Group sequential methods based on supremum logrank statistics under proportional and nonproportional hazards.

Despite the widespread use of Cox regression for modeling treatment effects in clinical trials, in immunotherapy oncology trials and other settings therapeutic benefits are not immediately realized thereby violating the proportional hazards assumption. Weighted logrank tests and the so-called Maxcombo test involving the combination of multiple logrank test statistics have been advocated to increase power for detecting effects in these and other settings where hazards are nonproportional. We describe a testing framework based on supremum logrank statistics created by successively analyzing and excluding early events, or obtained using a moving time window. We then describe how such tests can be conducted in a group sequential trial with interim analyses conducted for potential early stopping of benefit. The crossing boundaries for the interim test statistics are determined using an easy-to-implement Monte Carlo algorithm. Numerical studies illustrate the good frequency properties of the proposed group sequential methods.

Bayesian estimation of the binomial parameter in sequential experiments.

This article presents an objective Bayesian approach to estimating the binomial parameter in group sequential experiments with a binary endpoint. The idea of deriving design-dependent priors was first introduced using Jeffreys criterion. Another class of priors was developed based on the reference prior theory. A theoretical framework was established showing that explicit reference to the experimental design in the prior is fully Bayesian justified. Using a design-dependent prior which generalizes the reference prior, I propose a comprehensive and unified approach to the point and the interval estimations in group sequential experiments, and I evidence the good frequentist properties of the posterior estimators through comparative studies with the existing methods. The effect of the prior correction on the posterior estimates is studied in three classical designs of clinical trials. Finally, I discuss the idea of using this approach as a default choice for estimation upon sequential experiment termination.

New late-emphasis and combination tests based on infimum and supremum logrank statistics with application in oncology trials.

Immunotherapy cancer clinical trials routinely feature an initial period during which the treatment is given without evident therapeutic benefit, which may be followed by a period during which an effective therapy reduces the hazard for event occurrence. The nature of this treatment effect is incompatible with the proportional hazards assumption, which has prompted much work on the development of alternative effect measures of frameworks for testing. We consider tests based on individual and combination of early- and late-emphasis infimum and supremum logrank statistics, describe how they can be implemented, and evaluate their performance in simulation studies. Through this work and illustrative applications we conclude that this class of test statistics offers a new and powerful framework for assessing treatment effects in cancer clinical trials involving immunotherapies.

An objective Bayesian approach to estimation in multistage experiments.

This article presents a Bayesian approach to estimation in multistage experiments based on the reference prior theory. The idea of deriving design-dependent priors was first introduced using Jeffreys' criterion. A theoretical framework was then established by showing that explicit reference to the design is fully Bayesian justified and Bayesian objectivity cannot ignore such information. Extending the work to multi-parameter problems, a general form of priors was derived from the reference prior theory. In this article, I evidence the good frequentist properties of the reference posterior estimators with normally distributed data. As a notable advance, I address the issue of the point and the interval estimations upon experiment termination. The approach is applied to a data set collected in a clinical trial in schizophrenia with the possibility to stop the trial early if interim results provide sufficient evidence of efficacy or futility. Finally, I discuss the idea of using the reference posterior estimators as a default choice for objective estimation in multistage experiment.

Data-Driven Subgroup Identification in Confirmatory Clinical Trials.

Data-driven subgroup analysis plays an important role in clinical trials. This paper focuses on practical considerations in post-hoc subgroup investigations in the context of confirmatory clinical trials. The analysis is aimed at assessing the heterogeneity of treatment effects across the trial population and identifying patient subgroups with enhanced treatment benefit. The subgroups are defined using baseline patient characteristics, including demographic and clinical factors. Much progress has been made in the development of reliable statistical methods for subgroup investigation, including methods based on global models and recursive partitioning. The paper provides a review of principled approaches to data-driven subgroup identification and illustrates subgroup analysis strategies using a family of recursive partitioning methods known as the SIDES (subgroup identification based on differential effect search) methods. These methods are applied to a Phase III trial in patients with metastatic colorectal cancer. The paper discusses key considerations in subgroup exploration, including the role of covariate adjustment, subgroup analysis at early decision points and interpretation of subgroup search results in trials with a positive overall effect.

Cognitive Impairment and Diminished Neural Responses Constitute a Biomarker Signature of Negative Symptoms in Psychosis.

