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PubMed1995

Old age does not negate good cerebral outcome after cardiopulmonary resuscitation: analyses from the brain resuscitation clinical trials. The Brain Resuscitation Clinical Trial I and II Study Groups.

OBJECTIVE: To assess survival after cardiac arrest and to determine whether age is an independent determinant of late mortality or poor neurologic outcome. DESIGN: Analyses using results of Brain Resuscitation Clinical Trial I (1979 to 1984) and Brain Resuscitation Clinical Trial II (1984 to 1989), two randomized, double-blind studies of outcome following cardiac arrest. SETTING: A multicenter study in 12 acute care hospitals in nine countries (Brain Resuscitation Clinical Trial I), and 24 hospitals in eight countries (Brain Resuscitation Clinical Trial II). PATIENTS: A total of 774 patients who were initially comatose after successful resuscitation from cardiac arrest. The analyses include both in- and out-of-hospital cardiac arrests. RESULTS: The 6-month mortality rate for the entire group was 81%. Mortality rate was 94% for the oldest group (> 80 yrs) compared with 68% for the youngest group (< or = 45 yrs) (p < .01). Other independent predictors of mortality were history of diabetes mellitus, inhospital arrests, arrest time of > 5 mins, history of congestive heart failure, a noncardiac cause of arrest, and cardiopulmonary resuscitation time of > 20 mins. Of the 774 patients, 27% recovered good neurologic function. There was no statistically significant difference in neurologic recovery rates by age. Multivariate analysis showed that independent predictors of good neurologic recovery were: no history of diabetes mellitus, a cardiac cause of arrest, short arrest time, and short cardiopulmonary resuscitation time. CONCLUSION: Increasing age was a factor in postresuscitation mortality, but was not an independent predictor of poor neurologic outcome.

Age Factors↗

PubMed1989

The trials of clinical trials.

Controlled clinical trials are becoming increasingly frequent in neurology. A review of the literature indicates that several trials have serious flaws in study design and conduct that render the results questionable or uninterpretable. These reports, together with my own experience with the trial of plasmapheresis in the treatment of acute Guillain-Barré syndrome, have led me to conclude that while the formulation of the crucial research question and the definition of outcomes as a measure of efficacy are extremely important, the availability of a compliant patient population of appropriate size and the compliance by the study physicians are essential. Moreover, close cooperation with the statistician in planning the trial and the statistical strategy for analysis is also critical. Suggestions are made to aid the clinician in setting up the most efficacious trial and reporting the results.

Clinical Trials as Topic↗

PubMed2002

Coping with missing data in clinical trials: a model-based approach applied to asthma trials.

In most clinical trials, some patients do not complete their intended follow-up according to protocol, for a variety of reasons, and are often described as having 'dropped out' before the conclusion of the trial. Their subsequent measurements are missing, and this makes the analysis of the trial's repeated measures data more difficult. In this paper we briefly review the reasons for patient drop-out, and their implications for some commonly used methods of analysis. We then propose a class of models for modelling both the response to treatment and the drop-out process. Such models are readily fitted in a Bayesian framework using non-informative priors with the software BUGS. The results from such models are then compared with the results of standard methods for dealing with missing data in clinical trials, such as last observation carried forward. We further propose the use of a time transformation to linearize an asymptotic pattern of repeated measures over time and therefore simplify the modelling. All these ideas are illustrated using data from a five-arm asthma clinical trial.

Asthma↗

PubMed1996

A correlation study of averaged and single trial MEG signals: the average describes multiple histories each in a different set of single trials.

