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INTRODUCTION: Megatrials are large-scale randomised controlled clinical trials recruiting thousands of patients from large numbers of trial sites with the aim of providing reliable evidence on clinical outcomes of treatments. This review describes the characteristics, strengths and limitations of megatrials. METHODS: Review of the literature on methodology of megatrials was performed after searching the MEDLINE database. RESULTS: Megatrials are based on a pragmatic trial philosophy, and usually feature broad eligibility criteria, simple trial design, uncomplicated treatment regimes, routine clinical monitoring and adjunctive care, and streamlined data collection on clinical outcomes. An intention-to-treat analytical approach is normally used. The main strength of the megatrial is its ability to reliably detect moderate differences in important clinical outcomes. Biases are avoided by utilising the principles of randomised treatment allocation, blinding where possible and objectivity in assessment of outcomes. The megatrial is able to more precisely estimate treatment effects by using data from large numbers of patients. Results can be more readily generalised because of the wider spectrum of patients studied. Also, megatrials have an advantage over meta-analysis in that there is less heterogeneity. The assumption of qualitative homogeneity of effects underlying the interpretation of megatrial results is reasonable with proper selection of the trial population. Complex clinical and non-clinical outcomes are difficult to measure in megatrials. Hence, megatrials are unable to provide much insight into the mechanism(s) of action of drugs. Smaller explanatory trials or sub-studies designed to provide biological insight could usefully complement megatrials. CONCLUSION: Megatrials can provide reliable large-scale randomised controlled clinical trial (RCT) evidence of moderate treatment benefits. They are well complemented by smaller explanatory trials.
The primary source of scientific evidence are well designed and well executed randomised controlled clinical trials. However, the sources of scientific evidence are multifaceted. The concept of evidence based medicine is wider, encompassing the best available scientific data, the preference of patients and the professional experience of physicians. Decisions on therapies or other types of interventions are based on these three components. The authors give an overview of the evaluation of the results of randomised controlled clinical trials and present an easily applicable assessment list for practising physicians.
OBJECTIVE: Immunotherapy, and only immunotherapy, has reproducible, albeit limited efficacy in metastatic renal cell cancer (MRCC). Further improvement is warranted and progress will have to be investigated in randomised clinical trials, because the variable natural history of this disease precludes firm conclusions outside the context of controlled clinical studies. Currently, there is no general accepted standard arm to compare for those randomised clinical protocols. This needs to be established, which is the goal of this project. MATERIALS AND METHODS: Interferon-alpha (IFN-alpha) or interleukin-2 (Il-2) are registered for the use in MRCC. Taking this regulatory affair into consideration, a systematic literature research using Medline Sources was carried out to identify large controlled clinical studies in MRCC, in which one or both of the registered drugs were involved. Scientific value of the trials was weighed, and the applicability, efficacy, and safety of the control arm was analysed. RESULTS: 13 large controlled studies qualified for this purpose, and a total of 3065 patients were included. IFN-alpha monotherapy, the combination of IFN-alpha and Il-2, and the combination of IFN-alpha, Il-2 and 5-fluorouracil (5-FU) were used as a standard treatment in decreasing frequency, respectively. There is no valid scientific proof that a combination of immunotherapies prolongs survival over monotherapies, but the combination of surgery and immunotherapy leads to a clear survival benefit over immunotherapy alone. IFN-alpha monotherapy has considerable less side effects than Il-2 based regimens. CONCLUSION: An appealing safety profile, the applicability in an outpatient regimen, the possibility of less stringent selection criteria, and the proven life prolonging effect will make adjuvant monotherapy, in particular IFN-alpha monotherapy, after a tumournephrectomy currently the control-arm of choice in randomised trials for MRCC.
