Androgen-deprivation therapy is well-established for treating prostate cancer but associated with bone loss and an increased risk of fracture. We investigated the effects denosumab, a fully human monoclonal antibody against receptor activator nuclear factor-κB ligand, on mineral density fractures in men receiving androgen-deprivation nonmetastatic cancer.

To characterize changes in lean body mass (LBM) men with prostate cancer receiving androgen-deprivation therapy (ADT).We prospectively evaluated LBM a prespecified substudy of randomized controlled trial denosumab to prevent fractures ADT for nonmetastatic cancer. was measured by total-body dual-energy x-ray absorptiometry at study baseline and 12, 24, 36 months. The analyses included 252 patients (132, denosumab; 120, placebo) least one on-study assessment. Patients were stratified age (<...

Dysregulated complement activation is likely the primary driver of disease in C3 glomerulopathy (C3G) and contributes to other complement-mediated diseases, including immunoglobulin A nephropathy (IgAN), lupus nephritis (LN), membranous (PMN). No inhibitors are proven halt progression these diseases. Pegcetacoplan, a targeted C3b inhibitor, may mitigate kidney damage C3G glomerular diseases which have pathogenic role.This open-label, phase 2, 48-week study evaluated preliminary efficacy...

In a recently completed 3-year, randomized, double-blind study, denosumab, fully human monoclonal antibody against receptor activator of nuclear factor kappaB ligand, significantly increased bone mineral density and decreased new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. We conducted subgroup analyses to evaluate the relationships between subject characteristics effects denosumab on at multiple skeletal sites.A total 1,468 subjects were randomized...

Objective Slowly expanding lesions (SELs), a subgroup of chronic white matter that gradually expand over time, have been shown to predict disability accumulation in primary progressive multiple sclerosis (MS) disease. However, the relationships between SELs, acute lesion activity (ALA), overall (CLA) and progression are not well understood. In this study, we examined ASCEND phase III clinical trial, which compared natalizumab with placebo secondary MS (SPMS). Methods Patients complete...

Nonlinear mixed effects models (NLMMs) and self-modeling nonlinear regression (SEMOR) are often used to fit repeated measures data. They use a common function shared by all subjects model variation within each subject some fixed and/or random parameters between subjects. The parametric NLMM may be too restrictive, the semiparametric SEMOR ignores correlations subject. In this article we propose class of (SNMMs) that extend NLMMs, models, many other existing in natural way. A SNMM assumes...

Summary In this article, we develop a Bayesian adaptive design methodology for oncology basket trials with binary endpoints using model averaging framework. Most existing methods seek to borrow information based on the degree of homogeneity estimated response rates across all baskets. reality, an investigational product may only demonstrate activity subset baskets, and vary subset. A key benefit our approach is that it explicitly accounts possibility any baskets have similar some not. Our...

<h3>BACKGROUND AND PURPOSE:</h3> Slowly expanding/evolving lesions measured by conventional T1-weighted/T2-weighted brain MR imaging may contribute to progressive disability accumulation in MS. We evaluated the longitudinal change myelin and axonal tissue integrity white matter slowly means of magnetization transfer ratio DTI radial diffusivity. <h3>MATERIALS METHODS:</h3> were detected within Study Assess Efficacy, Safety, Tolerability, Pharmacokinetics BIIB033 Participants With Relapsing...

Summary . Medical studies often collect physiological and/or psychological measurements over time from multiple subjects, to study dynamics such as circadian rhythms. Under the assumption that expected response functions of all subjects are same after shift and scale transformations, shape‐ invariant models have been applied analyze this kind data. The parameters provide efficient interpretable data summaries, while common shape function is usually modeled nonparametrically, flexibility....

Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and turnover markers (BTMs) including serum type 1 C-telopeptide (sCTX), tartrate-resistant alkaline phosphatase 5b (TRAP-5b), procollagen-1 N-terminal telopeptide (P1NP). In a prespecified exploratory analysis of phase 3, multicenter, double-blind study, we evaluated the effects denosumab (60 mg subcutaneously every 6 months 3 years) versus placebo (1468 patients, 734 in each...

In a clinical trial with time-to-event endpoint the treatment effect can be measured in various ways. Under proportional hazards all reasonable measures (such as hazard ratio and difference restricted mean survival time) are consistent following sense: Take any control group distribution such that rate remains above zero; if there is no benefit by measure measures, magnitude of increases it measures. nonproportional hazards, however, curves cross, direction for pair inconsistent. this paper...

