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1.  Access to weight reduction interventions for overweight and obese patients in UK primary care: population-based cohort study 
BMJ Open  2015;5(1):e006642.
To investigate access to weight management interventions for overweight and obese patients in primary care.
UK primary care electronic health records.
A cohort of 91 413 overweight and obese patients aged 30–100 years was sampled from the Clinical Practice Research Datalink (CPRD). Patients with body mass index (BMI) values ≥25 kg/m2 recorded between 2005 and 2012 were included. BMI values were categorised using WHO criteria.
Interventions for body weight management, including advice, referrals and prescription of antiobesity drugs, were evaluated.
Primary and secondary outcome measures
The rate of body weight management interventions and time to intervention were the main outcomes.
Data were analysed for 91 413 patients, mean age 56 years, including 55 094 (60%) overweight and 36 319 (40%) obese, including 4099 (5%) with morbid obesity. During the study period, 90% of overweight patients had no weight management intervention recorded. Intervention was more frequent among obese patients, but 59% of patients with morbid obesity had no intervention recorded. Rates of intervention increased with BMI category. In morbid obesity, rates of intervention per 1000 patient years were: advice, 60.2 (95% CI 51.8 to 70.4); referral, 75.7 (95% CI 69.5 to 82.6) and antiobesity drugs 89.9 (95% CI 85.0 to 95.2). Weight management interventions were more often accessed by women, older patients, those with comorbidity and those in deprivation. Follow-up of body weight subsequent to interventions was infrequent.
Limited evidence of weight management interventions in primary care electronic health records may result from poor recording of advice given, but may indicate a lack of patient access to appropriate body weight management interventions in primary care.
PMCID: PMC4316417  PMID: 25586371
2.  A multicentre phase III randomised controlled single-masked clinical trial evaluating the clinical efficacy and safety of light-masks at preventing dark-adaptation in the treatment of early diabetic macular oedema (CLEOPATRA): study protocol for a randomised controlled trial 
Trials  2014;15(1):458.
This study will evaluate hypoxia, as a novel concept in the pathogenesis of diabetic macular oedema (DMO). As the oxygen demand of the eye is maximum during dark-adaptation, we hypothesize that wearing light-masks during sleep will cause regression and prevent the development and progression of DMO. The study protocol comprises both an efficacy and mechanistic evaluation to test this hypothesis.
This is a phase III randomised controlled single-masked multicentre clinical trial to test the clinical efficacy of light-masks at preventing dark-adaptation in the treatment of non-central DMO. Three hundred patients with non-centre-involving DMO in at least one eye will be randomised 1:1 to light-masks and control masks (with no light) to be used during sleep at night for a period of 24 months. The primary outcome is regression of non-central oedema by assessing change in the zone of maximal retinal thickness at baseline on optical coherence tomography (SD-OCT). Secondary outcomes will evaluate the prevention of development and progression of DMO by assessing changes in retinal thickness in different regions of the macula, macular volume, refracted visual acuity and level of retinopathy. Safety parameters will include sleep disturbance. Adverse events and measures of compliance will be assessed over 24 months. Participants recruited to the mechanistic sub-study will have additional retinal oximetry, multifocal electroretinography (ERG) and microperimetry to evaluate the role of hypoxia by assessing and comparing changes induced by supplemental oxygen and the light-masks at 12 months.
The outcomes of this study will provide insight into the pathogenesis of DMO and provide evidence on whether a simple, non-invasive device in the form of a light-mask can help prevent the progression to centre-involving DMO and visual impairment in people with diabetes.
PMCID: PMC4255925  PMID: 25417120
3.  Is a specialist breathlessness service more effective and cost-effective for patients with advanced cancer and their carers than standard care? Findings of a mixed-method randomised controlled trial 
BMC Medicine  2014;12(1):194.
Breathlessness is common in advanced cancer. The Breathlessness Intervention Service (BIS) is a multi-disciplinary complex intervention theoretically underpinned by a palliative care approach, utilising evidence-based non-pharmacological and pharmacological interventions to support patients with advanced disease. We sought to establish whether BIS was more effective, and cost-effective, for patients with advanced cancer and their carers than standard care.
A single-centre Phase III fast-track single-blind mixed-method randomised controlled trial (RCT) of BIS versus standard care was conducted. Participants were randomised to one of two groups (randomly permuted blocks). A total of 67 patients referred to BIS were randomised (intervention arm n = 35; control arm n = 32 received BIS after a two-week wait); 54 completed to the key outcome measurement. The primary outcome measure was a 0 to 10 numerical rating scale for patient distress due to breathlessness at two-weeks. Secondary outcomes were evaluated using the Chronic Respiratory Questionnaire, Hospital Anxiety and Depression Scale, Client Services Receipt Inventory, EQ-5D and topic-guided interviews.
BIS reduced patient distress due to breathlessness (primary outcome: −1.29; 95% CI −2.57 to −0.005; P = 0.049) significantly more than the control group; 94% of respondents reported a positive impact (51/53). BIS reduced fear and worry, and increased confidence in managing breathlessness. Patients and carers consistently identified specific and repeatable aspects of the BIS model and interventions that helped. How interventions were delivered was important. BIS legitimised breathlessness and increased knowledge whilst making patients and carers feel ‘not alone’. BIS had a 66% likelihood of better outcomes in terms of reduced distress due to breathlessness at lower health/social care costs than standard care (81% with informal care costs included).
BIS appears to be more effective and cost-effective in advanced cancer than standard care.
Trial registration
RCT registration at NCT00678405 (May 2008) and Current Controlled Trials ISRCTN04119516 (December 2008).
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0194-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4222435  PMID: 25358424
Breathlessness; Cancer; Advanced disease; Randomised controlled trial; Complex intervention; Mixed methods
4.  Effectiveness of behavioural weight loss interventions delivered in a primary care setting: a systematic review and meta-analysis 
Family Practice  2014;31(6):643-653.