Our understanding of the link between electrical events in the brain and behaviour is based on indirect measures. Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI) rely on haemodynamic processes which are slower by two to three orders of magnitude than the processes characterizing normal and pathological brain function. Direct invasive measurements of the electrical activity on the other hand produce too local a view which fails to show the large scale coherence which sustains awareness and cognition. On the opposite extreme, gross measures of the electrical activity like Electroencephalography (EEG) and single or few channel Magetoencephalography (MEG) had until recently to rely on simplistic point like models extracted from the averages of many repetitions of physiologically irrelevant stimuli. The introduction of multichannel probes with over 30 channels (Hämälainen et al. 1993), and the use of distributed source analysis (Ioannides et al. 1990a) opened up for the first time the possibility to study the response of single trials. In this work we address directly the question how representative is the description of events extracted from the analysis of the average signal. We use the simplest possible example: the cortical response to a simple 1 kHz tone, focusing on the early and by general admission "automatic" response around 100 ms after stimulus onset. To avoid the confounding inter-subject variability we have studied the responses over the left and right cortical areas to ipsi- and contralateral stimulation in a single subject; for testing reproducibility, we have used both the eyes open and eyes closed conditions. Since the computational demands involved in extracting a full three dimensional description from each trial are too great, we have complemented the distributed source analysis with special techniques, which allow us to scan through each and every single trial and identify each cortical activation similar to the ones picked out in the average signal. We are thus able to show conclusively that the sequence of events suggested by the analysis of the average signal is not representative of what is happening in individual trials. The sequence is made up of events which occurred in different trials reflecting probably the existence of many parallel routes each of which leads from the input at the ear to a final "computation".

Adult↗

PubMed1986

The Oxford Database of Perinatal Trials: developing a register of published reports of controlled trials.

A database of perinatal trials is currently being established to provide a resource for reviews of the safety and efficacy of interventions used in perinatal care and to foster cooperative and coordinated research efforts in the perinatal field. The database will ultimately comprise four main elements: a register of published reports of trials; a register of unpublished trials; a register of ongoing and planned trials; and data derived from pooled overviews (meta-analyses) of trials. This article describes the development of the first of these four elements.

Clinical Trials as Topic↗

PubMed1991

Data monitoring committees for multicenter clinical trials sponsored by the National Institutes of Health. I. Roles and membership of data monitoring committees for trials sponsored by the National Eye Institute.

The operational aspects of data monitoring committees for multicenter clinical trials have received little attention in the published literature, in contrast to a wealth of publications concerning the statistical aspects of data monitoring. Occasional anecdotal reports suggest that the role of these committees is complex and that responsibilities and decisions extend beyond choice of a stopping rule. In an effort to gain a better appreciation of the domain of responsibilities shared by all or most of the data monitoring committees (DMCs) for the 20 multicenter studies (30 clinical trials) sponsored by the National Eye Institute, one of the National Institutes of Health, published information was studied and key members of the DMCs for these studies were surveyed. Information about the membership of these important groups also was sought in order to guide those with responsibility for appointing future DMCs. Three tasks--all directly associated with monitoring accumulating data for evidence of benefit or harm to trial patients--were reported unanimously to be the responsibility of the DMCs. In addition, many responsibilities concerned with study oversight rather than data monitoring were assigned to the DMC in 75% or more of the trials. The domain of responsibilities common to a majority of the DMCs suggests that these groups function in most NEI-sponsored multicenter trials as combined data monitoring and policy boards, even when not so designated. The median size of the 20 DMCs was 10 members, with six appointed and four ex officio members. Ophthalmologists accounted for 38% of all DMC positions and statisticians for 33%.

Clinical Trials as Topic↗

PubMed2005

A randomized clinical trial of hospital-based, comprehensive cardiac rehabilitation versus usual care for patients with congestive heart failure, ischemic heart disease, or high risk of ischemic heart disease (the DANREHAB trial)--design, intervention, and population.

BACKGROUND: Current guidelines broadly recommend comprehensive cardiac rehabilitation (CR), although evidence for this is still limited. It is not known whether evidence from before 1995 is still valid. STUDY DESIGN: The DANish Cardiac ReHABilitation (DANREHAB) trial was designed as a centrally randomized clinical trial to clarify whether hospital-based comprehensive CR is superior to usual care for patients with congestive heart failure, ischemic heart disease, or high risk for ischemic heart disease. A combined primary outcome measure included total mortality, myocardial infarction, or readmissions due to heart disease based on linkage to public registries. The CR was an individually tailored, multidisciplinary program (6 weeks of intensive CR and 12 months of follow-up) including patient education, exercise training, dietary counseling, smoking cessation, psychosocial support, risk factor management, and clinical assessment. STUDY POPULATION: Of 5060 discharged patients, 1614 (32%) were eligible for the trial and 770 patients were randomized (47% of those eligible). Participants were younger (P < .001) and had less comorbidity than nonparticipants (P < .03). CONCLUSION: Our trial shows that a large-scale, centrally randomized clinical trial on comprehensive CR can be conducted among a broadly defined patient group, but reaching the stipulated number of 1800 patients was difficult. Although the study included relatively many women and older people, elderly patients and patients with high comorbidity were underrepresented, which may influence the external validity.

