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European Journal of Clinical... Mar 2022
Review
Topics: COVID-19; COVID-19 Vaccines; Control Groups; Humans; Placebos; Randomized Controlled Trials as Topic; Research Design
PubMed: 34837495
DOI: 10.1007/s00228-021-03259-x -
Handbook of Experimental Pharmacology 2019In this review, we explored different ways of controlling the placebo effects in clinical trials and described various factors that may increase/decrease the placebo... (Review)
Review
In this review, we explored different ways of controlling the placebo effects in clinical trials and described various factors that may increase/decrease the placebo effect in randomized placebo-controlled trials. These factors can be subdivided into four groups, and while not all factors are effective in every study and under all clinical conditions, they show on the whole that - even under the ideal condition of drug therapy, where blinded placebo provision is much easier and warranted than in, e.g., psychotherapy - many factors need to be controlled to ascertain that the goal of the clinical trials, fair assessment of superiority of the drug over placebo in placebo-controlled trials and fair assessment of non-inferiority of the drug compared to another drug in comparator trials, is reached. Ignorance towards the placebo effect, which was common in the past, is no longer acceptable; instead, it should be the goal of all therapeutic trials to minimize the placebo effect in clinical trials, while utilizing and maximizing it in clinical routine.
Topics: Placebo Effect; Placebos; Randomized Controlled Trials as Topic
PubMed: 31463606
DOI: 10.1007/164_2019_269 -
Journal of Clinical Epidemiology Jul 2017Active placebos are control interventions that mimic the side effects of the experimental interventions in randomized trials and are sometimes used to reduce the risk of... (Review)
Review
OBJECTIVES
Active placebos are control interventions that mimic the side effects of the experimental interventions in randomized trials and are sometimes used to reduce the risk of unblinding. We wanted to assess how often randomized clinical drug trials use active placebo control groups; to provide a catalog, and a characterization, of such trials; and to analyze methodological arguments for and against the use of active placebo.
STUDY DESIGN AND SETTING
An overview consisting of three thematically linked substudies. In an observational substudy, we assessed the prevalence of active placebo groups based on a random sample of 200 PubMed indexed placebo-controlled randomized drug trials published in October 2013. In a systematic review, we identified and characterized trials with active placebo control groups irrespective of publication time. In a third substudy, we reviewed publications with substantial methodological comments on active placebo groups (searches in PubMed, The Cochrane Library, Google Scholar, and HighWirePress).
RESULTS
The prevalence of trials with active placebo groups published in 2013 was 1 out of 200 (95% confidence interval: 0-2), 0.5% (0-1%). We identified and characterized 89 randomized trials (published 1961-2014) using active placebos, for example, antihistamines, anticholinergic drugs, and sedatives. Such trials typically involved a crossover design, the experimental intervention had noticeable side effects, and the outcomes were patient-reported. The use of active placebos was clustered in specific research settings and did not appear to reflect consistently the side effect profile of the experimental intervention, for example, selective serotonin reuptake inhibitors were compared with active placebos in pain trials but not in depression trials. We identified and analyzed 25 methods publications with substantial comments. The main argument for active placebo was to reduce risk of unblinding; the main argument against was the risk of unintended therapeutic effect.
CONCLUSION
Pharmacological active placebo control interventions are rarely used in randomized clinical trials, but they constitute a methodological tool which merits serious consideration. We suggest that active placebos are used more often in trials of drugs with noticeable side effects, especially in situations where the expected therapeutic effects are modest and the risk of bias due to unblinding is high.
Topics: Control Groups; Humans; Pharmaceutical Preparations; Placebo Effect; Randomized Controlled Trials as Topic; Research Design
PubMed: 28342907
DOI: 10.1016/j.jclinepi.2017.03.001 -
Pain Mar 2010
Topics: Humans; Pain; Placebo Effect; Placebos; Prefrontal Cortex
PubMed: 19892467
DOI: 10.1016/j.pain.2009.10.009 -
JAMA Network Open Jul 2022Nonspecific effects, particularly placebo effects, are thought to contribute significantly to the observed effect in surgical trials. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Nonspecific effects, particularly placebo effects, are thought to contribute significantly to the observed effect in surgical trials.
OBJECTIVE
To estimate the proportion of the observed effect of surgical treatment that is due to nonspecific effects (including the placebo effect).
DATA SOURCES
Published Cochrane reviews and updated, extended search of MEDLINE, Embase, and CENTRAL until March 2019.
STUDY SELECTION
Published randomized placebo-controlled surgical trials and trials comparing the effect of the same surgical interventions with nonoperative controls (ie, no treatment, usual care, or exercise program).
