EU Clinical Trials Research Articles

Does Addition of 10-MDP Monomer in Self-etch Adhesive Systems Improve the Clinical Performance of Noncarious Cervical Lesion Restorations? A Systematic Review and Meta-analysis.

Functional acidic monomers are able to chemically interact with hydroxyapatite, and this bond appears to be very stable. Therefore, this aspect of the 10-MDP molecule made it attractive and added to self-etch adhesives. The objective of this Systematic Review (SR) and Meta-analysis (MA) was to determine whether systems with the 10-methacryloyloxydecyl dihydrogen phosphate (10-MDP) functional monomer in their formula showed better clinical performance in restorations placed in noncarious cervical lesions (NCCL) when compared to systems without it. The PROSPERO registration number of the MA is CRD42016050538. An e-search was conducted through MEDLINE via PubMed, Cochrane Library, Scopus, Web of Science, OpenGrey, Clinical Trials, Current Controlled Trials, and EU Clinical Trials Register, and a search through the references of included studies was also performed. Randomized Controlled Clinical Trials, in which the effectiveness of self-etch adhesive systems, with or without the 10-MDP functional monomer for NCCL, was discussed, were included. Risk of bias was performed according to the Cochrane Collaboration tool, and the certainty of evidence was evaluated through GRADE. The data were grouped, heterogeneity (I2) was tested, and after duplicate removal, 4208 manuscripts were retrieved. From these, 11 studies were included in the qualitative analysis (risk of bias), with nine classified as low risk and two unclear. GRADE analysis detected moderate-to-high certainty of evidence, so the quantitative synthesis [Meta-analysis (MA)] was performed including the 11 studies. There were no statistical differences in the clinical performance of restorations conducted using "with or without 10-MDP" adhesive types, for all evaluated criteria (p=0.05), with heterogeneity ranging from 0% to 53%. Thus, the presence of 10-MDP functional monomer did not influence the clinical performance of restorations placed in NCCL.

O-098 Embryo selection using Artificial Intelligence (AI): Epistemic and ethical considerations

Abstract Study question What are the epistemic and ethical considerations of clinically implementing Artificial Intelligence (AI) algorithms in embryo selection? Summary answer AI embryo selection algorithms used to date are “black-box” models with significant epistemic and ethical issues, and there are no trials assessing their clinical effectiveness. What is known already The innovation of time-lapse imaging offers the potential to generate vast quantities of data for embryo assessment. Computer Vision allows image data to be analysed using algorithms developed via machine learning which learn and adapt as they are exposed to more data. Most algorithms are developed using neural networks and are uninterpretable (or “black box”). Uninterpretable models are either too complicated to understand or proprietary, in which case comprehension is impossible for outsiders. In the IVF context, these outsiders include doctors, embryologists and patients, which raises ethical questions for its use in embryo selection. Study design, size, duration We performed a scoping review of articles evaluating AI for embryo selection in IVF. We considered the epistemic and ethical implications of current approaches. Participants/materials, setting, methods We searched Medline, Embase, ClinicalTrials.gov and the EU Clinical Trials Register for full text papers evaluating AI for embryo selection using the following key words: artificial intelligence* OR AI OR neural network* OR machine learning OR support vector machine OR automatic classification AND IVF OR in vitro fertilisation OR embryo*, as well as relevant MeSH and Emtree terms for Medline and Embase respectively. Main results and the role of chance We found no trials evaluating clinical effectiveness either published or registered. We found efficacy studies which looked at 2 types of outcomes – accuracy for predicting pregnancy or live birth and agreement with embryologist evaluation. Some algorithms were shown to broadly differentiate well between “good-” and “poor-” quality embryos but not between embryos of similar quality, which is the clinical need. Almost universally, the AI models were opaque (“black box”) in that at least some part of the process was uninterpretable. “Black box” models are problematic for epistemic and ethical reasons. Epistemic concerns include information asymmetries between algorithm developers and doctors, embryologists and patients; the risk of biased prediction caused by known and/or unknown confounders during the training process; difficulties in real-time error checking due to limited interpretability; the economics of buying into commercial proprietary models, brittle to variation in the treatment process; and an overall difficulty troubleshooting. Ethical pitfalls include the risk of misrepresenting patient values; concern for the health and well-being of future children; the risk of disvaluing disability; possible societal implications; and a responsibility gap, in the event of adverse events. Limitations, reasons for caution Our search was limited to the two main medical research databases. Although we checked article references for more publications, we were less likely to identify studies that were not indexed in Medline or Embase, especially if they were not cited in studies identified in our search. Wider implications of the findings It is premature to implement AI for embryo selection outside of a clinical trial. AI for embryo selection is potentially useful, but must be done carefully and transparently, as the epistemic and ethical issues are significant. We advocate for the use of interpretable AI models to overcome these issues. Trial registration number not applicable

Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial

Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe. We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555). Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran. A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation. German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim.

