Immune-related serious adverse events with immune checkpoint inhibitors: Systematic review and network meta-analysis.

PURPOSE: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, though uncertainty exists regarding their immune-related safety. The objective of this study was to assess the comparative safety profile (odds ratio) of ICIs and estimate the absolute rate of immune-related serious adverse events (irSAEs) in cancer patients undergoing treatment with ICIs. METHODS: We searched for randomized trials till February 2021, including all ICIs for all cancers. Primary outcome was overall irSAEs, and secondary outcomes were pneumonitis, colitis, hepatitis, hypophysitis, myocarditis, nephritis, and pancreatitis. We conducted Bayesian network meta-analyses, estimated absolute rates and ranked treatments according to the surface under the cumulative ranking curve (SUCRA). RESULTS: We included 96 trials (52,811 participants, median age 62 years). Risk of bias was high in most trials. Most cancers were non-small cell lung cancer (28 trials) and melanoma (15 trials). The worst-ranked ICI was ipilimumab (SUCRA 14%; event rate 848/10,000 patients) while the best-ranked ICI was atezolizumab (SUCRA 82%; event rate 119/10,000 patients). CONCLUSION: Each ICI showed a unique safety profile, with certain events more frequently observed with specific ICIs, which should be considered when managing cancer patients.

Data monitoring committees in pediatric randomized controlled trials registered in ClinicalTrials.gov.

BACKGROUND: Data monitoring committees advise on clinical trial conduct through appraisal of emerging data to ensure participant safety and scientific integrity. While consideration of their use is recommended for trials performed with vulnerable populations, previous research has shown that data monitoring committees are reported infrequently in publications of pediatric randomized controlled trials. We aimed to assess the frequency of reported data monitoring committee adoption in ClinicalTrials.gov registry records and to examine the influence of key trial characteristics. METHODS: We conducted a cross-sectional data analysis of all randomized controlled trials performed exclusively in a pediatric population and registered in ClinicalTrials.gov between 2008 and 2021. We used the Access to Aggregate Content of ClinicalTrials.gov database to retrieve publicly available information on trial characteristics and data on safety results. Abstracted data included reported trial design and conduct parameters, population and intervention characteristics, reasons for prematurely halting, serious adverse events, and mortality outcomes. We performed descriptive analyses on the collected data and explored the influence of clinical, methodological, and operational trial characteristics on the reported adoption of data monitoring committees. RESULTS: We identified 13,928 pediatric randomized controlled trial records, of which 39.7% reported adopting a data monitoring committee, 49.0% reported not adopting a data monitoring committee, and 11.3% did not answer on this item. While the number of registered pediatric trials has been increasing since 2008, we found no clear time trend in the reported adoption of data monitoring committees. Data monitoring committees were more common in multicenter trials (50.6% vs 36.9% for single-center), multinational trials (60.2% vs 38.7% for single-country), National Institutes of Health-funded (60.3% vs 40.1% for industry-funded or 37.5% for other funders), and placebo-controlled (47.6% vs 37.5% for other types of control groups). Data monitoring committees were also more common among trials enrolling younger participants, trials employing blinding techniques, and larger trials. Data monitoring committees were more common in trials with at least one serious adverse event (52.6% vs 38.4% for those without) as well as for trials with reported deaths (70.3% vs 38.9% for trials without reported deaths). In all, 4.9% were listed as halted prematurely, most often due to low accrual rates. Trials with a data monitoring committee were more often halted for reasons related to scientific data than trials without a data monitoring committee (15.7% vs 7.3%). CONCLUSION: According to registry records, the use of data monitoring committees in pediatric randomized controlled trials was more frequent than previously reported in reviews of published trial reports. The use of data monitoring committees varied across key clinical and trial characteristics based on which their use is recommended. Data monitoring committees may still be underutilized in pediatric trials, and reporting of this item could be improved.

Potential drug-drug interactions in acute poisonings managed in the intensive care unit: Occurrence, risk factors and relationship to patient severity on admission.