Overweight and obesity have negative health effects. Primary care clinicians are best placed to intervene in weight management. Previous reviews of weight loss interventions have included studies from specialist settings. The aim of this review was to estimate the effect of behavioural interventions delivered in primary care on body weight in overweight and obese adults.
The review included randomized controlled trials (RCTs) of behavioural interventions in obese or overweight adult participants in a primary care setting, with weight loss as the primary outcome, and a minimum of 12 months of follow-up. A systematic search strategy was implemented in Medline, Embase, Web of Science and the Cochrane Central Registry of Controlled Trials. Risk of bias was assessed using the Cochrane Risk of Bias tool and behavioural science components of interventions were evaluated. Data relating to weight loss in kilograms were extracted, and the results combined using meta-analysis.
Fifteen RCTs, with 4539 participants randomized, were selected for inclusion. The studies were heterogeneous with respect to inclusion criteria and type of intervention. Few studies reported interventions informed by behavioural science theory. Pooled results from meta-analysis indicated a mean weight loss of −1.36kg (−2.10 to −0.63, P < 0.0001) at 12 months, and −1.23kg (−2.28 to −0.18, P = 0.002) at 24 months.
Behavioural weight loss interventions in primary care yield very small reductions in body weight, which are unlikely to be clinically significant. More effective management strategies are needed for the treatment of overweight and obesity.
PMCID: PMC4240316  PMID: 25298510
General practice; obesity; overweight; primary health care.
5.  Predicting adverse drug reactions in older adults; a systematic review of the risk prediction models 
Adverse drug reaction (ADR) risk-prediction models for use in older adults have been developed, but it is not clear if they are suitable for use in clinical practice. This systematic review aimed to identify and investigate the quality of validated ADR risk-prediction models for use in older adults. Standard computerized databases, the gray literature, bibliographies, and citations were searched (2012) to identify relevant peer-reviewed studies. Studies that developed and validated an ADR prediction model for use in patients over 65 years old, using a multivariable approach in the design and analysis, were included. Data were extracted and their quality assessed by independent reviewers using a standard approach. Of the 13,423 titles identified, only 549 were associated with adverse outcomes of medicines use. Four met the inclusion criteria. All were conducted in inpatient cohorts in Western Europe. None of the models satisfied the four key stages in the creation of a quality risk prediction model; development and validation were completed, but impact and implementation were not assessed. Model performance was modest; area under the receiver operator curve ranged from 0.623 to 0.73. Study quality was difficult to assess due to poor reporting, but inappropriate methods were apparent. Further work needs to be conducted concerning the existing models to enable the development of a robust ADR risk-prediction model that is externally validated, with practical design and good performance. Only then can implementation and impact be assessed with the aim of generating a model of high enough quality to be considered for use in clinical care to prioritize older people at high risk of suffering an ADR.
PMCID: PMC4178502  PMID: 25278750
aged; stratified care; prognosis; medication-related harm
6.  Development and evaluation of a brief self-completed family history screening tool for common chronic disease prevention in primary care 
The British Journal of General Practice  2013;63(611):e393-e400.
Family history is an important risk factor for many common chronic diseases, but it remains underutilised for diagnostic assessment and disease prevention in routine primary care.
To develop and validate a brief self-completed family history questionnaire (FHQ) for systematic primary care assessment for family history of diabetes, ischaemic heart disease, breast cancer, and colorectal cancer.
Design and setting
Two-stage diagnostic validation study in 10 general practices in eastern England.
Participants aged 18–50 years were identified via random sampling from electronic searches of general practice records. Participants completed a FHQ then had a three-generational ‘gold standard’ pedigree taken, to determine disease risk category. In stage 1, the FHQ comprised 12 items; in stage 2 the shorter 6-item FHQ was validated against the same ‘gold standard’.
There were 1147 participants (stage 1: 618; stage 2: 529). Overall, 32% were at increased risk of one or more marker conditions (diabetes 18.9%, ischaemic heart disease 13.3%, breast cancer 6.2%, colorectal cancer 2.2%). The shorter 6-item FHQ performed very well for all four conditions: pooled data from both stages show diabetes, sensitivity = 98%, specificity = 94%; ischaemic heart disease, sensitivity = 93%, specificity = 81%; breast cancer, sensitivity = 81%, specificity = 83%; colorectal cancer, sensitivity = 96%, specificity = 88%, with an area under the receiver operating characteristic curve of 0.90 for males and 0.89 for females.
This brief self-completed FHQ shows good diagnostic accuracy for identifying people at higher risk of four common chronic diseases. It could be used in routine primary care to identify patients who would be most likely to benefit from a more detailed pedigree and risk assessment, and consequent management strategies.
PMCID: PMC3662456  PMID: 23735410
breast cancer; colorectal cancer; ischaemic heart disease; diabetes mellitus, type 2; family history; primary health care; risk assessment
7.  Using the 7-point checklist as a diagnostic aid for pigmented skin lesions in general practice: a diagnostic validation study 
The British Journal of General Practice  2013;63(610):e345-e353.
GPs need to recognise significant pigmented skin lesions, given rising UK incidence rates for malignant melanoma. The 7-point checklist (7PCL) has been recommended by NICE (2005) for routine use in UK general practice to identify clinically significant lesions which require urgent referral.
To validate the Original and Weighted versions of the 7PCL in the primary care setting.
Design and setting
Diagnostic validation study, using data from a SIAscopic diagnostic aid randomised controlled trial in eastern England.
Adults presenting in general practice with a pigmented skin lesion that could not be immediately diagnosed as benign were recruited into the trial. Reference standard diagnoses were histology or dermatology expert opinion; 7PCL scores were calculated blinded to the reference diagnosis. A case was defined as a clinically significant lesion for primary care referral to secondary care (total 1436 lesions: 225 cases, 1211 controls); or melanoma (36).
