Are pilot trials useful for predicting randomisation and attrition rates in definitive studies: A review of publicly funded trials

BACKGROUND/AIMS: External pilot trials are recommended for testing the feasibility of main or confirmatory trials. However, there is little evidence that progress in external pilot trials actually predicts randomisation and attrition rates in the main trial. To assess the use of external pilot trials in trial design, we compared randomisation and attrition rates in publicly funded randomised controlled trials with rates in their pilots. METHODS: Randomised controlled trials for which there was an external pilot trial were identified from reports published between 2004 and 2013 in the Health Technology Assessment Journal. Data were extracted from published papers, protocols and reports. Bland-Altman plots and descriptive statistics were used to investigate the agreement of randomisation and attrition rates between the full and external pilot trials. RESULTS: Of 561 reports, 41 were randomised controlled trials with pilot trials and 16 met criteria for a pilot trial with sufficient data. Mean attrition and randomisation rates were 21.1% and 50.4%, respectively, in the pilot trials and 16.8% and 65.2% in the main. There was minimal bias in the pilot trial when predicting the main trial attrition and randomisation rate. However, the variation was large: the mean difference in the attrition rate between the pilot and main trial was -4.4% with limits of agreement of -37.1% to 28.2%. Limits of agreement for randomisation rates were -47.8% to 77.5%. CONCLUSION: Results from external pilot trials to estimate randomisation and attrition rates should be used with caution as comparison of the difference in the rates between pilots and their associated full trial demonstrates high variability. We suggest using internal pilot trials wherever appropriate

Disease management projects and the Chronic CareModel in action: Baseline qualitative research

Background: Disease management programs, especially those based on the Chronic Care Model (CCM),are increasingly common in the Netherlands. While disease management programs have beenwell-researched quantitatively and economically, less qualitative research has been done. Theoverall aim of the study is to explore how disease management programs are implementedwithin primary care settings in the Netherlands; this paper focuses on the early developmentand implementation stages of five disease management programs in the primary care setting,based on interviews with project leadership teams. Methods: At the five sites, eleven semi-structured interviews were conducted at the five selected siteswith sixteen professionals interviewed; all project leaders were interviewed. The interviewsfocused on each project's chosen chronic illness (diabetes, eating disorders, COPD, multimorbidity,CVRM) and project plan, barriers to development and implementation, the projectleaders' action and reactions, as well as their roles and responsibilities, and diseasemanagement strategies. Analysis was inductive and interpretive, based on the content of theinterviews. After analysis, the results of this research on disease management programs andthe Chronic Care Model are viewed from a traveling technology framework. Results: This analysis uncovered four themes that can be mapped to disease management and theChronic Care Model: (1) changing the health care system, (2) patient-centered care, (3)technological systems and barriers, and (4) integrating projects into the larger system. Projectleaders discussed the paths, both direct and indirect, for transforming the health care systemto one that addresses chronic illness. Patient-centered care was highlighted as needed and aparadigm shift for many. Challenges with technological systems were pervasive.

A retrospective analysis of conditional power assumptions in clinical trials with continuous or binary endpoints

Background Adaptive clinical trials may use conditional power (CP) to make decisions at interim analyses, requiring assumptions about the treatment effect for remaining patients. It is critical that these assumptions are understood by those using CP in decision-making, as well as timings of these decisions. Methods Data for 21 outcomes from 14 published clinical trials were made available for re-analysis. CP curves for accruing outcome information were calculated using and compared with a pre-specified objective criteria for original and transformed versions of the trial data using four future treatment effect assumptions: (i) observed current trend, (ii) hypothesised effect, (iii) 80% optimistic confidence limit, (iv) 90% optimistic confidence limit. Results The hypothesised effect assumption met objective criteria when the true effect was close to that planned, but not when smaller than planned. The opposite was seen using the current trend assumption. Optimistic confidence limit assumptions appeared to offer a compromise between the two, performing well against objective criteria when the end observed effect was as planned or smaller. Conclusion The current trend assumption could be the preferable assumption when there is a wish to stop early for futility. Interim analyses could be undertaken as early as 30% of patients have data available. Optimistic confidence limit assumptions should be considered when using CP to make trial decisions, although later interim timings should be considered where logistically feasible

