Thrombelastographic haemostatic status and antiplatelet therapy after coronary artery bypass surgery (TEG-CABG trial): assessing and monitoring the antithrombotic effect of clopidogrel and aspirin versus aspirin alone in hypercoagulable patients: study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Hypercoagulability, assessed by the thrombelastography (TEG) assay, has in several observational studies been associated with an increased risk of post-procedural thromboembolic complications. We hypothesize that intensified antiplatelet therapy with clopidogrel and aspirin, as compared to aspirin alone, will improve saphenous vein graft patency in preoperatively TEG-Hypercoagulable coronary artery bypass surgery (CABG) patients and reduce their risk for thromboembolic complications and death postoperatively. METHODS: This is a prospective randomized clinical trial, with an open-label design with blinded evaluation of graft patency. TEG-Hypercoagulability is defined as a TEG maximum amplitude above 69 mm. Two hundred and fifty TEG-Hypercoagulable patients will be randomized to either an interventional group receiving clopidogrel 75 mg daily for three months (after initial oral bolus of 300 mg) together with aspirin 75 mg or a control group receiving aspirin 75 mg daily alone. Monitoring of antiplatelet efficacy and on-treatment platelet reactivity to clopidogrel and aspirin will be conducted with Multiplate aggregometry. Graft patency will be assessed with Multislice computed tomography (MSCT) at three months after surgery. CONCLUSIONS: The present trial is the first randomized clinical trial to evaluate whether TEG-Hypercoagulable CABG patients will benefit from intensified antiplatelet therapy after surgery. Monitoring of platelet inhibition from instituted antithrombotic therapy will elucidate platelet resistance patterns after CABG surgery. The results could be helpful in redefining how clinicians can evaluate patients preoperatively for their postoperative thromboembolic risk and tailor individualized postoperative antiplatelet therapy. Trial registration Clinicaltrials.gov Identifier NCT01046942.     

Estimation of Population Vaccination Effectiveness from HIV Vaccine Trials

Longini , Datta , and Halloran (1996) proposed to design HIV vaccine trials in a way that will permit the simultaneous estimation of the vaccine effects on susceptibility to infection and on infectiousness of vaccine brak-throughs. The main feature of their design is the inclusion of steady partners of trial participants. They estimate four parameters from the vaccine trial: the probability that a susceptible person will become infected from his/her steady partner, the probability of becoming infected from outside the partnership, the vaccine efficacy for susceptibility and the vaccine efficacy for infectiousness. We show how the estimates of these parameters can be used to predict the attack rate in a given population during a specified period following mass-vaccination. This is an iterative method, as the attack rate depends on the HIV prevalence which, in turn, depends on the number of new cases during that period. The same method is also used to estimate the attack rate in that population during the same period in the absence of vaccination. The estimated attack rates allow us to estimate the population vaccination effectiveness, defined as the fraction HIV cases prevented by a vaccination program.     

Improving efficiency of inference in clinical trials with external control data

Suppose we are interested in the effect of a treatment in a clinical trial. The efficiency of inference may be limited due to small sample size. However, external control data are often available from historical studies. Motivated by an application to Helicobacter pylori infection, we show how to borrow strength from such data to improve efficiency of inference in the clinical trial. Under an exchangeability assumption about the potential outcome mean, we show that the semiparametric efficiency bound for estimating the average treatment effect can be reduced by incorporating both the clinical trial data and external controls. We then derive a doubly robust and locally efficient estimator. The improvement in efficiency is prominent especially when the external control data set has a large sample size and small variability. Our method allows for a relaxed overlap assumption, and we illustrate with the case where the clinical trial only contains a treated group. We also develop doubly robust and locally efficient approaches that extrapolate the causal effect in the clinical trial to the external population and the overall population. Our results also offer a meaningful implication for trial design and data collection. We evaluate the finite-sample performance of the proposed estimators via simulation. In the Helicobacter pylori infection application, our approach shows that the combination treatment has potential efficacy advantages over the triple therapy.     

