Chronic musculoskeletal pain is the leading cause of disability worldwide. The effectiveness of pharmacological treatments for chronic pain is often limited, and there is growing concern about the ...adverse effects of these treatments, including opioid dependence. Nonpharmacological approaches to chronic pain may be an attractive alternative or adjunctive treatment. We describe the effectiveness of a novel, theoretically based group pain management support intervention for chronic musculoskeletal pain.
We conducted a multi-centre, pragmatic, randomised, controlled effectiveness and cost-effectiveness (cost-utility) trial across 27 general practices and community musculoskeletal services in the UK. We recruited 703 adults with musculoskeletal pain of at least 3 mo duration between August 1, 2011, and July 31, 2012, and randomised participants 1.33:1 to intervention (403) or control (300). Intervention participants were offered a participative group intervention (COPERS) delivered over three alternate days with a follow-up session at 2 wk. The intervention introduced cognitive behavioural approaches and was designed to promote self-efficacy to manage chronic pain. Controls received usual care and a relaxation CD. The primary outcome was pain-related disability at 12 mo (Chronic Pain Grade CPG disability subscale); secondary outcomes included the CPG disability subscale at 6 mo and the following measured at 6 and 12 mo: anxiety and depression (Hospital Anxiety and Depression Scale HADS), pain acceptance (Chronic Pain Acceptance Questionnaire), social integration (Health Education Impact Questionnaire social integration and support subscale), pain-related self-efficacy (Pain Self-Efficacy Questionnaire), pain intensity (CPG pain intensity subscale), the census global health question (2011 census for England and Wales), health utility (EQ-5D-3L), and health care resource use. Analyses followed the intention-to-treat principle, accounted for clustering by course in the intervention arm, and used multiple imputation for missing or incomplete primary outcome data. The mean age of participants was 59.9 y, with 81% white, 67% female, 23% employed, 85% with pain for at least 3 y, and 23% on strong opioids. Symptoms of depression and anxiety were common (baseline mean HADS scores 7.4 standard deviation 4.1 and 9.2 4.6, respectively). Overall, 282 (70%) intervention participants met the predefined intervention adherence criterion. Primary outcome data were obtained from 88% of participants. There was no significant difference between groups in pain-related disability at 6 or 12 mo (12 mo: difference -1.0, intervention versus control, 95% CI -4.9 to 3.0), pain intensity, or the census global health question. Anxiety, depression, pain-related self-efficacy, pain acceptance, and social integration were better in the intervention group at 6 mo; at 12 mo, these differences remained statistically significant only for depression (-0.7, 95% CI -1.2 to -0.2) and social integration (0.8, 95% CI 0.4 to 1.2). Intervention participants received more analgesics than the controls across the 12 mo. The total cost of the course per person was £145 (US$214). The cost-utility analysis showed there to be a small benefit in terms of quality-adjusted life years (QALYs) (0.0325, 95% CI -0.0074 to 0.0724), and on the cost side the intervention was a little more expensive than usual care (i.e., £188 US$277, 95% CI -£125 -US$184 to £501 US$738), resulting in an incremental cost-effectiveness ratio of £5,786 (US$8,521) per QALY. Limitations include the fact that the intervention was relatively brief and did not include any physical activity components.
While the COPERS intervention was brief, safe, and inexpensive, with a low attrition rate, it was not effective for reducing pain-related disability over 12 mo (primary outcome). For secondary outcomes, we found sustained benefits on depression and social integration at 6 and 12 mo, but there was no effect on anxiety, pain-related self-efficacy, pain acceptance, pain intensity, or the census global health question at 12 mo. There was some evidence that the intervention may be cost-effective based on a modest difference in QALYs between groups.
ISRCTN Registry 24426731.
Pregnant women with epilepsy on antiepileptic drugs (AEDs) may experience a reduction in serum AED levels. This has the potential to worsen seizure control.
To determine if, in pregnant women with ...epilepsy on AEDs, additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels.
A double-blind, randomised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken. Stratified block randomisation with a 1 : 1 allocation method was carried out.
Fifty obstetric and epilepsy clinics in secondary and tertiary care units in the UK.
Pregnant women with epilepsy on one or more of the following AEDs: lamotrigine, carbamazepine, phenytoin or levetiracetam. Women with a ≥ 25% decrease in serum AED level from baseline were randomised to therapeutic drug monitoring or clinical features monitoring strategies.
In the therapeutic drug monitoring group, clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control. In the clinical features monitoring group, AED dosage adjustment was based only on clinical features.
Primary outcome - seizure deterioration, defined as time to first seizure and to all seizures after randomisation per woman until 6 weeks post partum. Secondary outcomes - pregnancy complications in mother and offspring, maternal quality of life, seizure rates in cohorts with stable serum AED level, AED dose exposure and adverse events related to AEDs.