For diagnosing clinically significant lesions there was a difference between the performance of the Original and Weighted 7PCLs (respectively, area under curve: 0.66, 0.69, difference = 0.03, P<0.001). For the identification of melanoma, similar differences were found. Increasing the Weighted 7PCL’s cut-off score from recommended 3 to 4 improved detection of clinically significant lesions in primary care: sensitivity 73.3%, specificity 57.1%, positive predictive value 24.1%, negative predictive value 92.0%, while maintaining high sensitivity of 91.7% and moderate specificity of 53.4% for melanoma.
The Original and Weighted 7PCLs both performed well in a primary care setting to identify clinically significant lesions as well as melanoma. The Weighted 7PCL, with a revised cut-off score of 4 from 3, performs slightly better and could be applied in general practice to support the recognition of clinically significant lesions and therefore the early identification of melanoma.
PMCID: PMC3635581  PMID: 23643233
diagnostic techniques and procedures; general practice; melanoma; pigmented skin lesions
8.  Multiple behaviour change intervention and outcomes in recently diagnosed type 2 diabetes: the ADDITION-Plus randomised controlled trial 
Diabetologia  2014;57(7):1308-1319.
The aim of this study was to assess whether or not a theory-based behaviour change intervention delivered by trained and quality-assured lifestyle facilitators can achieve and maintain improvements in physical activity, dietary change, medication adherence and smoking cessation in people with recently diagnosed type 2 diabetes.
An explanatory randomised controlled trial was conducted in 34 general practices in Eastern England (Anglo–Danish–Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care-Plus [ADDITION-Plus]). In all, 478 patients meeting eligibility criteria (age 40 to 69 years with recently diagnosed screen or clinically detected diabetes) were individually randomised to receive either intensive treatment (n = 239) or intensive treatment plus a theory-based behaviour change intervention led by a facilitator external to the general practice team (n = 239). Randomisation was central and independent using a partial minimisation procedure to balance stratifiers between treatment arms. Facilitators taught patients skills to facilitate change in and maintenance of key health behaviours, including goal setting, self-monitoring and building habits. Primary outcomes included physical activity energy expenditure (individually calibrated heart rate monitoring and movement sensing), change in objectively measured fruit and vegetable intake (plasma vitamin C), medication adherence (plasma drug levels) and smoking status (plasma cotinine levels) at 1 year. Measurements, data entry and laboratory analysis were conducted with staff unaware of participants’ study group allocation.
Of 475 participants still alive, 444 (93%; intervention group 95%, comparison group 92%) attended 1-year follow-up. There were no significant differences between groups in physical activity (difference: +1.50 kJ kg−1 day−1; 95% CI −1.74, 4.74), plasma vitamin C (difference: −3.84 μmol/l; 95% CI −8.07, 0.38), smoking (OR 1.37; 95% CI 0.77, 2.43) and plasma drug levels (difference in metformin levels: −119.5 μmol/l; 95% CI −335.0, 95.9). Cardiovascular risk factors and self-reported behaviour improved in both groups with no significant differences between groups.
For patients with recently diagnosed type 2 diabetes receiving intensive treatment in UK primary care, a facilitator-led individually tailored behaviour change intervention did not improve objectively measured health behaviours or cardiovascular risk factors over 1 year.
Trial registration
The trial is supported by the Medical Research Council, the Wellcome Trust, National Health Service R&D support funding (including the Primary Care Research and Diabetes Research Networks) and National Institute of Health Research under its Programme Grants for Applied Research scheme. The Primary Care Unit is supported by NIHR Research funds. Bio-Rad provided equipment for HbA1c testing during the screening phase.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3236-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC4052009  PMID: 24759957
ADDITION-Plus; Diabetes; General practice; Health behaviour; Randomised trial
9.  Does Electronic Monitoring Influence Adherence to Medication? Randomized Controlled Trial of Measurement Reactivity 
Annals of Behavioral Medicine  2014;48(3):293-299.
Electronic monitoring is recommended for accurate measurement of medication adherence but a possible limitation is that it may influence adherence.
To test the reactive effect of electronic monitoring in a randomized controlled trial.
A total of 226 adults with type 2 diabetes and HbA1c ≥58 mmol/mol were randomized to receiving their main oral glucose lowering medication in electronic containers or standard packaging. The primary outcomes were self-reported adherence measured with the MARS (Medication Adherence Report Scale; range 5–25) and HbA1c at 8 weeks.
Non-significantly higher adherence and lower HbA1c were observed in the electronic container group (differences in means, adjusting for baseline value: MARS, 0.4 [95 % CI −0.1 to 0.8, p = 0.11]; HbA1c (mmol/mol), −1.02 [−2.73 to 0.71, p = 0.25]).
Electronic containers may lead to a small increase in adherence but this potential limitation is outweighed by their advantages. Our findings support electronic monitoring as the method of choice in research on medication adherence. (Trial registration Current Controlled Trials ISRCT N30522359)
PMCID: PMC4223537  PMID: 24573909
Measurement reactivity; Medication adherence; Electronic monitoring; Diabetes
10.  Effectiveness of interventions to promote healthy diet in primary care: systematic review and meta-analysis of randomised controlled trials 
BMC Public Health  2013;13:1203.
A diet rich in fruit, vegetables and dietary fibre and low in fat is associated with reduced risk of chronic disease. This review aimed to estimate the effectiveness of interventions to promote healthy diet for primary prevention among participants attending primary care.
A systematic review of trials using individual or cluster randomisation of interventions delivered in primary care to promote dietary change over 12 months in healthy participants free from chronic disease or defined high risk states. Outcomes were change in fruit and vegetable intake, consumption of total fat and fibre and changes in serum cholesterol concentration.
