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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 -
Nutrients Mar 2018History has shown that without explicit and enforced guidelines, even well-intentioned researchers can fail to adequately examine the ethical pros and cons of study... (Review)
Review
History has shown that without explicit and enforced guidelines, even well-intentioned researchers can fail to adequately examine the ethical pros and cons of study design choices. One area in which consensus does not yet exist is the use of placebo groups in vitamin supplementation studies. As a prime example, we focus on vitamin D research. We aim to provide an overview of the ethical issues in placebo-controlled studies and guide future discussion about the ethical use of placebo groups. Research in the field of vitamin D shows variation in how placebo groups are used. We outline four types of control groups in use: active-control, placebo-control with restrictions on supplementation, placebo-control without supplementation restrictions, and placebo-control with rescue repletion therapy. The first two types highlight discrete ethical issues: active-control trials limit the ability to detect a difference; placebo-control trials that restrict supplementation potentially place subjects at risk of undue harm. The final two, placebo-control without supplementation restrictions or with rescue repletion therapy, offer potential solutions to these ethical challenges. Building on this, guidelines should be established and enforced on the use of placebo in supplementation studies. Furthermore, the field of vitamin D research has the potential to set an example worthy of emulation.
Topics: Dietary Supplements; Humans; Placebos; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Research Design; Severity of Illness Index; Vitamin D; Vitamin D Deficiency; Withholding Treatment
PubMed: 29533982
DOI: 10.3390/nu10030347 -
The Cochrane Database of Systematic... Apr 2018Depression is common in the postnatal period and can lead to adverse effects on the infant and wider family, in addition to the morbidity for the mother. It is not clear... (Review)
Review
BACKGROUND
Depression is common in the postnatal period and can lead to adverse effects on the infant and wider family, in addition to the morbidity for the mother. It is not clear whether antidepressants are effective for the prevention of postnatal depression and little is known about possible adverse effects for the mother and infant, particularly during breastfeeding. This is an update of a Cochrane Review last published in 2005.
OBJECTIVES
To assess the effectiveness of antidepressant medication for the prevention of postnatal depression, in comparison with any other treatment, placebo or standard care.
SEARCH METHODS
We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR ‒ both Studies and References), CENTRAL (Wiley), MEDLINE (OVID), Embase (OVID), PsycINFO (OVID), on 13 February 2018. We also searched the World Health Organization (WHO) trials portal (ICTRP) and ClinicalTrials.gov on 13 February 2018 to identify any additional unpublished or ongoing studies.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of initiation of antidepressants (alone or in combination with another treatment), compared with any other treatment, placebo or standard care for the prevention of postnatal depression among women who were either pregnant or had given birth in the previous six weeks and were not currently depressed at baseline.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. We requested missing information from investigators wherever possible and sought data to allow intention-to-treat analyses.
MAIN RESULTS
Two trials including a total of 81 participants fulfilled the inclusion criteria for this review. All participants in both studies had a history of postnatal depression and were not taking antidepressant medication at baseline. Both trials were conducted by the same research group. Risk of bias was low or unclear in most domains for both studies. We were unable to perform a meta-analysis due to the small number of studies.One study compared nortriptyline with placebo and did not find any evidence that nortriptyline was effective in preventing postnatal depression. In this study, 23% (6/26) of women who took nortriptyline and 24% (6/25) of women who took placebo experienced postnatal depression (RR 0.96, 95% CI 0.36 to 2.59, very low quality evidence) in the first 17 weeks postpartum. One woman taking nortriptyline developed mania; and one side effect, constipation, was more common among women taking nortriptyline than those taking placebo.The second study compared sertraline with placebo. In this study, 7% (1/14) of women who took sertraline developed postnatal depression in the first 17 weeks postpartum compared with 50% (4/8) of women who took placebo. It is uncertain whether sertraline reduces the risk of postnatal depression (RR 0.14, 95% CI 0.02 to 1.07, very low quality evidence). One woman taking sertraline had a hypomanic episode. Two side effects (dizziness and drowsiness) were more common among women taking sertraline than women taking placebo.Conclusions are limited by the small number of studies, small sample sizes and incomplete outcome data due to study drop-out which may have led to bias in the results. We have assessed the certainty of the evidence as very low, based on the GRADE system. No data were available on secondary outcomes of interest including child development, the mother‒infant relationship, breastfeeding, maternal daily functioning, family relationships or maternal satisfaction.