DATA EXTRACTION AND SYNTHESIS
Pairs of authors independently screened the search results, assessed full texts to identify eligible studies and the risk of bias of included studies, and extracted data. The proportion of all nonspecific effects was calculated as the change in the placebo control divided by the change in the active surgery and pooled in a random-effect meta-analysis. To estimate the magnitude of the placebo effect, we pooled the difference in outcome between placebo and nonoperative controls and used metaregression to estimate the association between the type of control group and the treatment effect (difference between the groups), adjusting for risk of bias, sample size, and type of outcome.
MAIN OUTCOMES AND MEASURES
Between- and within-group effect sizes expressed as Hedges g.
RESULTS
In this review, 100 trials were included comprising data from 62 trials with placebo controls (3 also included nonoperative controls), and 38 trials with nonoperative controls (32 interventions; 10 699 participants). Risk of bias across trials was comparable except for performance and detection bias, which was high in trials with nonoperative controls. The mean nonspecific effects accounted for 67% (95% CI, 61% to 73%) of the observed change after surgery; however, this varied widely between different procedures. The estimated surgical placebo effect had a standardized mean difference (SMD) of 0.13 (95% CI, -0.26 to 0.51). Trials with placebo and nonoperative controls found comparable treatment effects (SMD, -0.09 [95% CI, -0.35 to 0.18]; 15 interventions; 73 between-group effects; adjusted analysis: SMD, -0.11 [95% CI, -0.37 to 0.15]).
CONCLUSIONS AND RELEVANCE
In this review, the change in health state after surgery was composed largely of nonspecific effects, but no evidence supported a large placebo effect. Placebo-controlled surgical trials may be redundant when trials with nonoperative controls consistently report no substantial association from surgery compared with nonoperative treatment.
Topics: Control Groups; Exercise; Humans; Placebo Effect
PubMed: 35895060
DOI: 10.1001/jamanetworkopen.2022.23903 -
Indian Journal of Medical Ethics 2021Vaccines preventing Covid-19 have been approved in several countries. Is it still ethically acceptable to use placebo controls during the development of other vaccine...
Vaccines preventing Covid-19 have been approved in several countries. Is it still ethically acceptable to use placebo controls during the development of other vaccine options? If two of the most influential international guidelines of biomedical research are consulted, the Declaration of Helsinki and the CIOMS-guidelines, the answer is "no". We discuss the implications for ongoing vaccine research, and how placebo controls might be justified nevertheless. However, the ethical conflict remains highly problematic. We suggest that such ethical dilemmas should be avoided in the future by the introduction of a new system of global governance. Once vaccines are approved, a global regulation should oblige producers to provide the necessary amount of vaccine doses for the control groups of ongoing vaccine research.
Topics: Adult; Aged; Aged, 80 and over; COVID-19; COVID-19 Vaccines; Clinical Trials as Topic; Ethics, Medical; Female; Guidelines as Topic; Humans; International Cooperation; Male; Middle Aged; Pandemics; Placebos; SARS-CoV-2
PubMed: 33908353
DOI: 10.20529/IJME.2021.022 -
Vaccine Jan 2023The Corona pandemic and ongoing mass vaccinations raise the question of the nocebo mechanisms involved. Since immunization is usually administered to healthy people as a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The Corona pandemic and ongoing mass vaccinations raise the question of the nocebo mechanisms involved. Since immunization is usually administered to healthy people as a preventive health measure, adverse events (AE) following immunization are less accepted and could contribute to vaccine hesitancy. Assuming that vaccinees experience nocebo responses, the aim of this meta-analysis was to investigate the effect sizes of solicited adverse events (or assumed reactogenicity) reported in placebo groups in RCTs on seasonal influenza vaccination.
METHODS
Literature search via PubMed, Web of Science, and CENTRAL was conducted considering gray literature. Only RCTs with placebo groups using pharmacologically inert substances (like saline) were included. Quality was assessed using Cochrane Collaboration's Risk of Bias Tool. Effect sizes were estimated using a random mixed effects model based on k = 31 studies covering 14,326 participants in placebo groups.
RESULTS
Reported solicited AEs in placebo groups showed significant effect sizes of proportions (ES). In k = 13 analyzed placebo groups, 35 % of the participants reported at least one solicited systemic AE (p = 0.007). The most common particular solicited systemic AEs were headache (k = 27; 17 %; p = 0.001), malaise (k = 13; 12 %; p = 0.004), and hyperhidrosis (k = 4; 12 %; p < 0.001) within one week after vaccination.
CONCLUSION
The results show significant solicited AEs in placebo groups, indicating substantial nocebo responses after vaccination. Based on the fact that most vaccination programs include similar groups of healthy people, we expect that comparable nocebo effects occur during other campaigns. Health care professionals should be aware of the nocebo response and take action to prevent or decrease the burden of adverse events following immunization. Fear of side effects must be addressed early in order to diminish vaccine hesitancy. Prospero identifier: CRD42020156287, October 2019.
