Systematic review of randomised controlled trials of sildenafil (Viagra®) in the treatment of male erectile dysfunction.

Background: Sildenafil (Viagra®), a new oral drug for the treatment of erectile dysfunction, was licensed for use across Europe in 1998. Aim: To examine the effectiveness and safety of sildenafil as an oral treatment for erectile dysfunction. Design of study: Systematic review and meta-analysis.
Setting: All published or unpublished randomised controlled trials comparing sildenafil with a placebo or alternative therapies. Method: Published studies were sought by computerised searches of electronic databases using the keywords ‘sildenafil’ and ‘Viagra’. A hand search was also done of the British Medical Journal, Lancet, Journal of the American
Medical Association, New England Journal of Medicine, British Journal of General Practice, Drug, Inpharma and Scrip. An assessment of quality of all identified studies and data extraction was undertaken independently by two researchers. Results were combined in a meta-analysis where appropriate, using RevMan version 3. Results: Twenty-one trials were identified. All trials showed a statistically significant improvement in erectile or sexual function in patients using sildenafil compared with a placebo. A meta-analysis of 16 trials reporting a global efficacy response showed that men were 3.57 (95% CI = 2.93–4.43) times as likely to have improved erections on sildenafil compared with those on a placebo. The number needed to treat to have one man with improved erections was two. The drug has a relatively safe side-effect profile. Conclusions: Available research shows that sildenafil is an effective treatment for male erectile dysfunction. Many trial participants had some baseline erectile function and it is probable that in clinical practice, where the erectile function tends to be more impaired, the number needed to treat may be higher.

Cost-effectiveness of a family-based GP-mediated intervention targeting overweight and moderately obese children

Objective
 To assess from a societal perspective the incremental cost-effectiveness of a family-based GP-mediated intervention targeting overweight and moderately obese children. The intervention was modelled on the LEAP (live, eat and play) trial, a randomised controlled trial conducted by the Centre for Community Child Health, Melbourne, Australia in 2002–2003. This study was undertaken as part of the assessing cost-effectiveness (ACE) in obesity project which evaluated, using consistent methods, 13 interventions targeting unhealthy weight gain in children and adolescents.
Method
A logic pathway was used to model the effects of the intervention compared to no intervention on body mass index (BMI) and health outcomes (disability-adjusted life years—DALYs). Disease costs and health benefits were tracked until the cohort of eligible children reached the age of 100 years or death. Simulation-modelling techniques were used to present a 95% uncertainty interval around the cost-effectiveness ratio. The intervention was also assessed against a series of filters (‘equity’, ‘strength of evidence’, ‘acceptability’, ‘feasibility’, sustainability’ and ‘side-effects’) to incorporate additional factors that impact on resource allocation decisions.
Results
The intervention, as modelled, reached 9685 children aged 5–9 years with a BMI z-score of ≥3.0, and cost $AUD6.3M (or $AUD4.8M excluding time costs). It resulted in an incremental saving of 2300 BMI units which translated to 511 DALYs. The cost-offsets stemming from the intervention totalled $AUD3.6M, resulting in a net cost per DALY saved of $AUD4670 (dominated; $0.1M) (dominated means intervention costs more for less effect).
Conclusion
Compared to a ‘no intervention’ control group, the intervention was cost-effective under current assumptions, although the uncertainty intervals were wide. A key question related to the long-term sustainability of the small incremental weight loss reported, based on the 9-month follow-up results for LEAP.

Can a disease-specific education program augment self-management skills and improve Health-Related Quality of Life in people with hip or knee osteoarthritis?

Background: Patient education and self-management programs are offered in many countries to people with chronic conditions such as osteoarthritis (OA). The most well-known is the disease-specific Stanford Arthritis Self-Management Program (ASMP). While Australian and international clinical guidelines promote the concept of self-management for OA, there is currently little evidence to support the use of the ASMP. Several meta-analyses have reported that arthritis self-management programs had minimal or no effect on reducing pain and disability. However, previous studies have had methodological shortcomings including the use of outcome measures which do not accurately reflect program goals. Additionally, limited cost-effectiveness analyses have been undertaken and the cost-utility of the program has not been explored.

Methods/design: This study is a randomised controlled trial to determine the efficacy (in terms of Health-Related Quality of Life and self-management skills) and cost-utility of a 6-week group-based Stanford ASMP for people with hip or knee OA.