Analysis of time to first and to all seizures after randomisation was performed using a Cox proportional hazards model, and multivariate failure time analysis by the Andersen-Gill model. The effects were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Secondary outcomes were reported as mean differences (MDs) or odds ratios.
A total of 130 women were randomised to the therapeutic drug monitoring group and 133 to the clinical features monitoring group; 294 women did not have a reduction in serum AED level. A total of 127 women in the therapeutic drug monitoring group and 130 women in the clinical features monitoring group (98% of complete data) were included in the primary analysis. There were no significant differences in the time to first seizure (HR 0.82, 95% CI 0.55 to 1.2) or timing of all seizures after randomisation (HR 1.3, 95% CI 0.7 to 2.5) between both trial groups. In comparison with the group with stable serum AED levels, there were no significant increases in seizures in the clinical features monitoring (odds ratio 0.93, 95% CI 0.56 to 1.5) or therapeutic drug monitoring group (odds ratio 0.93, 95% CI 0.56 to 1.5) associated with a reduction in serum AED levels. Maternal and neonatal outcomes were similar in both groups, except for higher cord blood levels of lamotrigine (MD 0.55 mg/l, 95% CI 0.11 to 1 mg/l) or levetiracetam (MD 7.8 mg/l, 95% CI 0.86 to 14.8 mg/l) in the therapeutic drug monitoring group than in the clinical features monitoring group. There were no differences between the groups on daily AED exposure or quality of life. An increase in exposure to lamotrigine, levetiracetam and carbamazepine significantly increased the cord blood levels of the AEDs, but not maternal or fetal complications. Women with epilepsy perceived the need for weighing up their increased vulnerability to seizures during pregnancy against the side effects of AEDs.
Fewer women than the original target were recruited.
There is no evidence to suggest that regular monitoring of serum AED levels in pregnancy improves seizure control or affects maternal or fetal outcomes.
Further evaluation of the risks of seizure deterioration for various threshold levels of reduction in AEDs and the long-term neurodevelopment of infants born to mothers in both randomised groups is needed. An individualised prediction model will help to identify those women who need close monitoring in pregnancy.
Current Controlled Trials ISRCTN01253916.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 22, No. 23. See the NIHR Journals Library website for further project information.
There is an increasing demand by non-commercial funders that trialists should provide access to trial data once the primary analysis is completed. This has to take into account concerns about ...identifying individual trial participants, and the legal and regulatory requirements.
Using the good practice guideline laid out by the work funded by the Medical Research Council Hubs for Trials Methodology Research (MRC HTMR), we anonymised a dataset from a recently completed trial. Using this example, we present practical guidance on how to anonymise a dataset, and describe rules that could be used on other trial datasets. We describe how these might differ if the trial was to be made freely available to all, or if the data could only be accessed with specific permission and data usage agreements in place.
Following the good practice guidelines, we successfully created a controlled access model for trial data sharing. The data were assessed on a case-by-case basis classifying variables as direct, indirect and superfluous identifiers with differing methods of anonymisation assigned depending on the type of identifier. A final dataset was created and checks of the anonymised dataset were applied. Lastly, a procedure for release of the data was implemented to complete the process.
We have implemented a practical solution to the data anonymisation process resulting in a bespoke anonymised dataset for a recently completed trial. We have gained useful learnings in terms of efficiency of the process going forward, the need to balance anonymity with data utilisation and future work that should be undertaken.
Background:
Novel rationales for randomizing clusters rather than individuals appear to be emerging from the push for more pragmatic trials, for example, to facilitate trial recruitment, reduce the ...costs of research, and improve external validity. Such rationales may be driven by a mistaken perception that choosing cluster randomization lessens the need for informed consent. We reviewed a random sample of published cluster randomized trials involving only individual-level health care interventions to determine (a) the prevalence of reporting a rationale for the choice of cluster randomization; (b) the types of explicit, or if absent, apparent rationales for the use of cluster randomization; (c) the prevalence of reporting patient informed consent for study interventions; and (d) the types of justifications provided for waivers of consent. We considered cluster randomized trials for evaluating exclusively the individual-level health care interventions to focus on clinical trials where individual randomization is only theoretically possible and where there is a general expectation of informed consent.
Methods:
A random sample of 40 cluster randomized trials were identified by implementing a validated electronic search filter in two electronic databases (Ovid MEDLINE and Embase), with two reviewers independently extracting information from each trial. Inclusion criteria were the following: primary report of a cluster randomized trial, evaluating exclusively an individual-level health care intervention, published between 2007 and 2016, and conducted in Canada, the United States, European Union, Australia, or low- and middle-income country settings.
