Publications by authors named "Perrine Janiaud"

18 Publications

  • Page 1 of 1

Recruitment and Results Reporting of COVID-19 Randomized Clinical Trials Registered in the First 100 Days of the Pandemic.

JAMA Netw Open 2021 03 1;4(3):e210330. Epub 2021 Mar 1.

Department of Clinical Research, University of Basel, Basel, Switzerland.

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http://dx.doi.org/10.1001/jamanetworkopen.2021.0330DOI Listing
March 2021

Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis.

JAMA 2021 Feb 26. Epub 2021 Feb 26.

Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.

Importance: Convalescent plasma is a proposed treatment for COVID-19.

Objective: To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs).

Data Sources: PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021.

Study Selection: The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting.

Data Extraction And Synthesis: Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance-weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation.

Main Outcomes And Measures: All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events.

Results: A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was -1.21% (95% CI, -5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was -2.56% [95% CI, -13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences.

Conclusions And Relevance: Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.
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http://dx.doi.org/10.1001/jama.2021.2747DOI Listing
February 2021

The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days.

F1000Res 2020;9:1193. Epub 2020 Oct 2.

Meta-Research Innovation Center at Stanford (METRICS), Stanford University,, Stanford, California, USA.

: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.
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http://dx.doi.org/10.12688/f1000research.26707.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539080PMC
November 2020

The benefit-risk balance for biological agents in juvenile idiopathic arthritis: a meta-analysis of randomized clinical trials.

Rheumatology (Oxford) 2020 09;59(9):2226-2236

Laboratoire de Biométrie et Biologie Évolutive (UMR - CNRS 5558), University of Lyon, Lyon, France.

Objective: To assess the net benefit of biological agents (BA) used in JIA.

Methods: We systematically searched databases up to March 2019 for randomized controlled trials (RCT) performed in JIA disease. Separate random-effects meta-analyses were conducted for efficacy (ACR paediatric score 30%, ACRpedi30) and serious adverse events for safety. In order to standardize the baseline risk, we performed a meta-analysis of baseline risk in the control group (for both efficacy and safety meta-analysis). The net benefit was determined as the risk difference of efficacy subtracted by the risk difference of safety.

Results: We included 19 trials: 11 parallel RCTs (754 patients) and 8 withdrawal RCTs (704 patients). The net benefit ranged from 2.4% (adalimumab) to 17.6% (etanercept), and from 2.4% (etanercept) to 36.7%, (abatacept) in parallel and withdrawal trials assessing non-systemic JIA, respectively. In the systemic JIA category, the net benefit ranged from 22.8% (rilonacept) to 70.3% (canakinumab), and from 32.3% (canakinumab) to 58.2% (tocilizumab) in parallel and withdrawal trials, respectively.

Conclusion: The results suggest that a greater number of patients experienced therapeutic success without serious adverse events in the systemic onset JIA category compared with the BAs for non-systemic JIA categories. Baseline risk, design of trial and JIA categories impact the measure of net benefit of BAs in JIA patients.
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http://dx.doi.org/10.1093/rheumatology/keaa170DOI Listing
September 2020

Limited evidence of physical therapy on balance after stroke: A systematic review and meta-analysis.

PLoS One 2019 29;14(8):e0221700. Epub 2019 Aug 29.

Service de médecine physique et réadaptation, hôpital Henry Gabrielle, Hospices Civils de Lyon, Saint-Genis-Laval, France.

Background: Stroke results in balance disorders and these directly affect autonomy and quality of life. The purpose of this systematic review and meta-analysis was to determine the efficacy of physical therapy (PT) on balance and postural control after stroke.

Methods: We included all randomized controlled trials assessing the efficacy of PT on balance and postural control in adult patients after stroke without language restriction. Medline, Embase/Scopus, Cochrane Central Register of Controlled Trials, PEDro, Pascal, and Francis databases were searched until January 2019. Primary outcomes were balance (Berg Balance scale and Postural Assessment Scale for Stroke) and postural control with postural deviation or stability measurement in sitting or standing static evaluation. A pair of independent reviewers selected studies, extracted data, and assessed risk of bias. Meta-analyses with subgroups (categories of PT, time post-stroke, and lesion location) and meta-regression (duration of PT) were conducted.