Topics: Humans; Control Groups; Drug-Related Side Effects and Adverse Reactions; Influenza, Human; Seasons; Vaccination; Randomized Controlled Trials as Topic
PubMed: 36464541
DOI: 10.1016/j.vaccine.2022.11.033 -
Proceedings of the American Thoracic... Oct 2007There are valid scientific and ethical considerations for using a control group in a clinical trial. Placebo-controlled trials are justifiable when they are supported by... (Review)
Review
There are valid scientific and ethical considerations for using a control group in a clinical trial. Placebo-controlled trials are justifiable when they are supported by sound methodologic consideration and when their use does not expose research participants to excessive risk of harm. Consideration should be given to "best available therapy" control groups in the evaluation of a new therapy or intervention over an existing therapy. Investigators should keep in mind that one should not sacrifice the scientific merit of a trial to include a best-available-therapy control group as long as the placebo control group poses little harm to participants and, importantly, the trial offers potential benefit to the subject. The pros and cons of using placebo versus best-available-therapy control groups are discussed.
Topics: Asthma; Controlled Clinical Trials as Topic; Humans; Placebos
PubMed: 17878471
DOI: 10.1513/pats.200706-073JK -
The Cochrane Database of Systematic... Jun 2021Febrile seizures occurring in a child older than one month during an episode of fever affect 2-4% of children in Great Britain and the United States and recur in 30%.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Febrile seizures occurring in a child older than one month during an episode of fever affect 2-4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. This is an updated version of a Cochrane Review previously published in 2017.
OBJECTIVES
To evaluate primarily the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures; and also to evaluate any other drug intervention where there is a sound biological rationale for its use.
SEARCH METHODS
For the latest update we searched the following databases on 3 February 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 31 January 2020). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including the Cochrane Epilepsy Group. We imposed no language restrictions and contacted researchers to identify continuing or unpublished studies.
SELECTION CRITERIA
Trials using randomised or quasi-randomised participant allocation that compared the use of antiepileptics, antipyretics or recognised Central Nervous System active agents with each other, placebo, or no treatment.
DATA COLLECTION AND ANALYSIS
For the original review, two review authors independently applied predefined criteria to select trials for inclusion and extracted the predefined relevant data, recording methods for randomisation, blinding, and exclusions. For the 2016 update, a third review author checked all original inclusions, data analyses, and updated the search. For the 2020 update, one review author updated the search and performed the data analysis following a peer-review process with the original review authors. We assessed seizure recurrence at 6, 12, 18, 24, 36, 48 months, and where data were available at age 5 to 6 years along with recorded adverse effects. We evaluated the presence of publication bias using funnel plots.
MAIN RESULTS
We included 42 articles describing 32 randomised trials, with 4431 randomised participants used in the analysis of this review. We analysed 15 interventions of continuous or intermittent prophylaxis and their control treatments. Methodological quality was moderate to poor in most studies. We found no significant benefit for intermittent phenobarbital, phenytoin, valproate, pyridoxine, ibuprofen, or zinc sulfate versus placebo or no treatment; nor for diclofenac versus placebo followed by ibuprofen, paracetamol, or placebo; nor for continuous phenobarbital versus diazepam, intermittent rectal diazepam versus intermittent valproate, or oral diazepam versus clobazam. There was a significant reduction of recurrent febrile seizures with intermittent diazepam versus placebo or no treatment at six months (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.48 to 0.85; 6 studies, 1151 participants; moderate-certainty evidence), 12 months (RR 0.69, 95% CI 0.56 to 0.84; 8 studies, 1416 participants; moderate-certainty evidence), 18 months (RR 0.37, 95% CI 0.23 to 0.60; 1 study, 289 participants; low-certainty evidence), 24 months (RR 0.73, 95% CI 0.56 to 0.95; 4 studies, 739 participants; high-certainty evidence), 36 months (RR 0.58, 95% CI 0.40 to 0.85; 1 study, 139 participants; low-certainty evidence), 48 months (RR 0.36, 95% CI 0.15 to 0.89; 1 study, 110 participants; moderate-certainty evidence), with no benefit at 60 to 72 months (RR 0.08, 95% CI 0.00 to 1.31; 1 study, 60 participants; very low-certainty evidence). Phenobarbital versus placebo or no treatment reduced seizures at six months (RR 0.59, 95% CI 0.42 to 0.83; 6 studies, 833 participants; moderate-certainty