[RESEARCH] Effect of European Clinical Trials Directive on academic drug trials in Denmark: retrospective study of applications to the Danish Medicines Agency 1993-2006
Objective To determine the impact of the European Union’s Clinical Trials Directive on the number of academic drug trials carried out in Denmark.
Design Retrospective review of applications for drug trials to the Danish Medicines Agency, 1993-2006.
Review methods Applications for drug trials for alternate years were classified as academic or commercial trials. A random subset of academic trials was reviewed for number of participants in and intended monitoring of the trials.
Results Academic and commercial drug trials showed an identical steady decline from 1993 to 2006 and no noticeable change after 2004 when good clinical practice became mandatory for academic trials.
Conclusion The Clinical Trials Directive introduced in May 2004 to ensure good clinical practice for academic drug trials was not associated with a decline in research activity in Denmark; presumably because good clinical practice units had already been in place in Danish universities since 1999. With such an infrastructure academic researchers can do drug trials under the same regulations as drug companies.
[RESEARCH] Doctors' versus patients' global assessments of treatment effectiveness: empirical survey of diverse treatments in clinical trials
Objective To examine whether doctors’ global assessments of treatment effects agree with patients’ global assessments.
Design Survey of trials included in systematic reviews of treatments for diverse conditions.
Data sources Cochrane database of systematic reviews.
Data extracted Data on patients’ global assessments and on doctors’ global assessment for the same treatment against the same comparator.
Main outcome measures Relative odds ratio (ratio of odds ratios of global improvement with the experimental intervention versus control according to doctors compared with patients), and improvement rates according to doctors and patients.
Results Doctors’ global assessments were compared with patients’ global assessments for 63 different treatment comparisons (240 trials) in 18 conditions. The summary relative odds ratio across the comparisons was not significant (0.98, 95% confidence interval 0.88 to 1.08; I2=0%, 95% confidence interval 0% to 30%). In 62 of the 63 comparisons the effects of treatment rated by patients and by doctors did not differ beyond chance, but for single comparisons the confidence intervals were large. Rates of improvement on average did not differ between doctors’ assessments and patients’ assessments (summary relative odds ratio 0.98, 0.88 to 1.06; I2=0%, 0% to 24%).
Conclusion Doctors’ global assessments of the effects of treatments are on average similar to those of patients.
[RESEARCH] Limitations of rapid HIV-1 tests during screening for trials in Uganda: diagnostic test accuracy study
Objective To evaluate the limitations of rapid tests for HIV-1.
Design Diagnostic test accuracy study.
Setting Rural Rakai, Uganda.
Participants 1517 males aged 15-49 screened for trials of circumcision for HIV prevention.
Main outcome measures Sensitivity, specificity, negative predictive values, and positive predictive values of an algorithm using three rapid tests for HIV, compared with the results of enzyme immunoassay and western blotting as the optimal methods.
Results Rapid test results were evaluated by enzyme immunoassay and western blotting. Sensitivity was 97.7%. Among 639 samples where the strength of positive bands was coded if the sample showed positivity for HIV, the algorithm had low specificity (94.1%) and a low positive predictive value (74.0%). Exclusion of 37 samples (5.8%) with a weak positive band improved the specificity (99.6%) and positive predictive value (97.7%).
Conclusion Weak positive bands on rapid tests for HIV should be confirmed by enzyme immunoassay and western blotting before disclosing the diagnosis. Programmes using rapid tests routinely should use standard serological assays for quality control.
Trial registration Clinical Trials NCT00425984.
[RESEARCH] Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomised controlled trials for preventing recurrence
Objective To examine the effectiveness of parenteral corticosteroids for the relief of acute severe migraine headache and prevention of recurrent headaches.
Design Meta-analysis.
Data sources Electronic databases (Cochrane Central Register of Controlled Trials, Medline, Embase, LILACS, and CINAHL), conference proceedings, clinical practice guidelines, contacts with industry, and correspondence with authors.
Selection criteria Randomised controlled trials in which corticosteroids (alone or combined with standard abortive therapy) were compared with placebo or any other standard treatment for acute migraine in adults.
Review methods Two reviewers independently assessed relevance, inclusion, and study quality. Weighted mean differences and relative risks were calculated and are reported with 95% confidence intervals.
Results From 666 potentially relevant abstracts, seven studies met the inclusion criteria. All included trials used standard abortive therapy and subsequently compared single dose parenteral dexamethasone with placebo, examining pain relief and recurrence of headache within 72 hours. Dexamethasone and placebo provided similar acute pain reduction (weighted mean difference 0.37, 95% confidence interval –0.20 to 0.94). Dexamethasone was, however, more effective than placebo in reducing recurrence rates (relative risk 0.74, 95% confidence interval 0.60 to 0.90). Side effect profiles between dexamethasone and placebo groups were similar.
