Communicating clinical trial outcomes: Effects of presentation method on physicians’ evaluations of new treatments

Physicians expect a treatment to be more effective when its clinical outcomes are described as relative rather than as absolute risk reductions. We examined whether effects of presentation method (relative vs. absolute risk reduction)
remain when physicians are provided the baseline risk information, a vital piece of statistical information omitted in previous studies. Using a between-subjects design, ninety five physicians were presented the risk reduction associated
with a fictitious treatment for hypertension either as an absolute risk reduction or as a relative risk reduction, with or without including baseline risk information. Physicians reported that the treatment would be more effective and that they would be more willing to prescribe it when its risk reduction was presented to them in relative rather than in absolute terms. The relative risk reduction was perceived as more effective than absolute risk reduction even when the baseline risk information was explicitly reported. We recommend that information about absolute risk reduction be made available to physicians in the reporting of clinical outcomes. Moreover, health professionals should be cognizant of the potential biasing effects of risk information presented in relative risk terms

A randomised comparison of daunorubicin 90mg/m2 vs 60mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients

Modifying induction therapy in AML may improve the remission rate and reduce the risk of relapse thereby improving survival. Escalation of the daunorubicin dose to 90mg/m(2) has shown benefit for some patient subgroups when compared with a dose of 45mg/m(2) and has been recommended as a standard of care. However 60mg/m(2) is widely used and has never been directly compared to 90mg/m(2). As part of the UK NCRI AML17 trial 1206 adults with untreated AML or high risk MDS, mostly under 60 years of age, were randomised to a first induction course of chemotherapy which delivered either 90mg/m(2) or 60mg/m(2) on days 1,3 and 5 combined with cytosine arabinoside. All patients then received a second course which included daunorubicin 50mg/m(2) on days 1,3 and 5. There was no overall difference in complete remission rate (CR) (73% vs 75%, OR1.07 (0.83-1.39), p=0.6) or in any recognised subgroup. The 60 day mortality was increased in the 90mg/m2 arm (10% vs 5% (HR 1.98(1.30-3.02) p=0.001)), which resulted in no difference in overall 2 year survival (59% vs 60%, HR 1.16(0.95-1.43), p=0.15). In exploratory subgroup analysis there was no subgroup which showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. The trial is registered to www.isrctn.com as ISRCTN55675535.

SWAT-1: The effectiveness of a 'site visit' intervention on recruitment rates in a multi-centre randomised trial

Background: Recruitment rates in multi-centre randomised trials often fall below target recruitment rates, causing problems for study outcomes. The Studies Within A Trial (SWAT) Programme, established by the All-Ireland Hub for Trials Methodology Research in collaboration with the Medical Research Council Network of Hubs in the United Kingdom and others, is developing methods for evaluating aspects of trial methodology through the conduct of research within research. A recently published design for a SWAT-1 provides a protocol for evaluating the effect of a site visit by the principal investigator on recruitment in multi-centre trials.

Methods: Using the SWAT-1 design, the effect of a site visit, with the sole purpose of discussing trial recruitment, on recruitment rates in a large multicentre trial in the Republic of Ireland was evaluated. A controlled before and after intervention comparison was used, where the date of the site visit provides the time point for the intervention, and for the comparison to control sites. Site A received the intervention. Site B and Site C acted as the controls. Z-scores for proportions were calculated to determine within site recruitment differences. Odds ratios and 95% confidence intervals were calculated to determine between site recruitment differences.

Results: Recruitment rates were increased in Site A post-intervention (17% and 14% percentage point increases at 1 and 3 months, respectively). No differences in recruitment occurred in Site B or in Site C. Comparing between site differences, at 3 months post-intervention, a statistically significant difference was detected in favour of higher recruitment in Site A (34% versus 25%; odds ratio 1.57, 95% confidence interval 1.09 to 2.26).

Conclusions: This is the first reported example of a study in the SWAT programme.. It provides evidence that a site visit, combined with a scheduled meeting, increases recruitment in a clinical trial. Using this example, other researchers might be encouraged to consider conducting a similar study, allowing the findings of future SWAT-1s to be compared and combined, so that higher level evidence on the effect of a site visit by the principal investigator can be obtained.

