Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies

BackgroundInternational asthma guidelines recommend against epinephrine (adrenaline) administration in acute asthma unless associated with anaphylaxis or angio-oedema. However, administration of intramuscular epinephrine in addition to nebulised selective β2-agonist is recommended for acute severe or life-threatening asthma in many prehospital guidelines. We conducted a systematic review to determine the efficacy of epinephrine in comparison to selective β2-agonist in acute asthma.MethodsWe included peer-reviewed publications of randomised controlled trials (RCTs) that enrolled children or adults in any healthcare setting and compared epinephrine by any route to selective β2-agonist by any route for an acute asthma exacerbation. The primary outcome was treatment failure, including hospitalisation, need for intubation or death.ResultsThirty-eight of 1140 studies were included. Overall quality of evidence was low. Seventeen studies contributed data on 1299 participants to the meta-analysis. There was significant statistical heterogeneity, I2=56%. The pooled Peto’s OR for treatment failure with epinephrine versus selective β2-agonist was 0.99 (0.75 to 1.32), p=0.95. There was strong evidence that recruitment age group was associated with different estimates of the odds of treatment failure; with studies recruiting adults-only having lower odds of treatment failure with epinephrine. It was not possible to determine whether epinephrine in addition to selective β2-agonist improved outcomes.ConclusionThe low-quality evidence available suggests that epinephrine and selective β2-agonists have similar efficacy in acute asthma. There is a need for high-quality double-blind RCTs to determine whether addition of intramuscular epinephrine to inhaled or nebulised selective β2-agonist improves outcome.PROSPERO registration numberCRD42017079472.

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Colchicine for children with pericarditis: systematic review of clinical studies

Archives of Disease in Childhood ◽

10.1136/archdischild-2015-310287 ◽

2016 ◽

Vol 101 (10) ◽

pp. 953-956 ◽

Cited By ~ 11

Author(s):

Samer Alabed ◽

Giordano Pérez-Gaxiola ◽

Amanda Burls

Keyword(s):

Systematic Review ◽

Case Reports ◽

Data Extraction ◽

Experimental Studies ◽

Case Series ◽

Eligibility Criteria ◽

Double Blind ◽

Randomised Controlled

ObjectiveTo review the evidence for the efficacy and safety of colchicine in children with pericarditis.DesignSystematic review.Search strategyThe following databases were searched for studies about colchicine in children with pericarditis (June 2015): Cochrane Central, Medline, EMBASE and LILACS.Eligibility criteriaAll observational and experimental studies on humans with any length of follow-up and no limitations on language or publication status were included. The outcomes studied were recurrences of pericarditis and adverse events.Data extractionTwo authors extracted data and assessed quality of included studies using the Cochrane risk of bias tool for non-randomised trials.ResultsTwo case series and nine case reports reported the use of colchicine in a total of 86 children with pericarditis. Five articles including 74 paediatric patients were in favour of colchicine in preventing further pericarditis recurrences. Six studies including 12 patients showed that colchicine did not prevent recurrences of pericarditis.LimitationsNo randomised controlled trials (RCTs) were found.ConclusionsAlthough colchicine is an established treatment for pericarditis in adults, it is not routinely used in children. There is not enough evidence to support or discourage the use of colchicine in children with pericarditis. Further research in the form of large double-blind RCTs is needed to establish the efficacy of colchicine in children with pericarditis.

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Use of Azacitidine or Decitabine for the Up-Front Setting in Acute Myeloid Leukaemia: A Systematic Review and Meta-Analysis

Cancers ◽

10.3390/cancers13225677 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5677

Author(s):

Miriam Saiz-Rodríguez ◽

Jorge Labrador ◽

Beatriz Cuevas ◽

David Martínez-Cuadrón ◽

Verónica Campuzano ◽

...

Keyword(s):