Placebo-Controlled Clinical Trial of IncobotulinumtoxinA for Sialorrhea in Children: SIPEXI.

Background and ObjectivesTo investigate the efficacy and safety of repeated injections of incobotulinumtoxinA (incoBoNT/A) for treatment of chronic sialorrhea (drooling) associated with neurologic disorders (e.g., cerebral palsy, traumatic brain injury) or intellectual disability in children and adolescents in a prospective phase III study (SIPEXI [Sialorrhea Pediatric Xeomin Investigation]).MethodsThe study enrolled 2- to 17-year-old patients with sialorrhea due to neurologic disorders or intellectual disability. Patients received body weight–dependent doses of incoBoNT/A (20–75 U). A main period with 1 injection cycle (placebo-controlled, double-blind, 6- to 17-year-olds) was followed by an open-label extension with up to 3 further cycles. An additional cohort of 2- to 5-year-olds received active treatment throughout the study. Coprimary endpoints were the change in unstimulated salivary flow rate (uSFR) from baseline to week 4 and the carers' Global Impression of Change Scale (GICS) rating at week 4. Adverse events were recorded.ResultsIn the main period, 220 patients aged 6–17 years were randomized and treated (148 patients in incoBoNT/A group, 72 patients in placebo group). A total of 35 patients aged 2–5 years received incoBoNT/A (no placebo). A total of 214 patients aged 6–17 years and 33 patients aged 2–5 years continued treatment in the open-label extension period. For the 6- to 17-year-olds, a significant difference between incoBoNT/A and placebo was seen in mean uSFR decrease (difference −0.06 g/min; p = 0.0012) and the carers' GICS rating (difference 0.28 points; p = 0.032) at week 4, in favor of active treatment. The secondary endpoints consistently supported these results. A sustained benefit was observed during the extension. Incidences of adverse events were comparable between incoBoNT/A and placebo and did not increase notably with repeated injections. The most common adverse events were respiratory infections. Efficacy and safety were also favorable in the uncontrolled cohort of 2- to 5-year-olds.DiscussionBoth co–primary efficacy endpoints were reached and superiority of incoBoNT/A over placebo was confirmed. IncoBoNT/A (up to 75 U, up to 4 cycles) is an effective and well-tolerated treatment for sialorrhea associated with neurologic disorders in children.Trial Registration InformationClinicaltrials.gov: NCT02270736 (clinicaltrials.gov/ct2/show/results/NCT02270736); EU Clinical Trials Register: 2013-004532-30 (clinicaltrialsregister.eu/ctr-search/search?query=2013-004532-30).Classification of EvidenceThis study provides Class I evidence that injection of incobotulinumtoxinA decreases drooling in children aged 6 to 17 years with neurologic disorders.

Mineralocorticoid Receptor Antagonist Improves Cardiac Structure in Type 2 Diabetes: Data From the MIRAD Trial

ObjectivesThis study investigated the impact of the MR antagonist (MRA) eplerenone on LVM in type 2 diabetes patients at high risk for cardiovascular disease (CVD). BackgroundMRA activation is associated with cardiac fibrosis and increased left ventricular mass (LVM), which is an independent predictor of adverse CVD, including heart failure in patients with type 2 diabetes. MethodsA prespecified analysis of secondary endpoints in a randomized, double-blinded clinical trial of 140 patients with type 2 diabetes at high risk of or established CVD. Patients were randomized to receive high-dose eplerenone therapy (100 mg–200 mg) or placebo as an add-on to standard care for 26 weeks. Indexed LVM (LVMi) and T1 time were measured using cardiac magnetic resonance (CMR) imaging. Biomarkers included N-terminal pro–B-type natriuretic peptide (NT-proBNP), pro-collagen type I N-terminal propeptide (P1NP), and type III N-terminal propeptide (P3NP). ResultsOf 140 patients in the MIRAD trial, 104 patients were subject to CMR imaging (eplerenone: 54 patients; placebo: 50 patients). Mean LVMi at baseline was 74.2 ± 16 g/m2. The treatment effect (ie, between-group differences) was a decrease of 3.7 g/m2 following the eplerenone treatment (95% CI: −6.7 to −0.7; P = 0.017), with a corresponding decrease in absolute LVM. Plasma NT-proBNP concentrations decreased by 22% (P = 0.017) using eplerenone compared with placebo, and P1NP decreased 3.3 ng/mL (P = 0.019). No differences in T1 times or P3NP concentrations were observed between groups. ConclusionsThe addition of high-dose eplerenone in high-risk type 2 diabetes was associated with a clear reduction in LVMi and in NT-proBNP and P1NP levels, which may suggest a clinical benefit in heart failure prevention. (EU Clinical trials: Mineralocorticoid Receptor Antagonists in Type 2 Diabetes [MIRAD]; 2015-002519-14)

Mechanisms of action and adverse effects of the major therapeutic agents in trial for COVID-19 therapeutics: Review of literature

