Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on ...sputum culture conversion are absent.
We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D
3 or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for
TaqI and
FokI polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D
3. This trial is registered with
ClinicalTrials.gov number
NCT00419068.
126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90–2·16; p=0.14).
TaqI genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (p
interaction=0·03), with enhanced response seen only in patients with the
tt genotype (8·09, 95% CI 1·36–48·01; p=0·02).
FokI genotype did not modify the effect of vitamin D supplementation (p
interaction=0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6–88·2; p<0·0001).
Administration of four doses of 2·5 mg vitamin D
3 increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the
tt genotype of the
TaqI vitamin D receptor polymorphism.
British Lung Foundation.
Increasing patient-reported outcome measures in the 1980s and 1990s led to the development of recommendations at the turn of the millennium for standardising outcome measures in non-specific low back ...pain (LBP) trials. Whether these recommendations impacted use is unclear. Previous work has examined citation counts, but actual use and change over time, has not been explored. Since 2011, there has been some consensus on the optimal methods for reporting back pain trial outcomes. We explored reporting practice, outcome measure use, and publications over time.
We performed a systematic review of LBP trials, searching the European Guidelines for the management of LBP, extending the search to 2012. We abstracted data on publications by year, outcome measure use, analytical approach, and approaches taken to reporting trials outcomes. Data were analysed using descriptive statistics and regression analyses.
We included 401 trials. The number of published trials per year has increased by a factor of 4.5 from 5.4 (1980-1999) to 24.4 (2000-2012). The most commonly used outcome measures have been the Visual Analogue Scale for pain intensity, which has slowly increased in use since 1980/81 from 20% to 60% of trials by 2012, and the Roland-Morris Disability Questionnaire, which rose to 55% in 2002/2003, and then fell back to 28% by 2012. Most trialists (85%) report between-group mean differences. Few (8%) report individual improvements, and some (4%) report only within-group analyses. Student's t test, ANOVA, and ANCOVA regression, or mixed models, were the most common approaches to analysis.
Recommendations for standardising outcomes may have had a limited or inconsistent effect on practice. Since the research community is again considering outcome measures and modifying recommendations, groups offering recommendations should be cognisant that better ways of generating trialist buy-in may be required in order for their recommendations to have impact.
Re-randomisation trials involve re-enrolling and re-randomising patients for each new treatment episode they experience. They are often used when interest lies in the average effect of an ...intervention across all the episodes for which it would be used in practice. Re-randomisation trials are often analysed using independence estimators, where a working independence correlation structure is used. However, research into independence estimators in the context of re-randomisation has been limited.
We performed a simulation study to evaluate the use of independence estimators in re-randomisation trials. We focussed on a continuous outcome, and the setting where treatment allocation does not affect occurrence of subsequent episodes. We evaluated different treatment effect mechanisms (e.g. by allowing the treatment effect to vary across episodes, or to become less effective on re-use, etc), and different non-enrolment mechanisms (e.g. where patients who experience a poor outcome are less likely to re-enrol for their second episode). We evaluated four different independence estimators, each corresponding to a different estimand (per-episode and per-patient approaches, and added-benefit and policy-benefit approaches).
We found that independence estimators were unbiased for the per-episode added-benefit estimand in all scenarios we considered. We found independence estimators targeting other estimands (per-patient or policy-benefit) were unbiased, except when there was differential non-enrolment between treatment groups (i.e. when different types of patients from each treatment group decide to re-enrol for subsequent episodes). We found the use of robust standard errors provided close to nominal coverage in all settings where the estimator was unbiased.
Careful choice of estimand can ensure re-randomisation trials are addressing clinically relevant questions. Independence estimators are a useful approach, and should be considered as the default estimator until the statistical properties of alternative estimators are thoroughly evaluated.
Domestic violence affects one in four women and has significant health consequences. Women experiencing abuse identify doctors and other health professionals as potential sources of support. Primary ...care clinicians agree that domestic violence is a healthcare issue but have been reluctant to ask women if they are experiencing abuse.
To measure selected UK primary care clinicians' current levels of knowledge, attitudes, and clinical skills in this area.
Prospective observational cohort in 48 general practices from Hackney in London and Bristol, UK.
Administration of the Physician Readiness to Manage Intimate Partner Violence Survey (PREMIS), comprising five sections: responder profile, background (perceived preparation and knowledge), actual knowledge, opinions, and practice issues.
Two hundred and seventy-two (59%) clinicians responded. Minimal previous domestic violence training was reported by participants. Clinicians only had basic knowledge about domestic violence but expressed a positive attitude towards engaging with women experiencing abuse. Many clinicians felt poorly prepared to ask relevant questions about domestic violence or to make appropriate referrals if abuse was disclosed. Forty per cent of participants never or seldom asked about abuse when a woman presented with injuries. Eighty per cent said that they did not have an adequate knowledge of local domestic violence resources. GPs were better prepared and more knowledgeable than practice nurses; they also identified a higher number of domestic violence cases.