Systematic Review ◽

Acute Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Meta Analysis ◽

Response Rates ◽

Randomised Clinical Trial ◽

Treatment Schedule ◽

Similar Response ◽

Randomised Controlled ◽

Acute Myeloid

Irruption of decitabine and azacitidine has led to profound changes in the upfront management of older acute myeloid leukaemia (AML). However, they have not been directly compared in a randomised clinical trial. In addition, there are no studies comparing the optimal treatment schedule of each drug in AML. A systematic review and meta-analysis on the efficacy of decitabine and azacitidine monotherapy in newly diagnosed AML was conducted. Randomised controlled trials and retrospective studies were included. A total of 2743 patients from 23 cohorts were analysed (10 cohorts of azacitidine and 13 of decitabine). Similar response rates were observed for azacitidine (38%, 95% CI: 30–47%) compared to decitabine (40%, 95% CI: 32–48%) (p = 0.825). Overall survival (OS) between azacitidine (10.04 months, 95% CI: 8.36–11.72) and decitabine (8.79 months, 95% CI: 7.62–9.96) was also similar (p = 0.386). Patients treated with azacitidine showed a lower median OS when azacitidine was administered for 5 days (6.28 months, 95% CI: 4.23–8.32) compared to the standard 7-day schedule (10.83 months, 95% CI: 9.07–12.59, p = 0.002). Among patients treated with decitabine, response rates and OS were not significantly different between 5-day and 10-day decitabine regimens. Despite heterogeneity between studies, we found no differences in response rates and OS in AML patients treated with azacitidine or decitabine.

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Adrenaline (epinephrine) compared to selective beta-2-agonist in adults or children with acute asthma: a systematic review and meta-analysis

10.1101/2021.02.17.21251734 ◽

2021 ◽

Author(s):

Christina Baggott ◽

Jo Hardy ◽

Jenny Sparks ◽

Doñah Sabbagh ◽

Richard Beasley ◽

...

Keyword(s):

Systematic Review ◽

Treatment Failure ◽

Acute Asthma ◽

Meta Analysis ◽

Healthcare Setting ◽

Similar Efficacy ◽

Double Blind ◽

Statistical Heterogeneity ◽

Randomised Controlled ◽

Risk Of Treatment

AbstractBackgroundInternational asthma guidelines recommend against adrenaline administration in acute asthma unless associated with anaphylaxis or angioedema. However, administration of intra-muscular adrenaline in addition to nebulised selective β2-agonist is recommended for acute severe or life-threatening asthma in many pre-hospital guidelines. We conducted a systematic review to determine the efficacy of adrenaline in comparison to selective β2-agonist in acute asthma.MethodsWe included peer-reviewed publications of randomised controlled trials (RCTs) that enrolled children or adults in any healthcare setting and compared adrenaline by any route to selective β2-agonist by any route for an acute asthma exacerbation. The primary outcome was treatment failure, as indicated by hospitalisation, stay >24hrs in emergency department, need for intubation, or death.ResultsThirty-eight of 1,140 studies were included, involving 2,275 participants. Overall quality of evidence was low. There was significant statistical heterogeneity, I2=56%. The pooled odds ratio for treatment failure with adrenaline versus selective β2-agonist was 0.99 (0.74 to 1.34), p=0.96. There was strong evidence that recruitment age-group was associated with different estimates of the risk of treatment failure; with studies recruiting adults-only having a lower risk of treatment failure with adrenaline. It was not possible to determine whether adrenaline in addition to selective β2-agonist improved outcomes.ConclusionThe limited evidence available suggests that adrenaline and selective β2-agonists have similar efficacy in acute asthma and does not support the use of adrenaline in addition to selective β2-agonists in acute asthma. There is a need for high-quality double-blind RCTs to address this issue.PROSPERO registration number CRD42017079472

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S1335 Placebo Response Rates in Trials of Pharmacological Therapies for Irritable Bowel Syndrome: Systematic Review and Meta-Analysis

Gastroenterology ◽

10.1016/s0016-5085(10)61051-7 ◽

2010 ◽

Vol 138 (5) ◽

pp. S-231

Author(s):

Alexander C. Ford ◽

Paul Moayyedi

Keyword(s):

Systematic Review ◽

Irritable Bowel Syndrome ◽

Meta Analysis ◽

Placebo Response ◽

Response Rates ◽

Irritable Bowel

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The relation between the placebo response, observed treatment effect, and failure to meet primary endpoint: A systematic review of clinical trials of preventative pharmacological migraine treatments

Cephalalgia ◽

10.1177/0333102420960020 ◽

2020 ◽

pp. 033310242096002

Author(s):

Kathryn Evans ◽

Heather Romero ◽

Egilius LH Spierings ◽

Nathaniel Katz

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Primary Endpoint ◽

Response Rate ◽

Placebo Response ◽

Cochrane Central Register ◽

Double Blind ◽

Assay Sensitivity ◽

Central Register ◽

Significant Difference

Objective To evaluate the association between the degree of response to placebo in migraine studies and the observed difference between drug and placebo across studies of preventative treatments for migraine. Methods A systematic review was performed using MEDLINE and the Cochrane Central Register of Controlled Clinical Trials from January 1988 to June 2019. Randomized, double-blind, parallel-group, placebo-controlled trials on oral or injection preventative treatments for migraine were included. Single- and multi-variable linear regression analyses were performed on the placebo-subtracted response rate (i.e. placebo responders subtracted from active responders), and the proportion of placebo responders. Fisher’s exact tests were performed on the level of placebo response and the success in meeting the study’s primary endpoint. Results After adjusting for route of administration and number of randomized subjects, there was a statistically significant association between the proportion of patients who were placebo responders and the placebo-subtracted response rate (b = −0.27, p = 0.02). There was a statistically significant difference in trial success rate (60%) between studies with ≤20% placebo responders and studies with > 30% placebo responders ( p = 0.03). Conclusion Considering the detrimental impact that high placebo response can have on clinical trials, it is imperative to find effective solutions to decrease the placebo response and increase assay sensitivity.

