Search

Background: Lamotrigine has become one of the most commonly prescribed antiseizure medications (ASM) in epileptic women during pregnancy and therefore requires regular updates regarding its safety. The aim of this study was to estimate the association between in utero exposure to lamotrigine monotherapy and the occurrence of neurodevelopmental outcomes., Methods: All comparative studies assessing the occurrence of neurodevelopmental outcomes after epilepsy-indicated lamotrigine monotherapy exposure during pregnancy were searched. First, references were identified through a snowballing approach, then, through electronic databases (Medline and Embase) from 2015 to June 2022. One investigator evaluated study eligibility and extracted data and a second independent investigator reviewed the meta-analysis (MA). A systematic review and random-effects model approach were performed using a collaborative WEB-based meta-analysis platform (metaPreg.org) with a registered protocol (osf.io/u4gva)., Results: Overall, 18 studies were included. For outcomes reported by at least 4 studies, the pooled odds ratios and 95% confidence interval obtained with the number of exposed (N1) and unexposed children (N0) included were: neurodevelopmental disorders as a whole 0.84 [0.66;1.06] (N1 = 5,271; N0 = 22,230); language disorders or delay 1.16 [0.67;2.00] (N1 = 313; N0 = 506); diagnosis or risk of ASD 0.97 [0.61;1.53] (N1 = at least 5,262; N0 = 33,313); diagnosis or risk of ADHD 1.14 [0.75;1.72] (N1 = at least 113; N0 = 11,530) and psychomotor developmental disorders or delay 2.68 [1.29-5.56] (N1 = 163; N0 = 220). The MA of cognitive outcomes included less than 4 studies and retrieved a significant association for infants exposed to lamotrigine younger than 3 years old but not in the older age groups., Conclusion: Prenatal exposure to lamotrigine monotherapy is not found to be statistically associated with neurodevelopmental disorders as a whole, language disorders or delay, diagnosis or risk of ASD and diagnosis or risk of ADHD. However, the MA found an increased risk of psychomotor developmental disorders or delay and cognitive developmental delay in less than 3 years old children. Nevertheless, these findings were based exclusively on observational studies presenting biases and on a limited number of included children. More studies should assess neurodevelopmental outcomes in children prenatally exposed to lamotrigine., (© 2024. The Author(s).)

Competing Interests: Competing interests: DC reports an HIV grant from Janssen (2019-2020), personal fees from Gilead (2020) and Pfizer (2022) for lectures outside the submitted work. RT has been the coordinator of the IMI2 EBOVAC2 project in collaboration with Janssen (2014-2021). Other authors have no competing interests to disclose.

Clinical trials often last several months or even several years. As the trial progresses, it can be tempting to find out whether the data obtained already answers the question posed at the start of the trial in order to stop inclusions or monitoring earlier. However, knowing and taking into account interim results can sometimes compromise the integrity of the results, which is counterproductive. To minimise this risk and ensure that the treatments are assessed reliably, safety and/or efficacy criteria are monitored during the study by a Data Monitoring Committee. After receiving the results confidentially, the Data Monitoring Committee assesses the benefit/risk ratio of the study treatment and recommends that the trial be continued, modified or terminated. Data Monitoring Committee members issuing these recommendations have an important responsibility: a hasty decision to end the trial may lead to inconclusive results unable to answer the initial question and, inversely, delaying the decision to end the trial may expose the subjects to potentially ineffective or even harmful interventions. The Data Monitoring Committee's task is therefore particularly complex. With this in mind, the round table discussion at the Giens workshops was a chance to review the scientific justification for creating Data Monitoring Committees and to recall the need for their members to receive comprehensive training on the complexities of multiple analyses, confidentiality requirements applying to the results and the need for them to be aware that recommendations to end a trial must be based on data that is robust enough to assess the benefit/risk ratio of the treatment studied., (Copyright © 2023. Published by Elsevier Masson SAS.)