Beyond the direct toxicity resulting from each drug in the poisoned patient, additional toxicities may result from drug-drug interactions (DDIs). We aimed to determine the frequency of potential DDIs in the poisoned patient and investigate whether DDIs are associated with severity. We conducted a 1-year cohort study in a toxicological ICU. DDIs were identified using an electronic interaction-checker tool. Among our 354 ICU poisoned patients, 134 (38%) presented at least one potential DDI between acute poisoning drugs and 180 (51%) at least one potential DDI between acute poisoning and long-term treatment drugs. Using multivariate analyses, previous suicide attempt was associated with the presence of potential DDIs between acute poisoning drugs in suicide attempt patients (P = 0.014). Chronic alcoholism (P = 0.005) and tobacco smoking (P = 0.022) were associated with the presence of potential DDIs between acute poisoning and long-term treatment drugs in recreational drug users. Presence of potential DDIs between acute poisoning and long-term treatment drugs was associated with catecholamine infusion (P = 0.022) in suicidal self-exposure patients. Presence of potential pharmacodynamic DDIs between acute poisoning and long-term treatment drugs was associated with aspiration pneumonia onset in recreational drug users (P = 0.03). ICU poisoned patients present a high rate of potential DDIs that may influence the outcome.

Establishing and Evaluating a Study Questionnaire on Knowledge and Attitudes of Healthcare Professionals Towards Recreational and Medical Cannabis Across Europe.

BACKGROUND AND OBJECTIVE: The present survey was a preliminary to a European research project on the attitude and knowledge of healthcare professionals towards the use of medical cannabis. The objective was to evaluate the readability, understandability, and relevance of a first version of the study questionnaire before preparing the finalized questionnaire, which will be subsequently proposed to European healthcare professionals on a large scale. METHODS: A cross-sectional study was conducted between December 2019 and May 2020. We established an electronic evaluation questionnaire relating to the study questionnaire. This evaluation questionnaire was proposed to multidisciplinary experts from all over Europe. Feedback from the evaluation questionnaire was considered for improving and finalizing the study questionnaire. RESULTS: 66 evaluation questionnaires were collected from nine European countries (Cyprus, France, Germany, Italy, Lithuania, Portugal, Spain, Sweden, United Kingdom), which corresponded to a participation rate of 41.5%. Most participants were women (65.2%, n = 43). The mean age was 39.5 years ± 11.6. Each participant could specify several occupations. There were 25 pharmacologists, 24 physicians, ten pharmacists, four university teachers, three epidemiologists or public health experts, one nurse, one biotechnologist, one microbiologist, and one police researcher. Overall, 84.8% of participants were interested in the topic of the survey on the knowledge and attitudes of healthcare professionals towards recreational and medical cannabis across Europe. Participants were satisfied with all but six of the proposed questions. In addition, two additional questions were subject for comments despite a high level of satisfaction. Consequently, the concerned questions (n = 8) were modified. CONCLUSION: This evaluation survey was a necessary step to improve the quality of the future research project. The positive feedback encourages the authors to proceed with the project on a European scale, scheduled for 2021.

Analysis of clinical and methodological characteristics of early COVID-19 treatment clinical trials: so much work, so many lost opportunities.

BACKGROUND: The COVID-19 pandemic continues to rage on, and clinical research has been promoted worldwide. We aimed to assess the clinical and methodological characteristics of treatment clinical trials that have been set forth as an early response to the COVID-19 pandemic. METHODS: First, we reviewed all registered clinical trials on COVID-19. The World Health Organization International Trials Registry Platform and national trial registries were searched for COVID-19 trials through April 19th, 2020. For each record, independent researchers extracted interventions, participants, and methodological characteristics. Second, on September 14th, 2020 we evaluated the recruitment status and availability of the results of COVID-19 treatment trials previously identified. RESULTS: In April 2020, a total of 580 trials evaluating COVID-19 treatment were registered. Reporting quality was poor (core participant information was missing in 24.1 to 92.7%). Between 54.0 and 93.8% of the trials did not plan to include older people or those with a higher baseline risk. Most studies were randomised (67.9%), single-centre (58.3%), non-industry-funded (81.1%), to be conducted in China (47.6%), with a median duration of 184 days and a median sample size of 100 participants. Core endpoints (mortality, clinical status, and hospitalization length) were planned to be assessed in 5.2 to 13.1% of the trials. Five months later, 66 trials (11.4%) were reported as "Completed", and only 46 (7.9%) had public results available. One hundred forty-four of 580 trials (24.8%) either had the status "Not yet recruiting" or "Suspended", and 18 (3.1%) trials were prematurely stopped ("Terminated" or "Withdrawn") The number of completed trials and trials with results are much lower than anticipated, considering the planned follow-up. CONCLUSIONS: Our results raise concerns about the success of the initial global research effort on COVID-19 treatment. The clinical and methodological characteristics of early COVID-19 treatment trials limit their capability to produce clear answers to critical questions in the shortest possible time.