Results: A total of 145 studies (n = 5912) were selected from the 13,123 records identified. For balance, evidence was found in favor of the efficacy of functional task-training alone (standardized mean difference 0.39, 95% confidence interval [0.09; 0.68], heterogeneity I2 = 63%) or associated with musculoskeletal intervention and/or cardiopulmonary intervention (0.37, [0.19; 0.55], I2 = 48%), electrostimulation (0.91, [0.49; 1.34], I2 = 52%) immediately after intervention, compared to sham treatment or usual care (ST/UC). For postural deviation eyes open, assistive devices were more effective than no treatment (-0.21, [-0.37; -0.05], I2 = 0%) immediately after intervention; for postural stability eyes open, functional task-training and sensory interventions were more effective than ST/UC (0.97, [0.35; 1.59], I2 = 65% and 0.80, [0.46; 1.13], I2 = 37% respectively) immediately after intervention.

Conclusions: Functional task-training associated with musculoskeletal intervention and/or cardiopulmonary intervention and sensory interventions seem to be immediately effective in improving balance and postural stability, respectively. The heterogeneity of PT and the weak methodological quality of studies limited the interpretation and the confidence in findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221700PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715189PMC
March 2020

Do patients with cystic fibrosis participating in clinical trials demonstrate placebo response? A meta-analysis.

J Cyst Fibros 2019 07 13;18(4):461-467. Epub 2019 Feb 13.

UMR 5558 CNRS, Equipe EMET, Université Claude Bernard Lyon 1, Lyon, France; Centre de ressources et de compétences de la mucoviscidose, Hospices Civils de Lyon, Lyon, France. Electronic address:

Background: Patients' and families' expectation that a cure for cystic fibrosis (CF) will be found is high. In other debilitating conditions, high expectation has been shown to drive a strong placebo response (PR). Therefore, our goal was to evaluate PR on objective continuous outcomes (FEV, BMI) and the CF Questionnaire Revised-Respiratory Domain (CFQR-RD) monitored during randomised clinical trials (RCTs) for CF.

Methods: We conducted a meta-analysis after a systematic review of the literature carried out to identify RCTs with FEV, CFQR-RD and BMI as outcome measures. The standardised mean difference (SMD) was calculated to estimate the PR. A meta-regression analysis was conducted to assess other contributing factors on PR such as study design, trial duration, patient age and disease severity.

Results: Out of 289 RCTs found in the search, we identified 61 articles (published from 1987 to 2017) with respectively 59, 17 and 9 reporting FEV, CFQR-RD and BMI at the start and at the end of the RCTs. No significant PR was found on FEV or CFQR-RD. However, a small but significant PR was found on BMI SMD, 0.09 (95% CI (0.01; 0.17); p = 0.03).

Conclusion: The PR seems higher when measuring BMI. However, it is not clear whether this improvement can be explained by a PR alone.
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http://dx.doi.org/10.1016/j.jcf.2019.02.003DOI Listing
July 2019

New clinical trial designs in the era of precision medicine: An overview of definitions, strengths, weaknesses, and current use in oncology.

Cancer Treat Rev 2019 Feb 11;73:20-30. Epub 2018 Dec 11.

Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA 94305, USA; Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, CA 94305, USA. Electronic address:

With expanding knowledge in tumor biology and biomarkers, oncology therapies are increasingly moving away from the "one-size-fits-all" rationale onto biomarker-driven therapies tailored according to patient-specific characteristics, most commonly the tumor's molecular profile. The advent of precision medicine in oncology has been accompanied by the introduction of novel clinical trial designs that aim to identify biomarker-matched subgroups of patients that will benefit the most from targeted therapies. This innovation comes with the promise of answering more treatment questions, more efficiently and in less time. In this article, we give an overview of the different biomarker-based designs, comparing the features of enrichment, randomize-all, umbrella, and basket trials, and highlighting their advantages and disadvantages. We focus more on the novel designs known as master protocols, which include umbrella and basket trials. We have also conducted a search in ClinicalTrials.gov for registered oncology-related protocols of ongoing or completed trials labeled as umbrella or basket trials for solid tumors; we also included additional relevant trials retrieved from other reviews. We present and discuss the key features of the 30 eligible basket trials and 27 eligible umbrella trials. Only a minority of them are randomized (2 and 9, respectively), including three trials with adaptive randomization. Five of these trials have been completed as of July 2018. Precision medicine trial designs fuel new hopes for identifying best treatments, but there is also the potential for hype. The benefits and challenges associated with their use will need continued monitoring.
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http://dx.doi.org/10.1016/j.ctrv.2018.12.003DOI Listing
February 2019