The treatment of negative symptoms (NS) in psychosis represents an urgent unmet medical need given the significant functional impairment it contributes to psychosis syndromes. The lack of progress in treating NS is impacted by the lack of known pathophysiology or associated quantitative biomarkers, which could provide tools for research. This current analysis investigated potential associations between NS and an extensive battery of behavioral and brain-based biomarkers in 932 psychosis probands from the B-SNIP database. The current analyses examined associations between PANSS-defined NS and (1) cognition, (2) pro-/anti-saccades, (3) evoked and resting-state electroencephalography (EEG), (4) resting-state fMRI, and (5) tractography. Canonical correlation analyses yielded symptom-biomarker constructs separately for each biomarker modality. Biomarker modalities were integrated using canonical discriminant analysis to summarize the symptom-biomarker relationships into a "biomarker signature" for NS. Finally, distinct biomarker profiles for 2 NS domains ("diminished expression" vs "avolition/apathy") were computed using step-wise linear regression. NS were associated with cognitive impairment, diminished EEG response amplitudes, deviant resting-state activity, and oculomotor abnormalities. While a connection between NS and poor cognition has been established, association to neurophysiology is novel, suggesting directions for future mechanistic studies. Each biomarker modality was related to NS in distinct and complex ways, giving NS a rich, interconnected fingerprint and suggesting that any one biomarker modality may not adequately capture the full spectrum of symptomology.

A Slow- Compared with a Fast-Release Form of Oral Arginine Increases Its Utilization for Nitric Oxide Synthesis in Overweight Adults with Cardiometabolic Risk Factors in a Randomized Controlled Study.

BACKGROUND: Oral l-arginine supplements can have a beneficial effect on nitric oxide (NO)-related functions when subjects have cardiovascular disease risk factors. OBJECTIVE: The study was designed to determine the utilization for NO synthesis of oral l-arginine as a function of the cardiometabolic risk and the speed of absorption by comparing immediate-release arginine (IR-Arg), as in supplements, and sustained-release arginine (SR-Arg), which mimics the slow release of dietary arginine. METHODS: In a randomized, single-blind, 2-period crossover, controlled trial (1 wk of treatment, >2 wk of washout), using [(15)N-(15)N-(guanidino)]-arginine for the first morning dose, we compared the bioavailability (secondary outcome) and utilization for NO synthesis (primary outcome) of 1.5 g IR- and SR-Arg 3 times/d in 12 healthy overweight [body mass index (BMI; in kg/m(2)): 25-30] adults with the hypertriglyceridemic waist phenotype [HTW; plasma triglycerides (TGs): >150 mg/dL; waist circumference: >94 cm (men) or >80 cm (women)] and 15 healthy control adults (CON; BMI: 18.5-25; no elevated TGs and waist circumference). RESULTS: Plasma oral arginine areas under the curve were lower after supplementation with SR-Arg than with IR-Arg (112 ± 52.3 and 142 ± 50.8 µmol ⋅ h/L; P < 0.01). The utilization of oral arginine for NO synthesis was 58% higher in HTW subjects than in CON subjects and higher with SR-Arg than with IR-Arg (P < 0.05 both), particularly in HTW subjects (group-by-treatment interaction, P < 0.05). In HTW subjects administered the SR form, utilization for NO synthesis was 32% higher than with the IR form and 87% higher than in CON subjects who were administered the SR form. CONCLUSION: In overweight adults with the HTW phenotype, a slow- compared with a fast-release form of oral arginine markedly favors the utilization of arginine for NO synthesis. The utilization of low-dose, slow-release arginine for NO synthesis is higher in overweight adults with the HTW phenotype than in healthy controls, suggesting that the sensitivity of NO synthesis to the dietary arginine supply increases with cardiometabolic risk. The trial was registered at clinicaltrials.gov as NCT02352740.

l-Arginine Supplementation Alleviates Postprandial Endothelial Dysfunction When Baseline Fasting Plasma Arginine Concentration Is Low: A Randomized Controlled Trial in Healthy Overweight Adults with Cardiometabolic Risk Factors.

BACKGROUND: Vascular endothelial dysfunction, the hallmark of early atherosclerosis, is induced transiently by a high-fat meal. High doses of free l-arginine supplements reduce fasting endothelial dysfunction. OBJECTIVE: We sought to determine the effects of a low dose of a sustained-release (SR) l-arginine supplement on postprandial endothelial function in healthy overweight adults with cardiometabolic risk factors and to investigate whether this effect may vary by baseline arginine status. METHODS: In a randomized, double-blind, 2-period crossover, placebo-controlled trial (4-wk treatment, 4-wk washout), we compared the effects of 1.5 g SR-l-arginine 3 times/d (4.5 g/d) with placebo in 33 healthy overweight adults [body mass index (BMI, in kg/m(2)): 25 to >30] with the hypertriglyceridemic waist (HTW) phenotype [plasma triglycerides > 150 mg/dL; waist circumference > 94 cm (men) or > 80 cm (women)]. The main outcome variable tested was postprandial endothelial function after a high-fat meal (900 kcal), as evaluated by use of flow-mediated dilation (FMD) and Framingham reactive hyperemia index (fRHI), after each treatment. By use of subgroup analysis, we determined whether the effect was related to the baseline plasma arginine concentration. RESULTS: In the total population, the effects of SR-arginine supplementation on postprandial endothelial function were mixed and largely varied with baseline fasting arginine concentration (P-interaction < 0.05). In the lower half of the population (below the median of 78.2 µmol arginine/L plasma), but not the upper half, SR-arginine supplementation attenuated the postprandial decrease in both FMD (29% decrease with SR-arginine compared with 50% decrease with placebo) and fRHI (5% increase with SR-arginine compared with 49% decrease with placebo), resulting in significantly higher mean ± SEM values with SR-arginine (FMD: 4.0% ± 0.40%; fRHI: 0.41 ± 0.069) than placebo (FMD: 2.9% ± 0.31%; fRHI: 0.21 ± 0.060) at the end of the postprandial period (P < 0.05). CONCLUSIONS: Supplementation with low-dose SR-arginine alleviates postprandial endothelial dysfunction in healthy HTW adults when the baseline plasma arginine concentration is relatively low. The benefits of arginine supplementation may be linked to a lower ability to mobilize endogenous arginine for nitric oxide synthesis during a postprandial challenge. This trial was registered at clinicaltrials.gov as NCT02354794.