Recruitment and retention of participants in randomised controlled trials: a review of trials funded and published by the United Kingdom Health Technology Assessment Programme

Background Substantial amounts of public funds are invested in health research worldwide. Publicly funded randomised controlled trials (RCTs) often recruit participants at a slower than anticipated rate. Many trials fail to reach their planned sample size within the envisaged trial timescale and trial funding envelope. Objectives To review the consent, recruitment and retention rates for single and multicentre randomised control trials funded and published by the UK's National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme. Data sources and study selection HTA reports of individually randomised single or multicentre RCTs published from the start of 2004 to the end of April 2016 were reviewed. Data extraction Information was extracted, relating to the trial characteristics, sample size, recruitment and retention by two independent reviewers. Main outcome measures Target sample size and whether it was achieved; recruitment rates (number of participants recruited per centre per month) and retention rates (randomised participants retained and assessed with valid primary outcome data). Results This review identified 151 individually RCTs from 787 NIHR HTA reports. The final recruitment target sample size was achieved in 56% (85/151) of the RCTs and more than 80% of the final target sample size was achieved for 79% of the RCTs (119/151). The median recruitment rate (participants per centre per month) was found to be 0.92 (IQR 0.43–2.79) and the median retention rate (proportion of participants with valid primary outcome data at follow-up) was estimated at 89% (IQR 79–97%). Conclusions There is considerable variation in the consent, recruitment and retention rates in publicly funded RCTs. Investigators should bear this in mind at the planning stage of their study and not be overly optimistic about their recruitment projections

Evaluatie van disease management programma's in Nederland

In het ZonMw programma ‘Disease Management Chronische Ziekten’ (DMCZ) zijn 22 praktijkprojecten ontwikkeld, gevolgd en geëvalueerd. Deze ZonMw-praktijkprojecten hadden een looptijd van ongeveer drie jaar. Gedurende deze periode zijn de projecten systematisch gevolgd op een aantal proces- en effectmaten en kosten-effectiviteit. De verwachting is dat disease management programma's gebaseerd op Ed Wagner's chronische zorgmodel bijdragen aan betere kwaliteit van chronische zorgverlening. Inzicht in de korte en lange termijn effecten van implementatie van dit type programma's voor verschillende chronische aandoeningen is echter nog schaars. [...

The management of cardiovascular disease in the Netherlands: analysis of different programmes

Background: Disease management programmes are increasingly used to improve the efficacy and effectiveness of chronic care delivery. But, disease management programme development and implementation is a complex undertaking that requires effective decision-making. Choices made in the earliest phases of programme development are crucial, as they ultimately impact costs, outcomes and sustainability. Methods: To increase our understanding of the choices that primary healthcare practices face when implementing such programmes and to stimulate successful implementation and sustainability, we compared the early implementation of eight cardiovascular disease management programmes initiated and managed by healthcare practices in various regions of the Netherlands. Using a mixed-methods design, we identified differences in and challenges to programme implementation in terms of context, patient characteristics, disease management level, healthcare utilisation costs, development costs and health-related quality of life. Results: Shifting to a multidisciplinary, patient-centred care pathway approach to disease management is demanding for organisations, professionals and patients, and is especially vulnerable when sustainable change is the goal. Funding is an important barrier to sustainable implementation of cardiovascular disease management programmes, although development costs of the individual programmes varied considerably in relation to the length of the development period. The large number of professionals involved in combination with duration of programme development was the largest cost drivers. While Information and Communication Technology systems to support the new care pathways did not directly contribute to higher costs, delays in implementation indirectly did. Conclusions: Developing and implementing cardiovascular disease management programmes is time-consuming and challenging. Multidisciplinary, patient-centred care demands multifaceted changes in routine care. As care pathways become more complex, they also become more expensive. Better preparedness and training can prevent unnecessary delays during the implementation period and are crucial to reducing costs

Large rivers and orogens: the evolution of the Yarlung Tsangpo–Irrawaddy system and the eastern Himalayan syntaxis