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The purpose of this study was to compare, from a societal perspective, the cost effectiveness of topical prednicarbate 0.25% and fluocortin 0.75% in the treatment of inflammatory dermatoses, such as dermatitis and eczema, in Spain. Effectiveness and tolerability were determined by means of a meta-analysis of 17 randomised double-blind controlled clinical trials, using a MEDLINE search and a second-level reference search. The data were obtained on the basis of a per-protocol assessment system, and the Mantel-Haenszel method (as modified by Peto) was used to make the statistical analysis. In terms of economic assessment, a model was developed in which the expected total cost was determined by the cost of the medicine (adjusted to the recommended dosage) plus the costs derived from the ineffectiveness and/or adverse effects associated with the different treatments. A sensitivity analysis was carried out on the basis of changes in: (i) clinical effectiveness; (ii) price of prednicarbate; (iii) incidence of adverse reactions; (iv) costs associated with ineffectiveness and/or adverse effects; and (v) the regimen under which prednicarbate was administered. The meta-analysis showed that there was a statistically significant difference between the 2 alternatives (p = 0.001). The value of a combined odds ratio [and 95% confidence interval (95% CI)] for the combined studies of prednicarbate was 1.54 (95% CI 1.10 to 2.15), compared with 0.73 (95% CI 0.60 to 0.89) for fluocortin relative to moderate or moderate-to-high potency corticosteroids. Effectiveness was 84.9% for prednicarbate and 69.7% for fluocortin, while frequency of adverse effects was 3.5% for prednicarbate and 4.9% for fluocortin. The total expected cost per patient treated was found to be 4600 Spanish pesetas (Pta) [$US37.10; 1996 values] for prednicarbate and Pta5778 ($US46.60; 1996 values) for fluocortin. The total expected cost per patient successfully treated was Pta5608 ($US45.20) for prednicarbate and Pta8680 ($US70) for fluocortin. Prednicarbate has been shown to have a favourable cost-effectiveness ratio, when compared with fluocortin, for the treatment of dermatitis and eczema in Spain. Additional pharmacoeconomic studies on topical corticosteroids are required, including the use of new variables, long term analysis and/or the measurements of the effect of the drug on patients' quality of life.
BACKGROUND: Heated, humidified air is used by common cold sufferers since the invention of the steam kettle. There is scientific literature available investigating this mode of therapy using a rhinotherm. The present reviews addresses to the use of hot, humid air in common cold. OBJECTIVES: To assess the effects of inhaling heated water vapour with the help of a rhinotherm (an equipment designed to deliver heated water vapour to a person's nasal cavity), in the treatment of the common cold by comparing: a. symptoms b. viral shedding c. nasal resistance after a natural or experimentally induced common cold. SEARCH STRATEGY: In the initial review published in issue 3, 1999 of The Cochrane Library, we searched MEDLINE with MeSH headings: common cold, rhinopharyngitis, inhalation, steam, heated vapour, rhinothermy (January 1966 to July 1999). EMBASE, Current Contents, review articles, cross references were also searched. Attempts were also made to contact the manufacturers for any unpublished data. In this updated review, we have searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2003), MEDLINE (January 1966 to November Week 2, 2003), EMBASE (January 1990 to November 2003), and Current Contents (current five years). SELECTION CRITERIA: Randomized trials using heated water vapour in a standardized way in patients with the common cold or volunteers with experimental induction of rhinovirus infection were included in the review. DATA COLLECTION AND ANALYSIS: All the articles retrieved were initially subjected to a review for inclusion / exclusion criteria. Review articles, editorials, abstracts with inadequate outcome description were excluded. Studies selected for inclusion were subjected to a methodological assessment. MAIN RESULTS: The results of a systematic review of six trials with 319 participants, support the use of warm vapour inhalations in the common cold in terms of relief of symptoms (Odds Ratio with 95 % CI 0.31, 0.16-0.60, Relative risk 0.56, 0.4-0.79). Results on symptom score indices were equivocal. None of the studies demonstrated a worsening of clinical symptom scores. One study demonstrated increased nasal resistance one week after steam inhalation in contrast to an earlier study which showed improvement in the nasal resistance. There was no evidence of decreased viral shedding measured by virus isolation in the nasal secretions (Tyrrell 1989a) or measurement of viral titres in nasal washings among treatment group. The rhinovirus titres in the nasal washings from the treatment group were the same as those of the placebo group on day one prior to the treatment and on all four days after the treatment. The area under curve (Hendley 1994) was also similar in the placebo and treatment groups for titres of virus in the nasal washings as were the average viral titres across five days of follow up, the maximum values after treatment, and viral shedding velocity i.e. amount of virus shed per day (Hendley 1994). Minor side effects due to thermal stress were reported in all the studies. REVIEWERS' CONCLUSIONS: Three trials demonstrated beneficial effects on the symptoms of the common cold. One study from Israel showed a decrease in nasal resistance measured by peak nasal expiratory and inspiratory flow rate. Studies done in North America failed to show any objective improvement in outcome measures with the study intervention. A multi-centre double blind randomised controlled trial testing this therapy with uniform outcome measures is recommended.
