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A fundamental problem in the regulatory evaluation of a therapy is assessing whether the benefit outweighs the associated risks. This work proposes designing a trial that assesses a composite endpoint consisting of benefit and risk, hence, making the core of the design of the study, to assess benefit and risk. The proposed benefit risk measure consists of efficacy measure(s) and a risk measure that is based on a composite score obtained from pre-defined adverse events of interest (AEI). This composite score incorporates full aspects of adverse events of interest (i.e. the incidence, severity, and duration of the events). We call this newly proposed score the AEI composite score. After specifying the priorities between the components of the composite endpoint, a win-statistic (i.e. win ratio, win odds, or net benefit) is used to assess the difference between treatments in this composite endpoint. The power and sample size requirements of such a trial design are explored via simulation. Finally, using Dupixent published adult study results, we show how we can design a paediatric trial where the primary outcome is a composite of prioritized outcomes consisting of efficacy endpoints and the AEI composite score endpoint. The resulting trial design can potentially substantially reduce sample size compared to a trial designed to assess the co-primary efficacy endpoints, therefore it may address the challenge of slow enrollment and patient availability for paediatric studies.

Generalized pairwise comparisons and win statistics (i.e., win ratio, win odds and net benefit) are advantageous in analyzing and interpreting a composite of multiple outcomes in clinical trials. An important limitation of these statistics is their inability to adjust for covariates other than by stratified analysis. Because the win ratio does not account for ties, the win odds, a modification that includes ties, has attracted attention. We review and combine information on the win odds to articulate the statistical inferences for the win odds. We also show alternative variance estimators based on the exact permutation and bootstrap as well as statistical inference via the probabilistic index. Finally, we extend multiple-covariate regression probabilistic index models to the win odds with a univariate outcome. As an illustration we apply the regression models to the data in the CHARM trial.

The special issue on innovative design and analysis of complex clinical trials (Volume 30, Issue 6) is a compilation of invited papers from speakers at the April 2019 Duke-Industry Statistics Sympo...

Conventional analyses of a composite of multiple time-to-event outcomes use the time to the first event. However, the first event may not be the most important outcome. To address this limitation, generalized pairwise comparisons and win statistics (win ratio, win odds, and net benefit) have become popular and have been applied to clinical trial practice. However, win ratio, win odds, and net benefit have typically been used separately. In this article, we examine the use of these three win statistics jointly for time-to-event outcomes. First, we explain the relation of point estimates and variances among the three win statistics, and the relation between the net benefit and the Mann-Whitney U statistic. Then we explain that the three win statistics are based on the same win proportions, and they test the same null hypothesis of equal win probabilities in two groups. We show theoretically that the Z-values of the corresponding statistical tests are approximately equal; therefore, the three win statistics provide very similar p-values and statistical powers. Finally, using simulation studies and data from a clinical trial, we demonstrate that, when there is no (or little) censoring, the three win statistics can complement one another to show the strength of the treatment effect. However, when the amount of censoring is not small, and without adjustment for censoring, the win odds and the net benefit may have an advantage for interpreting the treatment effect; with adjustment (e.g., IPCW adjustment) for censoring, the three win statistics can complement one another to show the strength of the treatment effect. For calculations we use the R package WINS, available on the CRAN (Comprehensive R Archive Network).

The US Food and Drug Administration (FDA) has shown scientific discretion in interpreting the substantial evidence requirement for the approval of new drugs with its considerations on the use of single controlled or uncontrolled trials (Federal Food, Drug, and Cosmetic Act § 505(d), 21 USC 355(d), 1962). With the passage of the 21st Centuries Cures Act (21st Century Cures-patients. House, Energy and Commerce Committee, Washington, DC, 2019 available at: https://energycommerce.house.gov/sites/republicans.energycommerce.house.gov/files/analysis/21stCenturyCures/20140516PatientsWhitePaper.pdf ), the FDA is mandated to expand the role of real-world evidence (RWE) in support of drug approval. This mandate further broadens the scope of scientific discretion to include data collected outside clinical trials. We summarize the agency's past acceptance of real-world data (RWD) sources for supporting drug approval in new indications which have been reflected in US labels. In our summary, we focus on the type of RWD and statistical methodologies presented in these labels. Furthermore, two labels were selected for in-depth assessment of the RWE presented in these labels. Through these examples, we demonstrate the issues that can be raised in data collection that could affect interpretation. In addition, a brief discussion of statistical methods that can be used to incorporate RWE to clinical development is presented.