Results:
Twenty-five trials (62.5%, 95% confidence interval = 47.5%–77.5%) reported an explicit rationale for the use of cluster randomization. The most commonly reported rationales were those with logistical or administrative convenience (15 trials, 60%) and those that need to avoid contamination (13 trials, 52%); five trials (20%) were cited rationales related to the push for more pragmatic trials. Twenty-one trials (52.5%, 95% confidence interval = 37%–68%) reported written informed consent for the intervention, two (5%) reported verbal consent, and eight (20%) reported waivers of consent, while in nine trials (22.5%) consent was unclear or not mentioned. Reported justifications for waivers of consent included that study interventions were already used in clinical practice, patients were not randomized individually, and the need to facilitate the pragmatic nature of the trial. Only one trial reported an explicit and appropriate justification for waiver of consent based on minimum criteria in international research ethics guidelines, namely, infeasibility and minimal risk.
Conclusion:
Rationales for adopting cluster over individual randomization and for adopting consent waivers are emerging, related to the need to facilitate pragmatic trials. Greater attention to clear reporting of study design rationales, informed consent procedures, as well as justification for waivers is needed to ensure that such trials meet appropriate ethical standards.
Summary Background Depression is common and is associated with poor outcomes among elderly care-home residents. Exercise is a promising low-risk intervention for depression in this population. We ...tested the hypothesis that a moderate intensity exercise programme would reduce the burden of depressive symptoms in residents of care homes. Methods We did a cluster-randomised controlled trial in care homes in two regions in England; northeast London, and Coventry and Warwickshire. Residents aged 65 years or older were eligible for inclusion. A statistician independent of the study randomised each home (1 to 1·5 ratio, stratified by location, minimised by type of home provider local authority, voluntary, private and care home, private and nursing home and size of home <32 or ≥32 residents) into intervention and control groups. The intervention package included depression awareness training for care-home staff, 45 min physiotherapist-led group exercise sessions for residents (delivered twice weekly), and a whole home component designed to encourage more physical activity in daily life. The control consisted of only the depression awareness training. Researchers collecting follow-up data from individual participants and the participants themselves were inevitably aware of home randomisation because of the physiotherapists' activities within the home. A researcher masked to study allocation coded NHS routine data. The primary outcome was number of depressive symptoms on the geriatric depression scale-15 (GDS-15). Follow-up was for 12 months. This trial is registered with ISRCTN Register, number ISRCTN43769277. Findings Care homes were randomised between Dec 15, 2008, and April 9, 2010. At randomisation, 891 individuals in 78 care homes (35 intervention, 43 control) had provided baseline data. We delivered 3191 group exercise sessions attended on average by five study participants and five non-study residents. Of residents with a GDS-15 score, 374 of 765 (49%) were depressed at baseline; 484 of 765 (63%) provided 12 month follow-up scores. Overall the GDS-15 score was 0·13 (95% CI −0·33 to 0·60) points higher (worse) at 12 months for the intervention group compared with the control group. Among residents depressed at baseline, GDS-15 score was 0·22 (95% CI −0·52 to 0·95) points higher at 6 months in the intervention group than in the control group. In an end of study cross-sectional analysis, including 132 additional residents joining after randomisation, the odds of being depressed were 0·76 (95% CI 0·53 to 1·09) for the intervention group compared with the control group. Interpretation This moderately intense exercise programme did not reduce depressive symptoms in residents of care homes. In this frail population, alternative strategies to manage psychological symptoms are required. Funding National Institute for Health Research Health Technology Assessment.
Perfluorooctanesulfonate (PFOS) is a widely disseminated persistent compound found at low (part-per-billion) concentrations in serum and liver samples from humans and fish-eating wildlife. This study ...investigated the hypotheses that early hepatocellular peroxisomal proliferation and hepatic cellular proliferation are factors in chronic liver response to dietary dosing, that lowering of serum total cholesterol is an early clinical measure of response to treatment, and that liver and serum PFOS concentrations are proportional to dose and cumulative dose after sub-chronic treatment. PFOS was administered in diet as the potassium salt at 0, 0.5, 2.0, 5.0, and 20 parts per million (ppm) to Sprague Dawley rats for 4 or 14 weeks. At 4 weeks, effects included decreased serum glucose and an equivocal (<twofold) increase in hepatic palmitoyl CoA oxidase (PCoAO) activity in 20 ppm dose-group males and elevation of alanine aminotransferase (ALT) in 20 ppm dose-group females. At 14 weeks, the 20 ppm males had increased liver weight, decreased serum cholesterol, increased non-segmented neutrophils, and increased ALT. Relative liver weights and urea nitrogen were increased in both sexes at 14 weeks. Hepatocytic hypertrophy and cytoplasmic vacuolation were observed in the 5 or 20 ppm male and the 20 ppm female dose groups. An increase in hepatic PCoAO activity was not observed at 14 weeks, and the average hepatocyte proliferation index was not increased, although, individual animals had mild increases. Serum and liver PFOS concentrations were proportional to dose and cumulative dose. Serum concentrations were generally higher in females than in males. The liver-to-serum PFOS ratios ranged from approximately 3:1 to 12:1. After 14 weeks, the no-observed-adverse effect level (NOAEL) in males and females was 5 ppm. The NOAEL corresponded to mean serum PFOS concentrations of 44 ppm (μg/ml) in males and 64 ppm in females and mean liver PFOS concentrations of 358 ppm in males and 370 ppm in females. Results for this study: (1) did not provide strong evidence for hepatocellular peroxisomal or cellular proliferation at the doses tested; (2) suggested that lowering of serum total cholesterol may not be the earliest clinically-measurable response to treatment in the rat; and (3) confirmed that serum and liver PFOS concentrations on repeated dosing are proportional to dose and cumulative dose.
