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Overview of some fundamental designs for clinical trials and studies. Some tentative definitions are given in order to stimulate questions and perspectives for further research.
The aim of this study was to assess the usefulness of prophylactic antibiotics during insertion of a cardiac pacemaker, in order to avoid infection of exteriorisation of infectious origin. The study involved two groups. One hundred and eight patients made up group I, a control group without the use of prophylactic antibiotics. Group II consisted of 101 patients who were given an intravenous injection of 1 or 2 g of oxacillin before surgery, followed up by four days of oral oxacillin (3 g per day). Serum oxacillin levels at the end of the procedure were 0.37 +/- 0.09 mcg/ml, falling within the range of minimum inhibitory concentrations of methicillin-sensitive staphylococci. In the patients of the control group, followed up for 1 to 36 months (mean 12 +/- 11 months), during the first 2 months there were 2 infections, 4 exteriorisations and one cutaneous erosion over the pacemaker. In addition, one exteriorisation and one infection occurred at 17 and 29 months respectively. In patients with exteriorisation of their pacemaker device, there was nothing to suggest an infection and bacteriological specimens were sterile. No obvious infections nor any cutaneous complications occurred in the patients of group II, with prophylactic antibiotics, followed up for 1 to 21 months (mean 6 +/- 5 months). In conclusion, anti-staphylococcal antibiotic treatment appears not only to be capable of avoiding cardiac pacemaker infections but also of preventing exteriorisation of the pacemaker device, which may be linked to hidden infections. A randomised study is nevertheless necessary to confirm this hypothesis.
BACKGROUND: Oral lichen planus is a chronic autoimmune disease of unknown aetiology that affects the inner surface of the mouth. The symptomatic forms are painful,tend to worsen with age and with remissions being rare. Current treatment is palliative and not curative, many topical and systemic agents have been tried with little hard evidence for efficacy. OBJECTIVES: To assess the effectiveness and safety of any form of palliative therapy against placebo for the treatment of symptomatic oral lichen planus. SEARCH STRATEGY: Electronic databases, handsearching of conference proceedings and specific journals, researchers in the field, drug manufacturers. SELECTION CRITERIA: Any placebo-controlled trial of palliative therapy for symptomatic oral lichen planus, using a randomised or quasi-randomised design that measured changes in symptoms and/or clinical signs. DATA COLLECTION AND ANALYSIS: Change in symptoms (pain, discomfort) and clinical signs (visual impression, lesion measurements) at the end of therapy. Odds ratio of improvement vs no improvement for each trial outcome and pooling where appropriate. MAIN RESULTS: A total of nine RCTs were identified. The nine interventions were grouped into four separate classes (cyclosporines, retinoids, steroids and phototherapy) for comparison. No therapy was replicated exactly, the closest replication involved two trials using high and low dose cyclosporine mouthwash. Only trials recording the same outcomes in each therapeutic class were pooled. The largest number of pooled trials was three. Large odds ratios with very wide confidence intervals indicating a statistically significant treatment benefit were seen in all trials. However this has to be tempered by considerations of the small study sizes, the lack of replication, the difficulty in measuring outcome changes and the very high likelihood of publication bias. Only systemic agents were associated with treatment toxicities, all other side-effects were mild and mainly limited to local mucosal reactions. REVIEWER'S CONCLUSIONS: The review provides only weak evidence for the superiority of the assessed interventions over placebo for palliation of symptomatic OLP. The results highlight the need for larger placebo-controlled RCTs with more carefully selected and standardised outcome measures before between-treatment comparisons can be properly interpreted.