BACKGROUND: Pseudomonas aeruginosa is the commonest micro-organism associated with respiratory infections in cystic fibrosis. Retrospective studies have suggested that survival is increased by using an aggressive policy of intravenous antipseudomonal antibiotics at regular intervals, irrespective of symptoms. OBJECTIVES: To determine whether there is evidence that an elective (regular) versus symptomatic intravenous antibiotic regime is associated with an improvement in clinical status and survival rates in patients with cystic fibrosis. To identify any adverse effects associated with the use of elective intravenous antibiotics, including an increase in the development of resistant organisms. SEARCH STRATEGY: The Cochrane Cystic Fibrosis and Genetics Disorders Group Specialist Trials Register was used. This comprises references identified from comprehensive electronic database searches, hand searching relevant journals and abstracts from conference proceedings. Date of the most recent search of the Group's specialised register: October 2000. SELECTION CRITERIA: All randomised or pseudo-randomised controlled trials describing the use of elective compared with symptomatic intravenous antibiotic policies for any duration or dose regimen. Elective versus symptomatic intravenous antibiotic regimes against any organisms were considered. Patients with cystic fibrosis were of any age or disease severity. DATA COLLECTION AND ANALYSIS: Trials were independently assessed for inclusion criteria, methodological quality and data extraction by the two reviewers. MAIN RESULTS: Three trials were identified by the initial search. Two trials reporting results from a total of 79 patients were included in the review. Differences in study design and objectives meant that data could not be pooled for meta-analysis. Neither trial demonstrated significant differences in outcome measures between intervention and comparison groups. REVIEWER'S CONCLUSIONS: Studies are insufficient to identify conclusive evidence favouring a policy of elective intravenous antibiotic administration, despite its widespread use. Neither are the potential risks adequately evaluated. The results should be viewed with caution as patient numbers are small. Clearly there is a need for a well-designed, adequately powered, multi-centred randomised controlled trial to evaluate these issues.
BACKGROUND: The use of non-invasive ventilation (NIV) has been proposed as a means to temporarily reverse or slow the progression of worsening respiratory failure in cystic fibrosis (CF). OBJECTIVES: To compare the effect of NIV versus no NIV in people with CF. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. The reference lists of each trial were searched for additional publications that may contain other trials. Date of most recent search: January 2002. SELECTION CRITERIA: Relevant randomised controlled trials in which a form of pressure preset or volume preset NIV versus no NIV was used in people with acute or chronic respiratory failure in CF. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trials for inclusion criteria, methodological quality and data extraction. MAIN RESULTS: Six trials were identified and four trials met the inclusion criteria with a total of 55 participants. All of these trials only evaluated single treatment sessions. Two trials (36 participants) evaluated the use of NIV for airway clearance compared with an alternative physiotherapy method. These trials showed that airway clearance may be easier and people with CF may prefer to use NIV for airway clearance. There was no evidence that NIV increases sputum expectoration or improves lung function. Two trials (19 participants) evaluated the use of NIV for overnight ventilatory support. Of the primary outcomes examined in this review, only lung function was evaluated within the two trials. Due to the small numbers of participants and the differing statistical techniques used within the review and the primary trials, there were discrepancies in the results obtained by the RevMan analysis and the original trial analysis. No clear differences were found between NIV compared with either oxygen or room air. REVIEWER'S CONCLUSIONS: Non-invasive ventilation may be a useful adjunct to other airway clearance techniques, particularly in people with CF who have difficulty expectorating sputum. Non-invasive ventilation when used in addition to oxygen may improve gas exchange during sleep to a greater extent than oxygen therapy alone in moderate to severe disease. These benefits of NIV have only been demonstrated in single treatment sessions and its efficacy, safety and acceptability in the longer term are unknown. There is a need for long-term randomised controlled trials to determine the clinical effects of non-invasive ventilation in CF.