Due to the importance of precision medicine, it is essential identify right patients for treatment. Biomarkers, which have been commonly used in clinical research as well practice, can facilitate selection with a good response In this paper, we describe biomarker threshold adaptive design survival endpoints. first stage, determine subgroups one or more biomarkers such that these benefit most from new The analysis stage be based on historical pilot studies. second sample subjects determined...

Almost all of the current nonparametric regression methods, such as smoothing splines, generalized additive models, and varyingcoefficients assume a linear relationship when functions are regarded parameters. In this article we propose general class spline nonlinear models that allow to act nonlinearly. They arise in many fields either theoretical or empirical models. Our new estimation methods based on an extension Gauss–Newton method infinite-dimensional spaces backfitting procedure. We...

We consider the problem of modeling mean function in regression. Often there is enough knowledge to model some components parametrically. But for other vague and/or nuisance components, it often desirable leave them unspecified and be modeled nonparametrically. In this article, we propose a general class smoothing spline semiparametric nonlinear regression models (SNRMs) which assumes that depends on parameters nonparametric functions through known functional. SNRMs are natural extensions...

You have accessJournal of UrologyProstate Cancer: Advanced1 Apr 2011648 BENEFIT OF DENOSUMAB THERAPY IN PATIENTS WITH BONE METASTASES FROM CASTRATE RESISTANT PROSTATE CANCER: A NUMBER-NEEDED-TO-TREAT (NNT) ANALYSIS Kurt Miller, Karim Fizazi, Matthew Smith, Jose Pablo Moroto, Laurence Klotz, Janet Brown, Teuvo LJ Tammela, Neal Shore, Chunlei Ke, Karen Chung, and Carsten Goessl MillerKurt Miller Berlin, Germany More articles by this author , FizaziKarim Fizazi Paris, France SmithMatthew Smith...

Olga Marchenko, Qi Jiang, Aloka Chakravarty, Chunlei Ke, Haijun Ma, Jeff Maca, Estelle Russek-Cohen, Matilde Sanchez-Kam, Richard C. Zink & Christy Chuang-SteinOlga Marchenko (E-mail: olga.marchenko@quintiles.com), and Maca jeff.maca@quintiles.com), Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560. Chakravarty Aloka.Chakravarty@fda.hhs.gov), Russek-Cohen Estelle.Russek-Cohen@fda.hhs.gov), Food Drug Administration, Center for Evaluation Research, Division of Biometrics VII, Office...

5056 Background: ADT increases bone resorption, reduces mineral density (BMD), and fracture risk. Previously, we reported that denosumab, a fully human monoclonal antibody against RANKL, increased BMD reduced the incidence of vertebral fractures in men with PC on ADT. We now describe further detail effects denosumab at other skeletal sites. Methods: Men receiving for nonmetastatic were randomized to receive subcutaneous 60 mg every 6 months (n = 734) or placebo 734), daily calcium vitamin D...

For a clinical trial with time-to-event primary endpoint, the rate of accrual event interest determines timing analysis, upon which significant resources and strategic planning depend. It is important to be able predict analysis time early accurately. Currently available methods use either parametric or nonparametric models based on accumulating information about enrollment, event, study withdrawal rates implicitly assume that data are completely reported at performing prediction. This...

Composite endpoints with censored data are commonly used as study outcomes in clinical trials. For example, progression-free survival is a widely composite endpoint, disease progression and death the two components. Progression-free time often defined from randomization to earlier occurrence of or any cause. The censoring times components could be different for patients not experiencing endpoint event. Conventional approaches, such taking minimum time, may suffer efficiency loss produce...

Stratified randomization is widely used in clinical trials to achieve balance of the treatment assignment with regard important prognostic factors. Sometimes or stratification factor concerned patient medical and medication history, for which accurate information may not be available at time randomization. Therefore, value provided later identified incorrect. When such errors occur, patients allocated into strata they do belong to. The intended regarding factors disrupted. We evaluated...

9015 Background: A metaanalysis of 2 pivotal trials evaluated the effect denosumab treatment in a broad cancer population. Both studies were identically designed and analyzed, comparing vs ZA delaying or preventing skeletal-related events (SRE) patients with bone metastases, one breast other advanced (except prostate cancer) multiple myeloma. Methods: The effects respect to time first on-study SRE for noninferiority (primary endpoint; synthesis method) superiority (secondary endpoint,...