Elacestrant in metastatic breast cancer: Is the “standard of care” meeting standard requirements?

The EMERALD trial was an open label phase 3 trial evaluating elacestrant, the first oral selective estrogen receptor degrader (SERD), as compared to “standard of care”, in ER+/HER2- (hormone receptor positive, no HER2 overexpression) advanced or metastatic breast cancer.The EMERALD trial restricted the “standard of care” control arm to limited options that may have led to a substandard control arm. We describe how the EMERALD trial protocol allowed different clinically inappropriate scenarios in the control arm, according to prior therapy. The main relevant question remains the potential advantage of elacestrant over fulvestrant in fulvestrant-naive patients.Analyzing outcomes in subgroups according to prior and per-protocol therapy would help analyzing trial results. However, these subgroup results may be non-significant, and another randomized trial will be needed. Trials should be designed to answer directly clinical questions that are relevant.     

Continuous toxicity monitoring in phase II trials in oncology

The goal of a phase II trial in oncology is to evaluate the efficacy of a new therapy. The dose investigated in a phase II trial is usually an estimate of a maximum-tolerated dose obtained in a preceding phase I trial. Because this estimate is imprecise, stopping rules for toxicity are used in many phase II trials. We give recommendations on how to construct stopping rules to monitor toxicity continuously. A table is provided from which Pocock stopping boundaries can be easily obtained for a range of toxicity rates and sample sizes. Estimation of the probability of toxicity and response is also discussed.     

Investigating maximum power losses in survival studies with nonstratified randomization

In studies with nonstratified randomization, imbalances may occur which lead to power loss. We investigate how much power may be lost at worst, that is, with small but nonnegligible probability. The situation considered is a two-treatment trial with censored survival data, and three to five strata. We also derive asymptotic results, as the sample size and/or number of strata increase. In addition, we consider how much a projected sample size needs to be increased to be confident (at a certain probability level) that the intended power will be retained, conditionally on the unbalanced configuration.     

Aerobic endurance training versus relaxation training in patients with migraine (ARMIG): study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Migraine is one of the most frequent headache diseases and impairs patients' quality of life. Up to now, many randomized studies reported efficacy of prophylactic therapy with medications such as beta-blockers or anti-epileptic drugs. Non-medical treatment, like aerobic endurance training, is considered to be an encouraging alternative in migraine prophylaxis. However, there is still a lack of prospective, high-quality randomized trials. We therefore designed a randomized controlled trial to evaluate the efficacy of aerobic endurance training versus relaxation training in patients with migraine (ARMIG). METHODS: This is a single-center, open-label, prospective, randomized trial. Sixty participants with migraine are randomly allocated to either endurance training or a relaxation group. After baseline headache diary documentation over at least 4 weeks, participants in the exercise group will start moderate aerobic endurance training under a sport therapist's supervision at least 3 times a week over a 12-week period. The second group will perform Jacobson's progressive muscle relaxation training guided by a trained relaxation therapist, also at least 3 times a week over a 12-week period. Both study arms will train in groups of up to 10 participants. More frequent individual training is possible. The follow-up period will be 12 weeks after the training period. The general state of health, possible state of anxiety or depression, impairments due to the headache disorder, pain-related disabilities, the headache-specific locus of control, and the motor fitness status are measured with standardized questionnaires. DISCUSSION: The study design is adequate to generate meaningful results. The trial will be helpful in gaining important data on exercise training for non-medical migraine prophylaxis. Trial registration The trial is registered at ClinicalTrials.gov: NCT01407861.     

Stopping Rules for Clinical Trials Implicitly Incorporating Safety Information

Clinical trials research is mainly conducted for the purpose of evaluating the relative efficacy of two or more treatments. However, a positive response due to treatment is not sufficient to put forward a new product because one must also demonstrate safety. In such cases, clinical trials which show a positive effect would need to accrue enough patients to also demonstrate that the new treatment is safe. It is our purpose to show how the efficacy and safety problems can be combined to yield a more practical clinical trial design. In this paper we propose an asymmetric stopping rule which allows the experimenter to terminate a clinical trial early for a sufficiently negative result and to continue to a specified number of patients otherwise. As it turns out, a few interim tests will have negligible effects on the overall significance level.     