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Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis

The British Journal of Psychiatry ◽

10.1192/bjp.bp.109.076448 ◽

2011 ◽

Vol 198 (1) ◽

pp. 11-16 ◽

Cited By ~ 112

Author(s):

Corrado Barbui ◽

Andrea Cipriani ◽

Vikram Patel ◽

José L. Ayuso-Mateos ◽

Mark van Ommeren

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Outcome Data ◽

Allocation Concealment ◽

Controlled Trials ◽

Minor Depression ◽

Double Blind ◽

Significant Difference ◽

Study Heterogeneity ◽

Randomised Controlled

BackgroundDepression is a common condition that has been frequently treated with psychotropics.AimsTo review systematically the evidence of efficacy and acceptability of antidepressant and benzodiazepine treatments for patients with minor depression.MethodA systematic review and meta-analysis of double-blind randomised controlled trials comparing antidepressants or benzodiazepines v. placebo in adults with minor depression. Data were obtained from MEDLINE, CINAHL, EMBASE, PsycInfo, Cochrane Controlled Trials Register and pharmaceutical company websites. Risk of bias was assessed for the generation of the allocation sequence, allocation concealment, masking, incomplete outcome data, and sponsorship bias.ResultsSix studies met inclusion criteria. Three studies compared paroxetine with placebo; fluoxetine, amitriptyline and isocarboxazid were studied in one study each. No studies compared benzodiazepines with placebo. In terms of failures to respond to treatment (6 studies, 234 patients treated with antidepressants and 234 with placebo) no significant difference between antidepressants and placebo was found (relative risk (RR) 0.94, 95% CI 0.81–1.08). In terms of acceptability, data extracted from two studies (93 patients treated with antidepressants and 93 with placebo) showed no statistically significant difference between antidepressants and placebo (RR = 1.06, 95% CI 0.65–1.73). There was no statistically significant between-study heterogeneity for any of the reported analyses.ConclusionsThere is evidence showing there is unlikely to be a clinically important advantage for antidepressants over placebo in individuals with minor depression. For benzodiazepines, no evidence is available, and thus it is not possible to determine their potential therapeutic role in this condition.

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General lack of use of placebo in prophylactic, randomised, controlled trials in adult migraine. A systematic review

Cephalalgia ◽

10.1177/0333102415616880 ◽

2016 ◽

Vol 36 (10) ◽

pp. 960-969 ◽

Cited By ~ 9

Author(s):

Anders Hougaard ◽

Peer Tfelt-Hansen

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

International Headache Society ◽

Placebo Response ◽

Placebo Control ◽

Placebo Controls ◽

Prophylactic Drugs ◽

Highly Sensitive ◽

Prophylactic Drug ◽

Randomised Controlled

Background The Clinical Trials Subcommittee of the International Headache Society (IHS) recommends that a placebo arm is included in comparative randomised clinical trials (RCTs) of multiple prophylactic drugs due to the highly variable placebo response in migraine prophylaxis studies. The use of placebo control in such trials has not been systematically assessed. Methods We performed a systematic review of all comparative RCTs of prophylactic drug treatment of migraine published in English from 2002 to 2014. PubMed was searched using the Cochrane Highly Sensitive Search Strategy for identifying reports of RCTs. Results A placebo arm was used in <10% (three of 31) of prophylactic RCTs in migraine. In only 7.1% (two of 28) of the comparative RCTs without placebo was one drug superior to another drug. Thus in 26 RCTs, including one study requiring more than 75,000 patient days, no difference was identified across treatment arms and conclusions regarding drug superiority could not be drawn. Conclusions The majority of comparative, prophylactic migraine RCTs do not include a placebo arm. Failure to include a placebo arm may result in failure to demonstrate efficacy of potentially effective migraine-prophylactic agents. In order to benefit current and future patients, the current strong tendency to omit placebo-controls in these RCTs should be replaced by adherence to the guidelines of the IHS.

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