Power Considerations in Designing and Interpreting Adaptive Clinical Trials.

Adaptive clinical trials allow researchers to make preplanned modifications based on accumulating data from an ongoing trial while preserving the trial's integrity and validity. These modifications may include early termination in cases of successes or lack of efficacy, refining the sample size, altering treatments or doses, or focusing recruitment efforts on individuals most likely to benefit. In this issue of , Geisler et al.

Pathophysiological Sex Differences in Heart Failure Progression After Acute Coronary Syndrome: Insights From the EXAMINE Trial.

Background: Therapies can reduce the risk of heart failure (HF) development and progression in type 2 diabetes; nevertheless, the risk of these outcomes is greater in females than in males.

Methods And Results: To investigate sex differences in HF development and progression, we compared baseline circulating proteins (Olink Cardiovascular II panel) in males and females with type 2 diabetes and recent acute coronary syndrome for the outcome of HF hospitalization. Data were from the placebo-controlled Examination of Cardiovascular Outcomes with Alogliptin vs Standard of Care (EXAMINE) trial.

External validation and extension of the TIMI risk score for heart failure in diabetes for patients with recent acute coronary syndrome: An analysis of the EXAMINE trial.

Aims: The Thrombolysis in Myocardial Infarction Risk Score for Heart Failure (HF) in Diabetes (TRS-HF ) prognosticates HF hospitalization in people with type 2 diabetes (T2D). This study aimed to externally validate and extend its use for those with recent acute coronary syndrome (ACS).

Materials And Methods: The TRS-HF was externally validated in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial (n = 5380) and extended with natriuretic biomarkers.

Economic Evaluation of Cost and Time Required for a Platform Trial vs Conventional Trials.

Importance: Platform trial design allows the introduction of new interventions after the trial is initiated and offers efficiencies to clinical research. However, limited guidance exists on the economic resources required to establish and maintain platform trials.

Objective: To compare cost (US dollars) and time requirements of conducting a platform trial vs a series of conventional (nonplatform) trials using a real-life example.

Optimal adaptive promising zone designs.

We develop optimal decision rules for sample size re-estimation in two-stage adaptive group sequential clinical trials. It is usual for the initial sample size specification of such trials to be adequate to detect a realistic treatment effect with good power, but not sufficient to detect the smallest clinically meaningful treatment effect . Moreover it is difficult for the sponsors of such trials to make the up-front commitment needed to adequately power a study to detect .

A simulation-based comparison of estimation methods for adaptive and classical group sequential clinical trials.

Statistical methods for controlling the type-I error of hypothesis tests in adaptive group sequential clinical trials are well established and well understood. However, methods for obtaining statistically valid point estimates and confidence intervals for adaptive designs are not as well established or as well understood. At the end of an adaptive trial, one may calculate the repeated confidence interval (RCI), which provides conservative coverage of , or the backward image confidence interval (BWCI), which provides exact coverage of and is an extension of the stagewise adjusted confidence interval (SWCI, used in classical group sequential designs).

Robust group sequential designs for trials with survival endpoints and delayed response.

Randomized clinical trials in oncology typically utilize time-to-event endpoints such as progression-free survival or overall survival as their primary efficacy endpoints, and the most commonly used statistical test to analyze these endpoints is the log-rank test. The power of the log-rank test depends on the behavior of the hazard ratio of the treatment arm to the control arm. Under the assumption of proportional hazards, the log-rank test is asymptotically fully efficient.

Blood and Urine Biomarkers Predicting Worsening Kidney Function in Patients with Type 2 Diabetes Post-Acute Coronary Syndrome: An Analysis from the EXAMINE Trial.

Introduction: Worsening kidney function (WKF) is frequent among patients with type 2 diabetes (T2D) and a recent acute coronary syndrome (ACS) and is associated with a poor prognosis. An accurate prediction of WKF is clinically important.

Aims: Using data from the Cardiovascular Outcomes Study of Alogliptin in Patients with Type 2 Diabetes and Acute Coronary Syndrome trial including patients with T2D and a recent ACS, and a large biomarker panel incorporating proteins measured both in blood and urine, we aim to determine those with best performance for WKF prediction.