Conclusion When added to standard abortive therapy for migraine headache, single dose parenteral dexamethasone is associated with a 26% relative reduction in headache recurrence (number needed to treat=9) within 72 hours.
[RESEARCH] Internal and external validity of cluster randomised trials: systematic review of recent trials
Objectives To assess aspects of the internal validity of recently published cluster randomised trials and explore the reporting of information useful in assessing the external validity of these trials.
Design Review of 34 cluster randomised trials in primary care published in 2004 and 2005 in seven journals (British Medical Journal, British Journal of General Practice, Family Practice, Preventive Medicine, Annals of Internal Medicine, Journal of General Internal Medicine, Pediatrics).
Data sources National Library of Medicine (Medline) via PubMed.
Data extraction To assess aspects of internal validity we extracted data on appropriateness of sample size calculations and analyses, methods of identifying and recruiting individual participants, and blinding. To explore reporting of information useful in assessing external validity we extracted data on cluster eligibility, cluster inclusion and retention, cluster generalisability, and the feasibility and acceptability of the intervention to health providers in clusters.
Results 21 (62%) trials accounted for clustering in sample size calculations and 30 (88%) in the analysis; about a quarter were potentially biased because of procedures surrounding recruitment and identification of patients; individual participants were blind to allocation status in 19 (56%) and outcome assessors were blind in 15 (44%). In almost half the reports, information relating to generalisability of clusters was poorly reported, and in two fifths there was no information about the feasibility and acceptability of the intervention.
Conclusions Cluster randomised trials are essential for evaluating certain types of interventions. Issues affecting their internal validity, such as appropriate sample size calculations and analysis, have been widely disseminated and are now better addressed by researchers. Blinding of those identifying and recruiting patients to allocation status is recommended but is not always carried out. There may be fewer barriers to internal validity in trials in which individual participants are not recruited. External validity seems poorly addressed in many trials, yet is arguably as important as internal validity in judging quality as a basis for healthcare intervention.
[RESEARCH] Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials
Objective To explore the extent to which components of composite end points in randomised controlled trials vary in importance to patients, the frequency of events in the more and less important components, and the extent of variability in the relative risk reductions across components.
Design Systematic review of randomised controlled trials.
Data sources Cardiovascular randomised controlled trials published in the Lancet, Annals of Internal Medicine, Circulation, European Heart Journal, JAMA, and New England Journal of Medicine, from 1 January 2002 to 30 June 2003. Component end points of composite end points were categorised according to importance to patients as fatal, critical, major, moderate, or minor.
Results Of 114 identified randomised controlled trials that included a composite end point of importance to patients, 68% (n=77) reported complete component data for the primary composite end point; almost all (98%; n=112) primary composite end points included a fatal end point. Of 84 composite end points for which component data were available, 54% (n=45) showed large or moderate gradients in both importance to patients and magnitude of effect across components. When analysed by categories of importance to patients, the most important components were associated with lower event rates in the control group (medians of 3.3-3.7% for fatal, critical, and major outcomes; 12.3% for moderate outcomes; and 8.0% for minor outcomes). Components of greater importance to patients were associated with smaller treatment effects than less important ones (relative risk reduction of 8% for death and 33% for components of minor importance to patients).
Conclusion The use of composite end points in cardiovascular trials is frequently complicated by large gradients in importance to patients and in magnitude of the effect of treatment across component end points. Higher event rates and larger treatment effects associated with less important components may result in misleading impressions of the impact of treatment.
History underway in type 1 diabetes cure
Filed under: Type 1, Childhood, Research, Events, Support
Dr. Faustman's lab is currently collecting blood samples from individuals with established Type 1 diabetes. These samples are being used to quantify the number of autoreactive T-cells and develop the adequate dosage for Phase 1 of human trials to cure Type 1 diabetes.
The research has been presented and the NIH confirmed it. By reeducating the confused T-cells and instructing them not to attack healthy islets, an apparent cure of established type 1 diabetes in non-obese diabetic mice is possible. Now, Dr. Faustman is collecting human samples to bestow the same cure for diabetes in humans.
If you wish to be a part of this revolutionary event for curing Type 1 diabetes, please contact the Clinical Coordinator or call Dr. Faustman's lab at (617) 726-4084. Each participant is asked to bring a control person along with them - an unrelated person without Type 1 diabetes or another autoimmune disease. Diabetic or not - you can be a part of history in curing Type 1 diabetes!
[RESEARCH] Oral decontamination for prevention of pneumonia in mechanically ventilated adults: systematic review and meta-analysis
Objective To evaluate the effect of oral decontamination on the incidence of ventilator associated pneumonia and mortality in mechanically ventilated adults.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, CINAHL, the Cochrane Library, trials registers, reference lists, conference proceedings, and investigators in the specialty.