Objective To evaluate the efficacy and safety of highly purified human menotropin (HP-hMG) and recombinant follicle-stimulating hormone (rFSH) for controlled ovarian stimulation in a population of patients predicted to be high responders. Design Randomized, open-label, assessor-blinded, parallel-group, noninferiority trial. Setting Fertility centers. Patient(s) A total of 620 women with serum antimullerian hormone (AMH) ≥5 ng/mL. Intervention(s) Controlled ovarian stimulation with HP-hMG or rFSH in a GnRH antagonist assisted reproductive technology (ART) cycle. Fresh transfer of a single blastocyst was performed unless ovarian response was excessive, in which all embryos were cryopreserved. Subjects could undergo subsequent frozen blastocyst transfer within 6 months of randomization. Main Outcome Measure(s) Ongoing pregnancy rate (OPR) after fresh transfer (primary endpoint), as well as cumulative live birth, ovarian hyperstimulation syndrome (OHSS), and pregnancy loss rates. Results OPR/cycle start after fresh transfer was 35.5% with HP-hMG and 30.7% with rFSH (difference: 4.7%, 95% CI −2.7%, 12.1%); noninferiority was established. Compared to rFSH, HP-hMG was associated with significantly lower OHSS (21.4% vs. 9.7% respectively; difference: −11.7%, 95% CI −17.3%, −6.1%) and cumulative early pregnancy loss rates (25.5% vs. 14.5% respectively; difference: −11.0%, 95% CI −18.8%, −3.14%). Despite 43 more transfers in the rFSH group, cumulative live birth rates were similar with HP-hMG and rFSH at 50.6% and 51.5% respectively (difference: −0.8%, 95% CI −8.7%, 7.1%). Conclusion(s) In high responders, HP-hMG provided comparable efficacy to rFSH with fewer adverse events, including pregnancy loss, suggesting its optimized risk/benefit profile in this population. Clinical Trial Registration Number NCT02554279 ( clinicaltrials.gov ).

The win ratio has been studied methodologically and applied in data analysis and in designing clinical trials. Researchers have pointed out that the results depend on follow-up time and censoring time, which are sometimes used interchangeably. In this article, we distinguish between follow-up time and censoring time, show theoretically the impact of censoring on the win ratio, and illustrate the impact of follow-up time. We then point out that, if the treatment has long-term benefit from a more important but less frequent endpoint (eg, death), the win ratio can show that benefit by following patients longer, avoiding masking by more frequent but less important outcomes, which occurs in conventional time-to-first-event analyses. For the situation of nonproportional hazards, we demonstrate that the win ratio can be a good alternative to methods such as landmark survival rate, restricted mean survival time, and weighted log-rank tests.

Supplemental material, Supplementary_Material for Efficacy and safety of a ready-to-drink bowel preparation for colonoscopy: a randomized, controlled, non-inferiority trial by Lawrence Hookey, Gerald Bertiger, Kenneth Lee Johnson, Julia Ayala, Yodit Seifu and Stuart P Brogadir in Therapeutic Advances in Gastroenterology

Traditional site-monitoring techniques are not optimal in finding data fabrication and other nonrandom data distributions with the greatest potential for jeopardizing the validity of study results. TransCelerate BioPharma conducted an experiment testing the utility of statistical methods for detecting implanted fabricated data and other signals of noncompliance.TransCelerate tested statistical monitoring on a data set from a chronic obstructive pulmonary disease (COPD) clinical study with 178 sites and 1554 subjects. Fabricated data were selectively implanted in 7 sites and 43 subjects by expert clinicians in COPD. The data set was partitioned to simulate studies of different sizes. Analyses of vital signs, spirometry, visit dates, and adverse events included distributions of standard deviations, correlations, repeated values, digit preference, and outlier/inlier detection. An interpretation team, including clinicians, statisticians, site monitoring, and data management, reviewed the results and created an algorithm to flag sites for fabricated data.The algorithm identified 11 sites (19%), 19 sites (31%), 28 sites (16%), and 45 sites (25%) as having potentially fabricated data for studies 2A, 2, 1A, and 1, respectively. For study 2A, 3 of 7 sites with fabricated data were detected, 5 of 7 were detected for studies 2 and 1A, and 6 of 7 for study 1. Except for study 2A, the algorithm had good sensitivity and specificity (70%) for identifying sites with fabricated data.We recommend a cross-functional, collaborative approach to statistical monitoring that can adapt to study design and data source and use a combination of statistical screening techniques and confirmatory graphics.