Primary care clinicians' attitudes towards women experiencing domestic violence are generally positive but they only have basic knowledge of the area. Both GPs and practice nurses need more comprehensive training on assessment and intervention, including the availability of local domestic violence services.
Feasibility and pilot studies are essential components of planning or preparing for a larger randomized controlled trial (RCT). They are intended to provide useful information about the feasibility ...of the main RCT-with the goal of reducing uncertainty and thereby increasing the chance of successfully conducting the main RCT. However, research has shown that there are serious inadequacies in the reporting of pilot and feasibility studies. Reasons for this include a lack of explicit publication policies for pilot and feasibility studies in many journals, unclear definitions of what constitutes a pilot or feasibility RCT/study, and a lack of clarity in the objectives and methodological focus. All these suggest that there is an urgent need for new guidelines for reporting pilot and feasibility studies.
The aim of this paper is to describe the methods and processes in our development of an extension to the Consolidated Standards of Reporting Trials (CONSORT) Statement for reporting pilot and feasibility RCTs, that are executed in preparation for a future, more definitive RCT.
There were five overlapping parts to the project: (i)
-which involved establishing a working group and conducting a review of the literature; (ii)
-which entailed consultation with the CONSORT group, journal editors and publishers, the clinical trials community, and funders; (iii) a
-used to assess the agreement of experts on initial definitions and to generate a reporting checklist for pilot RCTs, based on the 2010 CONSORT statement extension applicable to reporting pilot studies; (iv) a
-to discuss, add, remove, or modify checklist items, with input from experts in the field; and (v)
which included a guideline document which gives an explanation and elaboration (E&E) and which will provide advice for each item, together with examples of good reporting practice. This final part also included a plan for dissemination and publication of the guideline.
We anticipate that implementation of our guideline will improve the reporting completeness, transparency, and quality of pilot RCTs, and hence benefit several constituencies, including authors of journal manuscripts, funding agencies, educators, researchers, and end-users.
ObjectivesTo systematically review the quality of reporting of pilot and feasibility of cluster randomised trials (CRTs). In particular, to assess (1) the number of pilot CRTs conducted between 1 ...January 2011 and 31 December 2014, (2) whether objectives and methods are appropriate and (3) reporting quality.MethodsWe searched PubMed (2011–2014) for CRTs with ‘pilot’ or ‘feasibility’ in the title or abstract; that were assessing some element of feasibility and showing evidence the study was in preparation for a main effectiveness/efficacy trial. Quality assessment criteria were based on the Consolidated Standards of Reporting Trials (CONSORT) extensions for pilot trials and CRTs.ResultsEighteen pilot CRTs were identified. Forty-four per cent did not have feasibility as their primary objective, and many (50%) performed formal hypothesis testing for effectiveness/efficacy despite being underpowered. Most (83%) included ‘pilot’ or ‘feasibility’ in the title, and discussed implications for progression from the pilot to the future definitive trial (89%), but fewer reported reasons for the randomised pilot trial (39%), sample size rationale (44%) or progression criteria (17%). Most defined the cluster (100%), and number of clusters randomised (94%), but few reported how the cluster design affected sample size (17%), whether consent was sought from clusters (11%), or who enrolled clusters (17%).ConclusionsThat only 18 pilot CRTs were identified necessitates increased awareness of the importance of conducting and publishing pilot CRTs and improved reporting. Pilot CRTs should primarily be assessing feasibility, avoiding formal hypothesis testing for effectiveness/efficacy and reporting reasons for the pilot, sample size rationale and progression criteria, as well as enrolment of clusters, and how the cluster design affects design aspects. We recommend adherence to the CONSORT extensions for pilot trials and CRTs.
Randomized trials labelled as “pragmatic” are attractive to funders, patients, and clinicians as the label implies that the results are directly applicable to clinical care. We examined how authors ...justify use of the label (e.g., by referring to one or more PRECIS PRagmatic Explanatory Continuum Indicator Summary-2 domains).
We reviewed primary trial reports published 2014–2019, registered in ClinicalTrials.gov and using the pragmatic label anywhere in the report.
Among 415 trials, the label was justified by reference to at least one design element in 282 (68.0%); of these, 240 (85.1%) referenced trial characteristics that can be mapped to one or more of the PRECIS-2 domains, most commonly eligibility (91, 32.3%), setting (90, 31.9%), flexibility delivery (89, 31.6%), and organization (75, 26.6%); 42 (14.9%) referenced characteristics that are not PRECIS-2 domains, most commonly type of intervention/comparator (48, 17%), recruitment without consent (22, 7.8%), routinely collected data (22, 7.8%), and cluster randomization (20, 7.1%). Most reports referenced only one or two design elements. Overall, 9/415 (2.2%) provided PRECIS wheels.
Current use of pragmatic labels is uninformative. Authors should clarify the decision the trial is intended to support and include a PRECIS-2 table to make the design transparent.
Intimate partner abuse is common in all societies and damages the health of survivors and their children in the short and long term. Advocacy may decrease the impact of this abuse on women's health.
...To assess the effects of advocacy interventions conducted within or outside of health care settings on women who have experienced intimate partner abuse.
