Rethinking clinical trials of transcranial direct current stimulation: Participant and assessor blinding is inadequate at intensities of 2mA

Copyright @ 2012 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and 85 reproduction in any medium, provided the original author and source are credited. The article was made available through the Brunel University Open Access Publishing Fund.Background: Many double-blind clinical trials of transcranial direct current stimulation (tDCS) use stimulus intensities of 2 mA despite the fact that blinding has not been formally validated under these conditions. The aim of this study was to test the assumption that sham 2 mA tDCS achieves effective blinding. Methods: A randomised double blind crossover trial. 100 tDCS-naïve healthy volunteers were incorrectly advised that they there were taking part in a trial of tDCS on word memory. Participants attended for two separate sessions. In each session, they completed a word memory task, then received active or sham tDCS (order randomised) at 2 mA stimulation intensity for 20 minutes and then repeated the word memory task. They then judged whether they believed they had received active stimulation and rated their confidence in that judgement. The blinded assessor noted when red marks were observed at the electrode sites post-stimulation. Results: tDCS at 2 mA was not effectively blinded. That is, participants correctly judged the stimulation condition greater than would be expected to by chance at both the first session (kappa level of agreement (κ) 0.28, 95% confidence interval (CI) 0.09 to 0.47 p = 0.005) and the second session (κ = 0.77, 95%CI 0.64 to 0.90), p = <0.001) indicating inadequate participant blinding. Redness at the reference electrode site was noticeable following active stimulation more than sham stimulation (session one, κ = 0.512, 95%CI 0.363 to 0.66, p<0.001; session two, κ = 0.677, 95%CI 0.534 to 0.82) indicating inadequate assessor blinding. Conclusions: Our results suggest that blinding in studies using tDCS at intensities of 2 mA is inadequate. Positive results from such studies should be interpreted with caution.GLM is supported by the National Health & Medical Research Council of Australia ID 571090

Double blinding-attack on entanglement-based quantum key distribution protocols

We propose a double blinding-attack on entangled-based quantum key distribution protocols. The principle of the attack is the same as in existing blinding attack except that instead of blinding the detectors on one side only, Eve is blinding the detectors of both Alice and Bob. In the BBM92 protocol, the attack allows Eve to get a full knowledge of the key and remain undetected even if Alice and Bob are using 100% efficient detectors. The attack can be easily extended to Ekert protocol, with an efficiency as high as 85.3%.Comment: 4 page

Journeys in The Country of The Blind: Entanglement Theory and The Effects of Blinding on Trials of Homeopathy and Homeopathic Provings

The idea of quantum entanglement is borrowed from physics and developed into an algebraic argument to explain how double-blinding randomized controlled trials could lead to failure to provide unequivocal evidence for the efficacy of homeopathy, and inability to distinguish proving and placebo groups in homeopathic pathogenic trials. By analogy with the famous double-slit experiment of quantum physics, and more modern notions of quantum information processing, these failings are understood as blinding causing information loss resulting from a kind of quantum superposition between the remedy and placebo

Assessment of the importance of double-blinding should be based on systematic reviews: a rebuttal : [Letter]

In their paper discussing the importance of double-blinding in controlled trials, Furberg and Soliman stated that one of the established and fundamental principles for avoiding the problem of bias is to keep the study participants and the investigators blinded, or masked, to the identity of the assigned interventions. As a support to this argument they described the subgroup findings of Karlowski et al.s trial, which examined the effect of vitamin C supplementation on the commoncold[2,3]. Furberg and Soliman put a great weight on the importance of double-blinding, yet they are lax on other fundamental principles of controlled trial.Non peer reviewe

Methods of Blinding in Reports of Randomized Controlled Trials Assessing Pharmacologic Treatments: A Systematic Review