Objective: Randomized controlled trials (RCTs) have demonstrated the superiority of metabolic surgery (MS) over medical therapy (MT) in patients with obesity and type 2 diabetes, leading, to a joint statement in 2016 proposing MS to patients with class I obesity and uncontrolled glycemia. Yet, these RCTs included few patients with class I obesity (body mass index 30-35 kg/m 2 ) and even fewer patients with overweight. Our aim was to provide an updated systematic review (SR) with meta-analysis (MA) of RCTs reporting diabetes remission (DR) after MS in these patients., Research Design and Methods: We included in the SR with MA only RCTs with at least 24-month follow-up found in Medline, Cochrane Library, Embase, and LiSSA between January 2008 and September 2022 comparing DR post-MT versus post-MS. We calculated relative risk (RR) and 95 % confidence intervals (CIs) using the Mantel-Haenszel random-effects approach to examine differences in DR between patients allocated to MS versus MT., Results: DR was significantly higher in MS versus MT after 36 months' follow-up in patients with obesity (RR = 6.65 [95 %CI 2.24;19.79]; I² = 27 %; 5 trials, 404 patients), but also specifically in patients with class I obesity (RR = 5.27 [1.31;21.23]; I² = 0 %; 4 trials, 80 patients). Furthermore, and in line with previous results, all additional MAs performed in patients with obesity in this work favor MS (specifically Roux-en-Y gastric bypass) over MT at 24, 36 (only) and 60 months of follow-up., Conclusions: Although the data available in patients with class I obesity and type 2 diabetes remains limited, MA shows higher rates of DR after MS compared with MT after 36 months' follow-up in these patients. Consequently, the French National Authority for Health French (HAS) recommends MS for these patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: To perform an overview of the overlap of systematic reviews (SRs) assessing direct oral anticoagulants and characterize these reviews in terms of bias and methodological quality (PROSPERO: CRD42022316273)., Study Design and Setting: A PubMed-indexed search was performed from inception to January 31, 2022 to identify SRs evaluating direct oral anticoagulants in patients treated for an acute venous thromboembolism. The risk of bias of these SRs was assessed according to the Risk Of Bias In Systematic reviews tool. Redundancy was defined as overlap in terms of the type of population considered, the interventions compared, and the studies included., Results: A total of 144 SRs were evaluated, of which 26 (18.1%) were classified as original, 87 (60.4%) as conceptual replications, and 31 (21.5%) as excessive replications. The risk of bias was high in 19 (73.1%) of the original SRs, 65 (74.7%) of the conceptual replications, and 21 (67.7%) of the excessive replications. Compared to the original SRs, the overall methodological quality was not improved in either conceptual or excessive replications., Conclusion: A large number of SRs was classified as replications; a fifth constituted excessive replications. The replications showed no improvement in overall methodological quality compared to the original SRs., Competing Interests: Declaration of competing interest Céline Chapelle, Edouard Ollier, Paul Bonjean, Clara Locher, and Paul Jacques Zufferey: none. Michel Cucherat has received personal fees from Bayer and BMS for consulting. Silvy Laporte has received personal fees from Bayer for consulting, personal fees continuing medical education lectures from Pfizer, and personal fees for continuing medical education lectures from Eli Lilly., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Use of proton pump inhibitors (PPI) are common among pregnant women to relieve gastrointestinal symptoms. The number of exposed pregnancies is therefore considerable, and a recent meta-analysis (MA) from 2020 raised concern about their teratogenicity. The aim of the study was to provide a MA of the risk of major congenital malformations (MCM) after PPI exposure during the first trimester of pregnancy. A systematic review and random-effects model approach were performed using a collaborative WEB-based meta-analysis platform (metaPreg.org) with a registered protocol (osf.io/u4gva). The primary outcome was the incidence of overall MCM. The secondary outcomes of interest were specific MCM reported by at least three studies. All comparative