Multicenter Randomized Controlled Trial of Withdrawal of Inhaled Corticosteroids in Cystic Fibrosis

Rationale: Lung inflammation and injury is critical in cystic fibrosis. An ideal antiinflammatory agent has not been identified but inhaled corticosteroids are widely used despite lack of evidence.

Objectives: To test the safety of withdrawal of inhaled corticosteroids with the hypothesis this would not be associated with an earlier onset of acute chest exacerbations.

Methods: Multicenter randomized double-blind placebo-controlled trial in 18 pediatric and adult UK centers. Eligibility criteria included age > 6.0 yr, FEV1 ? 40% predicted, and corticosteroid use > 3 mo. During the 2-mo run-in period, all patients received fluticasone; they then took either fluticasone or placebo for 6 mo.

Measurements and Main Results: Fluticasone group: n = 84, median age 14.6 yr, mean (SD) FEV1 76% (18); placebo group: n = 87, median age 15.8 yr, mean (SD) FEV1 76% (18). There was no difference in time to first exacerbation (primary outcome) with hazard ratio (95% confidence interval) of 1.07 (0.68 to 1.70) for fluticasone versus placebo. There was no effect of age, atopy, corticosteroid dose, FEV1, or Pseudomonas aeruginosa status. There was no change in lung function or differences in antibiotic or rescue bronchodilator use. Fewer patients in the fluticasone group withdrew from the study due to lung-related adverse events (9 vs. 15%); with a relative risk (95% confidence interval) of 0.59 (0.23–1.48) fluticasone versus placebo.

Conclusions: In this study population (applicable to 40% of patients with cystic fibrosis in the UK), it appears safe to consider stopping inhaled corticosteroids. Potential advantages will be to reduce the drug burden on patients, reduce adverse effects, and make financial savings.

Randomised controlled trial of effects of Helicobacter pylori infection and its eradication on heartburn and gastro-oesophageal reflux: the bristol helicobacter project

Objectives To investigate the effects of Helicobacter pylori infection and its eradication on heartburn and gastro-oesophageal reflux. Design Cross sectional study, followed by a randomised placebo controlled trial. Setting Seven general practices in Bristol, England. Participants 10 537 people, aged 20-59 years, with and without H pylori infection (determined by the 13C-urea breath test). Main outcome measures Prevalence of heartburn and gastro-oesophageal acid reflux at baseline and two years after treatment to eradicate H pylori infection. Results At baseline, H pylori infection was associated with increased prevalence of heartburn (odds ratio 1.14, 95% confidence interval 1.05 to 1.23) but not reflux (1.05, 0.97 to 1.14). In participants with H pylori infection, active treatment had no effect on the overall prevalence of heartburn (0.99, 0.88 to 1.12) or reflux (1.04, 0.91 to 1.19) and did not improve pre-existing symptoms of heartburn or reflux. Conclusions H pylori infection is associated with a slightly increased prevalence of heartburn but not reflux. Treatment to eradicate H pylori has no net benefit in patients with heartburn or gastro-oesophageal reflux

Randomized controlled trial of interferential therapy and manipulative therapy for acute low back pain.

Study Design. A multi-center assessor-blinded randomized clinical trial was conducted. Objectives. To investigate the relative effectiveness of interferential therapy and manipulative therapy for patients with acute low back pain when used as sole treatments and in combination. Summary of Background Data. Both manipulative therapy and interferential therapy are commonly used treatments for low back pain. Evidence for the effectiveness of manipulative therapy is available only for the short term. There is no evidence for interferential therapy and no study has investigated the effectiveness of interferential therapy combined with manipulative therapy. Methods. Consenting subjects (n=240) were randomly assigned to receive a copy of the Back Book and either manipulative therapy (MT; n=80), interferential therapy (IFT; n=80) or combined manipulative therapy and interferential therapy (CT; n=80). Follow-up outcome questionnaires were posted at discharge, 6 and 12 months. Results. The groups were balanced at baseline for low back pain and demographic characteristics. All interventions were found to significantly reduce functional disability and pain and increase quality of life at discharge and to maintain these improvements at 6 and 12 months. No significant differences were found between groups for reported LBP recurrence, work absenteeism, medication consumption, exercise participation and healthcare use at 12 months. Conclusions. For acute low back pain, interferential therapy whether used in isolation or in combination with manipulative therapy was as effective as manipulative therapy alone (in addition to the Back Book).