Six hundred participants referred to an orthopaedic surgeon or rheumatologist for hip or knee OA will be recruited from outpatient clinics at 2 public hospitals and community-based private practices within 2 private hospital settings in Victoria, Australia. Participants must be 18 years or over, fluent in English and able to attend ASMP sessions. Exclusion criteria include cognitive dysfunction, previous participation in self-management programs and placement on a waiting list for joint replacement surgery or scheduled joint replacement.

Eligible, consenting participants will be randomised to an intervention group (who receive the ASMP and an arthritis self-management book) or a control group (who receive the book only). Follow-up will be at 6 weeks, 3 months and 12 months using standardised self-report measures. The primary outcome is Health-Related Quality of Life at 12 months, measured using the Assessment of Quality of Life instrument. Secondary outcome measures include the Health Education Impact Questionnaire, Western Ontario and McMaster Universities Osteoarthritis Index (pain subscale and total scores), Kessler Psychological Distress Scale and the Hip and Knee Multi-Attribute Priority Tool. Cost-utility analyses will be undertaken using administrative records and self-report data. A subgroup of 100 participants will undergo qualitative interviews to explore the broader potential impacts of the ASMP.

Discussion: Using an innovative design combining both quantitative and qualitative components, this project will provide high quality data to facilitate evidence-based recommendations regarding the ASMP.

The TrueBlue study : is practice nurse-led collaborative care effective in the management of depression for patients with heart disease or diabetes?

Background: In the presence of type 2 diabetes (T2DM) or coronary heart disease (CHD), depression is under diagnosed and under treated despite being associated with worse clinical outcomes. Our earlier pilot study demonstrated that it was feasible, acceptable and affordable for practice nurses to extend their role to include screening for and monitoring of depression alongside biological and lifestyle risk factors. The current study will compare the clinical outcomes of our model of practice nurse-led collaborative care with usual care for patients with depression and T2DM or CHD.

Methods: This is a cluster-randomised intervention trial. Eighteen general practices from regional and metropolitan areas agreed to join this study, and were allocated randomly to an intervention or control group. We aim to recruit 50 patients with co-morbid depression and diabetes or heart disease from each of these practices. In the intervention group, practice nurses (PNs) will be trained for their enhanced roles in this nurse-led collaborative care study. Patients will be invited to attend a practice nurse consultation every 3 months prior to seeing their usual general practitioner. The PN will assess psychological, physiological and lifestyle parameters then work with the patient to set management goals. The outcome of this assessment will form the basis of a GP Management Plan document. In the control group, the patients will continue to receive their usual care for the first six months of the study before the PNs undergo the training and switch to the intervention protocol. The primary clinical outcome will be a reduction in the depression score. The study will also measure the impact on physiological measures, quality of life and on patient attitude to health care delivered by practice nurses.

Conclusion: The strength of this programme is that it provides a sustainable model of chronic disease management with monitoring and self-management assistance for physiological, lifestyle and psychological risk factors for high-risk patients with co-morbid depression, diabetes or heart disease. The study will demonstrate whether nurse-led collaborative care achieves better outcomes than usual care.

Motivational interviewing and cognitive behaviour therapy in the treatment of adolescent overweight and obesity : study design and methodology

Background

Despite the high prevalence and negative physical and psychosocial consequences of overweight and obesity in adolescents, very little research has evaluated treatment in this population. Consequently, clinicians working with overweight and obese adolescents have little empirical research on which to base their practise. Cognitive behavioural therapy has demonstrated efficacy in promoting behaviour change in many treatment resistant disorders. Motivational interviewing has been used to increase motivation for change and improve treatment outcomes. In this paper we describe the rationale and design of a randomised controlled trial testing the efficacy of motivational interviewing and cognitive behaviour therapy in the treatment of overweight and obese adolescents.
Methods

Participants took part in a motivational interview or a standard semi-structured assessment interview and were then randomly allocated to a cognitive behavioural intervention or a wait-list control condition. The cognitive behavioural intervention, the CHOOSE HEALTH Program, consisted of 13 individual treatment sessions (12 face-to-face, 1 phone call) followed by 9 maintenance sessions (7 phone calls, 2 face-to-face). Assessments were conducted prior to participation, after the treatment phase and after the maintenance phase of intervention. Improvement in body composition was the primary outcome; secondary outcomes included improved cardiovascular fitness, eating and physical activity habits, family and psychosocial functioning.
Conclusion

Despite the demonstrated effectiveness of motivational interviewing and cognitive behavioural therapy in the long-term management of many treatment resistant disorders, these approaches have been under-utilised in adolescent overweight and obesity treatment. This study provides baseline data and a thorough review of the study design and treatment approach to allow for the assessment of the efficacy of motivational interviewing and cognitive behavioural therapy in the treatment of adolescent overweight and obesity. Data obtained in this study will also provide much needed information about the behavioural and psychosocial factors associated with adolescent overweight and obesity.