Ten studies were included with 12,414 participants. The design and delivery of interventions were diverse with respect to grounding in behavioural theory and intervention intensity. A meta-analysis of three studies showed an increase in fruit consumption of 0.25 (0.01 to 0.49) servings per day, with an increase in vegetable consumption of 0.25 (0.06 to 0.44) serving per day. A further three studies that reported on fruit and vegetable consumption together showed a pooled increment of 0.50 (0.13 to 0.87) servings per day. The pooled effect on consumption of dietary fibre, from four studies, was estimated to be 1.97 (0.43 to 3.52) gm fibre per day. Data from five studies showed a mean decrease in total fat intake of 5.2% of total energy (1.5 to 8.8%). Data from three studies showed a mean decrease in serum cholesterol of 0.10 (-0.19 to 0.00) mmol/L.
Presently-reported interventions to promote healthy diet for primary prevention in primary care, which illustrate a diverse range of intervention methods, may yield small beneficial changes in consumption of fruit, vegetables, fibre and fat over 12 months. The present results do not exclude the possibility that more effective intervention strategies might be developed.
PMCID: PMC3890643  PMID: 24355095
Diet; Health promotion; Primary care; Systematic review; Meta-analysis
11.  Impact of body mass index on prevalence of multimorbidity in primary care: cohort study 
Family Practice  2013;31(1):38-43.
Multimorbidity is the co-occurrence of long-term conditions. Obesity is associated with an increased risk of long-term conditions including type 2 diabetes and depression.
To quantify the association between body mass index (BMI) category and multimorbidity in a large cohort registered in primary care.
The sample comprised primary care electronic health records of adults aged ≥30 years, sampled from the Clinical Practice Research Datalink between 2005 and 2011. Multimorbidity was defined as the co-occurrence of ≥2 of 11 conditions affecting seven organ systems. Age- and sex-standardized prevalence of multimorbidity was estimated by BMI category. Adjusted odds ratios associating BMI with additional morbidity were estimated adjusting for socioeconomic deprivation and smoking.
The sample comprised 300 006 adults. After excluding participants with BMI never recorded, data were analysed for 223 089 (74%) contributing 1 374 109 person–years. In normal weight men, the standardized prevalence of multimorbidity was 23%, rising to 27% in overweight, 33% in category I obesity, 38% in category II and 44% in category III obesity. In women, the corresponding values were 28%, 34%, 41%, 45% and 51%. In category III obesity, the adjusted odds, relative to normal BMI, were 2.24 (2.13–2.36) for a first condition; 2.63 (2.51–2.76) for a second condition and 3.09 (2.92–3.28) for three or more conditions. In a cross-sectional analysis, 32% of multimorbidity was attributable to overweight and obesity.
Multiple morbidity is highly associated with increasing BMI category and obesity, highlighting the potential for targeted primary and secondary prevention interventions in primary care.
PMCID: PMC3902211  PMID: 24132593
Cardiovascular diseases; comorbidity; diabetes mellitus; family practice; obesity; primary health care.
12.  Integration of Lyoplate Based Flow Cytometry and Computational Analysis for Standardized Immunological Biomarker Discovery 
PLoS ONE  2013;8(7):e65485.
Discovery of novel immune biomarkers for monitoring of disease prognosis and response to therapy in immune-mediated inflammatory diseases is an important unmet clinical need. Here, we establish a novel framework for immunological biomarker discovery, comparing a conventional (liquid) flow cytometry platform (CFP) and a unique lyoplate-based flow cytometry platform (LFP) in combination with advanced computational data analysis. We demonstrate that LFP had higher sensitivity compared to CFP, with increased detection of cytokines (IFN-γ and IL-10) and activation markers (Foxp3 and CD25). Fluorescent intensity of cells stained with lyophilized antibodies was increased compared to cells stained with liquid antibodies. LFP, using a plate loader, allowed medium-throughput processing of samples with comparable intra- and inter-assay variability between platforms. Automated computational analysis identified novel immunophenotypes that were not detected with manual analysis. Our results establish a new flow cytometry platform for standardized and rapid immunological biomarker discovery with wide application to immune-mediated diseases.
PMCID: PMC3701052  PMID: 23843942
13.  Study protocol for iQuit in Practice: a randomised controlled trial to assess the feasibility, acceptability and effectiveness of tailored web- and text-based facilitation of smoking cessation in primary care 
BMC Public Health  2013;13:324.
Primary care is an important setting for smoking cessation interventions. There is evidence for the effectiveness of tailored interventions for smoking cessation, and text messaging interventions for smoking cessation show promise. The intervention to be evaluated in this trial consists of two components: (1) a web-based program designed to be used by a practice nurse or other smoking cessation advisor (SCA); the program generates a cessation advice report that is highly tailored to relevant characteristics of the smoker; and (2) a three-month programme of automated tailored text messages sent to the smoker’s mobile phone. The objectives of the trial are to assess the acceptability and feasibility of the intervention and to estimate the short-term effectiveness of the intervention in increasing the quit rate compared with usual care alone.
The design is a two parallel group randomised controlled trial (RCT). 600 smokers who want to quit will be recruited in up to 30 general practices in the East of England. During a consultation with an SCA, they will be individually randomised by computer program to usual care (Control) or to usual care plus the iQuit system (Intervention). At the four-week follow-up appointment, the SCA will record smoking status and measure carbon monoxide level. There will be two further follow-ups, at eight weeks and six months from randomisation date, by postal questionnaire sent from and returned to the study centre or by telephone interview conducted by a research interviewer. The primary outcome will be self-reported abstinence for at least two weeks at eight weeks. A sample size of 300 per group would give 80% power to detect an increase in quit rate from 20% to 30% (alpha = 0.05, 2-sided test). The main analyses of quit rates will be conducted on an intention-to-treat basis, making the usual assumption that participants lost to follow up are smoking.