The SPHERE Study: Secondary prevention of heart disease in general practice: protocol of a randomised controlled trial of tailored practice and patient care plans with parallel qualitative, economic and policy analyses. [ISRCTN24081411]

Background: The aim of the SPHERE study is to design, implement and evaluate tailored practice and personal care plans to improve the process of care and objective clinical outcomes for patients with established coronary heart disease (CHD) in general practice across two different health systems on the island of Ireland.CHD is a common cause of death and a significant cause of morbidity in Ireland. Secondary prevention has been recommended as a key strategy for reducing levels of CHD mortality and general practice has been highlighted as an ideal setting for secondary prevention initiatives. Current indications suggest that there is considerable room for improvement in the provision of secondary prevention for patients with established heart disease on the island of Ireland. The review literature recommends structured programmes with continued support and follow-up of patients; the provision of training, tailored to practice needs of access to evidence of effectiveness of secondary prevention; structured recall programmes that also take account of individual practice needs; and patient-centred consultations accompanied by attention to disease management guidelines.

Methods: SPHERE is a cluster randomised controlled trial, with practice-level randomisation to intervention and control groups, recruiting 960 patients from 48 practices in three study centres (Belfast, Dublin and Galway). Primary outcomes are blood pressure, total cholesterol, physical and mental health status (SF-12) and hospital re-admissions. The intervention takes place over two years and data is collected at baseline, one-year and two-year follow-up. Data is obtained from medical charts, consultations with practitioners, and patient postal questionnaires. The SPHERE intervention involves the implementation of a structured systematic programme of care for patients with CHD attending general practice. It is a multi-faceted intervention that has been developed to respond to barriers and solutions to optimal secondary prevention identified in preliminary qualitative research with practitioners and patients. General practitioners and practice nurses attend training sessions in facilitating behaviour change and medication prescribing guidelines for secondary prevention of CHD. Patients are invited to attend regular four-monthly consultations over two years, during which targets and goals for secondary prevention are set and reviewed. The analysis will be strengthened by economic, policy and qualitative components.

Time for treating bone fracture using rhBMP-2: a randomised placebo controlled mouse fracture trial.

Although the mechanisms of osteoinduction by bone morphogenic proteins (BMPs) are increasingly understood, the most appropriate time to administer BMPs exogenously is yet to be clarified.The purpose of this study was to investigate when BMP may be administered to a fracture arena to maximise the enhancement of healing.Forty mice with externally fixed left femoral fractures were randomised into four groups: Group I, the control group was given a placebo of 30 ll saline at day 0; Groups II, III and IV were given 30 ll saline plus 2.5 lg rhBMP-2, at post-operative days 0, 4 or 8, respectively.Sequential radiographs were taken at days 0, 8, 16.On day 22 the mice were sacrificed and both femora were harvested for biomechanical assessment in 3-point bending and histological evaluation.Radiographic analysis indicated that healing of fractures in Groups II and III was significantly greater (p <0.05) than those in Groups I and IV, at both 16 and 22 days post-fracture. The highest median bone mineral content at the fracture site was evidenced in Group III and II.Furthermore, Group III also had the highest relative ultimate load values, followed by Groups II, IV and I.Greater percentage peak loads were observed between Group I and both Groups II and III (p <0.05). Histological examination confirmed that at 22 days post-fracture, only fractures in Groups II and III had united with woven bone, and Groups I and IV still had considerable amounts of fibrous tissue and cartilage at the fracture gap.Data presented herein indicates that there is a time after fracture when rhBMP administration is most effective, and this may be at the time of surgery as well as in the early fracture healing phases.

Design and physicochemical characterisation of a bioadhesive patch for dose-controlled topical delivery of imiquimod

Clinical use of the imidazoquinoline immunomodulator imiquimod for the topical treatment of dysplastic and neoplastic lesions has increased markedly in recent years. However, despite guidance from the manufacturer of the proprietary imiquimod cream, there seems to be little consensus between clinicians as to the topically applied dose. Given that patients often apply the cream themselves at home, further dosing variability is expected and, consequently, accurate comparison of the results of different published studies is dif?cult. This paper describes, for the ?rst time, the formulation and physicochemical characterisation of a bioadhesive patch for dose-controlled topical delivery of imiquimod as well as a new HPLC method for sensitive ?uorescence determination of imiquimod released from such systems. Patches containing imiquimod loadings of 4.75, 9.50 and 12.50 mg cm-2 all released signi?cantly more drug across a model membrane than the proprietary cream over a period of 6 h. Inclusion of imiquimod in patches did not adversely affect their physicochemical properties. Of major importance, patches contained de?ned drug loadings per unit area; therefore, their use could reduce inter-clinician variability. This would make critical comparison of clinical studies and determination of an appropriate imiquimod dose for successful treatment much simpler. Since bioadhesive formulations are capable of adhering to body tissues in moist environments, the use of a bioadhesive patch system may allow extension of the clinical uses of imiquimod to the treatment of neoplastic conditions of the oral cavity and cervix, as well as the vulva. © 2005 Elsevier B.V. All rights reserved.