Clinical and cost-effectiveness of internal limiting membrane peeling for patients with idiopathic full thickness macular hole. Protocol for a Randomised Controlled Trial : FILMS (Full-thickness macular hole and Internal Limiting Membrane peeling Study)

Background: A full-thickness macular hole (FTMH) is a common retinal condition associated with impaired vision. Randomised controlled trials (RCTs) have demonstrated that surgery, by means of pars plana vitrectomy and post-operative intraocular tamponade with gas, is effective for stage 2, 3 and 4 FTMH. Internal limiting membrane (ILM) peeling has been introduced as an additional surgical manoeuvre to increase the success of the surgery; i.e. increase rates of hole closure and visual improvement. However, little robust evidence exists supporting the superiority of ILM peeling compared with no-peeling techniques. The purpose of FILMS (Fullthickness macular hole and Internal Limiting Membrane peeling Study) is to determine whether ILM peeling improves the visual function, the anatomical closure of FTMH, and the quality of life of patients affected by this disorder, and the cost-effectiveness of the surgery. Methods/Design: Patients with stage 2–3 idiopathic FTMH of less or equal than 18 months duration (based on symptoms reported by the participant) and with a visual acuity ≤ 20/40 in the study eye will be enrolled in this FILMS from eight sites across the UK and Ireland. Participants will be randomised to receive combined cataract surgery (phacoemulsification and intraocular lens implantation) and pars plana vitrectomy with postoperative intraocular tamponade with gas, with or without ILM peeling. The primary outcome is distance visual acuity at 6 months. Secondary outcomes include distance visual acuity at 3 and 24 months, near visual acuity at 3, 6, and 24 months, contrast sensitivity at 6 months, reading speed at 6 months, anatomical closure of the macular hole at each time point (1, 3, 6, and 24 months), health related quality of life (HRQOL) at six months, costs to the health service and the participant, incremental costs per quality adjusted life year (QALY) and adverse events. Discussion: FILMS will provide high quality evidence on the role of ILM peeling in FTMH surgery. Trial registration: This trial is registered with Current Controlled Trials ISRCTN number 33175422 and Clinical Trials.gov identifier NCT00286507.Chief Scientist Office, Scotland (project ref no CZH/4/235), NHS GrampianPeer reviewedPublisher PD

Randomised trial of glutamine and selenium supplemented parenteral nutrition for critically ill patients

Background: Mortality rates in the Intensive Care Unit and subsequent hospital mortality rates in the UK remain high. Infections in Intensive Care are associated with a 2–3 times increased risk of death. It is thought that under conditions of severe metabolic stress glutamine becomes "conditionally essential". Selenium is an essential trace element that has antioxidant and anti-inflammatory properties. Approximately 23% of patients in Intensive Care require parenteral nutrition and glutamine and selenium are either absent or present in low amounts. Both glutamine and selenium have the potential to influence the immune system through independent biochemical pathways. Systematic reviews suggest that supplementing parenteral nutrition in critical illness with glutamine or selenium may reduce infections and mortality. Pilot data has shown that more than 50% of participants developed infections, typically resistant organisms. We are powered to show definitively whether supplementation of PN with either glutamine or selenium is effective at reducing new infections in critically ill patients. Methods/design: 2 × 2 factorial, pragmatic, multicentre, double-blind, randomised controlled trial. The trial has an enrolment target of 500 patients. Inclusion criteria include: expected to be in critical care for at least 48 hours, aged 16 years or over, patients who require parenteral nutrition and are expected to have at least half their daily nutritional requirements given by that route. Allocation is to one of four iso-caloric, iso-nitrogenous groups: glutamine, selenium, both glutamine & selenium or no additional glutamine or selenium. Trial supplementation is given for up to seven days on the Intensive Care Unit and subsequent wards if practicable. The primary outcomes are episodes of infection in the 14 days after starting trial nutrition and mortality. Secondary outcomes include antibiotic usage, length of hospital stay, quality of life and cost-effectiveness. Discussion: To date more than 285 patients have been recruited to the trial from 10 sites in Scotland. Recruitment is due to finish in August 2008 with a further six months follow up. We expect to report the results of the trial in summer 2009. Trial registration: This trial is registered with the International Standard Randomised Controlled Trial Number system. ISRCTN87144826Not peer reviewedPublisher PD

Methods for specifying the target difference in a randomised controlled trial : the Difference ELicitation in TriAls (DELTA) systematic review

Peer reviewedPublisher PD

Developing a placebo-controlled trial in surgery:issues of design, acceptability and feasibility