Body weight changes in patients with type 2 diabetes and a recent acute coronary syndrome: an analysis from the EXAMINE trial.

Background: Patients with type 2 diabetes (T2D) may experience frequent body weight changes over time. The prognostic impact of these weight changes (gains or losses) requires further study.

Aims: To study the associations between changes in body weight (intentional or unintentional) with subsequent outcomes.

Influence of sex, age and race on coronary and heart failure events in patients with diabetes and post-acute coronary syndrome.

Background: Women, older patients and non-White ethnic groups experience a substantial proportion of acute coronary syndromes (ACS), although they have been historically underrepresented in ACS randomized clinical trials (RCTs). To assess the influence of sex, age and race on major adverse cardiovascular events (MACE) and on heart failure events, we studied patients with type 2 diabetes in a large post-ACS trial (EXAMINE).

Methods: Differences in baseline characteristics and the respective composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE) and cardiovascular death or heart failure hospitalization (HF events) were evaluated by subgroups in a cohort of post-ACS patients with diabetes, using unadjusted and adjusted Cox regression modelling.

Gaining Efficiency in Clinical Trials With Cardiac Biomarkers: JACC Review Topic of the Week.

The momentum of cardiovascular drug development has slowed dramatically. Use of validated cardiac biomarkers in clinical trials could accelerate development of much-needed therapies, but biomarkers have been used less for cardiovascular drug development than in therapeutic areas such as oncology. Moreover, there are inconsistences in biomarker use in clinical trials, such as sample type, collection times, analytical methods, and storage for future research.

Red cell distribution width in patients with diabetes and myocardial infarction: An analysis from the EXAMINE trial.

Aim: To determine the clinical correlates of increased red blood cell distribution width (RDW), its potential mechanistic association with multiple circulating biomarkers, and its prognostic value in patients with type 2 diabetes (T2D) who had a recent acute coronary syndrome.

Methods: We used time-updated Cox models applied to patients enrolled in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial.

Results: A total of 5380 patients were included, the median age was 61 years and 32% were women.

Timing of randomization after an acute coronary syndrome in patients with type 2 diabetes mellitus.

Background: The timing of enrolment following an acute coronary syndrome (ACS) may influence cardiovascular (CV) outcomes and potentially treatment effect in clinical trials. Understanding the timing and type of clinical events after an ACS will allow for clinicians to better tailor evidence-based treatments to optimize therapeutic effect. Using a large contemporary trial in patients with type 2 diabetes mellitus (T2DM) post-ACS, we examined the impact of timing of enrolment on subsequent CV outcomes.

Multi-proteomic approach to predict specific cardiovascular events in patients with diabetes and myocardial infarction: findings from the EXAMINE trial.

Background: Patients with diabetes who had a recent myocardial infarction (MI) are at high risk of cardiovascular events. Therefore, risk assessment is important for treatment and shared decisions. We used data from EXAMINE trial to investigate whether a multi-proteomic approach would provide specific proteomic signatures and also improve the prognostic capacity for determining the risk of cardiovascular death, MI, stroke, heart failure [HF], all-cause death, and combinations of these outcomes.

Alogliptin after acute coronary syndrome in patients with type 2 diabetes: a renal function stratified analysis of the EXAMINE trial.

Background: The EXAMINE trial tested the efficacy and safety of alogliptin, an inhibitor of dipeptidyl peptidase 4, compared with placebo in 5380 patients with type 2 diabetes and a recent acute coronary syndrome. Because alogliptin is cleared by the kidney, patients were stratified according to screening renal function within two independently randomized strata: (1) estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m and (2) eGFR < 60 ml/min/1.

Adaptive multiarm multistage clinical trials.

Two methods for designing adaptive multiarm multistage (MAMS) clinical trials, originating from conceptually different group sequential frameworks are presented, and their operating characteristics are compared. In both methods pairwise comparisons are made, stage-by-stage, between each treatment arm and a common control arm with the goal of identifying active treatments and dropping inactive ones. At any stage one may alter the future course of the trial through adaptive changes to the prespecified decision rules for treatment selection and sample size reestimation, and notwithstanding such changes, both methods guarantee strong control of the family-wise error rate.

