What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies

Background

Traditional harvesting of the internal thoracic artery (ITA) for use as a conduit in coronary bypass surgery involves the dissection of a rim of tissue surrounding the artery on either side. Recent studies, primarily observational, have suggested that skeletonization of the ITA can improve conduit flow, increase length, and reduce the risk of deep sternal infection in high risk patients. Furthermore, skeletonization of the ITA can potentially preserve intercostal nerves and reduce post-operative pain and dysesthesias associated with ITA harvesting. In order to assess the effects of ITA skeletonization, we report a prospective, randomized, within-patient study design that shares many features of a cross-over study.

Methods

Patients undergoing bilateral internal thoracic artery harvest will be randomized to having one side skeletonized and the other harvested in a non-skeletonized manner. Outcome measures include ITA flow and length measured intra-operatively, post-operative pain and dysesthesia, evaluated at discharge, four weeks, and three months post-operatively, and sternal perfusion assessed using single photon emission computed tomography. Harvest times as well as safety endpoints of ITA injury will be recorded.

Discussion

This study design, using within-patient comparisons and paired analyses, minimizes the variability of the outcome measures, which is seldom possible in the evaluation of surgical techniques, with minimal chance of carryover effects that can hamper the interpretation of traditional cross-over studies. This study will provide a valid evaluation of clinically relevant effects of internal thoracic artery skeletonization in improving outcomes following coronary artery bypass surgery.     

Clinical trials of endothelin antagonists in heart failure: a question of dose?

Circulating plasma endothelin (ET)-1 concentrations are substantially elevated, and correlate with the hemodynamic severity and New York Heart Association (NYHA) class, in patients with chronic heart failure (CHF). In early preclinical studies involving different models of experimental heart failure, ET antagonists reduced cardiac pressures, increased cardiac output, and prolonged survival. ET receptor antagonists also impressively improved systemic and pulmonary hemodynamics in patients with CHF, without causing neurohormonal activation. However, recent clinical trials, including the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) and EARTH (Endothelin A Receptor Antagonist Trial in Heart Failure) studies, have shown neutral effects in terms of mortality and symptoms. This paper describes the possible reasons why benefit was not seen in these clinical studies, and suggests what lessons can be learnt from the way the studies were undertaken to apply to future studies.     

Early-phase clinical trials of anti-HIV Drugs——understanding and discussion

Innovative anti-HIV drugs developed by local sponsors in China have come into the stage of early-phase clinical trials. How to systemically design the clinical trials of innovative anti-HIV drugs still remains a challenge for them. This article references the literature and the experience of reviewers, to introduce general considerations concerning early-phase clinical trials of innovative anti-HIV drugs.     

Yield trials of steroid-producingDioscorea on Florida’s Everglades peat soils

Four steroid-bearing clones of Dioscorea tested in a replicated varietal trial on Everglades peat soil near Belle Glade, Florida, included three introductions of D. spiculiflora Hemsl. and one selection of D. composita Hemsl. On an acre basis, D. composita, P. I. 201783, produced over 21 tons of dry tubers and 1,049 lbs of crude sapogenins. Tuber and sapogenin yields front the highest producing D. spiculiflora, P. I. 252887, were approximately 1/3 and 1/2 respectively, of these amounts. Yield differences were not significant between plots harvested 2 1/2 and 3 1/2 years after planting. The failure of tubers to increase in size in the last growing season was attributed to the restriction on growth imposed by the high water table at the test site.     

Is there a place for placebo controlled trials of antiepileptic drugs?

In many patients who develop epilepsy the disease is short lived and the overall number of seizures small. The role of anticonvulsant drugs in such patients is uncertain. If treatment is merely suppressive and the disease self limiting then treatment may not be necessary in some patients. If, on the other hand, early treatment prevents the subsequent evolution to chronic epilepsy then it is imperative. To resolve this issue it is essential to undertake placebo controlled trials, in which a group of patients with newly diagnosed epilepsy is given active treatment and compared with a similar group given placebo alone.     