Evaluating early administration of the hydroxymethylglutaryl-CoA reductase inhibitor simvastatin in the prevention and treatment of delirium in critically ill ventilated patients (MoDUS trial): Study protocol for a randomized controlled trial

Background: The incidence of delirium in ventilated patients is estimated at up to 82%, and it is associated with longer intensive care and hospital stays, and long-term cognitive impairment and mortality. The pathophysiology of delirium has been linked with inflammation and neuronal apoptosis. Simvastatin has pleiotropic properties; it penetrates the brain and, as well as reducing cholesterol, reduces inflammation when used at clinically relevant doses over the short term. This is a single centre randomised, controlled trial which aims to test the hypothesis that treatment with simvastatin will modify delirium incidence and outcomes. 

Methods/Design: The ongoing study will include 142 adults admitted to the Watford General Hospital Intensive Care Unit who require mechanical ventilation in the first 72 hours of admission. The primary outcome is the number of delirium- and coma-free days in the first 14 days. Secondary outcomes include incidence of delirium, delirium- and coma-free days in the first 28 days, days in delirium and in coma at 14 and 28 days, number of ventilator-free days at 28 days, length of critical care and hospital stay, mortality, cognitive decline and healthcare resource use. Informed consent will be taken from patient's consultee before randomisation to receive either simvastatin (80 mg) or placebo once daily. Daily data will be recorded until day 28 after randomisation or until discharge from the ICU if sooner. Surviving patients will be followed up on at six months from discharge. Plasma and urine samples will be taken to investigate the biological effect of simvastatin on systemic markers of inflammation, as related to the number of delirium- and coma-free days, and the potential of cholinesterase activity and beta-amyloid as predictors of the risk of delirium and long-term cognitive impairment. 

Discussion: This trial will test the efficacy of simvastatin on reducing delirium in the critically ill. If patients receiving the statin show a reduced number of days in delirium compared with the placebo group, the inflammatory theory implicated in the pathogenesis of delirium will be strengthened. 

Tooth replacement for partially dentate elders: a randomised controlled trial

Objective: This study aimed to compare two different tooth replacement strategies for partially dentate older patients namely; removable partial dentures (RPDs) and functionally orientated treatment based on the shortened dental arch (SDA) concept. Method: 88 partially dentate older patients (mean age 69.4 years) completed a randomised controlled clinical trial. 43 patients received RPDs and 45 received functionally orientated treatment where resin bonded bridgework was used to provide 10 pairs of occluding contacts. Patients were followed for 1 year after treatment intervention. The impact of treatment on oral health-related quality of life (OHrQOL) and cost effectiveness were used as outcome measures. Each patient completed the short form of the Oral Health Impact Profile (OHIP-14) at baseline, 6 months and 1 year after treatment intervention. All costs involved in providing and maintaining each intervention were recorded including dental laboratory bills, materials and professional time. Result: Both the RPD (p=0.004) and the functionally orientated (p<0.001) treatment groups demonstrated statistically significant improvements in OHrQOL 1 year after treatment intervention. On average 9.4 visits were required to complete and maintain the RPDs over the 1 year period as compared to 5.3 visits for the functionally orientated group. The average laboratory cost for the RPDs was $537.45 per patient versus $367.89 for functionally orientated treatment. The cost of achieving the Minimally Important Difference of 5 scale points in OHIP-14 score with RPDs was $732.17. For the functionally orientated group the cost was $356.88. Therefore, functionally orientated treatment was more than twice as cost effective (1:2.05). Conclusion: For partially dentate older patients, functionally orientated treatment based on the SDA concept resulted in sustained, significant improvements in OHrQOL. Provision of functionally orientated treatment was also more than twice as cost effective compared to conventional treatment using RPDs.

Health professionals' and service users' perspectives of shared care for monitoring wet age-related macular degeneration: a qualitative study alongside the ECHoES trial

Objectives: To explore the views of eye health professionals and service users on shared community and hospital care for wet or neovascular age-related macular degeneration (nAMD).

Method: Using maximum variation sampling, 5 focus groups and 10 interviews were conducted with 23 service users and 24 eye health professionals from across the UK (consisting of 8 optometrists, 6 ophthalmologists, 6 commissioners, 2 public health representatives and 2 clinical eye care advisors to local Clinical Commissioning Groups). Data were transcribed verbatim and analysed thematically using constant comparative techniques derived from grounded theory methodology.