This trial will focus on acceptability, feasibility and short-term effectiveness. The findings will be used to refine the intervention and to inform the decision to proceed to a pragmatic trial to estimate longer-term effectiveness and cost-effectiveness.
Trial registration
PMCID: PMC3641973  PMID: 23575031
14.  Testing a peer support intervention for people with type 2 diabetes: a pilot for a randomised controlled trial 
BMC Family Practice  2013;14:5.
People with Type 2 diabetes face various psycho-social, self-management and clinical care issues and evidence is mixed whether support from others with diabetes, ‘peer support’, can help. We now describe a 2 month pilot study of different peer support interventions.
The intervention was informed by formative evaluation using semi-structured interviews with health professionals, community support groups and observation of diabetes education and support groups. Invitations to participate were mailed from 4 general practices and included a survey of barriers to care. Participants were randomized by practice to receive individual, group, combined (both individual and group) or no peer support. Evaluation included ethnographic observation, semi-structured interviews and questionnaires at baseline and post-intervention.
Of 1,101 invited, 15% expressed an interest in participating in the pilot. Sufficient numbers volunteered to become peer supporters, although 50% of these (8/16) withdrew. Those in the pilot were similar to other patients, but were less likely to feel they knew enough about diabetes (60.8% vs 44.6% p = 0.035) and less likely to be happy with the diabetes education/care to date (75.4% vs 55.4% p = 0.013). Key issues identified were the need to recruit peer supporters directly rather than through clinicians, to address participant diabetes educational needs early and the potential for group sessions to have lower participation rates than 1:1 sessions.
Recruitment to a full trial of peer support within the existing study design is feasible with some amendments. Attendance emerged as a key issue needing close monitoring and additional intervention during the trial.
PMCID: PMC3546024  PMID: 23297781
Diabetes; Peer support; Complex intervention; Self-management
15.  Screening for type 2 diabetes and population mortality over 10 years (ADDITION-Cambridge): a cluster-randomised controlled trial 
Lancet  2012;380(9855):1741-1748.
The increasing prevalence of type 2 diabetes poses a major public health challenge. Population-based screening and early treatment for type 2 diabetes could reduce this growing burden. However, uncertainty persists around the benefits of screening for type 2 diabetes. We assessed the effect of a population-based stepwise screening programme on mortality.
In a pragmatic parallel group, cluster-randomised trial, 33 general practices in eastern England were randomly assigned by the method of minimisation in an unbalanced design to: screening followed by intensive multifactorial treatment for people diagnosed with diabetes (n=15); screening plus routine care of diabetes according to national guidelines (n=13); and a no-screening control group (n=5). The study population consisted of 20 184 individuals aged 40–69 years (mean 58 years), at high risk of prevalent undiagnosed diabetes, on the basis of a previously validated risk score. In screening practices, individuals were invited to a stepwise programme including random capillary blood glucose and glycated haemoglobin (HbA1c) tests, a fasting capillary blood glucose test, and a confirmatory oral glucose tolerance test. The primary outcome was all-cause mortality. All participants were flagged for mortality surveillance by the England and Wales Office of National Statistics. Analysis was by intention-to-screen and compared all-cause mortality rates between screening and control groups. This study is registered, number ISRCTN86769081.
Of 16 047 high-risk individuals in screening practices, 15 089 (94%) were invited for screening during 2001–06, 11 737 (73%) attended, and 466 (3%) were diagnosed with diabetes. 4137 control individuals were followed up. During 184 057 person-years of follow up (median duration 9·6 years [IQR 8·9–9·9]), there were 1532 deaths in the screening practices and 377 in control practices (mortality hazard ratio [HR] 1·06, 95% CI 0·90–1·25). We noted no significant reduction in cardiovascular (HR 1·02, 95% CI 0·75–1·38), cancer (1·08, 0·90–1·30), or diabetes-related mortality (1·26, 0·75–2·10) associated with invitation to screening.
In this large UK sample, screening for type 2 diabetes in patients at increased risk was not associated with a reduction in all-cause, cardiovascular, or diabetes-related mortality within 10 years. The benefits of screening might be smaller than expected and restricted to individuals with detectable disease.
Wellcome Trust; UK Medical Research Council; National Health Service research and development support; UK National Institute for Health Research; University of Aarhus, Denmark; Bio-Rad.
PMCID: PMC3607818  PMID: 23040422
16.  Effect on Adherence to Nicotine Replacement Therapy of Informing Smokers Their Dose Is Determined by Their Genotype: A Randomised Controlled Trial 
PLoS ONE  2012;7(4):e35249.
The behavioural impact of pharmacogenomics is untested. We tested two hypotheses concerning the behavioural impact of informing smokers their oral dose of NRT is tailored to analysis of DNA.
Methods and Findings
We conducted an RCT with smokers in smoking cessation clinics (N = 633). In combination with NRT patch, participants were informed that their doses of oral NRT were based either on their mu-opioid receptor (OPRM1) genotype, or their nicotine dependence questionnaire score (phenotype). The proportion of prescribed NRT consumed in the first 28 days following quitting was not significantly different between groups: (68.5% of prescribed NRT consumed in genotype vs 63.6%, phenotype group, difference  =  5.0%, 95% CI −0.9,10.8, p  =  0.098). Motivation to make another quit attempt among those (n  =  331) not abstinent at six months was not significantly different between groups (p  =  0.23). Abstinence at 28 days was not different between groups (p = 0.67); at six months was greater in genotype than phenotype group (13.7% vs 7.9%, difference  =  5.8%, 95% CI 1.0,10.7, p  =  0.018).
Informing smokers their oral dose of NRT was tailored to genotype not phenotype had a small, statistically non-significant effect on 28-day adherence to NRT. Among those still smoking at six months, there was no evidence that saying NRT was tailored to genotype adversely affected motivation to make another quit attempt. Higher abstinence rate at six months in the genotype arm requires investigation.