RCT of a client-centred, caseworker-delivered smoking cessation intervention for a socially disadvantaged population

Background: Disadvantaged groups are an important target for smoking cessation intervention. Smoking rates are markedly higher among severely socially disadvantaged groups such as indigenous people, the homeless, people with a mental illness or drug and alcohol addiction, and the unemployed than in the general population. This proposal aims to evaluate the efficacy of a client-centred, caseworker delivered cessation support intervention at increasing validated self reported smoking cessation rates in a socially disadvantaged population.
Methods/Design: A block randomised controlled trial will be conducted. The setting will be a non-government organisation, Community Care Centre located in New South Wales, Australia which provides emergency relief and counselling services to predominantly government income assistance recipients. Eligible clients identified as smokers during a baseline touch screen computer survey will be recruited and randomised by a trained research assistant located in the waiting area. Allocation to intervention or control groups will be determined by time periods with clients randomised in one-week blocks. Intervention group clients will receive an intensive client centred smoking cessation intervention offered by the caseworker over two face-to-face and two telephone contacts. There will be two primary outcome measures obtained at one, six, and 12 month follow-up: 1) 24-hour expired air CO validated self-reported smoking cessation and 2) 7-day self-reported smoking cessation. Continuous abstinence will also be measured at six and 12 months follow up.
Discussion: This study will generate new knowledge in an area where the current information regarding the most effective smoking cessation approaches with disadvantaged groups is limited.

Effects of resistance exercise and fortified milk on skeletal muscle mass, muscle size, and functional performance in middle-aged and older men: an 18-mo randomized controlled trial

Limited data have suggested that the consumption of fluid milk after resistance training (RT) may promote skeletal muscle hypertrophy. The aim of this study was to assess whether a milk-based nutritional supplement could enhance the effects of RT on muscle mass, size, strength, and function in middle-aged and older men. This was an 18-mo factorial design (randomized control trial) in which 180 healthy men aged 50–79 yr were allocated to the following groups: 1) exercise + fortified milk, 2) exercise, 3) fortified milk, or 4) control. Exercise consisted of progressive RT with weight-bearing impact exercise. Men assigned to the fortified milk consumed 400 ml/day of low-fat milk, providing an additional 836 kJ, 1000 mg calcium, 800 IU vitamin D3, and 13.2 g protein per day. Total body lean mass (LM) and fat mass (FM) (dual-energy X-ray absorptiometry), midfemur muscle cross-sectional area (CSA) (quantitative computed tomography), muscle strength, and physical function were assessed. After 18 mo, there was no significant exercise by fortified milk interaction for total body LM, muscle CSA, or any functional measure. However, main effect analyses revealed that exercise significantly improved muscle strength (∼20–52%, P < 0.001), LM (0.6 kg, P < 0.05), FM (−1.1 kg, P < 0.001), muscle CSA (1.8%, P < 0.001), and gait speed (11%, P < 0.05) relative to no exercise. There were no effects of the fortified milk on muscle size, strength, or function. In conclusion, the daily consumption of low-fat fortified milk does not enhance the effects of RT on skeletal muscle size, strength, or function in healthy middle-aged and older men with adequate energy and nutrient intakes.

Building equity in chronic disease management in Thailand : a whole-system provincial trial of systematic, pro-active chronic illness care

Thailand has a history of implementing innovative and proactive policies to address the health needs of its population. Since 1962 Thailand has implemented initiatives that led to it having a health system characterized by a primary care focus, decentralization and mechanisms to maximize equity and universal access to basic care at the local level. Thai health structures initially evolved to meet challenges including infectious and developmental diseases and later HIV. Early in the 21st century chronic illness rapidly became the greatest cause of morbidity and mortality and the question has arisen how Thailand can adapt its strong health system to deal with the new epidemics. This article describes an effort to reorient provincial health services to meet the needs of the increasing number of people with diabetes and heart disease. It describes measures taken to build on the equity-promoting elements of the Thai health system. The project included; a situational analysis, development and implementation of a chronic disease self-management intervention implemented by nurses and alignment of provincial health services. The self-management intervention is currently being evaluated within a clustered randomized control trial. The evaluation has been developed to fit with the focus on equity in relation to both selection criteria and the outcomes that are being assessed.

