Multiple comparisons in non-inferiority trials: Reaction to recent regulatory guidance on multiple endpoints in clinical trials.

We consider analysis of active control, non-inferiority clinical trials with multiple primary endpoints for assessing efficacy of an investigational treatment. Many of the issues with multiple endpoints for non-inferiority trials are similar to issues for superiority trials, but there are important differences. Because non-inferiority trials typically make decisions with confidence interval bounds instead of p-values, care must be taken in adjusting for multiple hypotheses.

A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis.

Unlabelled: The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of CC chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis (LF). A randomized, double-blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score (NAS) ≥4, and LF (stages 1-3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo.

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.

Background: Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers.

Methods: In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug.

Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients.

Background: Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown.

Methods: Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days.

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity.

Background: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.

Methods: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily.

Recent Statistical Contributions to Medical Device Development.

Clinical trials in the development of new medical device products are in many ways analogous to clinical trials in the development of new drug or biologic products. However, the differences are important and not always intuitive to a statistician with only experience supporting development of drug and biologic products. In this paper we discuss some of the interesting differences with focus on the statistical innovation that is coming out of the medical device area.

Selection of hypothesis weights and ordering when testing multiple hypotheses in clinical trials.

This article discusses the problem of selecting free parameters of multiple testing procedures in confirmatory Phase III clinical trials with multiple objectives, including hypothesis weights and hypothesis ordering. We identify classes of multiple testing procedures that provide different interpretations of these parameters. This includes basic single-step procedures (Bonferroni procedure) that employ fixed hypothesis weights, as well as more powerful stepwise procedures (Holm, fallback, and chain procedures) that reweight the hypotheses during the testing process.

Multiple testing procedures in two pivotal clinical trials for approval of a new pharmaceutical product.

We consider analysis of two identical pivotal trials with correlated multiple hypotheses evaluated by the fixed-sequence, weighted Holm, or fallback procedure. For approval, at least one hypothesis must be rejected in both studies. Various weights are considered for the fallback and weighted Holm procedure to provide separation in a single study.

Ambient air total gaseous mercury concentrations in the vicinity of coal-fired power plants in Alberta, Canada.

The Lake Wabamun area, in Alberta, is unique within Canada as there are four coal-fired power plants within a 500 km(2) area. Continuous monitoring of ambient total gaseous mercury (TGM) concentrations in the Lake Wabamun area was undertaken at two sites, Genesee and Meadows. The data were analyzed in order to characterise the effect of the coal-fired power plants on the regional TGM.

A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial.

Background: Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, darusentan, in patients with treatment-resistant hypertension.

Methods: This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia.

Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials.

Aims: Use of inotropic agents in patients with heart failure (HF) has been limited by adverse effects on outcomes. However, administration of positive inotropes at lower doses and concomitant treatment with beta-blockers might increase benefit-risk ratio. We investigated the effects of low doses of the positive inotrope enoximone on symptoms, exercise capacity, and major clinical outcomes in patients with advanced HF who were also treated with beta-blockers and other guideline-recommended background therapy.

General multistage gatekeeping procedures.

A general multistage (stepwise) procedure is proposed for dealing with arbitrary gatekeeping problems including parallel and serial gatekeeping. The procedure is very simple to implement since it does not require the application of the closed testing principle and the consequent need to test all nonempty intersections of hypotheses. It is based on the idea of carrying forward the Type I error rate for any rejected hypotheses to test hypotheses in the next ordered family.

Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2.

Background: Ambrisentan is a propanoic acid-based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension.

Methods And Results: Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks.

A note on tree gatekeeping procedures in clinical trials.

Dmitrienko et al. (Statist. Med.

Efficacy and safety of darusentan in patients with resistant hypertension: results from a randomized, double-blind, placebo-controlled dose-ranging study.