The race to find an effective cure for COVID-19 is on. Most of the candidate drugs in various clinical trials are being re-purposed but none has been approved as at date. It is pertinent for the bedside physicians to understand the mechanisms of action of these agents and their peculiar adverse effects so they are properly guided on the risk/benefit of the drugs they choose in managing COVID-19 patients. Clinicaltrials.gov, the international clinical trials platform of the WHO, the EU clinical trials register and the Cochrane Central Register of Controlled Trials were searched for registered clinical trials. Studies in therapeutic trials were considered eligible for the work. Frequency table was made for the most common trialled drugs and the mechanisms of actions and adverse effects of the selected drugs were reviewed. Ten studies were selected for review in a descending order of their frequency in different therapeutic trials and these are ritonavir, lopinavir, chloroquine/ hydroxychloroquine, interferon, remdesvir, favipravir, umifenovir, darunavir, tocilizumab and methylprednisolone. The bedside physicians need to understand the mechanisms of action of these agents and their peculiar adverse effects for proper guidance on the risk/benefit of the drugs they choose in managing COVID- 19 patients.

Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial.

BackgroundInhibitors of the sodium-glucose cotransporter 2 (SGLT2) slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria.MethodsA randomised, double-blind, placebo-controlled, crossover trial with a single 50 mg dose of the SGLT2 inhibitor dapagliflozin and placebo in random order, separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal R2* (a low value corresponds to a high tissue oxygenation), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline, three- and six hours from tablet ingestion. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation, peripheral blood mononuclear cell mitochondrial oxygen consumption rate, and biomarkers of inflammation were evaluated at baseline and 12 h from medication. The study is registered in the EU Clinical Trials Register (EudraCT 2019–004,557–92), on ClinicalTrials.gov (NCT04193566), and is completed.FindingsBetween February 3, 2020 and October 23, 2020, 31 individuals were screened, and 19 eligible individuals were randomised. Three dropped out before receiving any of the interventions and one dropped out after receiving only placebo. We included 15 individuals (33% female) in the per-protocol analysis with a mean age of 58 (SD 14) years, median urinary albumin creatinine ratio of 46 [IQR 21–58] mg/g and an eGFR of 73 (32) ml/min/1·73m2. The mean changes in renal cortical R2* from baseline to six hours were for dapagliflozin -1·1 (SD 0·7) s−1 and for placebo +1·3 (0·7) s−1, resulting in a difference between interventions of -2·3 s−1 [95% CI -4·0 to -0·6]; p = 0·012. No between-intervention differences were found in any other MRI outcomes, physiological parameters or exploratory outcomes. There were no adverse events.InterpretationA single dose of 50 mg dapagliflozin acutely improved renal cortical R2* without changing renal perfusion or blood flow. This suggests improved renal cortical oxygenation due to a reduced tubular transport workload in the proximal tubules. Such improved oxygenation may in part explain the long-term beneficial renal effects seen with SGLT2 inhibitors, but it remains to be determined whether the observed effects can be achieved with lower doses, with chronic treatment and if they occur in type 2 diabetes as well.

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial

BackgroundThe major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak.MethodsThis randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1–9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020–001236–10).FindingsBetween March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56–73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76–1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27–0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26–1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63–1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3–13) in the imatinib group compared with 12 days (6–20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events.InterpretationThe study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings.FundingAmsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2.

Effect of selenium supplementation on musculoskeletal health in older women: a randomised, double-blind, placebo-controlled trial