Rationale and Objectives Consider a study evaluating the prognostic value of prostate-specific antigen (PSA), in the presence of Gleason score, in differentiating between early and advanced prostate cancer. This data set features subjects divided into two groups (early versus advanced cancer), with one manifest variable (PSA), one covariate (Gleason score), and one stratification variable (hospital, taking three values). We present a nonparametric method for estimating a shift in median PSA score between the two groups, after adjusting for differences in Gleason score and stratifying on hospital. This method can also be extended to cases involving multivariate manifest variable. Materials and Methods Our method uses estimating equations derived from an existing rank-based estimator of the area under the receiver operating characteristic curve (AUC). This existing AUC estimator is adjusted for stratification and for covariates. We use the adjusted AUC estimator to construct a family of tests by shifting manifest variables in one of the treatment groups by an arbitrary constant. The null hypothesis for these tests is that the AUC is half. We report the set of shift values for which the null hypothesis is not rejected as the resulting confidence region. Results Simulated data show performance consistent with the distributional approximations used by the proposed methodology. This methodology is applied to two examples. In the first example, the mean difference in PSA levels between advanced and nonadvanced prostate cancer patients is estimated, controlling for Gleason score. In the second example, to assess the degree to which age and baseline tumor size are prognostic factors for breast cancer recurrence, differences in age and tumor size between subjects with recurrent and nonrecurrent breast cancer, stratified on Tamoxifen treatment and adjusting for tumor grade, are estimated. Conclusions The proposed methodology provides a nonparametric method for a statistic measuring adjusted AUC to be used to estimate shift between two manifest variables.

Many angiotensin receptor blocker (ARB) monotherapy patients need at least two agents to control blood pressure (BP). We investigated whether initiating intensive treatment with combination amlodipine/valsartan was superior to moderate treatment with amlodipine/valsartan in patients previously uncontrolled on ARB monotherapy.In this 12-week study, patients aged at least 18 years on ARB (other than valsartan) for at least 28 days (with treatment-naïve patients or those not controlled on agents other than an ARB treated with open-label olmesartan 20 or 40 mg, respectively, for 28 days) and with uncontrolled mean sitting systolic blood pressure (MSSBP; ≥ 150-200 mmHg) were randomized to amlodipine/valsartan 5/320 mg (n = 369) or 5/160 mg (n = 359). At week 2, the dose was increased to 10/320 mg in the intensive arm. Hydrochlorothiazide 12.5 mg was added to both arms at week 4. Optional up-titration with hydrochlorothiazide 12.5 mg at week 8 was allowed if MSSBP was more than 140 mmHg.At baseline, mean office sitting BP was comparable in the intensive (163.9/95.5 mmHg) and moderate (163.3/95.0 mmHg) groups. Intensive treatment provided greater BP reductions versus moderate treatment (P0.05) from week 4 (-23.0/-10.4 versus -19.2/-8.7 mmHg; primary endpoint) to week 12 (-29.0/-14.8 versus -25.3/-12.3 mmHg). Adverse events were reported by a similar percentage of patients in both groups (36.3% intensive, 37.6% moderate); peripheral edema was more common with intensive versus moderate treatment (8.7 versus 4.5%; P = 0.025).Initiating treatment with an intensive dose of amlodipine/valsartan provides significantly greater BP lowering versus moderate treatment in hypertensive patients unresponsive to ARB monotherapy. Both treatment regimens were generally well tolerated based on adverse event reports, but the lack of routine laboratory testing after screening limits conclusions on tolerability.

Subgroup analyses were performed for the diabetic and nondiabetic cohorts from 3 randomized clinical trials that had evaluated the systolic blood pressure (SBP)-lowering efficacy and tolerability of an angiotensin receptor blocker, valsartan, alone or in combination with hydrochlorothiazide to determine when and how to initiate combination therapy in hypertensive patients with diabetes. Blood pressure reductions achieved with monotherapy were compared with combination therapy in the diabetic and nondiabetic cohorts. In addition, multivariate models were developed to predict the likelihood of the goal SBP of < 130 mm Hg being reached in a diabetic patient with monotherapy or combination therapy across the range of baseline SBP values. In 2 of the 3 trials, comparable reductions in SBP were seen in the diabetic and nondiabetic cohorts. In all 3 studies, however, combination therapy provided greater blood pressure-lowering efficacy than monotherapy. The probability of achieving goal SBP was greater for diabetic patients started on combination therapy compared with monotherapy.