AUTHORS' CONCLUSIONS
Due to the limitations of the current evidence base, such as the low statistical power of the included studies, it is not possible to draw any clear conclusions about the effectiveness of antidepressants for the prevention of postnatal depression. It is striking that no new eligible trials have been completed in the period of over a decade since the last published version of this review. Larger trials are needed which include comparisons of antidepressant drugs with other prophylactic treatments (e.g. psychological interventions), and examine adverse effects for the fetus or infant. Future reviews in this area may benefit from broadening their focus to examine the effectiveness of antidepressants for the prevention of perinatal (i.e. antenatal or postnatal) depression, which could include studies comparing antidepressant discontinuation with continuation for the prevention of relapse of depression during pregnancy and the postnatal period.
Topics: Antidepressive Agents; Depression, Postpartum; Female; Humans; Nortriptyline; Placebos; Randomized Controlled Trials as Topic; Sertraline
PubMed: 29669175
DOI: 10.1002/14651858.CD004363.pub3 -
Journal of Paediatrics and Child Health Jan 2018
Randomized Controlled Trial
Topics: Adolescent; Amitriptyline; Child; Female; Follow-Up Studies; Humans; Male; Migraine Disorders; Monitoring, Physiologic; Pain Measurement; Patient Safety; Placebos; Primary Prevention; Risk Assessment; Severity of Illness Index; Topiramate; Treatment Outcome
PubMed: 29314387
DOI: 10.1111/jpc.13800 -
Beneficial Microbes Oct 2017Our objective was to conduct a systematic review and meta-analysis for the use of modified (heat-killed or sonicated) probiotics for the efficacy and safety to prevent... (Meta-Analysis)
Meta-Analysis Review
Our objective was to conduct a systematic review and meta-analysis for the use of modified (heat-killed or sonicated) probiotics for the efficacy and safety to prevent and treat various diseases. Recent clinical research has focused on living strains of probiotics, but use in high-risk patients and potential adverse reactions including bacteremia has focused interest on alternatives to the use of live probiotics. We searched MEDLINE/PubMed, Embase, Cochrane Central Register of Controlled Trials, CINAHL, Alt Health Watch, Web of Science, Scopus, PubMed, from inception to February 14, 2017 for randomised controlled trials involving modified probiotic strains. The primary outcome was efficacy to prevent or treat disease and the secondary outcome was incidence of adverse events. A total of 40 trials were included (n=3,913): 14 trials (15 arms with modified probiotics and 20 control arms) for the prevention of diseases and 26 trials (29 arms with modified probiotics and 32 control arms) for treatment of various diseases. Modified microbes were compared to either placebo (44%), or the same living probiotic strain (39%) or to only standard therapies (17%). Modified microbes were not significantly more or less effective than the living probiotic in 86% of the preventive trials and 69% of the treatment trials. Modified probiotic strains were significantly more effective in 15% of the treatment trials. Incidence rates of adverse events were similar for modified and living probiotics and other control groups, but many trials did not collect adequate safety data. Although several types of modified probiotics showed significant efficacy over living strains of probiotics, firm conclusions could not be reached due to the limited number of trials using the same type of modified microbe (strain, daily dose and duration) for a specific disease indication. Further research may illuminate other strains of modified probiotics that may have potential as clinical biotherapeutics.
Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Placebos; Probiotics; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 28884589
DOI: 10.3920/BM2017.0032 -
Lasers in Medical Science Aug 2015This review aimed to evaluate the clinical outcome of different lasers management on orthodontic pain. Cochrane Library (Issue 7, 2014) and MEDLINE (1966-2014.7) were... (Meta-Analysis)
Meta-Analysis Review
This review aimed to evaluate the clinical outcome of different lasers management on orthodontic pain. Cochrane Library (Issue 7, 2014) and MEDLINE (1966-2014.7) were searched to collect randomized controlled trials on lasers for orthodontic pain. Studies meeting the inclusion criteria were systematically evaluated. The Cochrane Collaboration tools RevMan5.1.7 and GRADEpro 3.6 were used in this systematic review and meta-analysis. As a result, 11 randomized controlled trials (RCTs) studying on low-level laser therapy (LLLT) for orthodontic pain control were included. Meta-analysis and risk of bias assessment were implemented using RevMan5.1.7, and level of evidence assessments was measured by GRADEpro 3.6. In the outcome of the score of the most painful day, the comparison of laser versus placebo (pain associated with tooth movement) demonstrated that LLLT reduced the pain score significantly compared with placebo groups (MD = -4.39, 95% CI range -5.9--2.88, P < 0.00001). In the same way, the most painful day was significantly brought forward in laser versus control group (MD = -0.42, 95% CI range -0.74--0.10, P = 0.009). Furthermore, the outcome of the end of pain day showed a trend of pain termination earlier in laser versus control and placebo groups, but without statistical significance (MD = -1.37, 95% CI range -3.37-0.64, P = 0.18 and MD = -1.04, 95% CI range -4.22-2.15, P = 0.52). However, for the reason of downgrade factors, all the GRADE level of evidences of eight comparisons for three outcomes showed a very low quality. Therefore, for the methodological shortcomings and risk of bias of RCTs included, insufficient evidence was submitted to judge whether LLLT was effective in relieving orthodontic pain. Further and more perfect researches should be done in order to recommend LLLT as a routine method for orthodontic pain.