studies assessing these outcomes in PPI exposed pregnancies were searched from inception to April 2022. From the 211 initially identified studies, 11 were included in the MA. The pooled odds ratio (OR) for the primary outcome showed no significant results based on 5 618 exposed pregnancies (OR 1.10, 95% CI [0.95;1.26]; I²=0%). Similarly, no result was significant for the secondary outcomes. The total exposed sample size ranged from 3 161-5 085; OR ranged between 0.60 and 1.92; heterogeneity was between 0% and 23%. Based on the results of the present MA, first trimester PPI exposure was not associated with a significantly increased risk of overall or specific MCM. However, this MA included only observational studies which are prone to bias and there were insufficient data to evaluate PPI at a substance level. Future studies are needed to address this concern., Competing Interests: Declaration of Competing Interest The authors have indicated they have no potential conflicts of interest to disclose. This research did receive a specific grant from the French National Agency for the Safety of Medicines and Health Products., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Evidence-based medicine is the cornerstone of shared-decision making in healthcare today. The public deserves clear, transparent and trust-worthy information on drug efficacy. Yet today, many drugs are prescribed and used without solid evidence of efficacy. Clinical trials and randomised clinical trials (RCTs) are the best method to evaluate drug efficacy and side effects. In a shared medical decision-making approach, general practitioners need drug assessment based on patient-important outcomes. The aim of project rebuild the evidence base (REB) is to bridge the gap between the data needed in clinical practice and the data available from clinical research. The drugs will be assessed on clinical patient important outcomes and for a population. Using the Cochrane tools, we propose to analyse for each population and outcome: 1) a meta-analysis based on RCTs with a low risk of bias overall; 2) an evaluation of results of confirmatory RCTs; 3) a statistical analysis of heterrogeneity between RCTs and 4) an analysis of publication bias. Depending on the results of these analyses, the evidence will be categorized in 4 different levels: firm evidence, evidence (to be confirmed), signal or absence of evidence. Project REB proposes a method for reading and interpreting RCTs and their meta-analysis to produce quality data for general practitioners to focus on risk-benefit assessment in the interest of patients. If this data does not exist, it could enable clinical research to better its aim., (Copyright © 2022 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: Knowledge about the risks of drugs during pregnancy is continuously evolving due to the frequent publication of a large number of epidemiological studies. Systematic reviews and meta-analyses therefore need to be regularly updated to reflect these advances. To improve dissemination of this updated information, we developed an initiative of real-time full-scale living meta-analyses relying on an open online dissemination platform ( www.metapreg.org )., Method: All living meta-analyses performed in this project will be conducted in accordance with this master protocol after adaptation of the search strategy. A systematic literature search of PubMed and Embase will be performed. All analytical studies (e.g., cohort, case-control, randomized studies) reporting original empirical findings on the association between in utero exposure to drugs and adverse pregnancy outcomes will be included. Study screening and data extraction will be performed in a semi-automation way supervised by a biocurator. A risk of bias will be assessed using the ROBINS-I tools. All clinically relevant pregnancy adverse outcomes (malformations, stillbirths, neuro-developmental disorders, pre-eclampsia, etc.) available in the included studies will be pooled through random-effects meta-analysis. Heterogeneity will be evaluated by I 2 statistics., Discussion: Our living systematic reviews and subsequent updates will inform the medical, regulatory, and health policy communities as the news results evolve to guide decisions on the proper use of drugs during the pregnancy., Systematic Review Registration: Open Science Framework (OSF) registries., (© 2023. The Author(s).)