Correction to: Industry-funded versus non-profit-funded critical care research: a meta-epidemiological overview.

Intensive Care Med 2018 12;44(12):2323

Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA, 94305, USA.

The original article can be found online.
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http://dx.doi.org/10.1007/s00134-018-5437-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828205PMC
December 2018

Industry-funded versus non-profit-funded critical care research: a meta-epidemiological overview.

Intensive Care Med 2018 10 27;44(10):1613-1627. Epub 2018 Aug 27.

Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA, 94305, USA.

Purpose: To study the landscape of funding in intensive care research and assess whether the reported outcomes of industry-funded randomized controlled trials (RCTs) are more favorable.

Methods: We systematically assembled meta-analyses evaluating any type of intervention in the critical care setting and reporting the source of funding for each included RCT. Furthermore, when the intervention was a drug or biologic, we searched also the original RCT articles, when their funding information was unavailable in the meta-analysis. We then qualitatively summarized the sources of funding. For binary outcomes, separate summary odds ratios were calculated for trials with and without industry funding. We then calculated the ratio of odds ratios (RORs) and the summary ROR (sROR) across topics. ROR < 1 implies that the experimental intervention is relatively more favorable in trials with industry funding compared with trials without industry funding. For RCTs included in the ROR analysis, we also examined the conclusions of their abstract.

Results: Across 67 topics with 568 RCTs, 88 were funded by industry and another 73 had both industry and non-profit funding. Across 33 topics with binary outcomes, the sROR was 1.10 [95% CI (0.96-1.26), I = 1%]. Conclusions were not significantly more commonly unfavorable for the experimental arm interventions in industry-funded trials (21.3%) compared with trials without industry funding (18.2%).

Conclusion: Industry-funded RCTs are the minority in intensive care. We found no evidence that industry-funded trials in intensive care yield more favorable results or are less likely to reach unfavorable conclusions.
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http://dx.doi.org/10.1007/s00134-018-5325-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182357PMC
October 2018

Assessment of Pragmatism in Recently Published Randomized Clinical Trials.

JAMA Intern Med 2018 09;178(9):1278-1280

Departments of Medicine, Health Research and Policy, Biomedical Data Science, Statistics, Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California.

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http://dx.doi.org/10.1001/jamainternmed.2018.3321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142963PMC
September 2018

Real-world evidence: How pragmatic are randomized controlled trials labeled as pragmatic?

BMC Med 2018 04 3;16(1):49. Epub 2018 Apr 3.

Departments of Medicine, Health Research and Policy, Biomedical Data Science, Statistics, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA, 94305, USA.

Introduction: Pragmatic randomized controlled trials (RCTs) mimic usual clinical practice and they are critical to inform decision-making by patients, clinicians and policy-makers in real-world settings. Pragmatic RCTs assess effectiveness of available medicines, while explanatory RCTs assess efficacy of investigational medicines. Explanatory and pragmatic are the extremes of a continuum. This debate article seeks to evaluate and provide recommendation on how to characterize pragmatic RCTs in light of the current landscape of RCTs. It is supported by findings from a PubMed search conducted in August 2017, which retrieved 615 RCTs self-labeled in their titles as "pragmatic" or "naturalistic". We focused on 89 of these trials that assessed medicines (drugs or biologics).