BACKGROUND: Blinding is a cornerstone of therapeutic evaluation because lack of blinding can bias treatment effect estimates. An inventory of the blinding methods would help trialists conduct high-quality clinical trials and readers appraise the quality of results of published trials. We aimed to systematically classify and describe methods to establish and maintain blinding of patients and health care providers and methods to obtain blinding of outcome assessors in randomized controlled trials of pharmacologic treatments. METHODS AND FINDINGS: We undertook a systematic review of all reports of randomized controlled trials assessing pharmacologic treatments with blinding published in 2004 in high impact-factor journals from Medline and the Cochrane Methodology Register. We used a standardized data collection form to extract data. The blinding methods were classified according to whether they primarily (1) established blinding of patients or health care providers, (2) maintained the blinding of patients or health care providers, and (3) obtained blinding of assessors of the main outcomes. We identified 819 articles, with 472 (58%) describing the method of blinding. Methods to establish blinding of patients and/or health care providers concerned mainly treatments provided in identical form, specific methods to mask some characteristics of the treatments (e.g., added flavor or opaque coverage), or use of double dummy procedures or simulation of an injection. Methods to avoid unblinding of patients and/or health care providers involved use of active placebo, centralized assessment of side effects, patients informed only in part about the potential side effects of each treatment, centralized adapted dosage, or provision of sham results of complementary investigations. The methods reported for blinding outcome assessors mainly relied on a centralized assessment of complementary investigations, clinical examination (i.e., use of video, audiotape, or photography), or adjudication of clinical events. CONCLUSIONS: This review classifies blinding methods and provides a detailed description of methods that could help trialists overcome some barriers to blinding in clinical trials and readers interpret the quality of pharmalogic trials

Impact of blinding on estimated treatment effects in randomised clinical trials:meta-epidemiological study

International audienceAbstract Objectives To study the impact of blinding on estimated treatment effects, and their variation between trials; differentiating between blinding of patients, healthcare providers, and observers; detection bias and performance bias; and types of outcome (the MetaBLIND study). Design Meta-epidemiological study. Data source Cochrane Database of Systematic Reviews (2013-14). Eligibility criteria for selecting studies Meta-analyses with both blinded and non-blinded trials on any topic. Review methods Blinding status was retrieved from trial publications and authors, and results retrieved automatically from the Cochrane Database of Systematic Reviews. Bayesian hierarchical models estimated the average ratio of odds ratios (ROR), and estimated the increases in heterogeneity between trials, for non-blinded trials (or of unclear status) versus blinded trials. Secondary analyses adjusted for adequacy of concealment of allocation, attrition, and trial size, and explored the association between outcome subjectivity (high, moderate, low) and average bias. An ROR lower than 1 indicated exaggerated effect estimates in trials without blinding. Results The study included 142 meta-analyses (1153 trials). The ROR for lack of blinding of patients was 0.91 (95% credible interval 0.61 to 1.34) in 18 meta-analyses with patient reported outcomes, and 0.98 (0.69 to 1.39) in 14 meta-analyses with outcomes reported by blinded observers. The ROR for lack of blinding of healthcare providers was 1.01 (0.84 to 1.19) in 29 meta-analyses with healthcare provider decision outcomes (eg, readmissions), and 0.97 (0.64 to 1.45) in 13 meta-analyses with outcomes reported by blinded patients or observers. The ROR for lack of blinding of observers was 1.01 (0.86 to 1.18) in 46 meta-analyses with subjective observer reported outcomes, with no clear impact of degree of subjectivity. Information was insufficient to determine whether lack of blinding was associated with increased heterogeneity between trials. The ROR for trials not reported as double blind versus those that were double blind was 1.02 (0.90 to 1.13) in 74 meta-analyses. Conclusion No evidence was found for an average difference in estimated treatment effect between trials with and without blinded patients, healthcare providers, or outcome assessors. These results could reflect that blinding is less important than often believed or meta-epidemiological study limitations, such as residual confounding or imprecision. At this stage, replication of this study is suggested and blinding should remain a methodological safeguard in trials