With the objective of enhancing upper gastrointestinal (GI) tolerability, enteric-coated mycophenolate sodium (EC-MPS, myfortic, Novartis Pharma AG, Basel, Switzerland) has been developed. This double-blinded, 12-month study investigated whether renal transplant patients taking mycophenolate mofetil (MMF) can be safely converted to EC-MPS. Stable kidney transplant patients were randomized to receive EC-MPS (720 mg b.i.d.; n=159) or continue receiving MMF (1000 mg b.i.d.; n=163). The incidence of GI adverse events (AEs) was similar at 3 months (primary endpoint: EC-MPS 26.4%; MMF 20.9%; p=NS) and at 12 months (EC-MPS 29.6%; MMF 24.5%; p=NS). The increase from baseline in mean GI AE severity score, adjusted for duration, tended to be lower in EC-MPS patients (3 months: 0.15 vs. 0.20; 12 months: 0.23 vs. 0.47; p=NS). Neutropenia (

We describe and test a method for fitting noisy differential equation models to a time series of population counts, motivated by stage-structured models of insect and zooplankton populations. We consider semimechanistic models, in which the model struc- ture is derived from knowledge of the life cycle, but the rate equations are estimated nonparametrically from the time-series data. The method involves smoothing the population time series x(t) in order to estimate the gradient dx/dt, and then fitting rate equations using penalized regression splines. Computer-intensive methods are used to estimate and remove the biases that result from the data being discrete time samples with sampling errors from a continuous time process. Semimechanistic modeling makes it possible to test assumptions about the mechanisms behind population fluctuations without the results being confounded by possibly arbitrary choices of parametric forms for process-rate equations. To illustrate this application, we analyze time-series data on laboratory populations of blowflies Lucilia cuprina and Lucilia sericata. The models assume that the populations are limited by com- petition among adults affecting their current birth and death rates. The results correspond to the actual experimental conditions. For L. cuprina (where the model's structure is ap- propriate) a good fit can be obtained, while for L. sericata (where the model is inappropriate), the fitted model does not reproduce some major features of the observed cycles. A docu- mented set of R functions for all steps in the model-fitting process is provided as a sup- plement to this article.

Testing for nonindependence among the residuals from a regression or time series model is a common approach to evaluating the adequacy of a fitted model. This idea underlies the familiar Durbin–Watson statistic, and previous works illustrate how the spatial autocorrelation among residuals can be used to test a candidate linear model. We propose here that a version of Moran's I statistic for spatial autocorrelation, applied to residuals from a fitted model, is a practical general tool for selecting model complexity under the assumption of iid additive errors. The “space” is defined by the independent variables, and the presence of significant spatial autocorrelation in residuals is evidence that a more complex model is needed to capture all of the structure in the data. An advantage of this approach is its generality, which results from the fact that no properties of the fitted model are used other than consistency. The problem of smoothing parameter selection in nonparametric regression is used to illustr...

Exposure of rats to inescapable stressors (IS) results in persistent elevations in plasma corticosterone (CORT), which are selective to the trough of the circadian rhythm. Although affective disorders (depression, anxiety) in humans are also characterized by persistent hypothalamic-pituitary-adrenal axis (HPAA) activation, the predominant measure of HPAA activation in clinical studies is 24-h urinary cortisol. To facilitate interspecies comparisons regarding the persistent effects of stress on HPAA activity, we compared the effects of IS on plasma and urinary CORT in rats. Male Sprague-Dawley rats were exposed to three 2-h sessions of IS (40, 2.0 mA tailshocks) or remained in their home cages. The 24-h urine samples were collected daily from 2 days prior to stress to 5 days after stressor cessation, then weekly for 3 weeks. In addition, plasma samples were obtained at 08:00 (trough) and 20:00 hours (peak) for the first 3 days after stressor cessation and weekly for 3 weeks thereafter. Consistent with our earlier work, plasma CORT elevations were apparent in the trough, but not the peak samples for 3 days after stressor cessation. The 24-h urinary CORT levels were elevated during stressor exposure, and remained elevated for 3 days after stressor cessation. Persistent stress-induced urinary CORT elevations in rats are reminiscent of the clinical HPAA abnormalities described for major depression and affective disorders.