Discussion: 36% of these 89 trials were placebo-controlled, performed before licensing of the medicine, or done in a single-center. In our opinion, such RCTs overtly deviate from usual care and pragmatism. It follows, that the use of the term 'pragmatic' to describe them, conveys a misleading message to patients and clinicians. Furthermore, many other trials among the 615 coined as 'pragmatic' and assessing other types of intervention are plausibly not very pragmatic; however, this is impossible for a reader to tell without access to the full protocol and insider knowledge of the trial conduct. The degree of pragmatism should be evaluated by the trial investigators themselves using the PRECIS-2 tool, a tool that comprises 9 domains, each scored from 1 (very explanatory) to 5 (very pragmatic).

Conclusions: To allow for a more appropriate characterization of the degree of pragmatism in clinical research, submissions of RCTs to funders, research ethics committees and to peer-reviewed journals should include a PRECIS-2 tool assessment done by the trial investigators. Clarity and accuracy on the extent to which a RCT is pragmatic will help understand how much it is relevant to real-world practice.
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http://dx.doi.org/10.1186/s12916-018-1038-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883397PMC
April 2018

Use of available clinical evidence to extrapolate drug effects from adults to children.

Therapie 2018 Apr 16;73(2):119-125. Epub 2018 Feb 16.

UMR 5558, CRNS Lyon, university of Lyon 1, 69376 Lyon cedex 08, France; Service of pharmacotoxicology, CHU of Lyon, 69437 Lyon, France; INSERM CIC1407/UMR5558, hospices civils de Lyon, EPICIME-clinical investigation center, 69003 Lyon, France.

The extrapolation of the benefit risk ratio from adults to children is performed during drug development and often implicitly used by many paediatricians when prescribing off-label drugs in children. This is due to the specific constraints of paediatric clinical research leading to a lack of safety and efficacy data in children. Extrapolation frameworks for drug development have been proposed by several regulatory agencies. Using a meta-epidemiological approach, we explored the similarities and differences of the benefit, the benefit risk ratio and the perceived placebo effect between adults and children from meta-analyses including randomized double-blinded placebo-controlled trials evaluating a drug intervention in an indication in adults and children with separate data for both populations. We also explored the use of the effect model using adult data to predict the treatment effect in children and to calibrate future paediatric clinical trials. Our research highlights the importance of using all available evidence and quantitative methods before extrapolating the benefit risk ratio from adults to children and carrying out new studies in the context of the existing evidence. More generally, this should be applied to any research to avoid a waste of time and resources invested.
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http://dx.doi.org/10.1016/j.therap.2017.11.007DOI Listing
April 2018

Data sharing and reanalysis of randomized controlled trials in leading biomedical journals with a full data sharing policy: survey of studies published in and .

BMJ 2018 02 13;360:k400. Epub 2018 Feb 13.

Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA

Objectives: To explore the effectiveness of data sharing by randomized controlled trials (RCTs) in journals with a full data sharing policy and to describe potential difficulties encountered in the process of performing reanalyses of the primary outcomes.

Design: Survey of published RCTs.

Setting: PubMed/Medline.

Eligibility Criteria: RCTs that had been submitted and published by and subsequent to the adoption of data sharing policies by these journals.

Main Outcome Measure: The primary outcome was data availability, defined as the eventual receipt of complete data with clear labelling. Primary outcomes were reanalyzed to assess to what extent studies were reproduced. Difficulties encountered were described.

Results: 37 RCTs (21 from and 16 from ) published between 2013 and 2016 met the eligibility criteria. 17/37 (46%, 95% confidence interval 30% to 62%) satisfied the definition of data availability and 14 of the 17 (82%, 59% to 94%) were fully reproduced on all their primary outcomes. Of the remaining RCTs, errors were identified in two but reached similar conclusions and one paper did not provide enough information in the Methods section to reproduce the analyses. Difficulties identified included problems in contacting corresponding authors and lack of resources on their behalf in preparing the datasets. In addition, there was a range of different data sharing practices across study groups.

Conclusions: Data availability was not optimal in two journals with a strong policy for data sharing. When investigators shared data, most reanalyses largely reproduced the original results. Data sharing practices need to become more widespread and streamlined to allow meaningful reanalyses and reuse of data.