Influence of nitrogen fertilization on deoxynivalenol contamination of winter wheat — experimental field trials and evaluation of analytical methods

Experimental field trials were carried out to study the influence of N-fertilization on deoxynivalenol (DON) contamination of winter wheat. Within four years of investigation, no definite effect of mineral N-input at dosages varying between 0 and 240 kg N/ha could be observed on DON concentration in wheat grain. The main factors affecting DON contamination of wheat were theFusarium infection pressure, the weather conditions and the susceptibility of the wheat varieties againstFusarium head blight. DON was analyzed with enzyme-linked immunosorbent assay (ELISA) and, for comparison, some of the positive samples were additionally analyzed with high performance liquid chromatography (HPLC). There was a good correlation between the ELISA and the HPLC results for DON concentration in wheat.     

Do we protect or discriminate? Representation of senior adults in clinical trials

Aim

The analysis of barriers responsible for low recruitment of older patients in clinical trials and presentation of possible solutions are the subject of this review.

Background

Europe''s population is ageing, and the group of people who more frequently develop neoplasms increases. Oncologists are confronted with a new challenge – how to treat cancer in this group of patients, especially considering the lack of Evidence Based Medicine (EBM) guidelines for treatment of cancer in the elderly population.

Materials and methods

Medline search and analysis of studies published between 1999 and 2012, containing key words: senior adults, cancer, elderly in clinical trials.

Results

Detailed analysis of relevant studies demonstrated that senior adults are underrepresented in clinical trials. Moreover, there is a lack of trials exclusively designed for this heterogeneous group of patients. The analysis of reasons for low recruitment of older patients in clinical trials revealed barriers dependent on patient''s and physician''s attitudes as well as institutional and logistic problems.

Conclusions

It is necessary to widen the scale of trials of all phases in the group of seniors with appropriate assessment of toxicity. This will allow a proper stratification and obtaining representative groups for statistical analysis and credible trial results. Another priority is the design of trials dedicated exclusively to the elderly.     

Stakeholders’ views on the ethical challenges of pragmatic trials investigating pharmaceutical drugs

BackgroundWe explored the views of key stakeholders to identify the ethical challenges of pragmatic trials investigating pharmaceutical drugs. A secondary aim was to capture stakeholders’ attitudes towards the implementation of pragmatic trials in the drug development process.MethodsWe conducted semistructured, in-depth interviews among individuals from different key stakeholder groups (academia and independent research institutions, the pharmaceutical industry, regulators, Health Technology Assessment (HTA) agencies and patients’ organizations) through telephone or face-to-face sessions. Interviews were structured around the question “what challenges were experienced or perceived during the design, conduct and/or review of pragmatic trials.” Respondents were additionally asked about their views on implementation of pragmatic trials in the drug development process. Thematic analysis was used to identify the ethically relevant features across data sets.ResultsWe interviewed 34 stakeholders in 25 individual sessions and four group sessions. The four perceived challenges of ethical relevance were: (1) less controlled conditions creating safety concerns, (2) comparison with usual care potentially compromising clinical equipoise, (3) tailored or waivers of informed consent affecting patient autonomy, and (4) minimal interference with “real-world” practice reducing the knowledge value of trial results.ConclusionsWe identified stakeholder concerns regarding risk assessment, use of suboptimal usual care as a comparator, tailoring of informed consent procedures and ensuring the social value of pragmatic trials. These concerns increased when respondents were asked about pragmatic trials conducted before market authorization.

Electronic supplementary material

The online version of this article (doi:10.1186/s13063-016-1546-3) contains supplementary material, which is available to authorized users.     

Lead editorial: Trials – using the opportunities of electronic publishing to improve the reporting of randomised trials

Background

The purpose of this study is to compare the efficacy of prophylactic antibiotic for prevention of meningitis in acute traumatic pneumocephalus patients.

Methods

In this prospective, randomized controlled clinical trial, 200 selected head injury patients with traumatic pneumocephalus are randomly assigned to receive intravenous antibiotics (2 grams Ceftriaxone twice a day), oral antibiotics (Azithromycin) or placebo for at least 7 days after trauma. The patients will be followed for one month posttrauma.

Conclusion

The authors hope that this study helps clarifying the effectiveness and indications of antibiotics in prevention of meningitis in traumatic pneumocephalus after head injury and in specific subgroup of these patients.     