Background The information given to people considering taking part in a trial needs to be easy to understand if those people are to become, and then remain, trial participants. However, there is a ...tension between providing comprehensive information and providing information that is comprehensible. User-testing is one method of developing better participant information, and there is evidence that user-tested information is better at informing participants about key issues relating to trials. However, it is not clear if user-testing also leads to changes in the rates of recruitment in trials, compared to standard trial information. As part of a programme of research, we embedded 'studies within a trial' (SWATs) across multiple ongoing trials to see if user-tested materials led to better rates of recruitment. Methods Seven 'host' trials included a SWAT evaluation and randomised their participants to receive routine information sheets generated by the research teams, or information sheets optimised through user-testing. We collected data on trial recruitment and analysed the results across these trials using random effects meta-analysis, with the primary outcome defined as the proportion of participants randomised in a host trial following an invitation to take part. Results Six SWATs (n=27,805) provided data on recruitment. Optimised participant information sheets likely result in little or no difference in recruitment rates (7.2% versus 6.8%, pooled odds ratio = 1.03, 95% CI 0.90 to 1.19, p-value = 0.63, I.sup.2 = 0%). Conclusions Participant information sheets developed through user testing did not improve recruitment rates. The programme of work showed that co-ordinated testing of recruitment strategies using SWATs is feasible and can provide both definitive and timely evidence on the effectiveness of recruitment strategies. Trial registration Healthlines Depression (ISRCTN14172341) Healthlines CVD (ISRCTN27508731) CASPER (ISRCTN02202951) ISDR (ISRCTN87561257) ECLS (NCT01925625) REFORM (ISRCTN68240461) HeLP Diabetes (ISRCTN02123133) Keywords: Recruitment, Information, User-testing, Research methodology, Randomised controlled trial, SWATs
People need high-quality information to make decisions about research participation. Providing information in written format alone is conventional but may not be the most effective and acceptable ...approach. We developed a structure for the presentation of information using multimedia which included generic and trial-specific content. Our aim was to embed 'Studies Within A Trial' (SWATs) across multiple ongoing trials to test whether multimedia presentation of patient information led to better rates of recruitment.
Five trials included a SWAT and randomised their participants to receive a multimedia presentation alongside standard information, or standard written information alone. We collected data on trial recruitment, acceptance and retention and analysed the pooled results using random effects meta-analysis, with the primary outcome defined as the proportion of participants randomised following an invitation to take part.
Five SWATs provided data on the primary outcome of proportion of participants randomised. Multimedia alongside written information results in little or no difference in recruitment rates (pooled odds ratio = 0.96, 95% CI: 0.79 to 1.17, p-value = 0.671, I
= 0%). There was no effect on any other outcomes.
Multimedia alongside written information did not improve trial recruitment rates.
ISRCTN71952900, ISRCTN 06710391, ISRCTN 17160087, ISRCTN05926847, ISRCTN62869767.
In 2016, we published a conceptual framework outlining the conclusions of our work in defining pilot and feasibility studies. Since then, the CONSORT extension to randomised pilot and feasibility ...trials has been published and there have been further developments in the pilot study landscape. In this paper, we revisit and extend our framework to incorporate the various feasibility pathways open to researchers, which include internal pilot studies. We consider, with examples, when different approaches to feasibility and pilot studies are more effective and efficient, taking into account the pragmatic decisions that may need to be made. The ethical issues involved in pilot studies are discussed. We end with a consideration of the funders' perspective in making difficult resource decisions to include feasibility work and the policy implications of these; throughout, we provide examples of the uncertainties and compromises that researchers have to navigate to make progress in the most efficient way.
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