SummaryBackgroundObservational and preclinical studies show associations between selenium status, bone health, and physical function. Most adults in Europe have serum selenium below the optimum range. We hypothesised that selenium supplementation could reduce pro-resorptive actions of reactive oxygen species on osteoclasts and improve physical function.MethodsWe completed a 6-month randomised, double-blind, placebo-controlled trial. We recruited postmenopausal women older than 55 years with osteopenia or osteoporosis at the Northern General Hospital, Sheffield, UK. Participants were randomly assigned 1:1:1 to receive selenite 200 μg, 50 μg, or placebo orally once per day. Medication was supplied to the site blinded and numbered by a block randomisation sequence with a block size of 18, and participants were allocated medication in numerical order. All participants and study team were masked to treatment allocation. The primary endpoint was urine N-terminal cross-linking telopeptide of type I collagen (NTx, expressed as ratio to creatinine) at 26 weeks. Analysis included all randomly assigned participants who completed follow-up. Groups were compared with analysis of covariance with Hochberg testing. Secondary endpoints were other biochemical markers of bone turnover, bone mineral density, short physical performance battery, and grip strength. Mechanistic endpoints were glutathione peroxidase, highly sensitive C-reactive protein, and interleukin-6. This trial is registered with EU clinical trials, EudraCT 2016-002964-15, and ClinicalTrials.gov, NCT02832648, and is complete.Findings120 participants were recruited between Jan 23, 2017, and April 11, 2018, and randomly assigned to selenite 200 μg, 50 μg, or placebo (n=40 per group). 115 (96%) of 120 participants completed follow-up and were included in the primary analysis (200 μg [n=39], 50 μg [n=39], placebo [n=37]). Median follow-up was 25·0 weeks (IQR 24·7–26·0). In the 200 μg group, mean serum selenium increased from 78·8 (95% CI 73·5–84·2) to 105·7 μg/L (99·5–111·9). Urine NTx to creatinine ratio (nmol bone collagen equivalent:mmol creatinine) did not differ significantly between treatment groups at 26 weeks: 40·5 (95% CI 34·9–47·0) for placebo, 43·4 (37·4–50·5) for 50 μg, and 42·2 (37·5–47·6) for 200 μg. None of the secondary or mechanistic endpoint measurements differed between treatment groups at 26 weeks. Seven (6%) of 120 participants were withdrawn from treatment at week 13 due to abnormal thyroid-stimulating hormone concentrations (one in the 200 μg group, three in the 50 μg group, and three in the placebo group) and abnormal blood glucose (one in the 50 μg group). There were three serious adverse events: a non-ST elevation myocardial infarction at week 18 (in the 50 μg group), a diagnosis of bowel cancer after routine population screening at week 2 (in the placebo group), and a pulmonary embolus due to metastatic bowel cancer at week 4 (in the 200 μg group). All severe adverse events were judged by the principal investigator as unrelated to trial medication.InterpretationSelenium supplementation at these doses does not affect musculoskeletal health in postmenopausal women.FundingUK National Institute for Health Research Efficacy and Mechanism Evaluation programme.

COVID-19 and its cardiovascular effects: a systematic review of prevalence studies.

A small minority of people with coronavirus disease 2019 (COVID-19) develop a severe illness, characterised by inflammation, microvascular damage and coagulopathy, potentially leading to myocardial injury, venous thromboembolism (VTE) and arterial occlusive events. People with risk factors for or pre-existing cardiovascular disease may be at greater risk. To assess the prevalence of pre-existing cardiovascular comorbidities associated with suspected or confirmed cases of COVID-19 in a variety of settings, including the community, care homes and hospitals. We also assessed the nature and rate of subsequent cardiovascular complications and clinical events in people with suspected or confirmed COVID-19. We conducted an electronic search from December 2019 to 24 July 2020 in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, covid-19.cochrane.org, ClinicalTrials.gov and EU Clinical Trial Register. We included prospective and retrospective cohort studies, controlled before-and-after, case-control and cross-sectional studies, and randomised controlled trials (RCTs). We analysed controlled trials as cohorts, disregarding treatment allocation. We only included peer-reviewed studies with 100 or more participants, and excluded articles not written in English or only published in pre-print servers. Two review authors independently screened the search results and extracted data. Given substantial variation in study designs, reported outcomes and outcome metrics, we undertook a narrative synthesis of data, without conducting a meta-analysis. We critically appraised all included studies using the Joanna Briggs Institute (JBI) checklist for prevalence studies and the JBI checklist for case series. We included 220 studies. Most of the studies originated from China (47.7%) or the USA (20.9%); 9.5% were from Italy. A large proportion of the studies were retrospective (89.5%), but three (1.4%) wereRCTsand 20 (9.1%) were prospective. Using JBI's critical appraisal checklist tool for prevalence studies, 75 studies attained a full score of 9, 57 studies a score of 8, 31 studies a score of 7, 5 studies a score of 6, three studies a score of 5 and one a score of 3; using JBI's checklist tool for case series, 30 studies received a full score of 10, six studies a score of 9, 11 studies a score of 8, and one study a score of 5 We found that hypertension (189 studies, n = 174,414, weighted mean prevalence (WMP): 36.1%), diabetes (197 studies, n = 569,188, WMP: 22.1%) and ischaemic heart disease (94 studies, n = 100,765, WMP: 10.5%) are highly prevalent in people hospitalised with COVID-19, and are associated with an increased risk of death. In those admitted to hospital, biomarkers of cardiac stress or injury are often abnormal, and the incidence of a wide range of cardiovascular complications is substantial, particularly arrhythmias (22 studies, n = 13,115, weighted mean incidence (WMI) 9.3%), heart failure (20 studies, n = 29,317, WMI: 6.8%) and thrombotic complications (VTE: 16 studies, n = 7700, WMI: 7.4%). This systematic literature review indicates that cardiometabolic comorbidities are common in people who are hospitalised with a COVID-19 infection, and cardiovascular complications are frequent. We plan to update this review and to conduct a formal meta-analysis of outcomes based on a more homogeneous selected subsample of high-certainty studies.

Perioperative Nimodipine to Improve Cranial Nerve Function: A Systematic Review and Meta-Analysis.