Introduction: Data on adverse drug reactions (ADRs) of immune checkpoint inhibitors (ICIs) used in oncology are mainly derived from clinical trials or cancer-specific reviews. We aim to analyze ADRs that occurred in patients treated with ICIs in real life., Materials and Methods: We conducted an observational study on a historical cohort of the University Hospitals of Lyon. All patients who initiated an ICI treatment for any cancer in 2017 were included. Patients were followed from the first infusion until 90 days after the last one, death, date of last news or end of the study period (28 February 2019), whichever came first. Two pharmacovigilance specialists assessed the accountability and the severity of each ADR using Naranjo algorithm and common terminology criteria for adverse events (CTCAE) classification, respectively., Results: 248 patients were included. They were treated with anti-PD-(L)-1, mainly nivolumab (70.6%) and pembrolizumab (25.8%). Lung cancer (62.1%) and melanoma (20.2%) were the most represented cancers. 139 ADRs occurred in 93 patients (37.5%), on average at the 6 th cure (±6.8). ADRs mainly concerned skin (29.5%), endocrine (19.4%) and digestive (10.8%) systems. 17.3% of ADRs were grades III-V and two patients died because of ADRs. By comparing patients with (N=93) or without (N=155) ADRs, all characteristics appeared similar except for age, number of infusions received and death status. The spontaneous notification rate found in this study was 5.8% for all grade ADRs (N = 8) but raised to 23.8% when only grades higher than III were considered (N = 5)., Discussion/conclusion: Our results are consistent with literature data in frequency and type of serious ADRs. We found a lower frequency of ADRs of any grade, which could be explained by a fairer causality assessment in our study than in clinical trials., (Copyright © 2022 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

For the past few years, platform trials have experienced a significant increase, recently amplified by the COVID-19 pandemic. The implementation of a platform trial is particularly useful in certain pathologies, particularly when there is a significant number of drug candidates to be assessed, a rapid evolution of the standard of care or in situations of urgent need for evaluation, during which the pooling of protocols and infrastructure optimizes the number of patients to be enrolled, the costs, and the deadlines for carrying out the investigation. However, the specificity of platform trials raises methodological, ethical, and regulatory issues, which have been the subject of the round table and which are presented in this article. The round table was also an opportunity to discuss the complexity of sponsorship and data management related to the multiplicity of partners, funding, and governance of these trials, and the level of acceptability of their findings by the competent authorities., (Copyright © 2022. Published by Elsevier Masson SAS.)

Aims/hypothesis: Cardiovascular outcome trials (CVOTs) have demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, serious adverse drug reactions have been reported. The risk/benefit ratio of SGLT2i remains unquantified. We aimed to provide an estimation of their risk/benefit ratio in individuals with type 2 diabetes., Methods: We conducted a systematic review (MEDLINE, up to 14 September 2021) and meta-analysis. We included randomised CVOTs assessing SGLT2i in individuals with type 2 diabetes with or without other diseases. We used the Cochrane 'Risk of bias' assessment tool. The primary outcomes were overall mortality, major adverse cardiovascular events (MACE), hospitalisation for heart failure (HHF), end-stage renal disease (ESRD), amputation, diabetic ketoacidosis (DKA) and reported genital infections. For each outcome, we estimated the incidence rate ratio (IRR) with a 95% CI; we then computed the number of events expected spontaneously and with SGLT2i., Results: A total of 46,969 participants from five double-blind, placebo-controlled international trials (weighted mean follow-up 3.5 years) were included. The prevalence of previous CVD ranged from 40.6% to 99.2%. The definition of reported genital infections ranged from 'genital mycotic infection' to 'genital infections that led to discontinuation of the trial regimen or were considered to be serious adverse events'. The number of included studies for each outcomes was five. The use of SGLT2i decreased the risk of all-cause death (IRR 0.86 [95% CI 0.78, 0.95]), MACE (IRR 