This paper presents a method for Bayesian inference for the regression parameters in a linear model with independent and identically distributed errors that does not require the specification of a parametric family of densities for the error distribution. This method first selects a nonparametric kernel density estimate of the error distribution which is unimodal and based on the least-squares residuals. Once the error distribution is selected, the Metropolis algorithm is used to obtain the marginal posterior distribution of the regression parameters. The methodology is illustrated with data sets, and its performance relative to standard Bayesian techniques is evaluated using simulation results.

Chaotic systems are characterized by sensitivity to initial conditions, and this property can be measured by global Lyapunov exponents, which are measures of the average divergence rate of initially close trajectories. Wolff (1992) introduced local Lyapunov exponents and used them to obtain two diagnostic plots for differentiating between stochastic and deterministic time series. We extend the definition of the local Lyapunov exponent and the diagnostic plots to accommodate time series that arise from bivariate maps and investigate the behaviour of the local Lyapunov exponents and the corresponding diagnostic plots for some dynamical systems and stochastic time series. We consider the application of these diagnostic plots to some heart rate variability data. Les systemes chaotiques sont caracterises par la sensibilite aux conditions initiales, et cette propriete peut ětre mesuree par les exposants globaux de Lyapunov, qui sont des mesures du taux de divergence moyen de trajectoires initialement proches. Wolf (1992) a introduit les exposants Lyapunov locaux et les a utilises dans le but d'obtenir deux diagrammes diagnostiques pour faire la distinction entre des series temporelles stochastiques et deterministes. Nous etendons la definition de I'exposant Lyapunov local et des diagrammes diagnostiques afin d'accommoder les series temporelles decoulant de cartes bivariees, now etudions aussi le comportement des exposants Lyapunov locaux et des diagrammes diagnostiques correspondantes pour certains systemes dynamiques et des series temporelles stochastiques. Nous considerons I'application de ces diagrammes diagnostiques a des donnees au sujet de la variabilite des pulsations cardiaques.

Obstetrical brachial plexus palsy remains an unfortunate consequence of difficult childbirth. Sixty-six such patients were reviewed. Included were 28 patients (42 percent) with upper plexus involvement and 38 (58 percent) with total plexopathy. The natural history of spontaneous recovery in all of these patients has been determined using an appropriate grading mechanism. Sixty-one patients (92 percent) recovered spontaneously and five patients (8 percent) required primary brachial plexus exploration and reconstruction (median age 12 months), demonstrating that most patients do well. Additional analysis was undertaken to examine ways in which outcome might be predicted. The analysis does not consider whether or not the patient was operated upon. Good or poor recovery was determined by the spontaneous recovery observed. Discriminant analysis revealed that whereas elbow flexion at 3 months correlated well with spontaneous recovery at 12 months, when used as a single parameter it incorrectly predicted recovery in 12.8 percent of cases. Shoulder abduction was not a significant predictor of recovery. Numerous other early parameters correlated well with spontaneous recovery. When elbow flexion and elbow, wrist, thumb, and finger extension at 3 months were combined into a test score, the proportion of patients whose recovery was incorrectly predicted was reduced to 5.2 percent.

This study was conducted to assess time-to-effect with darifenacin in patients with overactive bladder (OAB). Efficacy and safety data were pooled from 1,059 patients (19–88 years, 85% women) randomized to darifenacin 7.5 or 15 mg once daily or matched placebo in three double-blind 12-week studies. Patients completed electronic bladder symptom diaries (number of micturitions/day; incontinence episodes/day; urgency episodes/day). A post hoc efficacy analysis was performed on the earliest recorded timepoints. The full analysis population comprised 1,053 patients. Statistically significant improvements were observed in all OAB symptoms (except nocturnal awakenings) for both darifenacin doses versus placebo at week 2, with further improvements over 6 and 12 weeks. Both darifenacin doses significantly improved all OAB symptoms from as early as days 6–8 versus placebo. Darifenacin 7.5 and 15 mg significantly reduced OAB symptoms throughout the study. The rapid onset-of-effect is desirable to patients with OAB and useful for their clinical management.