Nimodipine has emerged as a promising strategy for protection of cranial nerves following vestibular schwannoma (VS) resections. Our goal was to conduct a comprehensive analysis of clinical studies to determine the therapeutic efficacy of nimodipine in improving facial nerve and cochlear nerve function. We searched PubMed, Scopus, Cochrane Clinical Trial Registry, Clinicaltrials.gov, World Health Organization's International Clinical Trials Registry Platform, and EU Clinical Trials Registry to identify clinical studies up to May 11, 2020. We included studies evaluating perioperative administration of nimodipine as a strategy to prevent or treat facial nerve or cochlear nerve dysfunction following VS resections. Primary outcomes included preservation or recovery of House-Brackman scale for facial nerve function and Hearing and Equilibrium Guidelines for cochlear nerve function at the latest follow-up visit. Secondary outcomes included adverse events and administration strategies of nimodipine. Nine studies (603 patients) met inclusion, of which seven studies (559 patients) were included in the quantitative analysis. Overall, nimodipine significantly increased the odds of cranial nerve recovery compared with controls (odds ratio [OR] 2.87, 95% confidence intervals [CI] [2.08, 3.95]; I2 = 0%). Subgroup analysis demonstrated that nimodipine was only effective for cochlear nerve preservation (OR 2.78, 95% CI [1.74, 4.45]; I2 = 0%), but not for facial nerve function (OR 4.54, 95% CI [0.25, 82.42]; I2 = 33%). Although there is evidence supporting the perioperative role of nimodipine for VS resections, more studies are warranted to help clarify the effects of nimodipine therapy on cranial nerve preservation.

Interventions to Ameliorate the Psychosocial Effects of the COVID-19 Pandemic on Children-A Systematic Review.

The aim of this study was to identify interventions targeting children and their caregivers to reduce psychosocial problems in the course of the COVID-19 pandemic and comparable outbreaks. The review was performed using systematic literature searches in MEDLINE, Embase, PsycINFO and COVID-19-specific databases, including the CDC COVID-19 Research Database, the World Health Organisation (WHO) Global Database on COVID-19 Research and the Cochrane COVID-19 Study Register, ClinicalTrials.gov, the EU Clinical Trials Register and the German Clinical Trials Register (DRKS) up to 25th September 2020. The search yielded 6657 unique citations. After title/abstract and full text screening, 11 study protocols reporting on trials planned in China, the US, Canada, the UK, and Hungary during the COVID-19 pandemic were included. Four interventions targeted children ≥10 years directly, seven system-based interventions targeted the parents and caregivers of younger children and adolescents. Outcome measures encompassed mainly anxiety and depressive symptoms, different dimensions of stress or psychosocial well-being, and quality of supportive relationships. In conclusion, this systematic review revealed a paucity of studies on psychosocial interventions for children during the COVID-19 pandemic. Further research should be encouraged in light of the expected demand for child mental health management.

B-Cell Targeted Therapies in Patients with Multiple Sclerosis and Incidence of Headache: A Systematic Review and Meta-Analysis

Background: Multiple sclerosis (MS) treatment with B-cell targeted therapies, such as rituximab, ocrelizumab, ofatumumab and cladribine may be associated with an increased incidence of headache, thus proper management of a possible adverse effect may be necessary. We aimed to find, if any, and compare the association of B-cell targeted therapies with the incidence of headache in patients with multiple sclerosis. Methods: In a systematic based approach, the following databases were searched from inception till 6th of June 2020: Pubmed/MEDLINE, ClinicalTrials.gov, EU Clinical Trials Register. No limits were applied to publication year, sex or race. Only randomized clinical trials (RCTs) enrolling patients with multiple sclerosis comparing B-cell targeted therapies (rituximab, ocrelizumab, ofatumumab, ublituximab or cladribine) with placebo, were selected for the systematic review and further metanalysis. Two reviewers independently extracted individual study data and evaluated studies for risk of bias using Cochrane Risk of Bias version 2 tool (ROB-II). PRISMA guidelines were followed at all stages of the systematic review. Random effects meta-analysis to derive confidence intervals and to assess heterogeneity were conducted. The primary outcome was all-cause headache during the administration of B-cell targeting therapy in patients with multiple sclerosis. Findings: Nine randomized clinical trials (3785 participants) were included. Compared with placebo, treatment with B-cell targeting therapies was not associated with a statistically significant increase in headache risk (RR 1·12 [95% CI 0·96 – 1·30]; p=0·15; I2 = 9·32%). In a subgroup analysis, cladribine was statistically significant for an increase in headache risk (RR 1·20 [95% CI 1·006 – 1·42]; p=0·042; I2 = 0%; 3 studies with 2107 participants). Interpretation: Even though a trend is shown, B-cell targeted therapies do not correlate with an increased incidence of headache as an adverse effect. Further sub-analyses revealed a significant association between cladribine alone and increased incidence of headache. Further research is needed to unravel the underlying pathogenetic mechanism of headache induction, as well as, to establish headache prevention strategies. Funding statement: The authors declare no funding applied for this study Declaration of Interests: T.M. has received travel grants from Merck and Sanofi-Genzyme. M.B. has received travel grants from Merck, Teva-Specifar, Genesis Pharma, Pfizer. N.P. declares no conflict of interest. K.P. declares no conflict of interest. A.L. declares no conflict of interest. G.V. declares no conflict of interest. N.G. declares no conflict of interest. N.F. has received honoraria, consultation fees and/or research grants from Actelion, Amgen, Biogen, Celgene, Genesis Pharma, Eli Lilly, Merck Serono, Novartis, Receptos, Roche, Sanofi-Genzyme and Teva-Specifar. D.D.M. has received consulting, research, speaking fees and/or travel grants from Allergan, Amgen, Bayer, Biogen, Cefaly, ElectroCore, Eli-Lily, Genesis Pharma, Merck-Serono, Merz, Mylan, Novartis, Roche, Sanofi Genzyme and Teva -Specifar