Trial registration ISRCTN14352545.
PMCID: PMC3324463  PMID: 22509402
17.  An explanatory randomised controlled trial of a nurse-led, consultation-based intervention to support patients with adherence to taking glucose lowering medication for type 2 diabetes 
BMC Family Practice  2012;13:30.
Failure to take medication reduces the effectiveness of treatment leading to increased morbidity and mortality. We evaluated the efficacy of a consultation-based intervention to support objectively-assessed adherence to oral glucose lowering medication (OGLM) compared to usual care among people with type 2 diabetes.
This was a parallel group randomised trial in adult patients with type 2 diabetes and HbA1c≥7.5% (58 mmol/mol), prescribed at least one OGLM. Participants were allocated to a clinic nurse delivered, innovative consultation-based intervention to strengthen patient motivation to take OGLM regularly and support medicine taking through action-plans, or to usual care. The primary outcome was the percentage of days on which the prescribed dose of medication was taken, measured objectively over 12 weeks with an electronic medication-monitoring device (TrackCap, Aardex, Switzerland). The primary analysis was intention-to-treat.
211 patients were randomised between July 1, 2006 and November 30, 2008 in 13 British general practices (primary care clinics). Primary outcome data were available for 194 participants (91.9%). Mean (sd) percentage of adherent days was 77.4% (26.3) in the intervention group and 69.0% (30.8) in standard care (mean difference between groups 8.4%, 95% confidence interval 0.2% to 16.7%, p = 0.044). There was no significant adverse impact on functional status or treatment satisfaction.
This well-specified, theory based intervention delivered in a single session of 30 min in primary care increased objectively measured medication adherence, with no adverse effect on treatment satisfaction. These findings justify a definitive trial of this approach to improving medication adherence over a longer period of time, with clinical and cost-effectiveness outcomes to inform clinical practice.
Trial registration
Current Controlled Trials ISRCTN30522359
PMCID: PMC3499458  PMID: 22480341
Adherence; Brief intervention; Diabetes
18.  Protocol for the OUTREACH trial: a randomised trial comparing delivery of cancer systemic therapy in three different settings - patient's home, GP surgery and hospital day unit 
BMC Cancer  2011;11:467.
The national Cancer Reform Strategy recommends delivering care closer to home whenever possible. Cancer drug treatment has traditionally been administered to patients in specialist hospital-based facilities. Technological developments mean that nowadays, most treatment can be delivered in the out-patient setting. Increasing demand, care quality improvements and patient choice have stimulated interest in delivering some treatment to patients in the community, however, formal evaluation of delivering cancer treatment in different community settings is lacking. This randomised trial compares delivery of cancer treatment in the hospital with delivery in two different community settings: the patient's home and general practice (GP) surgeries.
Patients due to receive a minimum 12 week course of standard intravenous cancer treatment at two hospitals in the Anglia Cancer Network are randomised on a 1:1:1 basis to receive treatment in the hospital day unit (control arm), or their own home, or their choice of one of three neighbouring GP surgeries. Overall patient care, treatment prescribing and clinical review is undertaken according to standard local practice. All treatment is dispensed by the local hospital pharmacy and treatment is delivered by the hospital chemotherapy nurses. At four time points during the 12 week study period, information is collected from patients, nursing staff, primary and secondary care teams to address the primary end point, patient-perceived benefits (using the emotional function domain of the EORTC QLQC30 patient questionnaire), as well as secondary end points: patient satisfaction, safety and health economics.
The Outreach trial is the first randomised controlled trial conducted which compares delivery of out-patient based intravenous cancer treatment in two different community settings with standard hospital based treatment. Results of this study may better inform all key stakeholders regarding potential costs and benefits of transferring clinical services from hospital to the community.
Trial registration number
PMCID: PMC3214181  PMID: 22035502
cancer treatment; chemotherapy; community care; care closer to home; out-patient service delivery
19.  Study Protocol: Phase III single-blinded fast-track pragmatic randomised controlled trial of a complex intervention for breathlessness in advanced disease 
Trials  2011;12:130.
Breathlessness in advanced disease causes significant distress to patients and carers and presents management challenges to health care professionals. The Breathlessness Intervention Service (BIS) seeks to improve the care of breathless patients with advanced disease (regardless of cause) through the use of evidence-based practice and working with other healthcare providers. BIS delivers a complex intervention (of non-pharmacological and pharmacological treatments) via a multi-professional team. BIS is being continuously developed and its impact evaluated using the MRC's framework for complex interventions (PreClinical, Phase I and Phase II completed). This paper presents the protocol for Phase III.
Phase III comprises a pragmatic, fast-track, single-blind randomised controlled trial of BIS versus standard care. Due to differing disease trajectories, the service uses two broad service models: one for patients with malignant disease (intervention delivered over two weeks) and one for patients with non-malignant disease (intervention delivered over four weeks). The Phase III trial therefore consists of two sub-protocols: one for patients with malignant conditions (four week protocol) and one for patients with non-malignant conditions (eight week protocol). Mixed method interviews are conducted with patients and their lay carers at three to five measurement points depending on randomisation and sub-protocol. Qualitative interviews are conducted with referring and non-referring health care professionals (malignant disease protocol only). The primary outcome measure is 'patient distress due to breathlessness' measured on a numerical rating scale (0-10). The trial includes economic evaluation. Analysis will be on an intention to treat basis.
This is the first evaluation of a breathlessness intervention for advanced disease to have followed the MRC framework and one of the first palliative care trials to use fast track methodology and single-blinding. The results will provide evidence of the clinical and cost-effectiveness of the service, informing its longer term development and implementation of the model in other centres nationally and internationally. It adds to methodological developments in palliative care research where complex interventions are common but evidence sparse.