Results: The needs and preferences of those with nAMD appear to be at odds with the current service being provided. There was enthusiasm among health professionals and service users about the possibility of shared care for nAMD as it was felt to have the potential to relieve hospital eye service burden and represent a more patient-centred option, but there were a number of perceived barriers to implementation. Some service users and ophthalmologists voiced concerns about optometrist competency and the potential for delays with referrals to secondary care if stable nAMD became active again. The health professionals were divided as to whether shared care was financially more efficient than the current model of care. Specialist training for optometrists, under the supervision of ophthalmologists, was deemed to be the most effective method of training and was perceived to have the potential to improve the communication and trust that shared care would require.

Conclusions: While shared care is perceived to represent a promising model of nAMD care, voiced concerns suggest that there would need to be greater collaboration between ophthalmology and optometry, in terms of interprofessional trust and communication.

A pilot randomised controlled trial (RCT) investigating the effectiveness of reflexology for managing pregnancy low back and/or pelvic pain.

any pregnant women with low back and/or pelvic pain (LBPP) use pain medications to manage this pain, much of which is self-prescribed and potentially harmful. Therefore, there is a need to find effective nonpharmacological treatments for the condition. Reflexology has previously been shown to help nonspecific low back pain. Therefore; a pilot RCT was conducted investigating reflexology in the management of pregnancy-LBPP. 90 primiparous women were randomised to either usual care, a reflexology or footbath intervention. Primary outcome measures were; the Pain Visual Analogue Scale (VAS). 64 women completed the RCT; retention rates for the reflexology group were 80%, usual care group 83.33% and footbath group 50%. The reflexology group demonstrated a Clinically Important Change (CIC) in pain frequency (1.64 cm). Results indicate it is feasible to conduct an RCT in this area, although a footbath is an unsuitable sham treatment. Reflexology may help manage pregnancy-LBPP; however a fully powered trial is needed to confirm this.

THE SAAF STUDY: evaluation of the Safeguarding Children Assessment and Analysis Framework (SAAF), compared with management as usual, for improving outcomes for children and young people who have experienced, or are at risk of, maltreatment: study protocol for a randomised controlled trial

Background: Serious case reviews and research studies have indicated weaknesses in risk assessments conducted by child protection social workers. Social workers are adept at gathering information but struggle with analysis and assessment of risk. The Department for Education wants to know if the use of a structured decision-making tool can improve child protection assessments of risk.

Methods/design: This multi-site, cluster-randomised trial will assess the effectiveness of the Safeguarding Children Assessment and Analysis Framework (SAAF). This structured decision-making tool aims to improve social workers' assessments of harm, of future risk and parents' capacity to change. The comparison is management as usual.

Inclusion criteria: Children's Services Departments (CSDs) in England willing to make relevant teams available to be randomised, and willing to meet the trial's training and data collection requirements.

Exclusion criteria: CSDs where there were concerns about performance; where a major organisational restructuring was planned or under way; or where other risk assessment tools were in use.

Six CSDs are participating in this study. Social workers in the experimental arm will receive 2 days training in SAAF together with a range of support materials, and access to limited telephone consultation post-training. The primary outcome is child maltreatment. This will be assessed using data collected nationally on two key performance indicators: the first is the number of children in a year who have been subject to a second Child Protection Plan (CPP); the second is the number of re-referrals of children because of related concerns about maltreatment. Secondary outcomes are: i) the quality of assessments judged against a schedule of quality criteria and ii) the relationship between the three assessments required by the structured decision-making tool (level of harm, risk of (re) abuse and prospects for successful intervention).

Discussion: This is the first study to examine the effectiveness of SAAF. It will contribute to a very limited literature on the contribution that structured decision-making tools can make to improving risk assessment and case planning in child protection and on what is involved in their effective implementation.