BACKGROUND: Lambert-Eaton myasthenic syndrome is an autoimmune presynaptic disorder of neuromuscular transmission. Treatments attempt to overcome the harmful autoimmune process, or to improve residual neuromuscular transmission, in order to reverse muscle weakness. OBJECTIVES: The objective was to examine the efficacy of treatment in Lambert-Eaton myasthenic syndrome. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (December 2004), MEDLINE (January 1966 to December 2004) and EMBASE (January 1980 to December 2004), and checked bibliographies and contacted authors to identify additional published or unpublished data. SELECTION CRITERIA: All randomised or quasi-randomised trials of adults and children with a diagnosis of Lambert-Eaton myasthenic syndrome, with or without small-cell lung cancer, receiving any form of pharmacological or physical treatment. The primary outcome measure was change in muscle strength scale score (Quantitative Myasthenia Gravis score), or limb muscle strength measured by myometry. The secondary outcome measure was improvement in the mean amplitude of the resting compound muscle action potentials. The mean amplitude used was the mean of all muscles tested. DATA COLLECTION AND ANALYSIS: We identified three randomised controlled trials. MAIN RESULTS: Two controlled trials of the effects of 3,4-diaminopyridine compared with placebo in a total of 38 patients with Lambert-Eaton myasthenic syndrome were eligible, one of which was of crossover design. A third crossover trial compared intravenous immunoglobulin treatment to placebo in nine patients. Two trials of 3,4-diaminopyridine reported a significant improvement in muscle strength score, or myometric limb measurement following treatment, and a significant improvement in resting compound muscle action potential amplitude following 3,4-diaminopyridine, compared with placebo.A meta-analysis of the primary endpoint results was not possible because of marked differences in primary outcome measures. However, a meta-analysis of the secondary endpoint was possible. The overall weighted mean difference was 1.80 mV (95% confidence interval 0.82 to 2.78), favouring treatment.A crossover trial reported a significant improvement in myometric limb strength and a non-significant improvement in change in the mean resting compound muscle action potential amplitude when patients received intravenous immunoglobulin compared to placebo infusions. Clinical improvement lasted for up to eight weeks. AUTHORS' CONCLUSIONS: Limited evidence from randomised controlled trials showed that either 3,4-diaminopyridine or intravenous immunoglobulin improved muscle strength scores and compound muscle action potential amplitudes in patients with Lambert-Eaton myasthenic syndrome. There are insufficient data at present to quantify this treatment effect. Other possible treatments have not been tested in randomised controlled trials.
BACKGROUND: Treatments for managing articular cartilage defects of the knee, including drilling and abrasion arthroplasty, are not always effective. When they are, long-term benefits may not be maintained and osteoarthritis may develop, resulting in the need for a total knee replacement. An alternative is the surgical implantation of healthy cartilage cells into damaged areas (autologous cartilage implantation). OBJECTIVES: To determine the effectiveness of autologous cartilage implantation (ACI) in people with full thickness articular cartilage defects of the knee. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (15 December 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2005), MEDLINE (1966 to December 2005), CINAHL (1982 to December Week 2, 2004), EMBASE (1988 to 2005 Week 50), SPORTDiscus (1830 to January 2005) and the National Research Register Issue 3, 2005. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing ACI with any other type of treatment (including no treatment or placebo) for symptomatic cartilage defects of the medial or lateral femoral condyle, femoral trochlea or patella. DATA COLLECTION AND ANALYSIS: Two review authors selected studies for inclusion independently. We assessed study quality based on adequacy of the randomisation process, adequacy of the allocation concealment process, potential for selection bias after allocation and level of masking. Data was not pooled due to clinical and methodological heterogeneity in the studies. MAIN RESULTS: We included four randomised controlled trials (266 participants). One trial of ACI versus mosaicplasty reported statistically significant results for ACI at one year, but only in a post-hoc subgroup analysis of participants with medial condylar defects; 88% had excellent or good results with ACI versus 69% with mosaicplasty. A second trial of ACI versus mosaicplasty found no statistically significant difference in clinical outcomes at two years. There was no statistically significant difference in outcomes at two years in a trial comparing ACI with microfracture. In addition, one trial of matrix-guided ACI versus microfracture did not contain enough long-term results to reach definitive conclusions. AUTHORS' CONCLUSIONS: The use of ACI and other chondral resurfacing techniques is becoming increasingly widespread. However, there is at present no evidence of significant difference between ACI and other interventions. Additional good quality randomised controlled trials with long-term functional outcomes are required.
BACKGROUND: There is evidence that patients with chronic obstructive airways disease and asthma who take inhaled steroids have a low bone density. As most of a drug given from a metered dose inhaler is actually swallowed, the possibility that swallowed beclomethasone dipropionate acts topically in the gut to impair calcium absorption was investigated. Such an effect, if sustained, may be a causative factor of long term bone loss. METHODS: A two week randomised, double blind, placebo controlled, crossover trial was performed in 12 normal volunteers. Subjects were randomly allocated to swallow beclomethasone dipropionate capsules (500 micrograms twice a day) or placebo for one week. The alternate capsule was given throughout the second week. At the end of each week, calcium absorption was assessed by a strontium absorption test. Serum parathyroid hormone, plasma calcium, and plasma phosphate concentrations were determined on the last two days of each week. Twenty four hour urinary calcium, hydroxyproline, and cortisol concentrations were measured for four successive days in each week. RESULTS: All subjects completed the study. There was a 12% reduction in strontium absorption during the beclomethasone dipropionate ingestion week. There was also a 23% reduction in 24 hour urinary cortisol excretion during the same week. CONCLUSIONS: Calcium absorption (measured by a strontium absorption test) was reduced by oral administration of beclomethasone dipropionate for one week. Decreased calcium absorption due to swallowed corticosteroid may contribute to side effects of inhaled steroids and further long term studies are needed.