Fasiglifam-Induced Liver Injury in Patients With Type 2 Diabetes: Results of a Randomized Controlled Cardiovascular Outcomes Safety Trial.

Objective: To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in-man G-protein-coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes.

Research Design And Methods: A phase 3 multicenter randomized double-blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.

Optimal promising zone designs.

Clinical trials with adaptive sample size reassessment based on an unblinded analysis of interim results are perhaps the most popular class of adaptive designs (see Elsäßer et al., 2007). Such trials are typically designed by prespecifying a zone for the interim test statistic, termed the promising zone, along with a decision rule for increasing the sample size within that zone.

Average Clinician-Measured Blood Pressures and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Ischemic Heart Disease in the EXAMINE Trial.

Background Blood pressure ( BP ) treatment goals in patients with diabetes mellitus and increased cardiovascular risk remain controversial. Our study objective was to determine cardiovascular outcomes according to achieved BP s over the average follow-up period in the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) trial. Methods and Results EXAMINE was a cardiovascular outcomes trial in 5380 patients with type 2 diabetes mellitus and recent acute coronary syndromes.

Reassessing the Role of Surrogate End Points in Drug Development for Heart Failure.

With few notable exceptions, drug development for heart failure (HF) has become progressively more challenging, and there remain no definitively proven therapies for patients with acute HF or HF with preserved ejection fraction. Inspection of temporal trends suggests an increasing rate of disagreement between early-phase and phase III trial end points. Preliminary results from phase II HF trials are frequently promising, but increasingly followed by disappointing phase III results.

Extensile lateral versus sinus tarsi approach for displaced, intra-articular calcaneal fractures: a meta-analysis.

Background: Operative management of displaced, intra-articular calcaneal fractures is associated with improved functional outcomes but associated with frequent complications due to poor soft tissue healing. The use of a minimally invasive sinus tarsi approach to the fixation of these fractures may be associated with a lower rate of complications and therefore provide superior outcomes without the associated morbidity of operative intervention.

Methods: We reviewed four prospective and seven retrospective trials that compared the outcomes from the operative fixation of displaced intra-articular calcaneal fractures via either an extensile lateral approach or minimally invasive fixation via a sinus tarsi approach.

The distance of the femoral neurovascular bundle from the hip joint: an intraoperative guide to reduce iatrogenic injury.

Background: Iatrogenic injury to the femoral neurovascular bundle is not uncommon during primary and revision total hip replacement (THR) and can result in permanent weakness, pain and poor function. Prevention of injury to these structures relies on a sound knowledge of their relationships to the hip joint.

Methods: We studied 115 consecutive hip magnetic resonance imaging (MRI) results in order to identify objective relationships between these structures and the hip joint that can be used intraoperatively.

Total cardiovascular events analysis of the EXAMINE trial in patients with type 2 diabetes and recent acute coronary syndrome.

Alogliptin, a dipeptidyl peptidase-4 inhibitor, is approved for the treatment of patients with type 2 diabetes (T2DM). EXAMINE was a randomized controlled clinical trial designed to demonstrate the cardiovascular (CV) safety of alogliptin. In the trial, 5380 patients with established T2DM who had a recent acute coronary syndrome event (between 15 and 90 days) were randomized to treatment with either alogliptin or placebo.

High-sensitivity C-reactive protein, low-density lipoprotein cholesterol and cardiovascular outcomes in patients with type 2 diabetes in the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial.

Aims: We sought to assess the risk of major adverse cardiovascular events (MACE) by utilizing high-sensitivity C-reactive protein (hsCRP) level and low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and recent acute coronary syndrome.

Materials And Methods: Study participants enrolled in the EXAMINE trial (Clinical trials registration number: NCT00968708) and were stratified by baseline hsCRP levels (<1, 1-3 and >3 mg/L). They were also sub-divided into 4 groups according to baseline hsCRP (≤3 or >3 mg/L) and achieved LDL-C (<70 or ≥70 mg/dL) levels.