Is the Efficacy of Milnacipran in Fibromyalgia Predictable? A Data-Mining Analysis of Baseline and Outcome Variables.

OBJECTIVES: Minalcipran has been approved for the treatment of fibromyalgia in several countries including Australia. Australian agency considered that the overall efficacy is moderate, although clinically significant, and could be translated into a real and strong improvement in some patients. The determination of the characteristics of patients who could benefit the most from milnacipran (MLN) is the primary objective of this manuscript. MATERIALS AND METHODS: Data from the 3 pivotal phase 3 clinical trials of the Australian submission dossier were assembled into a database. A clustering method was implemented to exhibit natural groupings of homogeneous observations into clusters of efficacy outcomes and individual patients. Next, baseline characteristics were investigated using a data-mining method to determine the clinical features that may be predictive of a substantially improved effect of MLN on a set of efficacy outcomes. RESULTS: The clustering analysis reveals 3 symptom domains: "Pain and global," "Mood and central status," and "Function." We show that improvement in "Fatigue" goes with improvement in "Function." Furthermore, the predictive data-mining analysis exhibits 4 single baseline characteristics that are associated with a substantially improved effect of MLN on efficacy outcomes. These are high pain intensity, low anxiety or catastrophizing level, absence of major sleeping problems, and physical limitations in the daily life effort. DISCUSSION: Clustering and predictive data-mining methods provide additional insight about fibromyalgia, its symptoms, and treatment. The information is useful to physicians to optimize prescriptions in the daily practice and to regulatory bodies to refine indications.

Efficacy and safety of a new testosterone-in-adhesive matrix patch applied every 2 days for 1 year to hypogonadal men.

OBJECTIVES: To study long-term efficacy and safety of a testosterone-in-adhesive matrix patch, delivering 4.8 mg of testosterone daily. METHODS: Randomized, open label, multicenter 1-year study. 224 hypogonadal patients were included. 188 received 2 patches of 60 cm2 every 48 h and 36 patients had IM testosterone enanthate injection every 3 weeks. T, bioavailable T (BT), DHT, E2, LH, FSH and SHBG and clinical symptom scores (AMS and MSF-4) were assessed at 3, 6 and 12 months. RESULTS: In the patch group, T serum levels were above 3 ng/mL in 85% of patients and remained stable over time. BT, DHT and E2 levels were restored within physiological range. BT/T ratio varied from 20 to 70%. In the IM group, the percentages of "normalized" patients appeared to be lower, although the two groups cannot be adequately compared due to the kinetic profile of T following IM administration, resulting in greater variations of serum T levels, blood samplings occurring randomly at time of peak, trough, or in between. A significant correlation was found between T, BT and the MSF-4 changes. BT levels were significantly related to total AMS score. PSA values showed a mean (S.D.) increase of 0.13 (0.38), 0.23 (0.79) and 0.30 (1.47)ng/mL at weeks 14, 27 and 53, respectively. The patch was well tolerated with no negative impact either on lipid profile, or red blood cells. Administration site reactions occurred in 35 patients (18.8%). Adhesiveness was good (>or=75%) in >90% patients over the 1 year application period. CONCLUSION: Two 60 cm2 patches, allowed constant physiological levels of sexual hormones over time. This new patch was well tolerated, easy to use, well accepted by the patients and displayed a very good adhesiveness. Clinical efficacy was more related to BT than to T.

Bayesian sample size determination in non-sequential clinical trials: Statistical aspects and some regulatory considerations.

The most common Bayesian methods for sample size determination (SSD) are reviewed in the non-sequential context of a confirmatory phase III trial in drug development. After recalling the regulatory viewpoint on SSD, we discuss the relevance of the various priors applied to the planning of clinical trials. We then investigate whether these Bayesian methods could compete with the usual frequentist approach to SSD and be considered as acceptable from a regulatory viewpoint.