Diastolic dysfunction may precede development of heart failure in hypertensive patients. We randomized 228 patients with uncontrolled hypertension, preserved ejection fraction, and diastolic dysfunction to 2 targeted treatment strategies: intensive, with a systolic blood pressure target of P P P P P P =0.58). The degree of improvement in annular relaxation velocity was associated with the extent of systolic blood pressure reduction, and patients with the lowest achieved systolic blood pressure had the highest final diastolic relaxation velocities.

Enteric-coated mycophenolate sodium (EC-MPS) is an enteric-coated formulation of mycophenolic acid. A 12-month, multicenter, double-blind, randomized clinical study demonstrated that converting maintenance renal transplant patients from mycophenolate mofetil (MMF) to EC-MPS is safe and does not affect efficacy. In an open-label study extension, 130 patients initially randomized to MMF were converted to EC-MPS (newly exposed); 130 initially randomized to EC-MPS continued on EC-MPS (EC-MPS long-term). A composite endpoint of biopsy-proven acute rejection (BPAR), graft loss, or death occurred in 3 (2.3%) newly exposed and 2 (1.5%) EC-MPS long-term patients during the extension phase. One patient died and one lost his graft. BPAR occurred in 3 (2.3%) newly exposed patients and 1 (0.8%) EC-MPS long-term patient. During the first 12 months of the extension phase, incidence and type of adverse events was similar in both groups and comparable to that seen in the core study. Nine cases of malignancy were reported, mainly nonmelanoma skin cancers. EC-MPS dose adjustments for adverse events were required in12% of patients. At the end of the 12-month extension, 58 (44.6%) and 64 (49.2%) newly exposed and EC-MPS long-term patients, respectively, had reported at least one gastrointestinal adverse event. Mean serum creatinine remained stable at the 12-month visit of the extension study (137 micromol/L in the newly exposed and 142 micromol/L in the EC-MPS long-term groups). The results of this study demonstrate the long-term safety of EC-MPS and reconfirm the safety of converting MMF maintenance renal transplant patients to EC-MPS.

Objective: To evaluate the efficacy of initiating treatment with an intensive dose of amlodipine/valsartan (A/V 5/320 to 10/320 mg) vs a moderate dose of A/V (5/160 mg) in hypertensive patients (pts) unresponsive to ARB monotherapy using ambulatory blood pressure monitoring (ABPM). Methods: This analysis presents data in a subset of pts (n=80) in a 12-wk study. Pts aged >=18 years on ARB (other than V) for >=28 d (with treatment-naive pts or those not controlled on agents other than an ARB treated with olmesartan 20 or 40 mg, respectively, for 28 d) and with uncontrolled MSSBP (>=150– 140 mmHg. ABPM was compared with home and clinic BP. Results: As with clinic BP, intensive treatment provided significant 24 h ABP reductions vs moderate treatment (table). Numerically greater home BP reductions were observed with intensive vs moderate treatment (p=NS). In the overall study, AEs were reported by a similar percentage of pts in both groups (36.3% intensive, 37.6% moderate); the most common AEs were peripheral edema (8.7%, 4.5%) and dizziness (5.1%, 3.9%). Conclusion: ABPM results support an intensive treatment approach in this pt population.

Hypertensive patients (pts) with cardiometabolic syndrome (MetS) are at high-risk and require >=2 agents for BP control. Previously in a 12-week study, initial treatment with an intensive dose of amlodipine/valsartan (A/V 5/320 to 10/320 mg) provided significantly greater BP lowering and control than moderate dose (5/160 mg) in hypertensive patients (pts) unresponsive to ARB monotherapy. Here we present the data in a subset of MetS pts by ATP III criteria. Pts aged >=18 years on ARB (other than V) for >=28 days (with treatment-naive pts or those not controlled on agents other than ARB treated with open-label olmesartan 20 or 40 mg, respectively, for 28 days) and with uncontrolled mean sitting systolic BP (MSSBP; >=150- 140 mmHg. In the subset of 345 MetS pts (mean age 56 years, 51% women), baseline MSSBP was similar between groups (table). Intensive treatment provided significantly greater BP reductions vs moderate treatment from Week 4 (primary endpoint) to Week 12. At Weeks 4 and 8, significantly more pts in the intensive vs moderate arm achieved BP goal (