A cautionary note on design implications when the primary analysis is a stratified analysis of a binary endpoint

When the primary analysis is a stratified analysis of a binary endpoint, the commonly used CMH procedure could produce results that are quite different from those obtained by ignoring the stratification factor altogether. This means that when designing a trial with a primary endpoint that is binary, it is important that one keep in mind how the data will be analyzed. Only when design and analysis are considered in tandem will the study possess the desired properties. The discussion in this paper is illustrated by a hypothetical example, which nevertheless resembles the findings from a confirmatory trial involving the evaluation of a biologic for severe sepsis.     

Vagal stimulation for heart diseases: from animals to men. An example of translational cardiology

A significant series of experimental and clinical studies have demonstrated the close association between reduced vagal reflexes (baroreflex sensitivity, BRS) and increased sudden and non-sudden cardiovascular mortality. Subsequently, evidence was provided that, also among chronic heart failure (HF) patients, depressed BRS is associated with a poorer outcome. At the same time, the encouraging results with experimental and clinical attempts to increase cardiac vagal activity led to a few experimental studies with vagal stimulation (VS) in different models for HF. We first performed a pilot study for VS in HF patients, and then in 2011 we reported the results of a small size multicentre clinical trial. The 6-month and 1-year results are encouraging for feasibility, safety and appear to have a favourable clinical effect. An ongoing large clinical trial will provide a definitive assessment of the efficacy and usefulness of chronic VS in HF patients.     

Treatment Trials for Neonatal Seizures: The Effect of Design on Sample Size

Neonatal seizures are common in the neonatal intensive care unit. Clinicians treat these seizures with several anti-epileptic drugs (AEDs) to reduce seizures in a neonate. Current AEDs exhibit sub-optimal efficacy and several randomized control trials (RCT) of novel AEDs are planned. The aim of this study was to measure the influence of trial design on the required sample size of a RCT. We used seizure time courses from 41 term neonates with hypoxic ischaemic encephalopathy to build seizure treatment trial simulations. We used five outcome measures, three AED protocols, eight treatment delays from seizure onset (T_d) and four levels of trial AED efficacy to simulate different RCTs. We performed power calculations for each RCT design and analysed the resultant sample size. We also assessed the rate of false positives, or placebo effect, in typical uncontrolled studies. We found that the false positive rate ranged from 5 to 85% of patients depending on RCT design. For controlled trials, the choice of outcome measure had the largest effect on sample size with median differences of 30.7 fold (IQR: 13.7–40.0) across a range of AED protocols, T_d and trial AED efficacy (p<0.001). RCTs that compared the trial AED with positive controls required sample sizes with a median fold increase of 3.2 (IQR: 1.9–11.9; p<0.001). Delays in AED administration from seizure onset also increased the required sample size 2.1 fold (IQR: 1.7–2.9; p<0.001). Subgroup analysis showed that RCTs in neonates treated with hypothermia required a median fold increase in sample size of 2.6 (IQR: 2.4–3.0) compared to trials in normothermic neonates (p<0.001). These results show that RCT design has a profound influence on the required sample size. Trials that use a control group, appropriate outcome measure, and control for differences in T_d between groups in analysis will be valid and minimise sample size.     

Sacituzumab govitecan in metastatic triple negative breast cancer (TNBC): Four design features in the ASCENT trial potentially favored the experimental arm

