EU Clinical Trials Research Articles

Laparoscopic versus open esophagectomy for patients with esophageal cancer: Systematic review and meta-analyses of randomized controlled trials.

194 Background: There has been an increase in the use of minimally invasive approaches for complex cancer operations. However, its benefit has not been clearly demonstrated for esophageal cancers when compared to open procedures. The purpose of this meta-analysis was to compare operative and postoperative outcomes for partial minimally invasive esophagectomy (MIE) versus open esophagectomy (OE) for patients with esophageal carcinoma. Methods: We conducted a systematic review using CENTRAL, PubMed, Global Index Medicus, ClinicalTrials.gov, EU Clinical Trials Register, and WHO ICTRP until August 30, 2020 without restrictions on publication date, language, or publication status. We included randomized controlled trials evaluating MIEs and partial MIEs including laparoscopic approach with OE for esophageal cancer. All trials including any one of our primary outcome measures -mortality and morbidity- were included. Two authors assessed trials for inclusion. Meta-analyses were conducted for categorical outcomes when heterogeneity was low ( I2< 50%). We reported risk ratios with 95% confidence intervals and GRADE quality of evidence based on our risk of bias assessment. Results: Of 5638 retrieved studies, 10 studies representing 6 trials consisting of 951 patients were included. 347 underwent partial MIE, 106 total MIE, and 498 OE. These were categorized into four cohorts:Co-A: Partial MIE versus OE (4 trials); Co-B: Partial MIE with thoracotomy versus OE (2 trials); Co-C: Partial MIE with cervical incision versus OE (2 trials); Co-D: Complete MIE versus OE (2 trials). Co-A revealed that partial MIE was associated with lower risk of serious adverse events (0.54[0.36-0.83]; 3 trials; 471 participants; I2= 48%), with specifically lower rates of delayed gastric emptying (0.32[0.13-0.80]; 3 trials; 666 participants; I2= 0%), pulmonary complications (0.49[0.29-0.84]; 3 trials; 471 participants; I2= 27%), and mortality (0.67[0.54-0.83]; 4 trials; 692 participants; I2= 0%). Co-B revealed that partial MIE with thoracotomy was associated with lower risk of pulmonary complications (0.61[0.38-0.99]; 2 trials; 231 participants; I2= 0%) and mortality (0.66[0.50-0.87]; 2 trials; 231 participants; I2= 0%). Co-C revealed that partial MIE with cervical incisions were associated with lower risk of serious adverse events (0.38[0.22-0.64]; 1 trial; 240 participants), including pulmonary complications (0.29[0.13-0.65]); 1 trial; 240 participants) and mortality (0.68[0.50-0.94]; 2 trials; 461 participants). Co-D revealed no significant differences between MIE and OE. All significant findings reported originated from high-quality evidence. Conclusions: When compared with completely open esophagectomy, partial MIE is associated with lower risk of mortality and serious adverse events, especially delayed gastric emptying and pulmonary complications.

Effect of denosumab on osteolytic lesion activity after total hip arthroplasty: a single-centre, randomised, double-blind, placebo-controlled, proof of concept trial.

Osteolysis causes recurrent pain and disability after total hip arthroplasty. We investigated the effect of the human monoclonal antibody denosumab on osteolytic lesion activity in patients undergoing revision total hip arthroplasty surgery to show the biological proof of concept for a non-surgical treatment for the disease. We did a phase 2, randomised, double-blind, placebo-controlled, proof of concept superiority trial at Sheffield Teaching Hospitals, Sheffield, UK. Eligible patients aged 30 years or older and scheduled for revision surgery for symptomatic, radiographically confirmed osteolysis were randomly allocated (1:1) to subcutaneous denosumab (60 mg single-dose) or placebo by an independent pharmacist using a random number table. The primary outcome was the between-group difference in osteoclast number per mm of bone surface of biopsies taken from the osteolytic membrane-bone interface at surgery 8 weeks later, measured by quantitative histomorphometry in all patients who underwent revision surgery. Adverse events were analysed in all randomly assigned participants. This trial is registered with the EU Clinical Trials Register (EudraCT 2011-000541-20). Between Dec 12, 2012, and June 24, 2018, 51 patients were assessed for eligibility, of whom 24 were randomly assigned to study treatment. Two patients had their revision surgery cancelled for unrelated reasons, leaving 22 patients (ten in the denosumab group) for analysis of the primary outcome. There were 83% fewer osteoclasts at the osteolysis membrane-bone interface in the denosumab versus the placebo group (median 0·05 per mm [IQR 0·11] vs 0·30 mm [0·40], p=0·011). No deaths or treatment-related serious adverse events occurred. Seven adverse events, including one severe adverse event, occurred in four (36%) of 11 patients in the denosumab group. In the placebo group ten adverse events, including three severe adverse events, occurred in five (38%) of 13 patients. To our knowledge, this is the first clinical trial of an investigational drug for osteolysis that shows tissue-specific biological efficacy. These results justify the need for future trials that target earlier-stage disease to test for clinical efficacy in reducing the need for revision surgery. Amgen.

