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.

Effectiveness and cost-effectiveness of arthroscopic lavage in the treatment of osteoarthritis of the knee: a mixed methods study of the feasibility of conducting a surgical placebo-controlled trial (the KORAL study).

OBJECTIVES: To ascertain the acceptability of a randomised controlled trial comparing arthroscopic lavage with a placebo-surgical procedure for the management of osteoarthritis of the knee; and to assess the practical feasibility of mounting such a multicentre placebo-controlled trial. DESIGN: Mixed methods study including: focus groups with surgeons and anaesthetists; focus groups and interviews with potential participants; interviews with chairpersons of UK Multicentre Research Ethics Committees (MRECs); surveys of surgeons and anaesthetists; and a two-centre, three-arm pilot. SETTING: UK secondary care. PARTICIPANTS: Members of the British Association of Surgeons of the Knee and members of the British Society of Orthopaedic Anaesthetists took part in the focus groups and surveys. Surgeons and anaesthetists from two regional centres in the UK also contributed to focus groups, as did patients from consultant lists in two UK regional centres, and members of Arthritis Care. Chairpersons of six UK MRECs were interviewed. Participants were eligible for the pilot if they were adults (18 years or older) with radiological evidence of osteoarthritis of the knee who might be considered for arthroscopic lavage, and were fit for general anaesthetic (defined by the American Society of Anaesthesiologists grades 1 and 2), and able to give informed consent. INTERVENTIONS: Participants in the pilot study were randomised to arthrosocopic lavage (with or without debridement at the clinical discretion of the surgeon); placebo surgery; or non-operative management with specialist reassessment. MAIN OUTCOME MEASURES: The acceptability and feasibility of mounting a placebo-controlled trial for the evaluation of knee arthroscopic lavage. RESULTS: There was broad acceptance across all stakeholder groups of the need to find out more about the effectiveness of arthroscopic lavage. Despite this there was variation in opinion within all the groups about how researchers should approach this and whether or not it would be acceptable to investigate using placebo surgery. Within the health professional groups, there tended to be a split between those who were strongly opposed to the inclusion of a placebo surgery arm and those who were more in favour. For prospective trial participants who had osteoarthritis of the knee, the acceptability of the trial was discussed from a more individual perspective - reflecting on their personal reasons for or against participating. The majority of this group said they would consider taking part. The pilot study showed that, in principle, a placebo-controlled trial could be conducted. It showed that patients were willing to participate in a trial which would involve a placebo-surgical arm and that it was possible to undertake placebo surgery successfully and to blind patients to their allocation - although once patients knew their allocation, some patients allocated to surgery became more concerned about the possibility of undergoing placebo surgery, and withdrew. The experience of the pilot, however, showed that, despite full MREC approval, the study required major discussion and negotiation before local clinical approvals could be obtained. The fact that ethics approval had been granted did not mean that clinicians would automatically accept that the process was ethical. CONCLUSIONS: The study showed that, in principle, a placebo-controlled trial of arthroscopic lavage could be conducted in the UK, albeit with difficulty. Against the background of falling use of arthroscopic lavage the decision was, therefore, taken not to proceed to full-scale trial for this procedure. The study showed that for some health professionals the use of placebo surgery can never be justified. It highlighted the importance of the surgeon-anaesthetist relationship in this context and how acceptance of the trial design by both parties is essential to successful participation. It also highlighted the importance of informed consent for trial participants and the strength and influence of individuals' ethical perspectives in addition to collective ethics provided by MRECs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02328576.

Outcome of adults with acquired immunodeficiency syndrome in Auckland 1983-9.