In this phase 2, randomized, double-blind, placebo-controlled forced dose-titration study, 115 patients with resistant hypertension, receiving background therapy with >/=3 antihypertensive medications including a diuretic at full doses, were randomized 2:1 to increasing doses of darusentan (10, 50, 100, 150, and 300 mg), a selective endothelin receptor antagonist, or matching placebo once daily for 10 weeks. Darusentan treatment decreased mean systolic and diastolic blood pressure levels in a dose-dependent fashion compared with placebo; the largest reductions were observed at week 10 (300-mg dose) (systolic, -11.5+/-3.

The role of intention to treat in analysis of noninferiority studies.

In analysing clinical trials designed to show superiority of one treatment compared to another, it is standard to use an intention to treat analytic approach. In active-controlled noninferiority studies, this is not standard, due to concerns that such an analysis will inflate the chance of falsely rejecting the null hypothesis, accepting therapeutic noninferiority when it is not justified. The reasons for using intention to treat (ITT) approaches in superiority studies include a desire to capture all information on study subjects, a need to prevent bias, and assurance that comparative groups are, on average, equivalent in prognostic factors.

Randomization as a basis for inference in noninferiority trials.

Noninferiority testing in clinical trials is commonly understood in a Neyman-Pearson framework, and has been discussed in a Bayesian framework as well. In this paper, we discuss noninferiority testing in a Fisherian framework, in which the only assumption necessary for inference is the assumption of randomization of treatments to study subjects. Randomization plays an important role in not only the design but also the analysis of clinical trials, no matter the underlying inferential field.

Tree-structured gatekeeping tests in clinical trials with hierarchically ordered multiple objectives.

This paper discusses a new class of multiple testing procedures, tree-structured gatekeeping procedures, with clinical trial applications. These procedures arise in clinical trials with hierarchically ordered multiple objectives, for example, in the context of multiple dose-control tests with logical restrictions or analysis of multiple endpoints. The proposed approach is based on the principle of closed testing and generalizes the serial and parallel gatekeeping approaches developed by Westfall and Krishen (J.

Fallback tests in dose-response clinical trials.

This article introduces a general testing procedure for performing dose-control comparisons in dose-response trials with one or more endpoints. The procedure (termed multi-stage fallback procedure) is an extension of the fallback test proposed by Wiens (2003). The multi-stage fallback procedure features a simple stepwise form and improves the power of dose-control tests at higher doses by taking into account the ordering of the doses.

The fallback procedure for evaluating a single family of hypotheses.

In testing multiple hypotheses, control of the familywise error rate is often considered. We develop a procedure called the "fallback procedure" to control the familywise error rate when multiple primary hypotheses are tested. With the fallback procedure, the Type I error rate (alpha) is partitioned among the various hypotheses of interest.

First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study.

Purpose: We evaluated the efficacy of pegfilgrastim to reduce the incidence of febrile neutropenia associated with docetaxel in breast cancer patients.

Patients And Methods: Patients were randomly assigned to either placebo or pegfilgrastim 6 mg subcutaneously on day 2 of each 21-day chemotherapy cycle of 100 mg/m(2) docetaxel. The primary end point was the percentage of patients developing febrile neutropenia (defined as body temperature >/= 38.

Assessing the impact of endpoint shopping on power in confirmatory clinical trials.

When planning a confirmatory study, one of the important aspects is choosing a primary endpoint and evaluating power to show a difference. Data from preliminary studies are generally used for such planning. It is natural to want to use the endpoint from the preliminary study that best differentiates between test drug and control as the primary endpoint in the confirmatory study.

Testing for interaction in studies of noninferiority.

We consider the role of interaction tests in the context of active-controlled clinical trials that aim to demonstrate the noninferiority of an experimental treatment compared to a standard (control) treatment. When the subjects can be grouped into strata (e.g.

Choosing an equivalence limit for noninferiority or equivalence studies.

Studies that compare treatments with the purpose of demonstrating that the treatments are similar require an a priori definition of an equivalence limit, how different the treatments can be before the difference is of concern. Defining such an equivalence limit is one of the most difficult aspects of planning the study. Three principles are proposed for setting such limits, depending on the objective of the study: a putative placebo calculation, an approach based on clinically important differences, and methods based on statistical properties.