Trial Registration: Open Science Framework osf.io/c4zke.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809812PMC
http://dx.doi.org/10.1136/bmj.k400DOI Listing
February 2018

Trends in the number and the quality of trial protocols involving children submitted to a French Institutional Review Board.

BMC Med Res Methodol 2017 Aug 23;17(1):130. Epub 2017 Aug 23.

Evolutive Biology and Biometric Laboratory UMR5558 CNRS, Université Claude Bernard Lyon 1, 8 rue Guillaume Paradin, BP8071, 69376-CEDEX-08, Lyon, France.

Background: There is a great need for high quality clinical research for children. The European Pediatric Regulation aimed to improve the quality of clinical trials in order to increase the availability of treatments for children. The main purpose of this study was to assess the evolution of both the number and the quality of pediatric trial protocols that were submitted to a French Institutional Review Board (IRB00009118) before and after the initiation of the EU Pediatric Regulation.

Methods: All protocols submitted to the IRB00009118 between 2003 and 2014 and conducting research on subjects under eighteen years of age were eligible. The quality of randomized clinical trials was assessed according to the guidelines developed by the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network and ranked using the Jadad score.

Results: Out of 622 protocols submitted to the Institutional Review Board (IRB), 21% (133/622) included children. Among these 133 pediatric protocols, the number of submitted pediatric protocols doubled between the two studied periods. From 2003 to 2008, 47 protocols including 21 institutionally sponsored were submitted to the IRB and from 2009 until 2014, 86 protocols including 48 institutionally sponsored were submitted. No significant trend was observed on the quality of RCTs. The overall median score of RCTs on the Jadad scale was high (3.5), 70.0% of protocols had a Jadad score ≥ 3, and 30.0% had a score < 3.

Conclusion: Following the EU Pediatric Regulation, the number of pediatric protocols submitted to the IRB00009118 tends to increase, but no change was noticed regarding their quality.
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http://dx.doi.org/10.1186/s12874-017-0395-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569539PMC
August 2017

Is the perceived placebo effect comparable between adults and children? A meta-regression analysis.

Pediatr Res 2017 01 20;81(1-1):11-17. Epub 2016 Sep 20.

UMR 5558, CNRS, Claude Bernard University Lyon 1, Lyon, France.

Background: A potential larger perceived placebo effect in children compared with adults could influence the detection of the treatment effect and the extrapolation of the treatment benefit from adults to children. This study aims to explore this potential difference, using a meta-epidemiological approach.

Methods: A systematic review of the literature was done to identify trials included in meta-analyses evaluating a drug intervention with separate data for adults and children. The standardized mean change and the proportion of responders (binary outcomes) were used to calculate the perceived placebo effect. A meta-regression analysis was conducted to test for the difference between adults and children of the perceived placebo effect.

Results: For binary outcomes, the perceived placebo effect was significantly more favorable in children compared with adults (β = 0.13; P = 0.001). Parallel group trials (β = -1.83; P < 0.001), subjective outcomes (β = -0.76; P < 0.001), and the disease type significantly influenced the perceived placebo effect.

Conclusion: The perceived placebo effect is different between adults and children for binary outcomes. This difference seems to be influenced by the design, the disease, and outcomes. Calibration of new studies for children should consider cautiously the placebo effect in children.
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http://dx.doi.org/10.1038/pr.2016.181DOI Listing
January 2017

Impact of Aldosterone Antagonists on Sudden Cardiac Death Prevention in Heart Failure and Post-Myocardial Infarction Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

PLoS One 2016 18;11(2):e0145958. Epub 2016 Feb 18.

Laboratoire de Biologie et Biométrie Evolutive - Equipe Modélisation des Effets Thérapeutiques, UMR 5558 Université Claude Bernard Lyon1, Lyon, France.

Background And Objectives: Sudden cardiac death (SCD) is a severe burden of modern medicine. Aldosterone antagonist is publicized as effective in reducing mortality in patients with heart failure (HF) or post myocardial infarction (MI). Our study aimed to assess the efficacy of AAs on mortality including SCD, hospitalization admission and several common adverse effects.