BACKGROUND: Surgical placebos are controversial. This in-depth study explored the design, acceptability, and feasibility issues relevant to designing a surgical placebo-controlled trial for the evaluation of the clinical and cost effectiveness of arthroscopic lavage for the management of people with osteoarthritis of the knee in the UK. METHODS: Two surgeon focus groups at a UK national meeting for orthopaedic surgeons and one regional surgeon focus group (41 surgeons); plenary discussion at a UK national meeting for orthopaedic anaesthetists (130 anaesthetists); three focus groups with anaesthetists (one national, two regional; 58 anaesthetists); two focus groups with members of the patient organisation Arthritis Care (7 participants); telephone interviews with people on consultant waiting lists from two UK regional centres (15 participants); interviews with Chairs of UK ethics committees (6 individuals); postal surveys of members of the British Association of Surgeons of the Knee (382 surgeons) and members of the British Society of Orthopaedic Anaesthetists (398 anaesthetists); two centre pilot (49 patients assessed). RESULTS: There was widespread acceptance that evaluation of arthroscopic lavage had to be conducted with a placebo control if scientific rigour was not to be compromised. The choice of placebo surgical procedure (three small incisions) proved easier than the method of anaesthesia (general anaesthesia). General anaesthesia, while an excellent mimic, was more intrusive and raised concerns among some stakeholders and caused extensive discussion with local decision-makers when seeking formal approval for the pilot.Patients were willing to participate in a pilot with a placebo arm; although some patients when allocated to surgery became apprehensive about the possibility of receiving placebo, and withdrew. Placebo surgery was undertaken successfully. CONCLUSIONS: Our study illustrated the opposing and often strongly held opinions about surgical placebos, the ethical issues underpinning this controversy, and the challenges that exist even when ethics committee approval has been granted. It showed that a placebo-controlled trial could be conducted in principle, albeit with difficulty. It also highlighted that not only does a placebo-controlled trial in surgery have to be ethically and scientifically acceptable but that it also must be a feasible course of action. The place of placebo-controlled surgical trials more generally is likely to be limited and require specific circumstances to be met. Suggested criteria are presented. TRIAL REGISTRATION NUMBER: The trial was assigned ISRCTN02328576 through http://controlled-trials.com/ in June 2006. The first patient was randomised to the pilot in July 2007

Review of new regulations for the conduct of clinical trials of investigational medicinal products

The EU Clinical Trials Directive came into force on 1 May 2004 and has changed the face of Clinical Trials of investigational medicinal products in the UK. An enthusiastic registrar or consultant who comes up with an idea for a therapeutic intervention now needs to comply with a complex and demanding set of legal, ethical and regulatory requirements, contravention of which may lead to criminal proceedings. The aim of this review was to detail the relevant procedures and regulations and to provide a 'user-friendly' guide to obstetricians and gynaecologists wishing to conduct a clinical trial of an investigational medicinal product. Sources of further information are listed

Effect of apolipoprotein E genotype on hematoma volume after trauma

Object: the apolipoprotein E-epsilon4 (APOE-epsilon4) allele is associated with poor outcome after head injury and spontaneous intracerebral hemorrhage (SICH). The aims of this study were to determine if patients in whom one or more APOE-epsilon4 alleles are present are more likely to sustain intracranial mass lesions after head injury and to determine whether there is an isoform-specific effect on the size of the intracranial hematoma.Methods: the authors performed a computerized volumetric analysis of 142 hematomas visible on computerized tomography (CT) scans obtained in 129 patients. The APOE genotype was determined by subjecting buccal smear samples to polymerase chain reaction and restriction enzyme digestion.Allele frequencies were similar in head-injured patients with and without intracranial hematomas (p = 0.36). Univariate analysis revealed that in those patients with one or more APOE-epsilon4 alleles hematoma volume was greater (cube root-transformed values) than that found in patients without the APOE-epsilon4 allele (3.1 cm compared with 2.5 cm, p = 0.0039). The results of univariate analysis also suggested significant effects of patient age, injury severity (mild, moderate, or severe according to admission Glasgow Coma Scale scores) and hematoma location (extraaxial, intraaxial, or both) on hematoma volume. The mechanism of injury (assault, fall, or other) was marginally associated with hematoma volume (p = 0.052). Time from injury to CT scan, hypoxia, and hypotension had no significant effect on hematoma volume. The results of multiple linear regression analysis showed that the presence of an APOE-epsilon4 allele and an extraaxial hematoma location were independent predictors of hematoma volume, after adjusting for patient age, hours between injury and CT scan, injury severity, and injury mechanism.Conclusions: larger hematomas were found in head-injured patients with one or more APOE-epsilon4 alleles than in patients without the allele. This may contribute to the poorer outcomes observed in these patients