Topics: Adolescent; Adult; Child; Female; Humans; Lasers; Low-Level Light Therapy; Male; Pain; Pain Management; Placebos; Young Adult
PubMed: 25258106
DOI: 10.1007/s10103-014-1661-x -
Reviews in Medical Virology Nov 2017
Randomized Controlled Trial
Topics: Administration, Intravenous; Antibodies, Viral; Critical Illness; Cytomegalovirus Infections; DNA, Viral; Ganciclovir; Humans; Immunoglobulin G; Placebos; Respiration, Artificial; Sepsis; Treatment Outcome; Virus Activation; Wounds and Injuries
PubMed: 29143387
DOI: 10.1002/rmv.1957 -
Current Opinion in HIV and AIDS Jan 2016We discuss selected statistical issues in the design and analysis of preexposure prophylaxis (PrEP) trials. The general principles may inform thinking for other... (Review)
Review
PURPOSE OF REVIEW
We discuss selected statistical issues in the design and analysis of preexposure prophylaxis (PrEP) trials. The general principles may inform thinking for other interventions in HIV prevention.
RECENT FINDINGS
To date, four different designs have been used to determine the effectiveness of PrEP: randomized, double-blind, placebo-controlled; randomized, open-label, immediate or delayed access; nonrandomized comparison of HIV incidence according to the level of drug detected; comparison of the observed HIV incidence to the expected rate using historical control data. Open-label trials of PrEP, which assess public health effectiveness, complement the placebo-controlled trials which established the biological efficacy of TDF/FTC. Future trials of PrEP will be highly challenging to design since a no PrEP group is difficult to justify and the natural control regimen, TDF/FTC, is highly efficacious.
SUMMARY
Standard statistical paradigms for noninferiority trials should be reconsidered for evaluating alternative PrEP regimens.
Topics: Administration, Oral; Anti-HIV Agents; Biostatistics; Chemoprevention; Clinical Trials as Topic; Disease Transmission, Infectious; Double-Blind Method; HIV Infections; Humans; Placebos; Pre-Exposure Prophylaxis
PubMed: 26545264
DOI: 10.1097/COH.0000000000000218 -
The Cochrane Database of Systematic... Dec 2020Souvenaid is a dietary supplement with a patented composition (Fortasyn Connect™)which is intended to be used by people with Alzheimer's disease (AD). It has been...
BACKGROUND
Souvenaid is a dietary supplement with a patented composition (Fortasyn Connect™)which is intended to be used by people with Alzheimer's disease (AD). It has been designed to support the formation and function of synapses in the brain, which are thought to be strongly correlated with cognitive function. If effective, it might improve symptoms of Alzheimer's disease and also prevent the progression from prodromal Alzheimer's disease to dementia. We sought in this review to examine the evidence for this proposition.
OBJECTIVES
To assess the effects of Souvenaid on incidence of dementia, cognition, functional performance, and safety in people with Alzheimer's disease.
SEARCH METHODS
We searched ALOIS, i.e. the specialised register of the Cochrane Dementia and Cognitive Improvement Group, MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), Web of Science (ISI Web of Science), Cinahl (EBSCOhost), Lilacs (BIREME), and clinical trials registries up to 24 June 2020. We also reviewed citations of reference lists of landmark papers, reviews, and included studies for additional studies and assessed their suitability for inclusion in the review.
SELECTION CRITERIA
We included randomised, placebo-controlled trials which evaluated Souvenaid in people diagnosed with mild cognitive impairment (MCI) due to AD (also termed prodromal AD) or with dementia due to AD, and with a treatment duration of at least 16 weeks.
DATA COLLECTION AND ANALYSIS
Our primary outcome measures were incidence of dementia, global and specific cognitive function, functional performance, combined cognitive-functional outcomes and adverse events. We selected studies, extracted data, assessed the quality of trials and intended to conduct meta-analyses according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of the evidence using the GRADE approach. We present all outcomes grouped by stage of AD.