Efficacy, acceptability, and safety of antidepressants for low back pain: a systematic review and meta-analysis

BackgroundAntidepressant medicines are used to manage symptoms of low back pain. The efficacy, acceptability, and safety of antidepressant medicines for low back pain (LBP) are not clear. We aimed to evaluate the efficacy, acceptability, and safety of antidepressant medicines for LBP.MethodsWe searched CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, the EU Clinical Trials Register, and the WHO International Clinical Trial Registry Platform from inception to May 2020. We included published and trial registry reports of RCTs that allocated adult participants with LBP to receive an antidepressant medicine or a placebo medicine. Pairs of authors independently extracted data in duplicate. We extracted participant characteristics, study sample size, outcome values, and measures of variance for each outcome. We data using random-effects meta-analysis models and calculated estimates of effects and heterogeneity for each outcome. We formed judgments of confidence in the evidence in accordance with GRADE. We report our findings in accordance with the PRISMA statement. We prespecified all outcomes in a prospectively registered protocol. The primary outcomes were pain intensity and acceptability. We measured pain intensity at end-of-treatment on a 0–100 point scale and considered 10 points the minimal clinically important difference. We defined acceptability as the odds of stopping treatment for any reason.ResultsWe included 23 RCTs in this review. Data were available for pain in 17 trials and acceptability in 14 trials. Treatment with antidepressants decreased pain intensity by 4.33 points (95% CI − 6.15 to − 2.50) on a 0–100 scale, compared to placebo. Treatment with antidepressants increased the odds of stopping treatment for any reason (OR 1.27 [95% CI 1.03 to 1.56]), compared to placebo.ConclusionsTreatment of LBP with antidepressants is associated with small reductions in pain intensity and increased odds of stopping treatment for any reason, compared to placebo. The effect on pain is not clinically important. The effect on acceptability warrants consideration. These findings provide Level I evidence to guide clinicians in their use of antidepressants to treat LBP.Trial registrationWe prospectively registered the protocol for this systematic review on PROSPERO (CRD42020149275).

Randomized Controlled Trial of Solriamfetol for Excessive Daytime Sleepiness in OSA: An Analysis of Subgroups Adherent or Nonadherent to OSA Treatment

BackgroundSolriamfetol, a dopamine-norepinephrine reuptake inhibitor, is approved in the United States to improve wakefulness in adults with excessive daytime sleepiness (EDS) associated with OSA (37.5-150 mg/d).Research QuestionDoes solriamfetol have differential effects on EDS based on adherence to primary OSA therapy and does solriamfetol affect primary OSA therapy use?Study Design and MethodsParticipants were randomized to 12 weeks of placebo or solriamfetol 37.5, 75, 150, or 300 mg/d (stratified by primary OSA therapy adherence). Coprimary end points were week 12 change from baseline in 40-min Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) in the modified intention-to-treat population. Primary OSA therapy use (hours per night, % nights) and safety were evaluated.ResultsAt baseline, 324 participants (70.6%) adhered to OSA therapy (positive airway pressure use ≥ 4 h/night on ≥ 70% nights, surgical intervention, or oral appliance use on ≥ 70% nights) and 135 participants (29.4%) did not adhere. Least squares (LS) mean differences from placebo in MWT sleep latency (minutes) in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were 4.8 (95% CI, 0.6-9.0), 8.4 (95% CI, 4.3-12.5), 10.2 (95% CI, 6.8-13.6), and 12.5 (95% CI, 9.0-15.9) and among nonadherent participants were 3.7 (95% CI, –2.0 to 9.4), 9.9 (95% CI, 4.4-15.4), 11.9 (95% CI, 7.5-16.3), and 13.5 (95% CI, 8.8-18.3). On ESS, LS mean differences from placebo in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were –2.4 (95% CI, –4.2 to –0.5), –1.3 (95% CI, –3.1 to 0.5), –4.2 (95% CI, –5.7 to –2.7), and –4.7 (95% CI, –6.1 to –3.2) and among nonadherent participants were –0.7 (95% CI, –3.5 to 2.1), –2.6 (95% CI, –5.4 to 0.1), –5.0 (95% CI, –7.2 to –2.9), and –4.6 (95% CI, –7.0 to –2.3). Common adverse events included headache, nausea, anxiety, decreased appetite, nasopharyngitis, and diarrhea. No clinically meaningful changes were seen in primary OSA therapy use with solriamfetol.InterpretationSolriamfetol improved EDS in OSA regardless of primary OSA therapy adherence. Primary OSA therapy use was unaffected with solriamfetol.Trial RegistryClinicalTrials.gov; No.: NCT02348606; URL: www.clinicaltrials.gov; EU Clinical Trials Register; No.: EudraCT2014-005514-31; URL: www.clinicaltrialsregister.eu

A technical review of three clinical trials register resources indicates where improvements to the search interfaces are needed.