Adult↗

PubMed2004

Landmark studies: the Australia/New Zealand Heart Failure Collaborative Group (ANZ) Trial and the US Carvedilol Trials Program.

The safety, tolerability, and hemodynamic effects of carvedilol in patients with heart failure were first studied in the mid 1990s. Positive results in these early trials led to 5 prospective, randomized, double-blind, placebo-controlled trials-the Australia/New Zealand Heart Failure Collaborative Group (ANZ) study and the 4 component studies of the US Carvedilol Heart Failure Trials Program. These studies were conducted to determine the clinical impact of long-term carvedilol therapy. Findings from these trials showed that carvedilol is a powerful therapy (1) in patients with chronic heart failure caused by left ventricular (LV) systolic dysfunction, improving morbidity and mortality; and (2) in patients with symptomatic heart failure, improving LV ejection fraction, improving clinical status, and slowing disease progression, resulting in reduction of the combined risk of hospitalization and mortality. This article discusses the design, results, and clinical implications of these trials.

Adrenergic beta-Antagonists↗

PubMed2005

Design and analysis of trials with rare outcomes: examples from trials in herpes transmission and influenza prophylaxis.

For trials with rare outcomes, the number of events to be observed drives the power of the study rather than the proportions of subjects with the event and this is an important consideration when determining sample size. The stratified version of Fisher's exact test was described by Cox as long ago as 1966, but it is only recently that computing power has allowed this to be performed routinely. The issue of stratified analysis can also be addressed through permutation tests and their implementation for multicentre trials where randomisation is stratified by site has potential value. Where the time to event is available, analysis using a proportional hazards model has a potentially valuable role but estimates of differences in proportions are often required particularly for non-inferiority studies and typical software employed for these analyses uses an asymptotic approximation rather than an exact analysis. It is important to assess the impact of missing data on such trials. This can be approached through examination of the pattern of missing data and the covariates predicting discontinuation as well as through sensitivity analysis. Sensitivity analyses need to be done carefully using realistic alternative assumptions and an appealing approach is to impute events for subjects with missing data using the observed placebo rate. Issues of design and analysis for trials with rare outcomes are discussed in the context of two examples-one from a trial designed to investigate transmission of herpes and one that studied prophylaxis of influenza.

Chemoprevention↗

PubMed2005

A pragmatic 2 x 2 x 2 factorial cluster randomized controlled trial of educational outreach visiting and case conferencing in palliative care-methodology of the Palliative Care Trial [ISRCTN 81117481].

The demand for palliative care is increasing, yet there are few data on the best models of care nor well-validated interventions that translate current evidence into clinical practice. Supporting multidisciplinary patient-centered palliative care while successfully conducting a large clinical trial is a challenge. The Palliative Care Trial (PCT) is a pragmatic 2 x 2 x 2 factorial cluster randomized controlled trial that tests the ability of educational outreach visiting and case conferencing to improve patient-based outcomes such as performance status and pain intensity. Four hundred sixty-one consenting patients and their general practitioners (GPs) were randomized to the following: (1) GP educational outreach visiting versus usual care, (2) Structured patient and caregiver educational outreach visiting versus usual care and (3) A coordinated palliative care model of case conferencing versus the standard model of palliative care in Adelaide, South Australia (3:1 randomization). Main outcome measures included patient functional status over time, pain intensity, and resource utilization. Participants were followed longitudinally until death or November 30, 2004. The interventions are aimed at translating current evidence into clinical practice and there was particular attention in the trial's design to addressing common pitfalls for clinical studies in palliative care. Given the need for evidence about optimal interventions and service delivery models that improve the care of people with life-limiting illness, the results of this rigorous, high quality clinical trial will inform practice. Initial results are expected in mid 2005.