BACKGROUND: Pneumonia is an important cause of mortality in intensive care units. The incidence of pneumonia in such patients ranges between 7 and 40%, and the crude mortality from ventilator associated pneumonia may exceed 50%. Although not all deaths in patients with this form of pneumonia are directly attributable to pneumonia, it has been shown to contribute to mortality in intensive care units independently of other factors that are also strongly associated with such deaths. OBJECTIVES: The objective of this review was to assess the effects of antibiotics for preventing respiratory tract infections and overall mortality in adults receiving intensive care. Search strategy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 3, 2003), which contains the Acute Respiratory Infections (ARI) Group specialised trials register; MEDLINE (January 1966 to September 2003); EMBASE (January 1990 to September 2003); proceedings of scientific meetings and reference lists of articles from January 1984 to December 2002. We also contacted investigators in the field. Selection criteria. Randomised trials of antibiotic prophylaxis for respiratory tract infections and deaths among adult intensive care unit patients. Data collection and analysis. At least two reviewers independently extracted data and assessed trial quality. RESULTS: Overall 36 trials involving 6922 people were included. There was variation in the antibiotics used, patient characteristics and risk of respiratory tract infections and mortality in the control groups. In 17 trials (involving 4295 patients) that tested a combination of topical and systemic antibiotic, the average rates of respiratory tract infections and deaths in the control group were 36% and 29% respectively. There was a significant reduction of both respiratory tract infections (odds ratio 0.35, 95% confidence interval [CI] 0.29-0.41) and total mortality (odds ratio 0.78, 95% CI 0.68-0.89) in the treated group. On average 5 patients needed to be treated to prevent one infection and 21 patients to prevent one death. In 17 trials (involving 2664 patients) that tested topical antimicrobials alone (or comparing topical plus systemic versus systemic alone) the rates of respiratory tract infections and deaths in the control groups were 30 and 26% respectively. There was a significant reduction of respiratory tract infections (odds ratio 0.52, 95% CI 0.43-0.63), but not in total mortality (odds ratio 0.97, 95% CI 0.81-1.16) in the treated group. CONCLUSIONS: A combination of topical and systemic prophylactic antibiotics reduces respiratory tract infections and overall mortality in adult patients receiving intensive care. A treatment based on the use of topical prophylaxis alone reduces respiratory infections, but not mortality. The risk of occurrence of resistance as a negative consequence of antibiotic use was appropriately explored only in the most recent trial by de Jonge, which did not show any such effect.
OBJECTIVE: To examine the sensitivity and precision of Medline searching for randomised clinical trials. DESIGN: Comparison of results of Medline searches to a "gold standard" of known randomised clinical trials in ophthalmology published in 1988; systematic review (meta-analysis) of results of similar, but separate, studies from many fields of medicine. POPULATIONS: Randomised clinical trials published in 1988 in journals indexed in Medline, and those not indexed in Medline and identified by hand search, comprised the gold standard. Gold standards for the other studies combined in the meta-analysis were based on: randomised clinical trials published in any journal, whether indexed in Medline or not; those published in any journal indexed in Medline; or those published in a selected group of journals indexed in Medline. MAIN OUTCOME MEASURE: Sensitivity (proportion of the total number of known randomised clinical trials identified by the search) and precision (proportion of publications retrieved by Medline that were actually randomised clinical trials) were calculated for each study and combined to obtain weighted means. Searches producing the "best" sensitivity were used for sensitivity and precision estimates when multiple searches were performed. RESULTS: The sensitivity of searching for ophthalmology randomised clinical trials published in 1988 was 82%, when the gold standard was for any journal, 87% for any journal indexed in Medline, and 88% for selected journals indexed in Medline. Weighted means for sensitivity across all studies were 51%, 77%, and 63%, respectively. The weighted mean for precision was 8% (median 32.5%). Most searchers seemed not to use freetext subject terms and truncation of those terms. CONCLUSION: Although the indexing terms available for searching Medline for randomised clinical trials have improved, sensitivity still remains unsatisfactory. A mechanism is needed to "'register" known trials, preferably by retrospective tagging of Medline entries, and incorporating trials published before 1966 and in journals not indexed by Medline into the system.
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Twenty two patients were entered into a randomised controlled clinical trial comparing the efficacy of somatostatin and vasopressin in controlling acute variceal haemorrhage. Somatostatin was significantly more successful in controlling acute variceal haemorrhage than vasopressin (p = 0.003). Furthermore, no complications were observed during treatment with somatostatin.
Results from British trials of phenobarbitone and valproate for the prophylactic treatment of febrile convulsions were pooled and analysed on an intention to treat basis. The overall odds ratio for phenobarbitone was 0.8 and for valproate 1.42. Neither result was significant. Neither treatment can be recommended in the light of experience.