Review methods Two independent reviewers screened studies for inclusion, assessed trial quality, and extracted data. Eligible trials were randomised controlled trials enrolling mechanically ventilated adults that compared the effects of daily oral application of antibiotics or antiseptics with no prophylaxis.
Results 11 trials totalling 3242 patients met the inclusion criteria. Among four trials with 1098 patients, oral application of antibiotics did not significantly reduce the incidence of ventilator associated pneumonia (relative risk 0.69, 95% confidence interval 0.41 to 1.18). In seven trials with 2144 patients, however, oral application of antiseptics significantly reduced the incidence of ventilator associated pneumonia (0.56, 0.39 to 0.81). When the results of the 11 trials were pooled, rates of ventilator associated pneumonia were lower among patients receiving either method of oral decontamination (0.61, 0.45 to 0.82). Mortality was not influenced by prophylaxis with either antibiotics (0.94, 0.73 to 1.21) or antiseptics (0.96, 0.69 to 1.33) nor was duration of mechanical ventilation or stay in the intensive care unit.
Conclusions Oral decontamination of mechanically ventilated adults using antiseptics is associated with a lower risk of ventilator associated pneumonia. Neither antiseptic nor antibiotic oral decontamination reduced mortality or duration of mechanical ventilation or stay in the intensive care unit.
[RESEARCH] Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials
Objective To analyse the benefits and harms of statins in patients with chronic kidney disease (pre-dialysis, dialysis, and transplant populations).
Design Meta-analysis.
Data sources Cochrane Central Register of Controlled Trials, Medline, Embase, and Renal Health Library (July 2006).
Study selection Randomised and quasi-randomised controlled trials of statins compared with placebo or other statins in chronic kidney disease.
Data extraction and analysis Two reviewers independently assessed trials for inclusion, extracted data, and assessed trial quality. Differences were resolved by consensus. Treatment effects were summarised as relative risks or weighted mean differences with 95% confidence intervals by using a random effects model.
Results Fifty trials (30 144 patients) were included. Compared with placebo, statins significantly reduced total cholesterol (42 studies, 6390 patients; weighted mean difference –42.28 mg/dl (1.10 mmol/l), 95% confidence interval –47.25 to –37.32), low density lipoprotein cholesterol (39 studies, 6216 patients; –43.12 mg/dl (1.12 mmol/l), –47.85 to –38.40), and proteinuria (g/24 hours) (6 trials, 311 patients; –0.73 g/24 hour, –0.95 to –0.52) but did not improve glomerular filtration rate (11 studies, 548 patients; 1.48 ml/min (0.02 ml/s), –2.32 to 5.28). Fatal cardiovascular events (43 studies, 23 266 patients; relative risk 0.81, 0.73 to 0.90) and non-fatal cardiovascular events (8 studies, 22 863 patients; 0.78, 0.73 to 0.84) were reduced with statins, but statins had no significant effect on all cause mortality (44 studies, 23 665 patients; 0.92, 0.82 to 1.03). Meta-regression analysis showed that treatment effects did not vary significantly with stage of chronic kidney disease. The side effect profile of statins was similar to that of placebo. Most of the available studies were small and of suboptimal quality; mortality data were provided by a few large trials only.
Conclusion Statins significantly reduce lipid concentrations and cardiovascular end points in patients with chronic kidney disease, irrespective of stage of disease, but no benefit on all cause mortality or the role of statins in primary prevention has been established. Reno-protective effects of statins are uncertain because of relatively sparse data and possible outcomes reporting bias.
Early prevention of Type 1 diabetes human trials
Filed under: Type 1, Childhood, Drugs, Research
ImmunoMod has received an FDA Orphan Drug Grant award to pursue human trials focused on preventing the onset of Type 1 Diabetes by protecting beta cell function in early-stage diabetic youth.
When diabetes is first diagnosed, a short window of time known as "the honeymoon stage" exists to preserve the body's ability to create insulin. During this critical stage an individual has the best chance to protect the beta cells and stop the onset of the disease. Studies have shown that regeneration of damaged cells can occur if beta cells can be preserved. The problem to date has been the inability to prolong the preservation of these beta cells.
While some treatments have decelerated beta cell destruction, their effects have been temporary, caused toxic effects and required continuous treatment. ImmunoMod appears to effectively and safely protect beta cells for prolonged periods of time. The goal is to retard or reverse the destruction of these cells during the honeymoon phase, when cells first begin to lose function, which typically lasts about six months. I wonder if it's possible to reintroduce the honeymoon stage for Type 1 diabetics who have already been diabetic for decades?