MAIN RESULTS
We included three randomised, placebo-controlled trials investigating Souvenaid in 1097 community-dwelling participants with Alzheimer's disease. One study each included participants with prodromal AD, mild AD dementia and mild-to-moderate AD dementia. We rated the risks of bias of all trials as low. One study (in prodromal AD) was funded by European grants. The other two studies were funded by the manufacturer of Souvenaid. One trial investigated the incidence of dementia in people with prodromal AD at baseline, and found little to no difference between the Souvenaid group and the placebo group after 24 months (RR 1.09, 95% CI 0.82 to 1.43; 1 trial, 311 participants; moderate quality of evidence). In prodromal AD, and in mild and mild-to-moderate Alzheimer's disease dementia, Souvenaid probably results in little or no difference in global or specific cognitive functions (moderate quality of evidence). Everyday function, or the ability to perform activities of daily living, were measured in mild and mild-to-moderate AD dementia. Neither study found evidence of a difference between the groups after 24 weeks of treatment (moderate quality of evidence). Two studies investigated combined cognitive-functional outcomes with the Clinical Dementia Rating Sum of Boxes and observed conflicting results. Souvenaid probably results in slight improvement, which is below estimates of meaningful change, in participants with prodromal Alzheimer's disease after 24 months (moderate quality of evidence), but probably has little to no effect in mild-to-moderate Alzheimer's disease dementia after 24 weeks (moderate quality of evidence). Adverse effects observed were low in all trials, and the available data were insufficient to determine any connection with Souvenaid.
AUTHORS' CONCLUSIONS
Two years of treatment with Souvenaid probably does not reduce the risk of progression to dementia in people with prodromal AD. There is no convincing evidence that Souvenaid affects other outcomes important to people with AD in the prodromal stage or mild-to-moderate stages of dementia. Conflicting evidence on combined cognitive-functional outcomes in prodromal AD and mild AD dementia warrants further investigation. Adverse effects of Souvenaid seem to be uncommon, but the evidence synthesised in this review does not permit us to make a definitive statement on the long-term tolerability of Souvenaid. The effects of Souvenaid in more severe AD dementia or in people with AD at risk of nutritional deficiencies remain unclear.
Topics: Alzheimer Disease; Bias; Cognition; Dementia; Dietary Supplements; Disease Progression; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Phospholipids; Placebos; Prodromal Symptoms; Randomized Controlled Trials as Topic; Time Factors
PubMed: 33320335
DOI: 10.1002/14651858.CD011679.pub2 -
BMJ Open Jul 2023The substitution of an in-study control population with a historical control (HC) population is considered a viable option for reducing the necessary recruitment of... (Randomized Controlled Trial)
Randomized Controlled Trial
Substituting a randomised placebo control group with a historical placebo control in an endometriosis pain trial: a case study re-evaluating trial data using historical control data from another trial.
OBJECTIVE
The substitution of an in-study control population with a historical control (HC) population is considered a viable option for reducing the necessary recruitment of control patients. However, it is necessary to evaluate whether this method is applicable to studies on indications targeting endometriosis-associated pelvic pain (EAPP). This study aims to evaluate the potential bias in the results of an EAPP study with an HC arm.
METHODS
For this case study, we re-evaluated data from a randomised, placebo-controlled trial using dienogest daily to treat EAPP with an HC arm based on data from a second randomised, placebo-controlled trial in the same indication. Propensity Score (PS) matching was used to match between the treatment and HC arm on all baseline variables. To evaluate the effect of matching on the introduced bias, we evaluated efficacy parameters with the full treatment and control group, as well as the matched group.
RESULTS
The difference between means (placebo minus treatment) in change in pain, as measured on the Visual Analogue Scale from baseline to end of treatment, deviates in the comparison treatment/pool of HC (7.15 (0.22 to 14.08)) from the overall in-study group (reference: 11.89 (6.06 to 17.73)). After PS matching on the baseline variables, the difference between means (11.79 (4.09 to 19.5)) is close to the reference.
CONCLUSIONS
Using HC with PS matching has proven to be useful in the setting of treating EAPP, while emphasis must be given to the selection mechanism and the underlying assumptions. This case study has shown that even for studies which are very similar in design, heterogeneity and between-study variations are present. With the use of an HC arm, it was possible to reproduce similar results than in the original study, while the PS matching improved the comparability considerably. For the main endpoint, PS matching could reproduce the original study results.
TRIAL REGISTRATION NUMBER
NCT00225199, NCT00185341.
Topics: Female; Humans; Endometriosis; Control Groups; Pelvic Pain; Pain Measurement; Propensity Score
PubMed: 37479520
DOI: 10.1136/bmjopen-2022-063188