Refeeding risks in patients requiring intravenous nutrition support: Results of a two-centre, prospective, double-blind, randomised controlled trial.

Refeeding syndrome can result following excessive feeding of malnourished patients. The syndrome remains poorly defined but encompasses a range of adverse effects including electrolyte shifts, hyperglycaemia and other less well-defined phenomena. There are additional risks of underfeeding malnourished individuals. Studies of refeeding syndrome have generally focussed on critical care environments or patients with anorexia nervosa. Here we have conducted a two-centre, prospective, double-blind, randomised controlled trial amongst all patients referred to hospital nutrition support teams for intravenous nutrition support. We sought to determine whether electrolyte and other abnormalities suggestive of refeeding syndrome risk varied depending on initial rate of intravenous feeding. Patients at moderate or high risk of refeeding syndrome, as defined by United Kingdom National Institute of Health and Care Excellence guidelines, were screened for inclusion. Patients were randomised to receive either high (30kcal/kg/day, 0.25gN/kg/day) or low (15kcal/day, 0.125gN/kg/day) rate feeding for the first 48h prior to escalation to standard parenteral nutrition regimens. The primary outcome was rates of potential refeeding risks within the first 7 days as defined by electrolyte imbalance or hyperglycaemia requiring insulin. Secondary outcomes included effects on QTc interval, infections and length of hospital stay. Statistical analysis was performed with χ2 or Wilcoxon rank sum tests and all analysis was intention-to-treat. Problems with study recruitment led to premature termination of the trial. Registered on the EU Clinical Trials Register (EudraCT number 2007-005547-17). 534 patients were screened and 104 randomised to either high or low rate feeding based on risk of refeeding syndrome. Seven patients were withdrawn prior to collection of baseline demographics and were excluded from analysis. 48 patients were analysed for the primary outcome with potential refeeding risks identified in 46%. No differences in risks were seen between high and low rate feeding (p>0.99) or high and moderate risk feeding (p=0.68). There were no differences in QTc abnormalities, infection rates, or hospital length of stay between groups. In this randomised trial of rates of refeeding risk, in patients pre-stratified as being at high or moderate risk, we found no evidence of increased refeeding related disturbances in those commenced on high rate feeding compared to low rate. No differences were seen in secondary endpoints including cardiac rhythm analysis, infections or length of stay. Our study reflects real world experience of patients referred for nutrition support and highlights challenges encountered when conducting clinical nutrition research.

Shotgun Mass Spectrometry-Based Lipid Profiling Identifies and Distinguishes Between Chronic Inflammatory Diseases