Short versus long duration of dual antiplatelet therapy following drug-eluting stents: a meta-analysis of randomised trials

Background

Dual antiplatelet therapy (DAPT) remains the cornerstone therapy in the prevention of ischaemic events following drug-eluting stent (DES) implantation. Mandatory duration of DAPT after DES however, is a matter of debate. We aimed to evaluate safety and efficacy of short-term (up to 6 months) versus long-term (12 months) DAPT after DES implantation.

Methods

We searched PubMed, EMBASE, Cochrane databases, and international meetings for randomised clinical trials (RCTs) comparing short with long DAPT. We performed a systematic review and meta-analysis of major trials with primary outcomes: all-cause death, myocardial infarction, definite or probable stent thrombosis, stroke, and major bleeding event.

Results

Nine RCTs with a total number of 19,099 patients were pooled in the present meta-analysis. When compared with long DAPT, short DAPT was associated with a significant reduction in major bleeding events (0.62% vs. 1.10%, risk ratio (RR) 0.58, 95% confidence interval (CI) 0.39 to 0.86, p?<?0.007, I²?=?21%), whereas all-cause death (1.65% vs. 1.84%, RR 0.90, 95% CI 0.73 to 1.11, p?=?0.34, I2?=?0%), myocardial infarction (1.91% vs. 1.68%, RR 1.14, 95% CI 0.92 to 1.40, p?=?0.23, I2?=?0%), definite or probable stent thrombosis (0.62% vs. 0.47%, RR 1.25, 95% CI 0.84 to 1.86, p?=?0.27, I2?=?0%), and stroke (0.60% vs. 0.67%, RR 0.91, 95% CI 0.63 to 1.31, p?=?0.61, I2?=?0%) were similar.

Conclusions

Short DAPT following DES implantation results in a significant reduction of major bleeding events with no apparent increase in all-cause death, myocardial infarction, stent thrombosis, or stroke. Future dedicated trials should investigate the optimal strategies for patient-tailored DAPT in various subgroups.

     

Ethics of randomised controlled trials – not yet time to give up on equipoise

In this commentary on Fries and Krishnan's argument that 'design bias' undermines the status of equipoise as the ethical justification for randomised controlled trials, it is argued that their argument is analogous to Bayesian arguments for the use of informative priors in trial design, but that this does not undermine the importance of equipoise. In particular, mismatches between the outcomes of interest to industrial sponsors of research and outcomes of interest to patients and clinicians ensure that in many cases industry-sponsored trials can fail to reflect the reasonable equipoise of working clinicians.     

Doctors’ versus patients’ global assessments of treatment effectiveness: empirical survey of diverse treatments in clinical trials

Objective To examine whether doctors’ global assessments of treatment effects agree with patients’ global assessments.Design Survey of trials included in systematic reviews of treatments for diverse conditions.Data sources Cochrane database of systematic reviews.Data extracted Data on patients’ global assessments and on doctors’ global assessment for the same treatment against the same comparator.Main outcome measures Relative odds ratio (ratio of odds ratios of global improvement with the experimental intervention versus control according to doctors compared with patients), and improvement rates according to doctors and patients.Results Doctors’ global assessments were compared with patients’ global assessments for 63 different treatment comparisons (240 trials) in 18 conditions. The summary relative odds ratio across the comparisons was not significant (0.98, 95% confidence interval 0.88 to 1.08; I²=0%, 95% confidence interval 0% to 30%). In 62 of the 63 comparisons the effects of treatment rated by patients and by doctors did not differ beyond chance, but for single comparisons the confidence intervals were large. Rates of improvement on average did not differ between doctors’ assessments and patients’ assessments (summary relative odds ratio 0.98, 0.88 to 1.06; I²=0%, 0% to 24%).Conclusion Doctors’ global assessments of the effects of treatments are on average similar to those of patients.     

Effects of daily iron supplementation in primary-school–aged children: systematic review and meta-analysis of randomized controlled trials

Background:

Anemia is an important public health and clinical problem. Observational studies have linked iron deficiency and anemia in children with many poor outcomes, including impaired cognitive development; however, iron supplementation, a widely used preventive and therapeutic strategy, is associated with adverse effects. Primary-school–aged children are at a critical stage in intellectual development, and optimization of their cognitive performance could have long-lasting individual and population benefits. In this study, we summarize the evidence for the benefits and safety of daily iron supplementation in primary-school–aged children.