The ASCENT trial reports impressive results with a median overall survival (OS) increased from 6.7 months to 12.1 months with sacituzumab govitecan over single-agent chemotherapy, in metastatic triple negative breast cancer (TNBC) patients in second and subsequent line of therapy.We described design features in the ASCENT trial casting doubt on the extrapolation of the reported results to real world patients. First, the open-label design may exaggerate the effect of the experimental arm. Second, the choice of progression-free-survival (PFS) as a primary endpoint, debatable in metastatic TNBC, can lead to biases: early stopping rules may exaggerate efficacy results and informative censoring can bias PFS results interpretation. Third, the control arm was not a complete “physician''s choice”: it was restricted, preventing from using effective agents in this setting, and leading to a substandard control arm. Fourth and lastly, dose reduction and supportive care recommendations for the experimental drug were different between the trial protocol and the FDA labels, and favored the experimental arm as compared with the control arm.In conclusion, we described four design features in the ASCENT trial having the potential to favor the experimental arm or to penalize the control arm. It thus remains uncertain in which extent the reported outcomes will translate in the real world. Efforts should be made to avoid trial biases that will eventually prevent to conclude about their true impact in patients when applied broadly.     

Accounting for Behavior in Treatment Effects: New Applications for Blind Trials

The double-blind randomized controlled trial (DBRCT) is the gold standard of medical research. We show that DBRCTs fail to fully account for the efficacy of treatment if there are interactions between treatment and behavior, for example, if a treatment is more effective when patients change their exercise or diet. Since behavioral or placebo effects depend on patients’ beliefs that they are receiving treatment, clinical trials with a single probability of treatment are poorly suited to estimate the additional treatment benefit that arises from such interactions. Here, we propose methods to identify interaction effects, and use those methods in a meta-analysis of data from blinded anti-depressant trials in which participant-level data was available. Out of six eligible studies, which included three for the selective serotonin re-uptake inhibitor paroxetine, and three for the tricyclic imipramine, three studies had a high (>65%) probability of treatment. We found strong evidence that treatment probability affected the behavior of trial participants, specifically the decision to drop out of a trial. In the case of paroxetine, but not imipramine, there was an interaction between treatment and behavioral changes that enhanced the effectiveness of the drug. These data show that standard blind trials can fail to account for the full value added when there are interactions between a treatment and behavior. We therefore suggest that a new trial design, two-by-two blind trials, will better account for treatment efficacy when interaction effects may be important.     

Life- and person-centred help in Mecklenburg-Western Pomerania, Germany (DelpHi): study protocol for a randomised controlled trial

ABSTRACT: BACKGROUND: The provision of appropriate medical and nursing care for people with dementia is a major challenge for the healthcare system in Germany. New models of healthcare provision need to be developed, tested and implemented on the population level. Trials in which collaborative care for dementia in the primary care setting were studied have demonstrated its effectiveness. These studies have been conducted in different healthcare systems, however, so it is unclear whether these results extend to the specific context of the German healthcare system. The objective of this population-based intervention trial in the primary care setting is to test the efficacy and efficiency of implementing a subsidiary support system on a population level for persons with dementia who live at home. Methods and study design The study was designed to assemble a general physician-based epidemiological cohort of people above the age of 70 who live at home (DelpHi cohort). These people are screened for eligibility to participate in a trial of dementia care management (DelpHi trial). The trial is a cluster-randomised, controlled intervention trial with two arms (intervention and control) designed to test the efficacy and efficiency of implementing a subsidiary support system for persons with dementia who live at home. This subsidiary support system is initiated and coordinated by a dementia care manager: a nurse with dementia-specific qualifications who delivers the intervention according to a systematic, detailed protocol. The primary outcome is quality of life and healthcare for patients with dementia and their caregivers. This is a multidimensional outcome with a focus on four dimensions: (1) quality of life, (2) caregiver burden, (3) behavioural and psychological symptoms of dementia and (4) pharmacotherapy with an antidementia drug and prevention or suspension of potentially inappropriate medication. Secondary outcomes include the assessment of dementia syndromes, activities of daily living, social support health status, utilisation of health care resources and medication. DISCUSSION: The results will provide evidence for specific needs in ambulatory care for persons with dementia and will show effective ways to meet those needs. Qualification requirements will be evaluated, and the results will help to modify existing guidelines and treatment paths. Trial registration NCT01401582.     