AIMS: To assess the survival of Auckland residents diagnosed with AIDS between 1983 and 1989. METHODS: Retrospective case review RESULTS: Sixty nine Auckland residents were diagnosed with AIDS between 1983 and the end of 1989, and were cared for by the infectious disease unit, Auckland Hospital. The overall median survival was 289 days with 48% and 20% surviving at one and two years respectively. Survival was longer among those who were infected through homosexual contact, were younger, and not known to the infectious disease unit prior to the diagnosis of AIDS. Although survival was longer for those diagnosed in 1988 compared to earlier years, it was shorter again for those diagnosed in 1989. Pneumocystis carinii pneumonia, the AIDS defining condition in 63.8% of people, was found less frequently in 1989, and overall was associated with a longer survival than most of the other AIDS-defining diagnoses. A quarter of the people were not known to be infected with HIV prior to the AIDS-defining condition. CONCLUSION: In New Zealand, as in other countries, changes in treatment strategies of people with HIV infection may impinge on the survival of people with AIDS.

Occurrence of AIDS in New Zealand: the first seven years. MRC AIDS Epidemiology Group.

The 179 people in New Zealand with AIDS diagnosed up to the end of 1989 and notified by 30 June 1990 are reviewed. Retrospective data collection provided the first available information on date of diagnosis, ethnic affiliation, district of usual residence, and survival. Of the 179 people with AIDS, 173 were male. AIDS occurred most commonly between the ages of 30 and 50, but there were two children under 10. The standardised cumulative incidence rates (per 100,000) in the European, Maori, and Pacific Island populations were 5.3, 4.5, and 5.5, respectively. The majority affected (154) were men who had had sexual contact with men. Three of five intravenous drug users also reported such contact. Smaller numbers were presumed to have been infected through heterosexual contact (7), treatment of haemophilia (3), blood transfusions (2), or perinatally (1). In seven cases the mode of transmission was unknown. The proportion of people who had been living overseas when first diagnosed was initially high but declined, so that 134 were known to have been diagnosed in New Zealand. Of these, 107 lived in Auckland or Wellington. Survival analysis using the Kaplan-Meier method showed that the median time from diagnosis to death was 58 weeks.

Pharmacokinetics and effect on blood pressure of doxazosin in normal subjects and patients with renal failure.

The antihypertensive efficacy and pharmacokinetics of a single 1 mg oral dose of doxazosin were investigated in five healthy male volunteers, six patients with renal failure not on hemodialysis, and four patients with end-stage renal failure studied between two hemodialyses. The dialyzability of doxazosin was studied in five patients. The maximum fall in blood pressure of both volunteers and patients occurred between 4 and 8 hours. In four of five volunteers the blood pressure had returned to baseline within 10 to 12 hours, whereas in the patients with renal failure it took as long as 72 hours. Maximum plasma concentrations were reached in 2.6 to 3.6 hours. The mean AUC did not differ significantly between the groups. The mean (SE) elimination t1/2 was 12.6 hours (3.3) in the volunteers and 13.3 hours (1.8) in the patients with renal insufficiency (not significant). Doxazosin was not appreciably dialyzable.

Effect of oral penbutolol on renal haemodynamics of hypertensive patients with renal insufficiency.

Acute or chronic administration of most beta-adrenoreceptor blocking drugs is associated with a fall in renal blood flow and glomerular filtration rate. In patients with renal insufficiency this effect on renal function may be clinically important. Penbutolol is a non-cardioselective, pure laevo, beta-blocker with intrinsic sympathomimetic activity. Previous studies have suggested that penbutolol may increase the glomerular filtration rate. In this study eight hypertensive patients with renal insufficiency were studied during a three-week placebo period and then for four weeks while taking penbutolol in a dose of 40 or 80 mg daily. Penbutolol produced a fall in the pulse rate in all eight patients. Five of the eight patients had a fall in their supine and standing blood pressure. Effective renal plasma flow and glomerular filtration rate did not change significantly. In seven of the eight patients there was a fall in the calculated renal vascular resistance but the mean fall did not reach statistical significance. Penbutolol appears to be an effective beta-blocker and one that could be used appropriately in patients with renal insufficiency.