OBJECTIVES: In the majority of clinical trials patients are randomised equally between treatment groups. This approach maximises statistical power for a given total sample size. The objectives of this paper were to determine if, when research costs between treatments differ, it is more economically efficient to randomise additional patients to the cheaper treatment, and how the optimum randomisation ratio can be estimated. METHODS: Estimation of the most economically efficient randomisation ratio for four hypothetical clinical trials using cost-effectiveness analysis. RESULTS: When research costs differ between treatments, and there is no constraint on total sample size, it is always more cost-effective to randomise more patients to the cheaper treatment. For example, a cost ratio between the lesser and more expensive treatment of ten, results in a randomisation ratio of 3.2:1. CONCLUSIONS: Unequal randomisation ratios should be more widely used as this will achieve optimum statistical power for the lowest expenditure of research resources.
Mitiglinide [KAD 1229, S 21403], a derivative of benzylsuccinic acid, is a potassium channel antagonist undergoing development with Kissei for the treatment of type 2 diabetes mellitus. It has potent oral hypoglycaemic activity and is structurally different from the sulphonylureas, although it stimulates calcium influx by binding to the suphonylurea receptor on pancreatic beta-cells and closing K+ATP channels. Mitiglinide belongs to a family of meglitinide analogues that also includes repaglinide and nateglinide. Mitiglinide is licensed to Servier for Europe, where it is undergoing phase III development, and for Russia, the Commonwealth of Independent States, the Baltic Republics, the Middle East, Oceania, China (including Hong Kong) and Taiwan. Kissei exclusively licensed mitiglinide to Choongwae Pharma for South Korea in March 2003. In August 2002, Kissei and Takeda entered into a co-marketing agreement for mitiglinide in Japan. The companies will co-market the agent under a single brand name. Mitiglinide was licensed to Purdue Pharma for the US, Canada, Mexico and Central and South America. However, Kissei and Purdue Pharma terminated their agreement in February 2001 following Purdue Pharma's decision to concentrate on core areas such as oncology and analgesics. Kissei's US subsidiary, Kissei Pharma US, is currently carrying on the ongoing phase II clinical development in the US. However, in its Annual Report 2003, Kissei announced that it is considering outlicensing mitiglinide for development in marketing in North America. Mitiglinide has been recommended for approval in Japan for the management of postprandial hyperglycaemia in patients with type 2 diabetes. Kissei is also conducting phase II/III clinical trials with a combination of mitiglinide and an alpha-glucosidase inhibitor (additional indication) in patients with type 2 diabetes in Japan. In the US, the agent is being evaluated in phase II clinical trials with Kissei Pharma USA. Mitiglinide is also undergoing a phase-III, 12-month, multicentre, randomised, double-blind study in a total of 710 patients in comparison with repaglinide for the treatment of type 2 diabetes. This study will be followed by a 12-month open-label treatment with mitiglinide alone or in combination therapy. Servier (Australia) conducted a randomised, double-blind, multicentre phase III study in Australia comparing mitiglinide with metformin or a combination of the two for the treatment of type 2 diabetes.
A review of current treatment options in multiple myeloma is presented, including data on health-related quality of life and pharmacoeconomics. For induction chemotherapy, no combination of cytostatic drugs has been shown to be consistently superior to the simple cyclic oral treatment with melphalan and prednisone that has been available for 30 years. The total resource consumption and direct costs per patient treated with melphalan and prednisone is approximately $US10,000 (1995 values). As median survival is prolonged from less than a year in untreated patients to 30 to 36 months, this treatment must be considered cost effective. Interferon-alpha has a modest effect on progression-free and overall survival when added to chemotherapy regimens. However, the high cost and toxicity of this drug results in an unfavourable cost-utility ratio, estimated to be between $US50,000 to $US100,000 per quality-adjusted life-year gained. Clinical trials suggest that high dose chemotherapy followed by autologous stem cell support administered to patients who have achieved disease stabilisation or objective response to conventional induction chemotherapy, prolongs median survival by about 1.5 years. Preliminary cost-utility analyses suggest a cost per life-year gained of $US30,000 to $US40,000. Further potential improvements of this therapeutic modality are under way. Several bisphosphonates have been tested for the ability to prevent the skeletal complications of multiple myeloma. Monthly infusions of pamidronate have been shown in 1 randomised trial to significantly reduce the rate of skeletal complications. Unfortunately, the rapid and widespread acceptance of this therapy seems to preclude further prospective, placebo-controlled trials with cost-utility evaluation.