evidence), 12 months (RR 0.54, 95% CI 0.42 to 0.70; 7 studies, 807 participants; low-certainty evidence), and 24 months (RR 0.69, 95% CI 0.53 to 0.89; 3 studies, 533 participants; moderate-certainty evidence), but not at 18 months (RR 0.77, 95% CI 0.56 to 1.05; 2 studies, 264 participants) or 60 to 72 months follow-up (RR 1.50, 95% CI 0.61 to 3.69; 1 study, 60 participants; very low-certainty evidence). Intermittent clobazam compared to placebo at six months resulted in a RR of 0.36 (95% CI 0.20 to 0.64; 1 study, 60 participants; low-certainty evidence), an effect found against an extremely high (83.3%) recurrence rate in the controls, a result that needs replication. When compared to intermittent diazepam, intermittent oral melatonin did not significantly reduce seizures at six months (RR 0.45, 95% CI 0.18 to 1.15; 1 study, 60 participants; very-low certainty evidence). When compared to placebo, intermittent oral levetiracetam significantly reduced recurrent seizures at 12 months (RR 0.27, 95% CI 0.15 to 0.52; 1 study, 115 participants; very low-certainty evidence). The recording of adverse effects was variable. Two studies reported lower comprehension scores in phenobarbital-treated children. Adverse effects were recorded in up to 30% of children in the phenobarbital-treated groups and 36% in benzodiazepine-treated groups. We found evidence of publication bias in the meta-analyses of comparisons for phenobarbital versus placebo (seven studies) at 12 months but not at six months (six studies); and valproate versus placebo (four studies) at 12 months. There were too few studies to identify publication bias for the other comparisons. The methodological quality of most of the included studies was low or very low. Methods of randomisation and allocation concealment often did not meet current standards, and 'treatment versus no treatment' was more commonly seen than 'treatment versus placebo', leading to obvious risks of bias. AUTHORS' CONCLUSIONS: We found reduced recurrence rates for intermittent diazepam and continuous phenobarbital, with adverse effects in up to 30% of children. The apparent benefit for clobazam treatment in one trial needs to be replicated. Levetiracetam also shows benefit with a good safety profile; however, further study is required. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management, and, most importantly, the benign nature of the phenomenon.
Topics: Anticonvulsants; Antipyretics; Child; Child, Preschool; Confidence Intervals; Humans; Infant; Placebos; Publication Bias; Randomized Controlled Trials as Topic; Recurrence; Seizures, Febrile
PubMed: 34131913
DOI: 10.1002/14651858.CD003031.pub4 -
Gut Microbes 2018Bifidobacterium animalis subsp. lactis HN019 (HN019) ameliorates chronic idiopathic constipation. Our aim was to determine the efficacy and safety of 28-day... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Effects of 28-day Bifidobacterium animalis subsp. lactis HN019 supplementation on colonic transit time and gastrointestinal symptoms in adults with functional constipation: A double-blind, randomized, placebo-controlled, and dose-ranging trial.
Bifidobacterium animalis subsp. lactis HN019 (HN019) ameliorates chronic idiopathic constipation. Our aim was to determine the efficacy and safety of 28-day supplementation with 1 × 10 or 1 × 10 CFU of HN019/day for constipation. A total of 228 adults who were diagnosed with functional constipation according to the Rome III criteria were randomized in a double-blind and placebo-controlled trial. Colonic transit time (CTT), the primary outcome, and secondary outcomes that were measured using inventories-patient assessment of constipation symptoms (PAC-SYM) and quality of life (PAC-QoL), bowel function index (BFI), bowel movement frequency (BMF), stool consistency, degree of straining, bowel emptying, bloating, and pain severity-were assessed. Ancillary parameters and harms were also evaluated. There were no statistically significant differences in the primary or secondary outcomes between interventions. A post hoc analysis of 65 participants with fewer than 3 bowel movements per week (BMF ≤ 3/week) showed a physiologically relevant increase in weekly BMF in the high- (+2.0) and low-dose (+1.7) HN019 groups-by RMANOVA, the HN019 groups with BMF ≤ 3/week, pooled together, had a higher BMF versus placebo (P value = 0.01). Thus, improving low stool frequency could be a target of future interventions with HN019. High-dose HN019 also decreased the degree of straining at Day 28 versus placebo in those with BMF ≤ 3/week (P value = 0.02). Three unlikely related AEs-2 with low-dose HN019 and 1 with placebo-were followed until full recovery. In conclusion, although there were no differences in the primary analysis, HN019 is well tolerated and improves BMF in adults with low stool frequency.
Topics: Adolescent; Adult; Aged; Bifidobacterium animalis; Constipation; Double-Blind Method; Female; Gastrointestinal Transit; Humans; Male; Middle Aged; Placebos; Probiotics; Quality of Life; Treatment Outcome; Young Adult
PubMed: 29227175
DOI: 10.1080/19490976.2017.1412908