Aged↗

PubMed2006

Clinical trial optimization: Monte Carlo simulation Markov model for planning clinical trials recruitment.

INTRODUCTION: The patient recruitment process of clinical trials is an essential element which needs to be designed properly. METHODS: In this paper we describe different simulation models under continuous and discrete time assumptions for the design of recruitment in clinical trials. RESULTS: The results of hypothetical examples of clinical trial recruitments are presented. The recruitment time is calculated and the number of recruited patients is quantified for a given time and probability of recruitment. The expected delay and the effective recruitment durations are estimated using both continuous and discrete time modeling. CONCLUSION: The proposed type of Monte Carlo simulation Markov models will enable optimization of the recruitment process and the estimation and the calibration of its parameters to aid the proposed clinical trials. A continuous time simulation may minimize the duration of the recruitment and, consequently, the total duration of the trial.

Clinical Trials as Topic↗

PubMed2004

Clinical trials update from the European Society of Cardiology: SENIORS, ACES, PROVE-IT, ACTION, and the HF-ACTION trial.

This article provides information and a commentary on landmark trials presented at the European Society of Cardiology Congress in August 2004, relevant to the pathophysiology, prevention or treatment of heart failure. The SENIORS trial suggests that nebivolol is well tolerated and effective in older patients with heart failure, even if left ventricular systolic function is not markedly depressed. However, patients aged >75 years appeared to gain less benefit. Further data on the effects of nebivolol on symptoms and quality of life are awaited. Two new trials of long-term antibiotic prophylaxis after myocardial infarction (ACES and PROVE-IT) showed no benefit. The ACTION trial showed no reduction in serious cardiovascular events with nifedipine GITS in patients with chronic stable angina, despite a substantial reduction in blood pressure. The HF-ACTION trial announced that the first 700 patients of a projected 3000 had been randomised to either an exercise program or encouragement to exercise but without a formal program. The primary outcome measure is death or hospitalisation for any reason.

Adrenergic beta-Antagonists↗

PubMed2026

Post-trial 12-month follow-up of TRACE (targeted research on addictive and compulsive eating) randomised controlled trial participants: A brief report.

Few treatment interventions for addictive eating have evaluated long-term effectiveness. This post-trial follow-up study evaluates secondary changes in addictive eating symptoms and quality of life at 12-months in a sample of individuals who participated in the TRACE (Targeted Research for Addictive and Compulsive Eating) RCT. Thirty-three adults out of possible 144 (82% female), median age 53 years, randomised to either the active intervention (five telehealth sessions delivered over 3-months), passive intervention (self-guided workbook) or control group completed an online post-trial survey. Pre- and immediate post-intervention (3-months) outcomes were compared to 12-months post-trial outcomes. Positive effects reported in the short term showed a rebound effect at post-trial follow-up in ∼50% of participants. The findings suggest that longer term support is needed to maintain changes in addictive eating behaviours and improve quality of life. Future research is needed to identify optimal intervention durations and support options for sustained change. Australian New Zealand Clinical Trials Registry (ACTRN12621001079831).

Humans↗

PubMed2005

Models of Phase 1 vaccine trials: optimization of trial design to minimize risks of multiple serious adverse events.

A mathematical model of Phase 1 vaccine trial design was used to investigate strategies for minimizing the number of serious adverse events (SAEs) that could be encountered in the first Phase 1 trials of new vaccine formulations. For a relatively standard dose escalation trial with three dose groups each with 10 subjects, an optimal balanced between risk of more than one serious adverse event and trial design is achieved by splitting each dose group into two subgroups of three and seven. Based on the modeling, for a two vaccination, dose-escalating Phase 1 trial, a design where all subjects receive the first vaccination before any subject receives a second vaccination generally carries a lower risk of multiple serious adverse events than other designs.

Clinical Trials, Phase I as Topic↗

PubMed1999

Improvement in three-month angiographic outcome suggested after primary angioplasty for acute myocardial infarction (Zwolle trial) compared with successful thrombolysis (APRICOT trial). Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis.