Clinical trials registers form an important part of the search for studies in systematic reviews of intervention effectiveness but the search interfaces and functionality of registers can be challenging to search systematically and resource intensive to search well. We report a technical review of the search interfaces of three leading trials register resources: ClinicalTrials.gov, the EU Clinical Trials Register and the WHO International Clinical Trials Registers Platform. The technical review used a validated checklist to identify areas where the search interfaces of these trials register resources performed well, where performance was adequate, where performance was poor, and to identify differences between search interfaces. The review found low overall scores for each of the interfaces (ClinicalTrials.gov 55/165, the EU Clinical Trials Register 25/165, the WHO International Clinical Trials Registers Platform 32/165). This finding suggests a need for joined-up dialogue between the producers of the registers and researchers who search them via these interfaces. We also set out a series of four proposed changes which might improve the search interfaces. Trials registers are an invaluable resource in systematic reviews of intervention effectiveness. With the continued growth in systematic reviews, and initiatives such as 'AllTrials', there is an anticipated need for these resources. We conclude that small changes to the search interfaces, and improved dialogue with providers, might improve the future search functionality of these valuable resources.

Endometriosis-Related Pain Reduction During Bleeding and Nonbleeding Days in Women Treated with Elagolix.

ObjectiveIn this post hoc analysis, we evaluated the impact of elagolix on dysmenorrhea and nonmenstrual pelvic pain across menstrual period (bleeding days) and nonmenstrual (nonbleeding) days.MethodsData from two randomized, 6-month, placebo-controlled trials (Elaris Endometriosis (EM)-I and EM-II) of elagolix (150 mg once daily (QD) and 200 mg twice daily (BID)) in premenopausal women with moderate to severe endometriosis-associated pain (N = 1686) were pooled. Women recorded the presence of menstrual period and severity of dysmenorrhea or nonmenstrual pelvic pain in a daily electronic diary.ResultsAt baseline, women in the placebo group and both elagolix treatment groups reported moderate or severe dysmenorrhea, on average, 81% of their menstrual period days and moderate/severe nonmenstrual pelvic pain, on average, 56% of their nonmenstrual (nonbleeding) days. Compared with placebo at month 6, elagolix-treated women had a significantly lower mean (standard deviation (SD)) percentage of menstrual period days with moderate or severe dysmenorrhea (elagolix 150 mg QD = 52.4 (38.9), p = 0.002; elagolix 200 mg BID = 38.5 (43.6), p < 0.001, placebo = 61.3 (33.7)) and a significantly lower mean (SD) percentage of nonmenstrual (nonbleeding) days with moderate or severe nonmenstrual pelvic pain (elagolix 150 mg QD = 31.1 (35.8), p < 0.001; elagolix 200 mg BID = 19.7 (29.9), p < 0.001; placebo = 35.6 (33.9)).ConclusionFollowing 6 months of elagolix treatment, women who still menstruated had a lower proportion of menstrual period days with moderate or severe dysmenorrhea compared with placebo, demonstrating pain reduction despite continued menses. Additionally, pain did not shift from dysmenorrhea to nonmenstrual pelvic pain, as the percentage of days with moderate or severe nonmenstrual pelvic pain was also reduced for elagolix-treated women compared with placebo.Trial RegistrationThe Elaris EM-I study is registered with the US National Library of Medicine, www.ClinicalTrials.gov, NCT01620528. The Elaris EM-II study is registered with the US National Library of Medicine, www.ClinicalTrials.gov, NCT01931670. Both studies are registered with the EU Clinical Trial Register, www.clinicaltrialsregister.ed, 2011-004295-11.