Randomised controlled trials and 'unexpected' adverse events associated with newly released drugs : improvements in pharmacovigilance systems are necessary for real-time identification of patient safety risks

Adverse drug events are one of the major causes of morbidity in developed countries, yet the drugs involved in these events have been trialled and approved on the basis of randomised controlled trials (RCTs), regarded as the study design that will produce the best evidence.

Though the focus on adverse drug events has been primarily on processes and outcomes associated with the use of these approved drugs, attention needs to be directed to the way in which the RCT study design is structured. The implementation of controls to achieve internal validity in RCTs may be the very controls that reduce external validity, and contribute to the levels of adverse drug events associated with the release of a new drug to the wider patient population.

An examination of these controls, and the effects they can have on patient safety, underscore the importance of knowing about how the clinical trials of a drug are undertaken, rather than relying only on the recorded outcomes.

As the majority of new drugs are likely to be prescribed to older patients who have one or more comorbidities in addition to that targeted by a new drug, and as the RCTs of those drugs typically under-represent the elderly and exclude patients with multiple comorbidities, timely assessment of drug safety signals is essential.

It is unlikely that regulatory jurisdictions will undertake a reassessment of safety issues for drugs that are already approved. Instead, reliance has been placed on adverse drug event reporting systems. Such systems have a very low reporting rate, and most adverse drug events remain unreported, to the eventual cost to patients and healthcare systems.

This makes it essential for near real-time systems that can pick up safety signals as they occur, so that modifications to the product information (or removal of the drug) can be implemented.

Scaling-up from an implementation trial to state-wide coverage : results from the preliminary Melbourne Diabetes Prevention Study

Background
The successful Greater Green Triangle Diabetes Prevention Program (GGT DPP), a small implementation trial, has been scaled-up to the Victorian state-wide ‘Life!’ programme with over 10,000 individuals enrolled. The Melbourne Diabetes Prevention Study (MDPS) is an evaluation of the translation from the GGT DPP to the Life! programme. We report results from the preliminary phase (pMDPS) of this evaluation.
Methods
The pMDPS is a randomised controlled trial with 92 individuals aged 50 to 75 at high risk of developing type 2 diabetes randomised to Life! or usual care. Intervention consisted of six structured 90-minute group sessions: five fortnightly sessions and the final session at 8 months. Participants underwent anthropometric and laboratory tests at baseline and 12 months, and provided self-reported psychosocial, dietary, and physical activity measures. Intervention group participants additionally underwent these tests at 3 months. Paired t tests were used to analyse within-group changes over time. Chi-square tests were used to analyse differences between groups in goals met at 12 months. Differences between groups for changes over time were tested with generalised estimating equations and analysis of covariance.
Results
Intervention participants significantly improved at 12 months in mean body mass index (−0.98 kg/m2, standard error (SE) = 0.26), weight (−2.65 kg, SE = 0.72), waist circumference (−7.45 cm, SE = 1.15), and systolic blood pressure (−3.18 mmHg, SE = 1.26), increased high-density lipoprotein-cholesterol (0.07 mmol/l, SE = 0.03), reduced energy from total (−2.00%, SE = 0.78) and saturated fat (−1.54%, SE = 0.41), and increased fibre intake (1.98 g/1,000 kcal energy, SE = 0.47). In controls, oral glucose at 2 hours deteriorated (0.59 mmol/l, SE = 0.27). Only waist circumference reduced significantly (−4.02 cm, SE = 0.95).

Intervention participants significantly outperformed controls over 12 months for body mass index and fibre intake. After baseline adjustment, they also showed greater weight loss and reduced saturated fat versus total energy intake.

At least 5% weight loss was achieved by 32% of intervention participants versus 0% controls.
Conclusions
pMDPS results indicate that scaling-up from implementation trial to state-wide programme is possible. The system design for Life! was fit for purpose of scaling-up from efficacy to effectiveness.