Re‐Formulating Non‐inferiority Trials as Superiority Trials: The Case of Binary Outcomes

Non‐inferiority trials are conducted for a variety of reasons including to show that a new treatment has a negligible reduction in efficacy or safety when compared to the current standard treatment, or a more complex setting of showing that a new treatment has a negligible reduction in efficacy when compared to the current standard yet is superior in terms of other treatment characteristics. The latter reason for conducting a non‐inferiority trial presents the challenge of deciding on a balance between a suitable reduction in efficacy, known as the non‐inferiority margin, in return for a gain in other important treatment characteristics/findings. It would be ideal to alleviate the dilemma on the choice of margin in this setting by reverting to a traditional superiority trial design where a single p ‐value for superiority of both the most important endpoint (efficacy) and the most important finding (treatment characteristic) is provided. We discuss how this can be done using the information‐preserving composite endpoint (IPCE) approach and consider binary outcome cases in which the combination of efficacy and treatment characteristics, but not one itself, paints a clear picture that the novel treatment is superior to the active control (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Target populations for first-in-human embryonic stem cell research in spinal cord injury

Geron recently announced that it had begun enrolling patients in the world's first-in-human clinical trial involving cells derived from human embryonic stem cells (hESCs). This trial raises important questions regarding the future of hESC-based therapies, especially in spinal cord injury (SCI) patients. We address some safety and efficacy concerns with this research, as well as the ethics of fair subject selection. We consider other populations that might be better for this research: chronic complete SCI patients for a safety trial, subacute incomplete SCI patients for an efficacy trial, and perhaps primary progressive multiple sclerosis (MS) patients for a combined safety and efficacy trial.     

Reversal of profound vecuronium-induced neuromuscular block under sevoflurane anesthesia: sugammadex versus neostigmine

Background

The perioperative period is characterized by an intense inflammatory response. Perioperative inflammation promotes postoperative morbidity and increases mortality. Blunting the inflammatory response to surgical trauma might thus improve perioperative outcomes. We are studying three interventions that potentially modulate perioperative inflammation: corticosteroids, tight glucose control, and light anesthesia.

Methods/Design

The DeLiT Trial is a factorial randomized single-center trial of dexamethasone vs placebo, intraoperative tight vs. conventional glucose control, and light vs deep anesthesia in patients undergoing major non-cardiac surgery. Anesthetic depth will be estimated with Bispectral Index (BIS) monitoring (Aspect medical, Newton, MA). The primary outcome is a composite of major postoperative morbidity including myocardial infarction, stroke, sepsis, and 30-day mortality. C-reactive protein, a measure of the inflammatory response, will be evaluated as a secondary outcome. One-year all-cause mortality as well as post-operative delirium will be additional secondary outcomes. We will enroll up to 970 patients which will provide 90% power to detect a 40% reduction in the primary outcome, including interim analyses for efficacy and futility at 25%, 50% and 75% enrollment.

Discussion

The DeLiT trial started in February 2007. We expect to reach our second interim analysis point in 2010. This large randomized controlled trial will provide a reliable assessment of the effects of corticosteroids, glucose control, and depth-of-anesthesia on perioperative inflammation and morbidity from major non-cardiac surgery. The factorial design will enable us to simultaneously study the effects of the three interventions in the same population, both individually and in different combinations. Such a design is an economically efficient way to study the three interventions in one clinical trial vs three.

Trial registration

This trial is registered at Clinicaltrials.gov #: NTC00433251     

Monitoring futility and efficacy in phase II trials with Bayesian posterior distributions—A calibration approach

A multistage single arm phase II trial with binary endpoint is considered. Bayesian posterior probabilities are used to monitor futility in interim analyses and efficacy in the final analysis. For a beta‐binomial model, decision rules based on Bayesian posterior probabilities are converted to “traditional” decision rules in terms of number of responders among patients observed so far. Analytical derivations are given for the probability of stopping for futility and for the probability to declare efficacy. A workflow is presented on how to select the parameters specifying the Bayesian design, and the operating characteristics of the design are investigated. It is outlined how the presented approach can be transferred to statistical models other than the beta‐binomial model.