Clinical Safety and Efficacy of Pegcetacoplan in a Phase 2 Study of Patients with C3 Glomerulopathy and Other Complement-Mediated Glomerular Diseases.

Introduction: 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), and primary membranous nephropathy (PMN). No complement inhibitors are proven to halt disease progression in these diseases. Pegcetacoplan, a targeted C3 and C3b inhibitor, may mitigate complement-mediated kidney damage in C3G and other glomerular diseases in which complement may have a pathogenic role.

Treatment effect measures under nonproportional hazards.

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

Synthesizing studies for comparing different treatment sequences in clinical trials.

With advances in cancer treatments and improved patient survival, more patients may go through multiple lines of treatment. It is of clinical importance to choose a sequence of effective treatments (eg, lines of treatment) for individual patients with the goal of optimizing their long-term clinical outcome (eg, survival). Several important issues arise in cancer studies.

Chronic lesion activity and disability progression in secondary progressive multiple sclerosis.

Objective: Slowly expanding lesions (SELs), a subgroup of chronic white matter lesions 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 chronic lesion activity (CLA) and disability progression are not well understood. In this study, we examined the ASCEND phase III clinical trial, which compared natalizumab with placebo in secondary progressive MS (SPMS).

Bayesian adaptive basket trial design using model averaging.

In this article, we develop a Bayesian adaptive design methodology for oncology basket trials with binary endpoints using a Bayesian model averaging framework. Most existing methods seek to borrow information based on the degree of homogeneity of estimated response rates across all baskets. In reality, an investigational product may only demonstrate activity for a subset of baskets, and the degree of activity may vary across the subset.

Biomarker threshold adaptive designs for survival endpoints.

Due to the importance of precision medicine, it is essential to identify the right patients for the right treatment. Biomarkers, which have been commonly used in clinical research as well as in clinical practice, can facilitate selection of patients with a good response to the treatment. In this paper, we describe a biomarker threshold adaptive design with survival endpoints.

Predicting analysis time in events-driven clinical trials using accumulating time-to-event surrogate information.

For clinical trials with time-to-event endpoints, predicting the accrual of the events of interest with precision is critical in determining the timing of interim and final analyses. For example, overall survival (OS) is often chosen as the primary efficacy endpoint in oncology studies, with planned interim and final analyses at a pre-specified number of deaths. Often, correlated surrogate information, such as time-to-progression (TTP) and progression-free survival, are also collected as secondary efficacy endpoints.

Statistical Considerations on the Evaluation of Imbalances of Adverse Events in Randomized Clinical Trials.

Adverse events (AEs) data compose the main body of safety data in clinical trials. Medically important imbalances of AEs in large double-blind randomized controlled trials (RCTs) are signals of potential adverse drug reactions. They will be further evaluated for causality and shape the initial label that gives users necessary information on the safe use of the drug.

Choosing Appropriate Metrics to Evaluate Adverse Events in Safety Evaluation.

Safety assessment and monitoring are critical throughout the life cycle of drug development. The evaluation of safety information, specifically adverse events, from clinical trials has always been challenging for a number of reasons, such as the unexpectedness and rarity of some important adverse events, the fact that some events can recur, and the events' variability in duration and severity. To accurately characterize and communicate the risk profile of a drug, the choice of metrics is critical.

A counterfactual p-value approach for benefit-risk assessment in clinical trials.

Clinical trials generally allow various efficacy and safety outcomes to be collected for health interventions. Benefit-risk assessment is an important issue when evaluating a new drug. Currently, there is a lack of standardized and validated benefit-risk assessment approaches in drug development due to various challenges.

Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials.

Background: Patients with bone metastases from advanced cancer often experience skeletal-related events (SRE), which cause substantial pain and morbidity. Denosumab, a fully human monoclonal antibody that inhibits RANK Ligand (RANKL), is a novel bone-targeted agent with a distinct mechanism of action relative to the bisphosphonate zoledronic acid, for prevention of SRE. This pre-planned analysis evaluates the efficacy and safety of denosumab versus zoledronic acid across three pivotal studies.

The issue of multiplicity in noninferiority studies.

Background: In a clinical study to evaluate noninferiority (NI) of an experimental drug relative to an established therapy, it is common to further test superiority of the experimental drug after NI is established. It has been shown that no multiplicity issue exists between NI and superiority tests of the primary endpoint. However, when there is an additional, or secondary, endpoint that will be tested for superiority in a hierarchical fashion to the NI testing of the primary endpoint, it is not clear whether the overall type I error rate is strictly controlled among all the tests.

Sarcopenia during androgen-deprivation therapy for prostate cancer.

Purpose: To characterize changes in lean body mass (LBM) in men with prostate cancer receiving androgen-deprivation therapy (ADT).

Patients And Methods: We prospectively evaluated LBM in a prespecified substudy of a randomized controlled trial of denosumab to prevent fractures in men receiving ADT for nonmetastatic prostate cancer. LBM was measured by total-body dual-energy x-ray absorptiometry at study baseline and at 12, 24, and 36 months.

Predicting analysis time in event-driven clinical trials with event-reporting lag.

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

Denosumab and changes in bone turnover markers during androgen deprivation therapy for prostate cancer.

Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and increases bone turnover markers (BTMs) including serum type 1 C-telopeptide (sCTX), tartrate-resistant alkaline phosphatase 5b (TRAP-5b), and procollagen-1 N-terminal telopeptide (P1NP). In a prespecified exploratory analysis of a phase 3, multicenter, double-blind study, we evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) versus placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and predose at months 6, 12, 24, and 36 in the overall population.

Estimating area under the curve and relative exposure in a pharmacokinetic study with data below quantification limit.

Area under the drug-concentration-over-time curve (AUC) is an important endpoint for many phase I/II clinical trials and laboratory assays. Drug concentrations are measured using laboratory assays with a lower limit of quantification (LLOQ). How to calculate AUC when some drug concentration data are below the LLOQ remains as a challenge.

Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer.

Purpose: In a recently completed 3-year, randomized, double-blind study, denosumab, a 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 and the effects of denosumab on bone mineral density at multiple skeletal sites.

Materials And Methods: A total of 1,468 subjects were randomized 1:1 to receive 60 mg subcutaneous denosumab every 6 months or placebo for 36 months.

Denosumab in men receiving androgen-deprivation therapy for prostate cancer.

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

Methods: In this double-blind, multicenter study, we randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group).

Shape-invariant modeling of circadian rhythms with random effects and smoothing spline ANOVA decompositions.

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 the expected response functions of all subjects are the same after shift and scale transformations, shape-invariant models have been applied to analyze this kind of data. The shift and scale parameters provide efficient and interpretable data summaries, while the common shape function is usually modeled nonparametrically, to provide flexibility.