0.91 [95% CI 0.86, 0.96]), HHF (IRR 0.69 [95% CI 0.62, 0.76]) and ESRD (IRR 0.67 [95% CI 0.53, 0.84]), and increased the risk of DKA (IRR 2.59 [95% CI 1.57, 4.27]) and genital infection (IRR 3.50 [95% CI 3.09, 3.95]) but not of amputation (IRR 1.23 [95% CI 1.00, 1.51]). For 1000 individuals treated over 3.5 years, SGLT2i are expected, on average, to decrease the number of deaths from 70 to 61, to prevent nine MACE, 11 HHF and two cases of ESRD, while inducing two DKA occurrences and 36 genital infections; 778 individuals are expected to avoid all the following outcomes: MACE, HHF, ESRD, amputation, DKA and genital infection., Conclusions/interpretation: Our study is limited to aggregate data. In a population of individuals with type 2 diabetes and a high CVD risk, the cardiovascular and renal benefits of SGLT2i remain substantial despite the risk of DKA and even the hypothetical risk of amputation., Trial Registration: OSF Registries: https://doi.org/10.17605/OSF.IO/J3R7Y FUNDING: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To compare and rank the effect of glucocorticoid-sparing agents in giant cell arteritis (GCA), for which several drugs have been evaluated but with a benefit-risk balance that remains uncertain., Methods: The MEDLINE and Clinical Trials databases were searched up to November 2021; all randomized controlled trials investigating glucocorticoids in GCA were included. The glucocorticoid regimen was dichotomized into short (≤6 months) or prolonged (>6 months) use. Risk of relapse and safety were estimated using network meta-analysis with frequentist random effects models., Results: Of the 96 records screened, 8 trials were included (572 patients). The trials compared glucocorticoids and a sparing agent: tocilizumab (2 trials), oral methotrexate (3 trials), infliximab (1 trial), etanercept (1 trial), and adalimumab (1 trial). The pooled prevalence of GCA relapse was 52.6% (95% CI, 38.1 to 66.9). The risk of relapse was significantly lower with tocilizumab compared with methotrexate (relative risk [RR], 0.41; 95% CI, 0.17 to 0.97) and prolonged (RR, 0.41; 95% CI, 0.20 to 0.83) and short (RR, 0.32; 95% CI, 0.16 to 0.66) glucocorticoid use. The risk of relapse was not significantly different with methotrexate compared with short (RR, 0.79; 95% CI, 0.48 to 1.31) and prolonged (RR, 0.95; 95% CI, 0.31 to 2.89) glucocorticoid use. The frequency of serious adverse events and serious infection was comparable between the different drugs. The certainty of the evidence was low to very low., Conclusion: This meta-analysis suggests that tocilizumab may be superior to other sparing agents to prevent GCA relapse, but with a low to very low certainty of evidence, and that safety is comparable to the other drugs., Registration: The protocol of the meta-analysis is registered in the international prospective register of systematic reviews PROSPERO (https://www.crd.york.ac.uk/prospero/; registration CRD42020112387)., (Copyright © 2022 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the feasibility and acceptance of the semi-automated meta-analysis (SAMA). The objectives are twofold, namely (1) to compare expert opinion on the quality of protocols, methods, and results of one conventional meta-analysis (CMA) and one SAMA and (2) to compare the time to execute the CMA and the SAMA., Methods: Experts evaluated the protocols and manuscripts/reports of the CMA and SAMA conducted independently on the safety of metronidazole in pregnancy. Expert opinion was collected using AMSTAR 2 checklist. Time spent was recorded using case report forms., Results: The overall scores of the opinion of all experts for protocols, methods, and results for SAMA (6.75) and CMA (6.87) were not statistically different (p = 0.88). The experts' confidence in the results of each MA was 7.89 ± 1.17 and 8.11 ± 0.92, respectively. The time to completion was 14 working days for SAMA and 24.7 for CMA. MA tasks such as calculation of effect estimates, subgroup/sensitivity analysis, and publication bias investigation required no investment in time for SAMA., Conclusion: In conclusion, our study demonstrated the feasibility of SAMA and suggests acceptance for risk assessment by an expert committee. Our results suggest that SAMA reduces the time required for a MA without altering expert confidence in the methodological and scientific rigor. As our study was limited to one example, the generalization of our results requires confirmation by other studies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)