It has been shown that primary percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction results in higher patency rates than thrombolytic therapy. However, no data are available on differences in long-term angiographic outcome after successful primary PTCA compared with successful thrombolysis. Therefore, we compared angiographic data of the Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis (APRICOT) trial and the Zwolle primary PTCA trial. In the APRICOT trial 248 patients underwent coronary angiography at a mean of 24 hours after thrombolysis and had a patent infarct-related vessel (Thrombolysis In Myocardial Infarction-3 trial flow) when entering the study. Reocclusion rates were assessed at a second angiography after 3 months. In the Zwolle trial 136 patients had a successful primary PTCA. At 3 months 131 patients underwent a second angiography. Quantitative coronary angiography showed a significant lower mean diameter stenosis of the infarct-related vessel after primary PTCA (27 +/- 12% vs 57 +/-12%; p = 0.00001). At 3 months this difference was sustained (35 +/- 22% vs 63 +/- 26%; p = 0.00001). After thrombolysis the reocclusion rate at 3 months was 29% compared with 5% after primary PTCA (p = 0.0001). Results show that compared with successful thrombolytic therapy, primary PTCA for acute myocardial infarction results in an improved infarct-related vessel status not only short term but also long term, with a low reocclusion rate.

Aged↗

PubMed2002

Implementing the EGASIS trial, an international multicenter acute intervention trial in stroke.

This paper describes some of the problems that were encountered during implementation of the Early GABA-ergic Activation Study In Stroke (EGASIS), a large international multicenter clinical trial evaluating the neuroprotective effect of diazepam in acute stroke. The focus is on obtaining funding for such a large international nonprofit trial, getting approval from all national and local ethics committees, shipping trial medication, and trial insurance. For each topic the specific problems and ways in which they were solved are described. Several recommendations for facilitating the running of a large international multicenter clinical trial such as EGASIS are made.

Clinical Trials as Topic↗

PubMed2002

Streamlining IRB review in multisite trials through single-study IRB Cooperative Agreements: experience of the Beta-Carotene and Retinol Efficacy Trial (CARET).

With their extensive data and specimen repositories, clinical trials are a long-term, valuable resource to health researchers. However, assuring protection of participants' rights can be challenging, particularly when such trials are conducted at multiple sites with multiple Institutional Review Boards (IRBs). One little-used mechanism that can streamline IRB review in multisite trials while maintaining participants' protections is the single-study IRB Cooperative Agreement. This agreement is entirely different from reciprocity agreements between institutions. Beginning in 1996, the Beta-Carotene and Retinol Efficacy Trial established single-study IRB Cooperative Agreements among its performance sites, which reduced the average time to complete IRB approval from over 6 months to 1 month for each of many substudies. We describe our experience and make recommendations for other multisite clinical trials.

Clinical Trials as Topic↗

PubMed2002

Enhancing the technology of clinical trials and the trials model to evaluate newly developed, targeted antidepressants.

Concern about disappointing results from recent multi-center trials of new antidepressants prompted several ACNP workshops on "improving the technology of clinical trials." The workshops focused on technical problems, such as patient screening, reliability of clinical ratings, and the role of the placebo control. They aimed to determine how to more effectively apply the current clinical trials model for evaluating antidepressant drugs. The problems confronting the field of clinical trials, however, extend beyond technology. They also included conceptual issues concerning changes in the understanding of depressive disorders and of the multiple actions of antidepressant drugs. Such problems have been further complicated by the rapidly changing field of drug development itself, which is continually refining the targeting of new antidepressant agents. Drugs are increasingly being developed to try to change specific behavioral facets more rapidly and may be less likely, therefore, to act initially on "whole" disorders. To address such issues, a symposium was held in Rhodes in 2000 that focused on such conceptual changes with the goal of developing recommendations to revise the clinical evaluation model. Its purpose was to integrate new knowledge on depression and the mechanisms of action of antidepressant drugs toward developing more efficient methods of drug development. Since the evaluation process will eventually require changes in governmental policy, senior staff from the National Institute of Mental Health (NIMH) , Unites States and Food and Drug Administration (FDA), Unites States participated as well as members of academia, industry and clinical practice. Recommendations for altering clinical trial methodology were made in four areas: patient selection, methodology of evaluation, measuring onset of action, and FDA and NIMH perspectives on current practice. This article discusses these four areas and presents the consensus of the panel participants.

Antidepressive Agents↗