We searched: CENTRAL and DARE (Cochrane Library Issue 3, 2008), MEDLINE (1966 to 31/7/08), EMBASE (1980 to 2008 week 30), and 11 other databases, to end July 2008. We also searched relevant websites, reference lists and forward citation tracking of included studies, and handsearched six key journals. We contacted principal investigators and experts in the field.
Randomised controlled trials comparing advocacy interventions for women with experience of intimate partner abuse against usual care.
Two reviewers independently assessed trial quality and undertook data extraction. For binary outcomes we calculated a standardised estimation of the odds ratio (OR) and for continuous data we calculated either a standardised mean difference (SMD) or a weighted mean difference (WMD), both with a 95% confidence interval.
We included ten trials involving 1527 participants. The studies were heterogeneous in respect of: intensity of advocacy, outcome measures and duration of follow-up (immediately post-intervention to three years), permitting meta-analysis for only a minority of outcomes. Intensive advocacy (12 hours or more duration) may help terminate physical abuse in women leaving domestic violence shelters or refuges at 12-24 months follow-up (OR 0.43, 95% CI 0.23 to 0.80), but not at up to 12 months follow-up. The evidence indicates that intensive advocacy may improve quality of life at up to 12 months follow-up, but the confidence intervals included zero (WMD 0.23, 95% CI 0.00 to 0.46). Depression did not improve following intensive advocacy at up to 12 months follow-up (WMD -0.05, 95% CI -0.19 to 0.09), nor did psychological distress (SMD -0.16, 95% CI -0.39 to 0.06). Only two meta-analyses of brief advocacy interventions (less than 12 hours duration) were possible; an increased use of safety behaviours was consistent with the receipt of brief advocacy both at up to 12 months (WMD 0.60, 95% CI 0.14 to 1.06) and at 12-24 months (WMD 0.48, 95% CI 0.04 to 0.92) follow up.
Based on the evidence reviewed, it is possible that intensive advocacy for women recruited in domestic violence shelters or refuges reduces physical abuse one to two years after the intervention but we do not know if it has a beneficial effect on their quality of life and mental health. Similarly, there is insufficient evidence to show if less intensive interventions in healthcare settings for women who still live with the perpetrators of violence are effective.
Cluster randomised trials (CRTs) are commonly analysed using mixed-effects models or generalised estimating equations (GEEs). However, these analyses do not always perform well with the small number ...of clusters typical of most CRTs. They can lead to increased risk of a type I error (finding a statistically significant treatment effect when it does not exist) if appropriate corrections are not used.
We conducted a small simulation study to evaluate the impact of using small-sample corrections for mixed-effects models or GEEs in CRTs with a small number of clusters. We then reanalysed data from TRIGGER, a CRT with six clusters, to determine the effect of using an inappropriate analysis method in practice. Finally, we reviewed 100 CRTs previously identified by a search on PubMed in order to assess whether trials were using appropriate methods of analysis. Trials were classified as at risk of an increased type I error rate if they did not report using an analysis method which accounted for clustering, or if they had fewer than 40 clusters and performed an individual-level analysis without reporting the use of an appropriate small-sample correction.
Our simulation study found that using mixed-effects models or GEEs without an appropriate correction led to inflated type I error rates, even for as many as 70 clusters. Conversely, using small-sample corrections provided correct type I error rates across all scenarios. Reanalysis of the TRIGGER trial found that inappropriate methods of analysis gave much smaller P values (P ≤ 0.01) than appropriate methods (P = 0.04-0.15). In our review, of the 99 trials that reported the number of clusters, 64 (65 %) were at risk of an increased type I error rate; 14 trials did not report using an analysis method which accounted for clustering, and 50 trials with fewer than 40 clusters performed an individual-level analysis without reporting the use of an appropriate correction.
CRTs with a small or medium number of clusters are at risk of an inflated type I error rate unless appropriate analysis methods are used. Investigators should consider using small-sample corrections with mixed-effects models or GEEs to ensure valid results.
There is currently a lot of interest in pilot studies conducted in preparation for randomised controlled trials. This paper focuses on sample size requirements for external pilot studies for cluster ...randomised trials. We consider how large an external pilot study needs to be to assess key parameters for input to the main trial sample size calculation when the primary outcome is continuous, and to estimate rates, for example recruitment rates, with reasonable precision. We used simulation to provide the distribution of the expected number of clusters for the main trial under different assumptions about the natural cluster size, intra-cluster correlation, eventual cluster size in the main trial, and various decisions made at the piloting stage. We chose intra-cluster correlation values and pilot study size to reflect those commonly reported in the literature. Our results show that estimates of sample size required for the main trial are likely to be biased downwards and very imprecise unless the pilot study includes large numbers of clusters and individual participants. We conclude that pilot studies will usually be too small to estimate parameters required for estimating a sample size for a main cluster randomised trial (e.g. the intra-cluster correlation coefficient) with sufficient precision and too small to provide reliable estimates of rates for process measures such as recruitment or follow-up rates.
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