Aims: Inflammation impacts several acute and chronic diseases causing localized stress and cell death, releasing tissue-specific lipids into the circulation from inflamed cells and tissues. The plasma lipidome may be expected to reflect the type of inflammation. However, deep lipid profiles of major chronic inflammatory diseases have not been compared. Methods and Results: We compared the plasma lipidomes of patients suffering from two etiologically distinct chronic inflammatory diseases, atherosclerosis-related cardiovascular disease (CVD) including ischemic stroke (IS), and systemic lupus erythematosus (SLE), to each other and to age-matched controls. The controls had never suffered from any of these diseases. Plasma lipidomes were screened by a top-down shotgun MS-based analysis without liquid chromatographic separation. Lipid profiling of 596 lipids based on MS was performed on a cohort of 427 individuals. Machine learning classifiers based on the plasma lipidomes of patients suffering from CVD and SLE allowed clear distinction of these two chronic inflammatory diseases from each other. We demonstrate convincing evidence for the capability of lipidomics to separate the studied chronic and inflammatory diseases from controls based on independent validation test set classification performance (CVD vs control - Sensitivity: 0.90, Specificity: 0.98; IS vs control - Sensitivity: 1.0, Specificity: 1.0; SLE vs control – Sensitivity: 1, Specificity: 0.88) and from each other (SLE vs CVD ‒ Sensitivity: 0.91, Specificity: 1). Preliminary linear discriminant analysis plots using all data clearly separated the clinical groups from each other and from the controls. In addition, CVD severities, as classified into five clinical groups, were partially separable by linear discriminant analysis. Conclusions: Dysregulation of the plasma lipidome is characteristic of chronic inflammatory diseases. Lipid profiling accurately identifies the diseases and in the case of CVD also identifies sub-classes. Dysregulated lipids are partially but not fully counterbalanced by statin treatment. Clinical Trial Registration Details: This study was registered with the Clinical Trials number NCT04786431 Funding Information: This work was supported by PTDC/MED-PAT/29395/2017 financially supported by Fundacao paraKS is CEO and shareholder of of Lipotype GmbH. CL and MG are KS is CEO and shareholder of of Lipotype GmbH. CL and MG are employees of Lipotype GmbH. All other authors declare that they do not have any competing interestsemployees of Lipotype GmbH. All other authors declare that they do not have any competing interests424 a Ciencia e a Tecnologia (FCT), through national funds and co-funded by FEDER under the PT2020 Partnership. ND was a holder of PhD fellowship from the FCT (Ref. N°:SFRH/BD/51877/2012), attributed 10 by Inter-University Doctoral Programme in Ageing and Chronic Disease (PhDOC). LA was a holder of a FCT PhD fellowship (PD/BD/114254/2016), attributed by the ProRegem Doctoral Programme in 2016. Declaration of Interests: KS is CEO and shareholder of of Lipotype GmbH. CL and MG are employees of Lipotype GmbH. All other authors declare that they do not have any competing interests. Ethics Approval Statement: The entire process was approved by the Ethical Review Board of the Faculty of Medicine of the New University of Lisbon and the Ethics Committee for Health of the Centro Hospitalar de Lisboa Ocidental, that includes the Hospital Santa Cruz, the Hospital Egas Moniz and Hospital Sao Francisco Xavier, and the Ethics Committee for Health of the Hospital Fernando Fonseca. All experiments were performed in accordance with the guidelines and regulations including, the Universal Declaration on Bioethics and Human Rights of UNESCO, 2005; The Charter of Fundamental rights of the EU, 2012; Ethical principles for medical research involving human subjects - Declaration of Helsinki, 2013; EU Regulation 2016/679 and Good Clinical Practice guidelines (Directive 2001/20/EC) and EU Clinical Trials Directive (2005/28/EC). Moreover, they complied with national legislations for the scientific use of human biological samples (Law No 12/2005 and No 131/2014).

Intramuscular neridronate for the treatment of complex regional pain syndrome type 1: a randomized, double-blind, placebo-controlled study.

Background:Complex regional pain syndrome type-1 (CRPS-1) is a severely disabling painful disease challenging to treat. This multicenter, randomized, double-blind placebo-controlled trial examined the efficacy of intramuscular (i.m.) neridronate in CRPS-1 patients.Methods:A total of 78 patients diagnosed with CRPS-1 (aged 59.5 ± 10.3, 66.7% female) were randomly assigned to 25 mg (i.m.) neridronate (N = 41) given once daily for 16 consecutive days or placebo control (N = 37). Efficacy was assessed after 30 days using a visual analogue scale (VAS) pain score and the number of patients achieving ⩾50% reduction in VAS score. Change in clinical signs and symptoms, quality of life (QoL) using Short Form Health Survey (SF-36) and the McGill Pain Questionnaire were also assessed.Results:After 30 days, VAS score decreased significantly to a greater extent in neridronate-treated patients versus placebo (31.9 ± 23.3 mm versus 52.3 ± 27.8 mm, p = 0.0003). Furthermore, the proportion of patients achieving a VAS reduction of ⩾50% was greater in the neridronate group (65.9% versus 29.7%, p = 0.0017). Clinical signs and symptoms were improved significantly in the neridronate group versus placebo for edema (72.5% versus 79.9%, p = 0.03), pain during motion (70% versus 83.3%, p = 0.0009), allodynia (20% versus 63.3%, p = 0.0004), and hyperalgesia (20% versus 56.7%, p = 0.0023). Whereas no difference was observed for QoL measures using the SF-36 questionnaire, three of the four pain variables using the McGill Pain Questionnaire improved significantly in the neridronate group. No serious drug-related adverse events were reported during the study.Conclusion:In patients with acute CRPS-1, i.m. injections of 25 mg neridronate were associated with clinically relevant benefit compared with placebo controls.Trial registration:EU Clinical Trials Register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001156-28

Profiling of circulating tumor DNA and tumor tissue for treatment selection in patients with advanced and refractory carcinoma: a prospective, two-stage phase II Individualized Cancer Treatment trial.