Once- versus Twice-Daily Aspirin in Patients at High Risk of Thrombotic Events: Systematic Review and Meta-Analysis.

BACKGROUND: Acetylsalicylic acid (ASA) is a frequently used antiplatelet agent, although some individuals have reduced antiplatelet responses on ASA, with recurrent ischemic events. It has been proposed that shortening the ASA dosing interval may overcome the time-dependent renewal of the drug target, leading to a greater antiplatelet effect. We conducted a systematic review of randomized controlled trials (RCTs) to determine the efficacy of once- versus twice-daily ASA in conditions with increased platelet turnover. METHODS: We conducted a systematic review and meta-analysis by searching the CENTRAL, MEDLINE, and Embase databases for RCTs assessing once- versus twice-daily ASA. Data were screened, extracted, and appraised by two independent reviewers, and were pooled using a random-effects model. The primary outcomes were major adverse cardiovascular events (MACEs) and serum thromboxane B2 (TxB2). Other pharmacodynamic measures were retrieved as secondary outcomes. Results were reported as mean differences with corresponding 95% confidence intervals (CIs). We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Seven RCTs were included, enrolling 379 participants overall. None of the studies reported clinical outcomes. Pooled results showed that compared with once-daily ASA, twice-daily ASA was associated with a decrease in mean TxB2 of 1.42 ng/mL (95% CI - 2.71 to - 0.13; I2 = 66%). We found no differences in subgroup analyses based on disease subtype, trial blinding, or trial design. A greater antiplatelet activity of the twice-daily regimen was also found when using PFA-100-ADP methods, although not when using the VerifyNow, LTA-AA, and multiplate methods. CONCLUSIONS: Twice-daily ASA was associated with a greater antiplatelet effect compared with standard once-daily ASA.

Suspected adverse reaction to compounded preparations prescribed for weight loss: two cases of cerebral venous thrombosis.

We report two cases of cerebral venous thrombosis associated with the use of compounded preparations containing several active substances prescribed for weight loss. In both cases there is suspicion of additive/synergic interaction with oral contraceptives. The adverse drug reactions were considered serious, being life-threatening and causing hospitalisation for days.

Nocebo response in Parkinson's disease: A systematic review and meta-analysis.

OBJECTIVE: To estimate the magnitude of the nocebo response in Parkinson's disease and explore possible associations with study characteristics. METHODS: Databases were searched up to February 2017. Placebo-controlled, parallel-group randomized controlled trials investigating pharmacological interventions in people with Parkinson's disease were included. Data were derived from the last measured within-group response in the placebo and intervention arms of randomized controlled trials, after independent extraction. A random-effects model was used to pool study data. The main outcome was the nocebo response, measured as the proportion of placebo-treated participants experiencing any adverse events (AEs). We also measured the proportion of patients with serious AEs (SAEs), and the rates of study dropouts (including due to AEs) and death. PROSPERO registration number is CRD42017070471. RESULTS: We included 236 randomized controlled trials, with a combined population of 17,381 participants allocated to placebo. The nocebo response was 56.0% (95% CI, 51.7%-60.4%; 148 trials; I2 = 98%). SAEs were reported in 4.0% (95% CI, 3.4%-4.6%, 157 trials; I2 = 73%) of placebo-treated patients, dropouts in 14.0% (95% CI, 12.5%-15.5%, 225 trials; I2 = 91%), dropouts due to AEs in 5.7% (95% CI, 5.1%-6.4%, 219 trials; I2 = 73%). Deaths occurred in 0.6% (95% CI, 0.5%-0.7%, 227 trials; I2 = 0%). Similar proportions were identified in patients in intervention arms. CONCLUSIONS: The magnitude of the nocebo response in parallel-designed randomized controlled trials in Parkinson's disease is substantial and should be considered in the interpretation of safety results and in the design and interpretation of future clinical trials.