyrexia, cough, upper respiratory tract infection, and headache. Diabetes was reported in 1 black female patient during open-label treatment. Metformin was initiated to manage the condition and was continued for the remainder of the study. There were no unanticipated changes in the neurocognitive evaluations conducted at baseline and at the end of the open-label phase. There were no AEs on growth or annual weight gain.
One patient experienced a serious AE (SAE; acute gastroenteritis), which was judged to be unrelated to valsartan, during the double-blind phase of the study. During the 52-week, open-label phase, 18 patients (7.7%) experienced a total of 34 SAEs. Of these, only 2 were considered to be drug-related: 1 case of gastroenteritis (valsartan 40 mg) and 1 case of hyperkalemia (valsartan 80 mg). Diarrhea, pyrexia, and gastroenteritis were the only SAEs reported by more than 1 patient (2 occurrences each). Increased serum creatinine and hyperkalemia were observed in 1 patient each. Both patients were renal transplant recipients and neither case was judged to be related to valsartan. In the patient with hyperkalemia, serum potassium returned to normal within 2 days after valsartan was discontinued.
No deaths occurred during the study. A total of 4 patients withdrew from the study due to AEs during phases 1 and 2. During the open-label phase, 7 patients (3.6%) withdrew from the study following an AE.
There were no significant changes in the mean values of any of the laboratory assessments between baseline and the end of the study. Liver enzymes, total cholesterol, triglycerides, and glucose levels were unaffected by treatment with valsartan. Similarly, there were no significant changes in the levels of hemoglobin and hematocrit.
Twenty-two patients (10%) had elevated creatinine concentrations and 9 patients (4%) had elevated potassium concentrations at some point during the study. Mean serum creatinine increased from 62.7 mmol/L to 69.0 mmol/L in the study population. Mean serum potassium was essentially unchanged from baseline (4.18 mmol/L) to the end of the study (4.19 mmol/L). The frequency of AEs experienced by Val/Val patients during the double-blind phases of the study were compared with Val/Pbo patients. Patients experiencing an increase of >50% in serum creatinine were more frequent in the Val/Pbo-treated groups at all 3 doses. In contrast, patients who experienced an increase in serum potassium of >20% were observed more frequently in the medium- and high-dose Val/Val groups. Finally, uric acid was noted to increase by more than 50% more frequently in the Val/Val groups.
The FDA Modernization Act, enacted in 1997, has resulted in a significant increase in pediatric trials of hypertensive medications in recent years. As a result, many commonly prescribed antihypertensive medications, such as ACE inhibitors, ARBs, and calcium channel blockers, have been evaluated in hypertensive children aged 6 to 16 years in well-controlled, prospective, multicenter studies.11,12,17,19,20 The results from most of these studies have demonstrated that these agents were effective in lowering BP and were well tolerated in children. The safety profiles observed in children were not different from those observed in adult patients. Results from the current study demonstrated that a dose-dependent SSBP reduction was observed with valsartan in hypertensive children aged 6 to 16 years. The efficacy of valsartan in reducing BP was further confirmed in a randomized 2-week, placebo-withdrawal period. The antihypertensive effect of valsartan was not influenced by the demographic make-up of the patient population. Valsartan was well tolerated, and no unexpected AEs were reported during the study.
The mean daily dose of valsartan administered to patients in phases 1 and 2 of the study ranged from 0.4 mg/kg to 2.7 mg/kg. Valsartan was shown to reduce SSBP and SDBP in a dose-dependent fashion in children aged 6 to 16 years. The reduction in BP appeared to be maximal within 2 weeks after starting therapy. No further reduction in mean SSBP or SDBP was observed in patients who continued on valsartan during phase 2. Randomized withdrawal to active drug or placebo confirmed the antihypertensive effectiveness of valsartan, especially in the medium- and high-dose groups.
It has been reported that black patients with hypertension respond poorly to certain classes of antihypertensive medications.21 To assess the impact of demographic make-up of the patient population on the efficacy and safety of valsartan in hypertensive children, an adequate number of patients from predefined subgroups were enrolled, including school children (50% older than 12 years), black children (46.8%), female patients (39.5%), and children from the United States and outside the United States (50% each). Approximately one half (54%) of the children were obese (body mass index ≥95th percentile for sex and age), a finding not surprising considering the accepted relationship between obesity and hypertension. (Previous reports have demonstrated hypertension prevalence of up to 30% in obese adolescents.22) Subgroup analyses revealed few differences between groups. The magnitude of the response to valsartan increased with dose in all subgroups. Weight group, race, sex, and maturation did not appear to influence response to valsartan. There were no differences in response based on age group (6–11 years vs 12–16 years) in phase 1. However, the younger children appeared to have lower placebo-corrected SDBP (but not SSBP) than the older patients. This observation might be explained by the greater likelihood that hypertension is caused by renal diseases in younger children.23,24 Renal diseases are a common cause of resistant hypertension in adults.25,26 Less is known about the impact of renal disease on hypertension treatment in children; however, in the recent multicenter observational Chronic Kidney Disease in Children study,27 antihypertensive treatment failed to control hypertension in nearly half (48.5%) of children (mean age, 11 years) with hypertension and chronic kidney disease.