OBJECTIVES: To determine the current efficacy of type of surgery in the treatment of obstructive sleep apnoea. SEARCH STRATEGY: Electronic searches of the Cochrane Airways Group Sleep Apnoea RCT Register, MEDLINE, EMBASE and Cinahl. The references of relevant review articles were handsearched. Experts in the field were contacted to identify unpublished studies. SELECTION CRITERIA: The inclusion criteria were all randomised or quasi-randomised controlled comparisons of any surgical intervention for obstructive sleep apnoea versus other surgical or non-surgical intervention for obstructive sleep apnoea or no intervention. DATA COLLECTION AND ANALYSIS: No completed RCTs were identified by the search. MAIN RESULTS: A total of 666 articles were identified and assessed. No articles fulfilled the inclusion criteria. CONCLUSIONS: A thorough search with broad inclusion criteria yielded no evidence from randomised controlled trials to support the use of surgery in the treatment of obstructive sleep apnoea. Patients should be made aware of the lack of good trial-based evidence for the operations. An urgent need for high quality RCTs in this area was identified.
BACKGROUND: Combining radiation and hormone therapy (administration of selective estrogen receptor modulators) has become common clinical practice in recent years for receptor positive breast cancer. Little is known about a possible interaction of both treatment modalities if they are given simultaneously. Tamoxifen (antiestrogen molecule, triphenylethylene derivative) may theoretically render cancer cells less responsive to radiotherapy arresting hormone-receptor-positive cells in G0/G1 phase and increase the risk of breast and lung fibrosis stimulating the secretion of transforming growth factor beta in human fibroblasts. PURPOSE: This article reviews the published data to assess the impact of sequencing of hormonal and radiation therapy on outcomes in breast cancer. METHODS: Computerised searches for publications debating the sequencing of hormonal therapy relative to radiation therapy were done using MEDLINE data. RESULTS: Results of tamoxifen experiments with cell culture regarding radioprotection of tumour clonogens are conflicting. In contrast to in vitro results, in animal studies no protective effect of tamoxifen was observed. In one in vitro study, letrozole (non-steroid selective aromatase inhibitor) had a radiosensitizing effect on breast-cancer lines. No randomised clinical trials to date have studied sequencing of tamoxifen or other selective estrogen receptor modulators and radiotherapy. Results from retrospective clinical studies which included treatment arms with and without tamoxifen showed reduction in tumour recurrence with tamoxifen. Some of these studies have noted increased risk of lung and breast fibrosis with tamoxifen with radiotherapy. Results of three articles examined the effect of tamoxifen sequence showed no adverse effect on local control or survival in sequential versus concurrent tamoxifen and radiation patients. One of the three studies also assessed the risk of complications with respect to the timing of tamoxifen with radiotherapy. There was no difference in the rates of complications between the two groups. The association of radiation and selective aromatase inhibitors or aromatase inactivators has not been addressed in clinical studies. CONCLUSIONS: Combined application of tamoxifen and radiotherapy improves survival and local control in breast cancer. Available clinical studies do not indicate that the simultaneous application of tamoxifen and radiotherapy is disadvantageous, as was suggested by some of the in vitro studies. The risk of subcutaneous breast and lung fibrosis might be slightly increased if tamoxifen is given simultaneously with radiotherapy. Both treatment modalities should be started early after surgery. There is no sufficient evidence to withhold tamoxifen administration during irradiation of breast cancer. The issue of optimal sequencing of hormonal and radiotherapy should be addressed in randomised clinical trials.
Atherothrombotic cardiovascular disease is a leading cause of death in women, especially in the postmenopause. It is controversial whether postmenopausal hormone replacement therapy is protective with regard to cardiovascular disease. On the one hand, observational studies consistently show that the risk of cardiovascular disease is 35 to 50% lower among users of hormonal replacement than among non-users. In addition, hormonal replacement is associated with an improvement of the lipid profile and several other potentially beneficial effects. On the other hand, two recent placebo-controlled randomised trials did not find evidence in favour of cardiovascular protection by hormonal replacement. This discrepancy may be explained by insufficient adjustment for lifestyle factors in observational studies and insufficient consideration of methodological flaws in experimental studies, both of which lead to an overestimation of the protective effect of hormonal replacement. Hormonal replacement may affect the pathophysiology of atherothrombosis in several ways, both positive and negative. Progress in this field requires the isolation of the positive effects.