Vasopressin and methylprednisolone for in-hospital cardiac arrest — Protocol for a randomized, double-blind, placebo-controlled trial

ObjectiveTo describe the clinical trial “Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest” (VAM-IHCA). MethodsThe VAM-IHCA trial is an investigator-initiated, multicenter, randomized, placebo-controlled, parallel group, double-blind, superiority trial of vasopressin and methylprednisolone during adult in-hospital cardiac arrest. The study drugs consist of 40 mg methylprednisolone and 20 IU of vasopressin given as soon as possible after the first dose of adrenaline. Additional doses of vasopressin (20 IU) will be administered after each adrenaline dose for a maximum of four doses (80 IU).The primary outcome is return of spontaneous circulation and key secondary outcomes include survival and survival with a favorable neurological outcome at 30 days. 492 patients will be enrolled. The trial was registered at the EU Clinical Trials Register (EudraCT Number: 2017-004773-13) on Jan. 25, 2018 and ClinicalTrials.gov (Identifier: NCT03640949) on Aug. 21, 2018. ResultsThe trial started in October 2018 and the last patient is anticipated to be included in January 2021. The primary results will be reported after 3-months follow-up and are, therefore, anticipated in mid-2021. ConclusionThe current article describes the design of the VAM-IHCA trial. The results from this trial will help clarify whether the combination of vasopressin and methylprednisolone when administered during in-hospital cardiac arrest improves outcomes.

Efficacy and Safety of Medicines Targeting Neurotrophic Factors in the Management of Low Back Pain: Protocol for a Systematic Review and Meta-analysis.

BackgroundLow back pain (LBP) is the leading cause of years lived with disability worldwide. Most people with LBP receive the diagnosis of nonspecific LBP or sciatica. Medications are commonly prescribed but have limited analgesic effects and are associated with adverse events. A novel treatment approach is to target neurotrophins such as nerve growth factor (NGF) to reduce pain intensity. NGF inhibitors have been tested in some randomized controlled trials (RCTs) in recent years, showing promise for the treatment of chronic LBP; however, their efficacy and safety need to be evaluated to guide regulatory actions.ObjectiveThe aim of this study is to evaluate the efficacy and safety of medicines targeting neurotrophins in patients with LBP and sciatica.MethodsIn this systematic review, we will include published and unpublished records of parallel RCTs and the first phase of crossover RCTs that compare the effects of medicines targeting neurotrophins with any control group. We will search the CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, EU Clinical Trials Register, and WHO International Clinical Registry Platform databases from inception. Pairs of authors will independently screen the records for eligibility, and we will independently extract data in duplicate. We will conduct a quantitative synthesis (meta-analysis) with the studies that report sufficient data and compare the medicines of interest versus placebo. We will use random-effects models and calculate estimates of effects and heterogeneity for each outcome. We will assess the risk of bias for each study using the Cochrane Collaboration tool, and form judgments of confidence in the evidence according to GRADE recommendations. We will use the PRISMA statement to report the findings. We plan to conduct subgroup analyses by condition, type of medication, and time point. We will also assess the impact of a potential new trial on an existing meta-analysis. Data from studies that meet inclusion criteria but cannot be included in the meta-analysis will be reported narratively.ResultsThe protocol was registered on the Open Science Framework on May 19, 2020. As of December 2020, we have identified 1932 records.ConclusionsThis systematic review and meta-analysis will assess the evidence for the efficacy and safety of NGF inhibitors for pain in patients with nonspecific LBP and sciatica. The inclusion of new studies and unpublished data may improve the precision of the effect estimates and guide regulatory actions of the medications for LBP and sciatica.Trial RegistrationOpen Science Framework; https://osf.io/b8adn/International Registered Report Identifier (IRRID)DERR1-10.2196/22905

Clinical trials of anticoagulation in COVID-19: a systematic review

&lt;p class="abstract"&gt;A high prevalence of thrombotic events is observed in coronavirus-2019 (COVID-19). Optimal anticoagulation becomes a critical part of treatment and higher-dose prophylactic anticoagulation is being practiced. Prospective evidence to confirm the safety and efficacy of these regimens is lacking. We performed a systematic review of existing studies of anticoagulation in COVID-19. The ClinicalTrials.gov registry, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and the EU Clinical Trials Register (EudraCT) were searched from inception to September 1, 2020. PRISMA guidelines were followed. Qualitative and quantitative analysis were performed. We identified 36 clinical studies involving anticoagulation in COVID-19. Most common study location was the United States (n=12, 33%). Thirty studies were randomized-controlled (83%) of which 22 were open-label. Median sample size was 309 (IQR 139-952) and study duration was 233 days (IQR 174-357). Most common study setting was critical and non-critical care (n=21, 58%). Most common single primary outcome was all-cause mortality (n=15, 42%) but thrombotic events represent the overall most common primary outcome (n=28, 77%). Low molecular weight heparin (LMWH) was the most common agent studied (n=25, 69%) followed by unfractionated heparin (UFH) (n=14, 38.8%) and factor Xa antagonists (n=8, 22.2%). Therapeutic-intensity prophylaxis was the most common dosage regimen studied in comparison to routine thromboprophylaxis dose in 76% and 86% of studies with LMWH and UFH respectively. Five studies (14%) used intermediate-dose prophylaxis. Bleeding is studied as an outcome variable in 19 studies (53%). Our review identifies studies of anticoagulation in COVID-19 and the pharmacological agents used, dosage intensities, and the outcomes analyzed.&lt;/p&gt;&lt;p class="abstract"&gt; &lt;/p&gt;