Trial Registration NCT00678405
PMCID: PMC3114770  PMID: 21599896
20.  Protocol for the ADDITION-Plus study: a randomised controlled trial of an individually-tailored behaviour change intervention among people with recently diagnosed type 2 diabetes under intensive UK general practice care 
BMC Public Health  2011;11:211.
The increasing prevalence of type 2 diabetes poses both clinical and public health challenges. Cost-effective approaches to prevent progression of the disease in primary care are needed. Evidence suggests that intensive multifactorial interventions including medication and behaviour change can significantly reduce cardiovascular morbidity and mortality among patients with established type 2 diabetes, and that patient education in self-management can improve short-term outcomes. However, existing studies cannot isolate the effects of behavioural interventions promoting self-care from other aspects of intensive primary care management. The ADDITION-Plus trial was designed to address these issues among recently diagnosed patients in primary care over one year.
ADDITION-Plus is an explanatory randomised controlled trial of a facilitator-led, theory-based behaviour change intervention tailored to individuals with recently diagnosed type 2 diabetes. 34 practices in the East Anglia region participated. 478 patients with diabetes were individually randomised to receive (i) intensive treatment alone (n = 239), or (ii) intensive treatment plus the facilitator-led individual behaviour change intervention (n = 239). Facilitators taught patients key skills to facilitate change and maintenance of key behaviours (physical activity, dietary change, medication adherence and smoking), including goal setting, action planning, self-monitoring and building habits. The intervention was delivered over one year at the participant's surgery and included a one-hour introductory meeting followed by six 30-minute meetings and four brief telephone calls. Primary endpoints are physical activity energy expenditure (assessed by individually calibrated heart rate monitoring and movement sensing), change in objectively measured dietary intake (plasma vitamin C), medication adherence (plasma drug levels), and smoking status (plasma cotinine levels) at one year. We will undertake an intention-to-treat analysis of the effect of the intervention on these measures, an assessment of cost-effectiveness, and analyse predictors of behaviour change in the cohort.
The ADDITION-Plus trial will establish the medium-term effectiveness and cost-effectiveness of adding an externally facilitated intervention tailored to support change in multiple behaviours among intensively-treated individuals with recently diagnosed type 2 diabetes in primary care. Results will inform policy recommendations concerning the management of patients early in the course of diabetes. Findings will also improve understanding of the factors influencing change in multiple behaviours, and their association with health outcomes.
Trial registration
PMCID: PMC3076276  PMID: 21463520
21.  Trial Protocol: Communicating DNA-based risk assessments for Crohn's disease: a randomised controlled trial assessing impact upon stopping smoking 
BMC Public Health  2011;11:44.
Estimates of the risk of developing Crohn's disease (CD) can be made using DNA testing for mutations in the NOD2 (CARD15) gene, family history, and smoking status. Smoking doubles the risk of CD, a risk that is reduced by stopping. CD therefore serves as a timely and novel paradigm within which to assess the utility of predictive genetic testing to motivate behaviour change to reduce the risk of disease. The aim of the study is to describe the impact upon stopping smoking of communicating a risk of developing CD that incorporates DNA analysis. We will test the following main hypothesis:
Smokers who are first degree relatives (FDRs) of CD probands are more likely to make smoking cessation attempts following communication of risk estimates of developing CD that incorporate DNA analysis, compared with an equivalent communication that does not incorporate DNA analysis.
A parallel groups randomised controlled trial in which smokers who are FDRs of probands with CD are randomly allocated in families to undergo one of two types of assessment of risk for developing CD based on either:
i. DNA analysis, family history of CD and smoking status, or
ii. Family history of CD and smoking status
The primary outcome is stopping smoking for 24 hours or longer in the six months following provision of risk information. The secondary outcomes are seven-day smoking abstinence at one week and six month follow-ups. Randomisation of 470 smoking FDRs of CD probands, with 400 followed up (85%), provides 80% power to detect a difference in the primary outcome of 14% between randomised arms, at the 5% significance level.
This trial provides one of the strongest tests to date of the impact of communicating DNA-based risk assessment on risk-reducing behaviour change. Specific issues regarding the choice of trial design are discussed.
Trial Registration
PMCID: PMC3036624  PMID: 21247480
22.  Trial Protocol: Using genotype to tailor prescribing of nicotine replacement therapy: a randomised controlled trial assessing impact of communication upon adherence 
BMC Public Health  2010;10:680.
The behavioural impact of pharmacogenomics is untested; informing smokers of genetic test results for responsiveness to smoking cessation medication may increase adherence to this medication. The objective of this trial is to estimate the impact upon adherence to nicotine replacement therapy (NRT) of informing smokers that their oral dose of NRT has been tailored to a DNA analysis. Hypotheses to be tested are as follows:
I Adherence to NRT is greater among smokers informed that their oral dose of NRT is tailored to an analysis of DNA (genotype), compared to one tailored to nicotine dependence questionnaire score (phenotype).
II Amongst smokers who fail to quit at six months, motivation to make another quit attempt is lower when informed that their oral dose of NRT was tailored to genotype rather than phenotype.
An open label, parallel groups randomised trial in which 630 adult smokers (smoking 10 or more cigarettes daily) using National Health Service (NHS) stop smoking services in primary care are randomly allocated to one of two groups:
i. NRT oral dose tailored by DNA analysis (OPRM1 gene) (genotype), or
ii. NRT oral dose tailored by nicotine dependence questionnaire score (phenotype)
The primary outcome is proportion of prescribed NRT consumed in the first 28 days following an initial quit attempt, with the secondary outcome being motivation to make another quit attempt, amongst smokers not abstinent at six months. Other outcomes include adherence to NRT in the first seven days and biochemically validated smoking abstinence at six months. The primary outcome will be collected on 630 smokers allowing sufficient power to detect a 7.5% difference in mean proportion of NRT consumed using a two-tailed test at the 5% level of significance between groups. The proportion of all NRT consumed in the first four weeks of quitting will be compared between arms using an independent samples t-test and by estimating the 95% confidence interval for observed between-arm difference in mean NRT consumption (Hypothesis I). Motivation to make another quit attempt will be compared between arms in those failing to quit by six months (Hypothesis II).