Study protocol for "Moving bright, eating smart"- a phase 2 clinical trial on the acceptability and feasibility of a diet and physical activity intervention to prevent recurrence in colorectal cancer survivors

Background: Colorectal cancer is the second most common cancer and cancer-killer in Hong Kong with an alarming increasing incidence in recent years. The latest World Cancer Research Fund report concluded that foods low in fibre, and high in red and processed meat cause colorectal cancer whereas physical activity protects against
colon cancer. Yet, the influence of these lifestyle factors on cancer outcome is largely unknown even though cancer survivors are eager for lifestyle modifications. Observational studies suggested that low intake of a Western-pattern diet and high physical activity level reduced colorectal cancer mortality. The Theory of Planned
Behaviour and the Health Action Process Approach have guided the design of intervention models targeting a wide range of health-related behaviours.
Methods/design: We aim to demonstrate the feasibility of two behavioural interventions intended to improve colorectal cancer outcome and which are designed to increase physical activity level and reduce consumption of a Western-pattern diet. This three year study will be a multicentre, randomised controlled trial in a 2x2 factorial
design comparing the “Moving Bright, Eating Smart” (physical activity and diet) programme against usual care. Subjects will be recruited over a 12-month period, undertake intervention for 12 months and followed up for a further 12 months. Baseline, interim and three post-intervention assessments will be conducted. Two hundred and twenty-two colorectal cancer patients who completed curative treatment without evidence of recurrence will be recruited into the study. Primary outcome measure will be whether physical activity and dietary targets are met at the end of the 12-month intervention. Secondary outcome measures include the magnitude and
mechanism of behavioural change, the degree and determinants of compliance, and the additional health benefits and side effects of the intervention.
Discussion: The results of this study will establish the feasibility of targeting the two behaviours (diet and physical activity) and demonstrate the magnitude of behaviour change. The information will facilitate the design of a further larger phase III randomised controlled trial with colorectal cancer outcome as the study endpoint to determine whether this intervention model would reduce colorectal cancer recurrence and mortality.

Lipidomic profiling of chylomicron triacylglycerols in response to high fat meals

Using lipidomic methodologies the impact that meal lipid composition and metabolic syndrome (MetS) exerts on the postprandial chylomicron triacylglycerol (TAG) response was examined. Males (9 control; 11 MetS) participated in a randomised crossover trial ingesting two high fat breakfast meals composed of either dairy-based foods or vegetable oil-based foods. The postprandial lipidomic molecular composition of the TAG in the chylomicron-rich (CM) fraction was analysed with tandem mass spectrometry coupled with liquid chromatography to profile CM TAG species and targeted TAG regioisomers. Postprandial CM TAG concentrations were significantly lower after the dairy-based foods compared with the vegetable oil-based foods for both control and MetS subjects. The CM TAG response to the ingested meals involved both significant and differential depletion of TAG species containing shorter-and medium-chain fatty acids (FA) and enrichment of TAG molecular species containing C16 and C18 saturated, monounsaturated and diunsaturated FA. Furthermore, there were significant changes in the TAG species between the food TAG and CM TAG and between the 3- and 5-h postprandial samples for the CM TAG regioisomers. Unexpectedly, the postprandial CM TAG concentration and CM TAG lipidomic responses did not differ between the control and MetS subjects. Lipidomic analysing of CM TAG molecular species revealed dynamic changes in the molecular species of CM TAG during the postprandial phase suggesting either preferential CM TAG species formation and/or clearance.

Application of the gradient boosted method in randomised clinical trials: participant variables that contribute to depression treatment efficacy of duloxetine, SSRIs or placebo

Randomised, placebo-controlled trials of treatments for depression typically collect outcomes data but traditionally only analyse data to demonstrate efficacy and safety. Additional post-hoc statistical techniques may reveal important insights about treatment variables useful when considering inter-individual differences amongst depressed patients. This paper aims to examine the Gradient Boosted Model (GBM), a statistical technique that uses regression tree analyses and can be applied to clinical trial data to identify and measure variables that may influence treatment outcomes.

Youth depression alleviation: the Fish Oil Youth Depression Study (YoDA-F): A randomized, double-blind, placebo-controlled treatment trial.

US authorities have recommended 'black-box' warnings for antidepressants because of the increased risk of suicidality for individuals up to age 25. There is thus a clinical and ethical imperative to provide effective treatment for youth depression with an acceptable risk-benefit balance. Long-chain omega-3 polyunsaturated fatty acids (PUFAs) play an important role in a range of physiological processes in living organisms. Supplementation with omega-3 PUFAs has been shown to have a range of beneficial effects on both physical and mental health, and results of previous trials suggest that omega-3 PUFAs may be a safe and effective treatment for depression. However, conclusions from these trials have been limited by their relatively small sample sizes.