Parents’ and young people’s involvement in designing a trial of ventilator weaning

Consulting with users is considered best practice and is highly recommended in designing new trials. As part of our feasibility work, we undertook a consultation exercise with parents, ex-patients and young people prior to designing a trial of protocol-based ventilator weaning. Our aims were to (1) ascertain views on the relevance and importance of the trial; (2) determine the important parent/patient outcome measures; and (3) ascertain views on informed consent in a cluster randomized controlled trial. We conducted audio-recorded face-to-face, telephone and focus group interviews with parents and young people. Data were content analysed to generate information to address our specific consultation objectives. The setting was the north-western region of England. A total of 16 participants were interviewed: 2 parents of paediatric intensive care unit (PICU) survivors; 1 PICU survivor; and 13 young people from the former Medicines for Children Research Network. The trial objectives were deemed important and relevant, and participants considered the most important outcome measure to be the length of time on ventilation. Parents and young people did not consider written informed consent to be a necessary requirement in the context of this trial, rather awareness of unit participation in the trial was important with the opportunity of opting out of data collection. This consultation provided useful, pragmatic insights to inform trial design. We encountered significant challenges in recruiting parents and young people for this consultation exercise, and novel recruitment methods need to be considered for future work in this field. Patient and public involvement is essential to ensure that future trials answer parent-relevant questions and have meaningful outcome measures, as well as involving parents and young people in the general development of health care services.

Core Outcomes in Ventilation Trials (COVenT): protocol for a core outcome set using a Delphi survey with a nested randomised trial and observational cohort study

Background
Among clinical trials of interventions that aim to modify time spent on mechanical ventilation for critically ill patients there is considerable inconsistency in chosen outcomes and how they are measured. The Core Outcomes in Ventilation Trials (COVenT) study aims to develop a set of core outcomes for use in future ventilation trials in mechanically ventilated adults and children.

Methods/design
We will use a mixed methods approach that incorporates a randomised trial nested within a Delphi study and a consensus meeting. Additionally, we will conduct an observational cohort study to evaluate uptake of the core outcome set in published studies at 5 and 10 years following core outcome set publication. The three-round online Delphi study will use a list of outcomes that have been reported previously in a review of ventilation trials. The Delphi panel will include a range of stakeholder groups including patient support groups. The panel will be randomised to one of three feedback methods to assess the impact of the feedback mechanism on subsequent ranking of outcomes. A final consensus meeting will be held with stakeholder representatives to review outcomes.

Discussion
The COVenT study aims to develop a core outcome set for ventilation trials in critical care, explore the best Delphi feedback mechanism for achieving consensus and determine if participation increases use of the core outcome set in the long term.

Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy:a randomized controlled trial

Background: Small adenomas may be missed during colonoscopy, but chromoscopy has been reported to enhance detection. The aim of this randomized-controlled trial was to determine the effect of total colonic dye spray on adenoma detection during routine colonoscopy.

Methods: Consecutive outpatients undergoing routine colonoscopy were randomized to a dye-spray group (0.1% indigo carmine used to coat the entire colon during withdrawal from the cecum) or control group (no dye).

Results: Two hundred fifty-nine patients were randomized, 124 to the dye-spray and 135 to the control group; demographics, indication for colonoscopy, and quality of the preparation were similar between the groups. Extubation from the cecum took a median of 9:05 minutes (range: 2:4824:44 min) in the dye-spray group versus 4:52 minutes (range: 1:42-15:21 min] in the control group (p <0.0001). The proportion of patients with at least 1 adenoma and the total number of adenomas were not different between groups. However, in the dye-spray group significantly more diminutive adenomas (

Conclusions: Dye-spray increases the detection of small adenomas in the proximal colon and patients with multiple adenomas, but long-term outcomes should be studied to determine the clinical value of these findings.

Effectiveness of a Multifaceted Intervention for Potentially Inappropriate Prescribing in Older Patients in Primary Care: A Cluster-Randomized Controlled Trial (OPTI-SCRIPT Study)

PURPOSE Potentially inappropriate prescribing (PIP) is common in older people and can result in increased morbidity, adverse drug events, and hospitalizations. The OPTI-SCRIPT study (Optimizing Prescribing for Older People in Primary Care, a cluster-randomized controlled trial) tested the effectiveness of a multifaceted intervention for reducing PIP in primary care.