Plasma renin and A-II activities were not measured in this study. No assertions can be made regarding correlation of response to baseline activity of the RAAS. Since there were relatively few patients in the subgroups, caution is indicated when generalizing from these results.
Although direct comparisons cannot be made, the response observed in children is comparable with that seen in the adult population.28–30 Valsartan treatment in adults resulted in a dose-dependent reduction in both SSBP and SDBP when compared with placebo over a dose range of 10 mg to 320 mg.31 In this study, the valsartan 20-mg dose was not different from placebo. The magnitude of response was similar to that seen after 4 weeks of therapy using comparable doses in adults.28 AEs in adults were similar to those observed in children. Dizziness was significantly more common in adult patients who received 320 mg of valsartan than in those who received lower doses (9.3% vs 2.1%–3.4% at doses of 20–160 mg).29
BP reductions were also comparable with those seen in children aged 6 to 16 years treated with losartan.19 Comparable reductions in mean SSBP and SDBP were observed in adults treated with either valsartan (80–160 mg) or losartan (50–100 mg) for up to 8 weeks.32
Overall, valsartan was well tolerated. Short-term data from phase 2 suggests that the AEs observed in valsartan-treated patients are similar to those observed with placebo, although the number of patients studied was relatively small and AEs in the placebo group might still be attributable to valsartan during the first few days of phase 2. Headaches were observed in >5% of patients. Headaches are a relatively common complaint in children with and without hypertension. It is difficult to know whether the headaches observed in the patients in this study were due to valsartan or other causes. Dose-related dizziness seen in adults29 was also observed in a small number of children. New-onset diabetes was uncommon in this study, and no patient discontinued the study prematurely as a result of diabetes development. Other AEs were relatively uncommon, generally mild to moderate in severity, and rarely resulted in discontinuation of therapy. AEs that occur with a very low frequency may not have been detected in this study.
Only two AEs were both serious and deemed to be related to therapy. Of these AEs, hyperkalemia has been described in the adult population and is a predictable effect of A-II receptor blockade. In patients with renal or renovascular disease, serum potassium levels should be monitored, especially in patients who are concurrently treated with ACE inhibitors or potassium-sparing diuretics.
Valsartan appeared to provide dose-dependent reductions in SSBP and SDBP in children with hypertension over a dose range of 0.1 mg/kg to 4.6 mg/kg (10 mg–160 mg). Doses >160 mg or 4.6 mg/kg were not tested. Overall, valsartan was safe and well tolerated. Headaches and dose-dependent dizziness may occur. Renal function and serum potassium should be monitored in at-risk patients. Based on data from phases 1 and 2 of the study, an initial once-daily dose of valsartan 40 mg is recommended for children aged 6 to 16 years. Doses <0.4 mg/kg may not be effective. If BP response is inadequate, the valsartan dose may be titrated to a maximum of 160 mg (maximum weight-adjusted dose up to 4.6 mg/kg for children <35 kg). An extemporaneously formulated solution can be prepared for children who are unable to swallow commercially available tablets.17 Valsartan should be considered when use of an ARB is clinically appropriate.
Acknowledgments and disclosures: The authors acknowledge all investigators and study coordinators at the participating centers and all patients for their commitment to the study, which was sponsored by Novartis Pharmaceuticals Corporation. Editorial assistance was provided on the final draft of this manuscript by a professional medical writer, Joanne Bentley (ACUMED, Tytherington, UK); this support was funded by Novartis Pharmaceuticals Corporation. Thomas Wells, Jeffrey Blumer, Kevin E.C. Meyers, Jose Pacheco Ribeiro Neto, Rejane Meneses, and Mieczysław Litwin have no conflicts of interest to disclose and all have participated or are participating in other trials sponsored by Novartis. Johan Vande Walle has acted as a consultant for Novartis and has participated in other trials sponsored by Novartis. Guangyang Han, Susan Solar-Yohay, and Victor Shi are employees of Novartis Pharmaceuticals Corporation.