This is the first clinical trial evaluating the behavioural impact on adherence of prescribing medication using genetic rather than phenotypic information. Specific issues regarding the choice of design for trials of interventions of this kind are discussed.
Trial details
Funder: Medical Research Council (MRC)
Grant number: G0500274
ISRCTN: 14352545
Date trial stated: June 2007
Expected end date: December 2009
Expected reporting date: December 2010
PMCID: PMC2996370  PMID: 21062464
23.  Explaining Behavior Change after Genetic Testing: The Problem of Collinearity between Test Results and Risk Estimates 
Genetic testing  2008;12(3):381-386.
This paper explores whether and how the behavioral impact of genotype disclosure can be disentangled from the impact of numerical risk estimates generated by genetic tests. Secondary data analyses are presented from a randomized controlled trial of 162 first-degree relatives of Alzheimer’s disease (AD) patients. Each participant received a lifetime risk estimate of AD. Control group estimates were based on age, gender, family history, and assumed ε4-negative apolipoprotein E (APOE) genotype; intervention group estimates were based upon the first three variables plus true APOE genotype, which was also disclosed. AD-specific self-reported behavior change (diet, exercise, and medication use) was assessed at 12 months. Behavior change was significantly more likely with increasing risk estimates, and also more likely, but not significantly so, in ε4-positive intervention group participants (53% changed behavior) than in control group participants (31%). Intervention group participants receiving ε4-negative genotype feedback (24% changed behavior) and control group participants had similar rates of behavior change and risk estimates, the latter allowing assessment of the independent effects of genotype disclosure. However, collinearity between risk estimates and ε4-positive genotypes, which engender high-risk estimates, prevented assessment of the independent effect of the disclosure of an ε4 genotype. Novel study designs are proposed to determine whether genotype disclosure has an impact upon behavior beyond that of numerical risk estimates.
PMCID: PMC2925186  PMID: 18666860
24.  Impact of an informed choice invitation on uptake of screening for diabetes in primary care (DICISION): randomised trial 
Objective To compare the effect of an invitation promoting informed choice for screening with a standard invitation on attendance and motivation to engage in preventive action.
Design Randomised controlled trial.
Setting Four English general practices.
Participants 1272 people aged 40-69 years, at risk for diabetes, identified from practice registers using a validated risk score and invited to attend for screening.
Intervention Intervention was a previously validated invitation to inform the decision to attend screening, presenting diabetes as a serious potential problem, and providing details of possible costs and benefits of screening and treatment in text and pie charts. This was compared with a brief, standard invitation simply describing diabetes as a serious potential problem.
Main outcome measures The primary end point was attendance for screening. The secondary outcome measures were intention to make changes to lifestyle and satisfaction with decisions made among attenders.
Results The primary end point was analysed for all 1272 participants. 55.8% (353/633) of those in the informed choice group attended for screening, compared with 57.6% (368/639) in the standard invitation group (mean difference −1.8%, 95% confidence interval −7.3% to 3.6%; P=0.51). Attendance was lower among the more deprived group (most deprived third 47.5% v least deprived third 64.3%; P<0.001). Interaction between deprivation and effect of invitation type on attendance was not significant. Among attenders, intention to change behaviour was strong and unaffected by invitation type.
Conclusions Providing information to support choice did not adversely affect attendance for screening for diabetes. Those from more socially deprived groups were, however, less likely to attend, regardless of the type of invitation received. Further attention to invitation content alone is unlikely to achieve equity in uptake of preventive services.
Trial registration Current Controlled Trials ISRCTN 73125647.
PMCID: PMC2869404  PMID: 20466791
25.  Protocol for the MoleMate™ UK Trial: a randomised controlled trial of the MoleMate system in the management of pigmented skin lesions in primary care [ISRCTN 79932379] 
BMC Family Practice  2010;11:36.
Suspicious pigmented lesions are a common presenting problem in general practice consultations; while the majority are benign a small minority are melanomas. Differentiating melanomas from other pigmented lesions in primary care is challenging: currently, 95% of all lesions referred to a UK specialist are benign. The MoleMate system is a new diagnostic aid, incorporating a hand-held SIAscopy scanner with a primary care diagnostic algorithm. This trial tests the hypothesis that adding the MoleMate system to current best primary care practice will increase the proportion of appropriate referrals of suspicious pigmented lesions to secondary care compared with current best practice alone.
The MoleMate UK Trial is a primary care based multi-centre randomised controlled trial, with randomisation at patient level using a validated block randomisation method for two age groups (45 years and under; 46 years and over). We aim to recruit adult patients seen in general practice with a pigmented skin lesion that cannot immediately be diagnosed as benign and the patient reassured. The trial has a 'two parallel groups' design, comparing 'best practice' with 'best practice' plus the MoleMate system in the intervention group. The primary outcome is the positive predictive value (PPV) of referral defined as the proportion of referred lesions seen by secondary care experts that are considered 'clinically significant' (i.e. biopsied or monitored). Secondary outcomes include: the sensitivity, specificity and negative predictive value (NPV) of the decision not to refer; clinical outcomes (melanoma thickness, 5 year melanoma incidence and mortality); clinician outcomes (Index of Suspicion, confidence, learning effects); patient outcomes (satisfaction, general and cancer-specific worry), and cost-utility.
The MoleMate UK Trial tests a new technology designed to improve the management of suspicious pigmented lesions in primary care. If effective, the MoleMate system could reduce the burden on skin cancer clinics of patients with benign pigmented skin lesions, and improve patient care in general practice.
PMCID: PMC2881908  PMID: 20459846

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