The eastern Himalayan syntaxis has experienced some of the highest rates of deformation and erosion in the orogen during the Late Cenozoic, and the Yarlung Tsangpo, Brahmaputra, Irrawaddy, Salween, and Mekong rivers are the key erosional systems in that region. The Yarlung Tsangpo drains southern Tibet and the deep Siang River gorge through the eastern Himalayan syntaxis before joining the Brahmaputra in northeastern India. It has been proposed that the Yarlung Tsangpo drained into other large rivers of southern Asia, such as the Irrawaddy, Salween and Red River. We have used uranium/lead dating and hafnium measurements of detrital zircons from Cenozoic sedimentary deposits in Central Myanmar to demonstrate that the Yarlung Tsangpo formerly drained into the Irrawaddy River in Myanmar through the eastern syntaxis, and that this ancient river system was established by (at least) the Middle–Late Eocene. The Yarlung Tsangpo–Irrawaddy river disconnected in the Early Miocene driven by increased deformation in the eastern syntaxis and headward erosion by tributaries of the Brahmaputra. Our results highlight the significance of the sedimentary record of large orogen-parallel rivers and provide key chronological constraints on landscape evolution during the Early Miocene phase of the Himalayan orogeny

An investigation of how fungal infection influences drug penetration through onychomycosis patient's nail plates

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)The treatment of onychomycosis remains problematic even though there are several potent antifungal agents available for patient use. The aim of this investigation was to understand if the structural modifications that arise when a patient's nail become infected plates influences the permeation of drugs into the nail following topical application. It was hoped that through improving understanding of the nail barrier in the diseased state, the development of more effective topical treatments for onychomycosis could be facilitated. The permeation of three compounds with differing hydrophobicities; caffeine, terbinafine and amorolfine, (clogD at pH 7.4 of -0.55, 3.72 and 4.49 respectively), was assessed across both healthy and onychomycosis infected, full thickness, human nail plate sections. Transonychial water loss (TOWL) measurements performed on the healthy and diseased nails supported previous observations that the nail behaves like a porous barrier given the lack of correlation between TOWL values with the thicker, diseased nails. The flux of the more hydrophilic caffeine was two-fold greater across diseased in comparison to the healthy nails, whilst the hydrophobic molecules terbinafine and amorolfine showed no statistically significant change in their nail penetration rates. Caffeine flux across the nail was found to correlate with the TOWL measurements, though no correlation existed for the more hydrophobic drugs. This data supported the notion that the nail pores, opened up by the infection, facilitated the passage of hydrophilic molecules, whilst the keratin binding of hydrophobic molecules meant that their transport through the nail plate was unchanged. Therefore, in order to exploit the structural changes induced by nail fungal infection it would be beneficial to develop a small molecular weight, hydrophilic antifungal agent, which exhibits low levels of keratin binding.Peer reviewe

The soil geochemistry in the Beardmore Glacier Region, Antarctica: Implications for terrestrial ecosystem history

Although most models suggest continental Antarctica was covered by ice during the Last Glacial Maximum (LGM) it has been speculated that endemic species of soil invertebrates could have survived the Pleistocene at high elevation habitats protruding above the ice sheets. We analyzed a series of soil samples from different elevations at three locations along the Beardmore Glacier in the Transantarctic Mountains (in order of increasing elevation): Ebony Ridge (ER), Cloudmaker (CM), and Meyer Desert (MD). Geochemical analyses show the MD soils, which were exposed during the LGM, were the least weathered compared to lower elevations, and also had the highest total dissolved solids (TDS). MD soils are dominated by nitrate salts (NO₃/Cl ratios >10) that can be observed in SEM images. High δ¹⁷O and δ¹⁸O values of the nitrate indicate that its source is solely of atmospheric origin. It is suggested that nitrate concentrations in the soil may be utilized to determine a relative “wetting age” to better assess invertebrate habitat suitability. The highest elevation sites at MD have been exposed and accumulating salts for the longest times, and because of the salt accumulations, they were not suitable as invertebrate refugia during the LGM