Methods: We searched Embase, PubMed, Web of Science, Cochrane library and clinicaltrial.gov for randomized controlled trials (RCTs) assigning AAs in patients with HF or post MI through May 2015. The comparator included standard medication or placebo, or both. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Event rates were compared using a random effects model. Prospective RCTs of AAs with durations of at least 8 weeks were selected if they included at least one of the following outcomes: SCD, all-cause/cardiovascular mortality, all-cause/cardiovascular hospitalization and common side effects (hyperkalemia, renal function degradation and gynecomastia).

Results: Data from 19,333 patients enrolled in 25 trials were included. In patients with HF, this treatment significantly reduced the risk of SCD by 19% (RR 0.81; 95% CI, 0.67-0.98; p = 0.03); all-cause mortality by 19% (RR 0.81; 95% CI, 0.74-0.88, p<0.00001) and cardiovascular death by 21% (RR 0.79; 95% CI, 0.70-0.89, p<0.00001). In patients with post-MI, the matching reduced risks were 20% (RR 0.80; 95% CI, 0.66-0.98; p = 0.03), 15% (RR 0.85; 95% CI, 0.76-0.95, p = 0.003) and 17% (RR 0.83; 95% CI, 0.74-0.94, p = 0.003), respectively. Concerning both subgroups, the relative risks respectively decreased by 19% (RR 0.81; 95% CI, 0.71-0.92; p = 0.002) for SCD, 18% (RR 0.82; 95% CI, 0.77-0.88, p < 0.0001) for all-cause mortality and 20% (RR 0.80; 95% CI, 0.74-0.87, p < 0.0001) for cardiovascular mortality in patients treated with AAs. As well, hospitalizations were significantly reduced, while common adverse effects were significantly increased.

Conclusion: Aldosterone antagonists appear to be effective in reducing SCD and other mortality events, compared with placebo or standard medication in patients with HF and/or after a MI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145958PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758660PMC
July 2016

Different treatment benefits were estimated by clinical trials performed in adults compared with those performed in children.

J Clin Epidemiol 2015 Oct 9;68(10):1221-31. Epub 2015 Jul 9.

UMR 5558 CRNS Lyon, University of Lyon 1, France; Clinical Investigation Center, EPICIME, INSERM CIC 1407/UMR 5558 CNRS, Bron, France; Department of Clinical Pharmacology, Hospices Civils de Lyon, Lyon, France. Electronic address:

Objective: Our main objective was to see whether the therapeutic benefit observed in placebo controlled randomized controlled trials (RCTs) is different between adults and children.

Study Design And Setting: We searched three electronic databases for meta-analyses that included double-blind, placebo-controlled RCTs with separate results for adults and children. The selected reviews were classified according to disease and drug used. The heterogeneity of treatment response between adults and children was measured using ratio of odds ratios (RORs).

Results: We selected 89 meta-analyses and calculated RORs for 124 drugs. Heterogeneity in the direction of the treatment effect was observed in one drug and heterogeneity in the quantity of the treatment effect for 13 drugs, indicating significantly different treatment effect in adults when compared with children. RORs were not significantly different from 1 for 110 drugs. For 36 of these drugs, the treatment effect was confirmed in both populations.

Conclusion: We found different treatment benefits estimated by clinical trials performed in adults compared with those performed in children for 14 of 124 drugs. Data on dose adjustment and child age groups from RCTs were not adequately reported to investigate their influence on the treatment benefit dissimilarities.
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http://dx.doi.org/10.1016/j.jclinepi.2015.06.021DOI Listing
October 2015

Extrapolation will never replace randomized clinical trials.

J Clin Epidemiol 2016 Mar 4;71:109-10. Epub 2015 Jul 4.

UMR 5558 CRNS Lyon, University of Lyon 1, France; Clinical Investigation Center, EPICIME, INSERM CIC 1407/UMR 5558 CNRS, Bron, France; Department of Clinical Pharmacology, Hospices Civils de Lyon, Lyon, France.

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http://dx.doi.org/10.1016/j.jclinepi.2015.06.019DOI Listing
March 2016