METHODS We conducted a cluster-randomized controlled trial among 21 general practitioner practices and 196 patients with PIP. Intervention participants received a complex, multifaceted intervention incorporating academic detailing; review of medicines with web-based pharmaceutical treatment algorithms that provide recommended alternative-treatment options; and tailored patient information leaflets. Control practices delivered usual care and received simple, patient-level PIP feedback. Primary outcomes were the proportion of patients with PIP and the mean number of potentially inappropriate prescriptions. We performed intention-to-treat analysis using random-effects regression.

RESULTS All 21 practices and 190 patients were followed. At intervention completion, patients in the intervention group had significantly lower odds of having PIP than patients in the control group (adjusted odds ratio = 0.32; 95% CI, 0.15–0.70; P = .02). The mean number of PIP drugs in the intervention group was 0.70, compared with 1.18 in the control group (P = .02). The intervention group was almost one-third less likely than the control group to have PIP drugs at intervention completion, but this difference was not significant (incidence rate ratio = 0.71; 95% CI, 0.50–1.02; P = .49). The intervention was effective in reducing proton pump inhibitor prescribing (adjusted odds ratio = 0.30; 95% CI, 0.14–0.68; P = .04).

CONCLUSIONS The OPTI-SCRIPT intervention incorporating academic detailing with a pharmacist, and a review of medicines with web-based pharmaceutical treatment algorithms, was effective in reducing PIP, particularly in modifying prescribing of proton pump inhibitors, the most commonly occurring PIP drugs nationally.

Effect of a Web-Based Behavior Change Program on Weight Loss and Cardiovascular Risk Factors in Overweight and Obese Adults at High Risk of Developing Cardiovascular Disease:Randomized Controlled Trial

BACKGROUND: Web-based programs are a potential medium for supporting weight loss because of their accessibility and wide reach. Research is warranted to determine the shorter- and longer-term effects of these programs in relation to weight loss and other health outcomes.

OBJECTIVE: The aim was to evaluate the effects of a Web-based component of a weight loss service (Imperative Health) in an overweight/obese population at risk of cardiovascular disease (CVD) using a randomized controlled design and a true control group.

METHODS: A total of 65 overweight/obese adults at high risk of CVD were randomly allocated to 1 of 2 groups. Group 1 (n=32) was provided with the Web-based program, which supported positive dietary and physical activity changes and assisted in managing weight. Group 2 continued with their usual self-care (n=33). Assessments were conducted face-to-face. The primary outcome was between-group change in weight at 3 months. Secondary outcomes included between-group change in anthropometric measurements, blood pressure, lipid measurements, physical activity, and energy intake at 3, 6, and 12 months. Interviews were conducted to explore participants' views of the Web-based program.

RESULTS: Retention rates for the intervention and control groups at 3 months were 78% (25/32) vs 97% (32/33), at 6 months were 66% (21/32) vs 94% (31/33), and at 12 months were 53% (17/32) vs 88% (29/33). Intention-to-treat analysis, using baseline observation carried forward imputation method, revealed that the intervention group lost more weight relative to the control group at 3 months (mean -3.41, 95% CI -4.70 to -2.13 kg vs mean -0.52, 95% CI -1.55 to 0.52 kg, P<.001), at 6 months (mean -3.47, 95% CI -4.95 to -1.98 kg vs mean -0.81, 95% CI -2.23 to 0.61 kg, P=.02), but not at 12 months (mean -2.38, 95% CI -3.48 to -0.97 kg vs mean -1.80, 95% CI -3.15 to -0.44 kg, P=.77). More intervention group participants lost ≥5% of their baseline body weight at 3 months (34%, 11/32 vs 3%, 1/33, P<.001) and 6 months (41%, 13/32 vs 18%, 6/33, P=.047), but not at 12 months (22%, 7/32 vs 21%, 7/33, P=.95) versus control group. The intervention group showed improvements in total cholesterol, triglycerides, and adopted more positive dietary and physical activity behaviors for up to 3 months verus control; however, these improvements were not sustained.

CONCLUSIONS: Although the intervention group had high attrition levels, this study provides evidence that this Web-based program can be used to initiate clinically relevant weight loss and lower CVD risk up to 3-6 months based on the proportion of intervention group participants losing ≥5% of their body weight versus control group. It also highlights a need for augmenting Web-based programs with further interventions, such as in-person support to enhance engagement and maintain these changes.