Interventions for preventing oral mucositis for patients with cancer receiving treatment

Interventions for preventing oral mucositis for patients with cancer receiving treatmentTreatment for cancer (including bone marrow transplant) can cause oral mucositis (severe ulcers in the mouth). This painful condition can cause difficulties in eating, drinking and swallowing, and may also be associated with infections which may require the patient to stay longer in hospital. Different strategies are used to try and prevent this condition, and the review of trials found that some of these are effective. Two interventions, cryotherapy (ice chips) and keratinocyte growth factor (palifermin®) showed some benefit in preventing mucositis. Sucralfate is effective in reducing the severity of mucositis, and a further seven interventions, aloe vera, amifostine, intravenous glutamine, granulocyte‐colony stimulating factor (G‐CSF), honey, laser and antibiotic lozenges containing polymixin/tobramycin/amphotericin (PTA) showed weaker evidence of benefit. These were evaluated in patients with different types of cancer, undergoing different types of cancer treatment. Benefits may be restricted to the disease and treatment combinations evaluated

Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma

Background In acute asthma inhaled beta₂-agonists are often administered by nebuliser to relieve bronchospasm, but some have argued that metered-dose inhalers with a holding chamber (spacer) can be equally effective. Nebulisers require a power source and need regular maintenance, and are more expensive in the community setting. Objectives To assess the effects of holding chambers (spacers) compared to nebulisers for the delivery of beta₂-agonists for acute asthma. Search methods We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies to identify additional trials. Date of last search: February 2013. Selection criteria Randomised trials in adults and children (from two years of age) with asthma, where spacer beta₂-agonist delivery was compared with wet nebulisation. Data collection and analysis Two review authors independently applied study inclusion criteria (one review author for the first version of the review), extracted the data and assessed risks of bias. Missing data were obtained from the authors or estimated. Results are reported with 95% confidence intervals (CIs). Main results This review includes a total of 1897 children and 729 adults in 39 trials. Thirty-three trials were conducted in the emergency room and equivalent community settings, and six trials were on inpatients with acute asthma (207 children and 28 adults). The method of delivery of beta₂-agonist did not show a significant difference in hospital admission rates. In adults, the risk ratio (RR) of admission for spacer versus nebuliser was 0.94 (95% CI 0.61 to 1.43). The risk ratio for children was 0.71 (95% CI 0.47 to 1.08, moderate quality evidence). In children, length of stay in the emergency department was significantly shorter when the spacer was used. The mean duration in the emergency department for children given nebulised treatment was 103 minutes, and for children given treatment via spacers 33 minutes less (95% CI -43 to -24 minutes, moderate quality evidence). Length of stay in the emergency department for adults was similar for the two delivery methods. Peak flow and forced expiratory volume were also similar for the two delivery methods. Pulse rate was lower for spacer in children, mean difference -5% baseline (95% CI -8% to -2%, moderate quality evidence), as was the risk of developing tremor (RR 0.64; 95% CI 0.44 to 0.95, moderate quality evidence). Authors' conclusions Nebuliser delivery produced outcomes that were not significantly better than metered-dose inhalers delivered by spacer in adults or children, in trials where treatments were repeated and titrated to the response of the participant. Spacers may have some advantages compared to nebulisers for children with acute asthma

Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma

In acute asthma inhaled beta 2-agonists are often administered to relieve bronchospasm by wet nebulisation, but some have argued that metered-dose inhalers with a holding chamber (spacer) can be equally effective. Nebulisers require a power source and need regular maintenance, and are more expensive in the community setting.ObjectivesTo assess the effects of holding chambers (spacers) compared to nebulisers for the delivery of beta 2-agonists for acute asthma.Search strategyWe last searched the Cochrane Airways Group trials register in January 2006 and the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2005).Selection criteriaRandomised trials in adults and children (from two years of age) with asthma, where spacer beta 2-agonist delivery was compared with wet nebulisation.Data collection and analysisTwo reviewers independently applied study inclusion criteria (one reviewer for the first version of the review), extracted the data and assessed trial quality. Missing data were obtained from the authors or estimated. Results are reported with 95% confidence intervals (CI).Main resultsThis review has been updated in January 2006 and four new trials have been added. 2066 children and 614 adults are now included in 25 trials from emergency room and community settings. In addition, six trials on in-patients with acute asthma (213 children and 28 adults) have been reviewed. Method of delivery of beta 2-agonist did not appear to affect hospital admission rates. In adults, the relative risk of admission for spacer versus nebuliser was 0.97 (95% CI 0.63 to 1.49). The relative risk for children was 0.65 (95% CI: 0.4 to 1.06). In children, length of stay in the emergency department was significantly shorter when the spacer was used, with a mean difference of -0.47 hours (95% CI: -0.58 to -0.37). Length of stay in the emergency department for adults was similar for the two delivery methods. Peak flow and forced expiratory volume were also similar for the two delivery methods. Pulse rate was lower for spacer in children, mean difference -7.6% baseline (95% CI: -9.9 to -5.3% baseline).Authors' conclusionsMetered-dose inhalers with spacer produced outcomes that were at least equivalent to nebuliser delivery. Spacers may have some advantages compared to nebulisers for children with acute asthma

Interventions for treating oral mucositis for patients with cancer receiving treatment

Background Treatment of cancer is increasingly effective but is associated with short and long term side effects. Oral and gastrointestinal side effects, including oral candidiasis, remain a major source of illness despite the use of a variety of agents to treat them. Objectives To assess the effectiveness of interventions for the treatment of oral candidiasis for patients with cancer receiving chemotherapy or radiotherapy or both. Search strategy Computerised searches of Cochrane Oral Health Group and PaPaS Trials Registers (to 1 June 2010), CENTRAL via the Cochrane Library (Issue 2, 2010, 1 June 2010), MEDLINE via OVID (1 June 2010), EMBASE via OVID (1 June 2010), CINAHL via EBSCO (1 June 2010), CANCERLIT via PubMed (1 June 2010), OpenSIGLE (1 June 2010) and LILACS via Virtual Health Library (1 June 2010) were undertaken. Reference lists fromrelevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. Selection criteria All randomised controlled trials comparing agents prescribed to treat oral candidiasis in people receiving chemotherapy or radiotherapy for cancer. The outcomes were eradication of oral candidiasis, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and patient quality of life. Data collection and analysis Data were independently extracted, in duplicate, by two review authors. Trial authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. Risk ratios (RR) were calculated using fixed-effect models. Main results Ten trials involving 940 patients, satisfied the inclusion criteria and are included in this review. Drugs absorbed from the gastrointestinal (GI) tract were beneficial in eradication of oral candidiasis compared with drugs not absorbed from the GI tract (three trials: RR = 1.29, 95% confidence interval (CI) 1.09 to 1.52), however there was significant heterogeneity. A drug absorbed from the GI tract, ketoconazole, wasmore beneficial than placebo in eradicating oral candidiasis (one trial: RR = 3.61, 95% CI 1.47 to 8.88). Clotrimazole, at a higher dose of 50 mg was more effective than a lower 10 mg dose in eradicating oral candidiasis, when assessed mycologically (one trial: RR = 2.00, 95% CI 1.11 to 3.60). Only one of the ten trials was assessed as at low risk of bias. Authors' conclusions There is insufficient evidence to claimor refute a benefit for any antifungal agent in treating candidiasis. Further well designed, placebo-controlled trials assessing the effectiveness of old and new interventions for treating oral candidiasis are needed. Clinicians need to make a decision on whether to prevent or treat oral candidiasis in patients receiving treatment for cancer. This review is published as a Cochrane Review in the Cochrane Database of Systematic Reviews 2010, Issue 7. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Review.</p