The clinical application of a new method for using the insect growth regulator, pyriproxyfen, for controlling flea populations in cat-owning homes is evaluated for the first time. In a multicentric, controlled and randomised trial, 107 flea-infested cats were treated with a minimum dose of 10 mg/kg bodyweight pyriproxyfen as a 10 per cent spot-on application on two occasions, with a three-month interval between doses. For comparison, 99 cats received lufenuron suspension orally, once a month, for six months. Flea counts decreased significantly over time in each group and were significantly lower in the pyriproxyfen group than in cats treated with the reference product. The percentage of 'zero-flea' cats increased from 49 per cent on day 30 to 88 per cent on day 180 in the pyriproxyfen group and from 30 to 71 per cent in the lufenuron group at the same time points (P<0.05). Appropriately timed topical applications of pyriproxyfen, therefore, offer a method of flea control in the domestic environment.
Local control and sphincter preservation are the two challenges of anal canal cancer treatment. These tumors are radio- and chemo-sensitive and treatment moved from surgical approach, with abdominoperineal resection, to definitive radiation therapy with or without concurrent chemotherapy. Randomised trials proved the benefit of combined modality with chemoradiotherapy and of mitomycine C (MMC) compared with radiotherapy alone, with a toxic death rate of about 2%. Indications of chemoradiotherapy are locally advanced tumor T2 > or = 4 cm, T3-4 or N1-3 but the best modalities of combined treatment are still under debate. Standard chemotherapy is 5 flurouracile (5FU) + MMC, but cisplatinum (CDDP) is an effective and well tolerated substitute for MMC. Favourable results with CDDP-containing regimen in term of toxicity and carcinologic control have been reported in phase II and retrospective studies. Total radiation dose, overall duration of radiation therapy, duration of the gap and indications of additional boost are not clear, but it is demonstrated that overall duration of treatment should be as short as possible to improve the therapeutic radio. Phase II and III studies are ongoing, to evaluate the best chemotherapy regimen between 5FU+MMC and 5FU+CDDP, the benefit of neoadjuvant or maintenance chemotherapy and the interest of increased total dose. Next future could be the utilisation of oral 5FU. This article is a review of past randomised trials, phases II and retrospective study on radiochemotherapy of anal canal carcinoma.
Anaemia is a key component of diabetic nephropathy, but its importance has only recently been recognised. Recombinant human erythropoietin (epoetin) is an established treatment for renal anaemia, and may help to reduce complications associated with diabetic nephropathy, such as cardiovascular disease. The limited experience with the use of epoetin in this patient group prompts the urgent need for clinical data on anaemia correction in early diabetic nephropathy, particularly with regard to benefits on cardiovascular risk reduction. The Anaemia CORrection in Diabetes (ACORD) study will investigate the effects of anaemia correction on cardiac structure and function in patients with early diabetic nephropathy. This 15-month multicentre study will recruit 160 adult patients with diabetes, mild or moderate chronic kidney disease (with creatinine clearance >or=30 ml/min at screening) and moderate anaemia (haemoglobin [Hb], 10.5-13.0 g/dl). Patients will be randomised to one of two groups: the early treatment group will receive subcutaneous epoetin beta (NeoRecormon) at study entry to maintain target Hb levels of 13-15 g/dl, while the control group will reflect current practice and will not receive epoetin therapy until Hb levels decline below 10.5 g/dl. The primary efficacy variable, change in left ventricular mass index, will be evaluated at 15 months following randomisation; secondary efficacy variables will include changes in cardiac structure and function over the study period. The ACORD study should provide valuable information on the benefits of anaemia correction in patients with early diabetic nephropathy. The study will also increase awareness of the importance of treating anaemia associated with diabetes.
Operative treatment of intra-articular calcaneal fractures with anatomical reduction and early mobilisation has lead to a considerable improvement of the functional results of these severe injuries over the recent two decades. New tendencies like modified approaches tailored according to the vascular anatomy, arthroscopic control of joint reduction in conjunction with open or percutaneous procedures, early flap coverage for severe open fractures or closed fractures with full thickness skin necrosis, the use of interlocking plates that further minimises the need of bone grafting and subtalar arthrolysis at the time of hardware removal for fibrous overgrowth have the potential for further improvement of the outcome. The observation from several comparative studies that operative treatment leads to superior results in displaced intra-articular calcaneal fractures has been qualified in a recent prospective, randomised multicentre trial. This paper presents and the authors' experience with the demanding operative treatment of these fractures together with new developments aiming at improving the clinical results.