Methods:

We searched electronic databases (including MEDLINE and Embase) and other sources (July 2013) for randomized and quasi-randomized controlled trials involving daily iron supplementation in children aged 5–12 years. We combined the data using random effects meta-analysis.

Results:

We identified 16 501 studies; of these, we evaluated 76 full-text papers and included 32 studies including 7089 children. Of the included studies, 31 were conducted in low- or middle-income settings. Iron supplementation improved global cognitive scores (standardized mean difference 0.50, 95% confidence interval [CI] 0.11 to 0.90, p = 0.01), intelligence quotient among anemic children (mean difference 4.55, 95% CI 0.16 to 8.94, p = 0.04) and measures of attention and concentration. Iron supplementation also improved age-adjusted height among all children and age-adjusted weight among anemic children. Iron supplementation reduced the risk of anemia by 50% and the risk of iron deficiency by 79%. Adherence in the trial settings was generally high. Safety data were limited.

Interpretation:

Our analysis suggests that iron supplementation safely improves hematologic and nonhematologic outcomes among primary-school–aged children in low- or middle-income settings and is well-tolerated.An estimated 25% of school-aged children worldwide are anemic.¹ Iron deficiency is thought to account for about half of the global cases of anemia² and is associated with inadequate dietary iron and, in developing settings, hookworm and schistosomiasis.³ In developed settings, anemia is prevalent among disadvantaged populations, including newly arrived refugees, indigenous people⁴ and some ethnic groups (e.g., Hispanic people in the United States).^5,6 About 3% of primary-school–aged children in Canada are anemic.⁷ Programs to address anemia are constrained by concerns that iron supplements cause adverse effects, including an increased risk of infections such as malaria in endemic areas.⁸In observational studies, iron deficiency has been associated with impaired cognitive and physical development. It has been estimated that each 10 g/L decrement in hemoglobin reduces future intelligence quotient (IQ) by 1.73 points.⁹ However, observational data are susceptible to confounding,¹⁰ and a causal relation between iron deficiency and cognitive impairment has not been confirmed.¹¹ Randomized controlled trials should overcome confounding, but results of trials examining this question have not agreed.Optimizing cognitive and physical development in primary-school–aged children could have life-long benefits.¹² However, anemia-control recommendations must balance safety and efficacy. We performed a systematic review of the effects of daily iron supplementation, a commonly used strategy to combat anemia,² in primary-school–aged children. We examined cognitive, growth and hematologic outcomes and adverse effects across all settings.     

What is meant by intention to treat analysis? Survey of published randomised controlled trials

ObjectivesTo assess the methodological quality of intention to treat analysis as reported in randomised controlled trials in four large medical journals.DesignSurvey of all reports of randomised controlled trials published in 1997 in the BMJ, Lancet, JAMA, and New England Journal of Medicine.Results119 (48%) of the reports mentioned intention to treat analysis. Of these, 12 excluded any patients who did not start the allocated intervention and three did not analyse all randomised subjects as allocated. Five reports explicitly stated that there were no deviations from random allocation. The remaining 99 reports seemed to analyse according to random allocation, but only 34 of these explicitly stated this. 89 (75%) trials had some missing data on the primary outcome variable. The methods used to deal with this were generally inadequate, potentially leading to a biased treatment effect. 29 (24%) trials had more than 10% of responses missing for the primary outcome, the methods of handling the missing responses were similar in this subset.ConclusionsThe intention to treat approach is often inadequately described and inadequately applied. Authors should explicitly describe the handling of deviations from randomised allocation and missing responses and discuss the potential effect of any missing response. Readers should critically assess the validity of reported intention to treat analyses.

Key messages

• Intention to treat gives a pragmatic estimate of the benefit of a change in treatment policy rather than of potential benefit in patients who receive treatment exactly as planned
• Full application of intention to treat is possible only when complete outcome data are available for all randomised subjects
• About half of all published reports of randomised controlled trials stated that intention to treat was used, but handling of deviations from randomised allocation varied widely
• Many trials had some missing data on the primary outcome variable, and methods used to deal with this were generally inadequate, potentially leading to bias
• Intention to treat analyses are often inadequately described and inadequately applied