Background:Molecular profiling (MP) represents an opportunity to match patients to a targeted therapy and when tumor tissue is unavailable, circulating tumor deoxyribonucleic acid (ctDNA) can be harnessed as a non-invasive analyte for this purpose. We evaluated the success of a targeted therapy selected by profiling of ctDNA and tissue in patients with advanced and refractory carcinoma.Patients and methods:A blood draw as well as an optional tissue biopsy were obtained for MP. Whole-genome sequencing and a cancer hotspot panel were performed, and publicly available databases were used to match the molecular profile to targeted treatments. The primary endpoint was the progression-free survival (PFS) ratio (PFS on MP-guided therapy/PFS on the last evidence-based therapy), whereas the success of the targeted therapy was defined as a PFS ratio ⩾1.2. To test the impact of molecular profile-treatment matching strategies, we retrospectively analyzed selected cases via the CureMatch PreciGENE™ decision support algorithm.Results:Interim analysis of 24 patients yielded informative results from 20 patients (83%). A potential tumor-specific drug could be matched in 11 patients (46%) and eight (33%) received a matched treatment. Median PFS in the matched treatment group was 61.5 days [interquartile range (IQR) 49.8–71.0] compared with 81.5 days (IQR 68.5–117.8) for the last evidence-based treatment, resulting in a median PFS ratio of 0.7 (IQR 0.6–0.9). Hence, as no patient experienced a PFS ratio ⩾1.2, the study was terminated. Except for one case, the CureMatch analysis identified either a two-drug or three-drug combination option.Conclusions:Our study employed a histotype–agnostic approach to harness molecular profiling data from both ctDNA and metastatic tumor tissue. The outcome results indicate that more innovative approaches to study design and matching algorithms are necessary to achieve improved patient outcomes.EU Clinical Trials Registry (https://www.clinicaltrialsregister.eu): EudraCT: 2014-005341-44

Dalfampridine improves slowed processing speed in multiple sclerosis patients with mild motor disability: post hoc analysis of a randomized controlled trial.

Objective:To evaluate baseline characteristics predictive of improving information processing speed in multiple sclerosis (MS) and the relationship between cognitive and motor response to dalfampridine (DA) treatment.Methods:This is a post hoc analysis of a randomized, double-blind, placebo-controlled trial in patients with MS randomized to receive DA 10 mg or placebo twice daily for 12 consecutive weeks. Here, we include only data from 71 patients in the arm treated with DA. According to the median value of Symbol Digit Modalities Test (SDMT) response, patients were categorized as “full responders” (FR) or “partially responders” (PR).Results:There was higher possibility of being FR in the presence of a baseline lower Expanded Disability Status Scale [odds ratio (OR) 0.69; 95% confidence interval (CI) 0.5–0.97, p = 0.034], a higher Multiple Sclerosis Functional Composite value (OR 1.37; 95%CI 1.05–1.8, p = 0.022), a lower Timed 25-Foot Walk Test (OR 0.76; 95% CI 0.6–0.98, p = 0.033), and a lower 9-Hole Peg Test with dominant hand (OR 0.92; 95% CI 0.86–0.99, p = 0.029). FR group did not show any significant improvement of motor performance compared with PR group.Conclusion:The current analysis shows that in MS patients with cognitive deficit, the greatest improvement in SDMT provided by DA was observed in patients with milder motor impairment; cognitive and motor responses to treatments are not related.Trial registration:EU Clinical Trials Register; ID 2013-002558-64 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-002558-64)

Alone laser versus bevacizumab plus laser for diffuse diabetic macular edema (ALBA randomized trial).

Purpose:To report the 12-month results of laser (treatment G1) versus intravitreal bevacizumab combined with laser (treatment G2) in patients with diffuse diabetic macular edema (DME).Methods:In this single-center randomized independent controlled trial, 32 patients were randomized to G1 (n = 15) or G2 (n = 17). In G1, laser was given at baseline and then pro re nata (PRN). In G2, three intravitreal bevacizumab (1.25 mg) injections were given once every 6 weeks, then laser and then PRN. Analysis was performed by treatment as administered. This study was registered in clinicaltrials.gov as NCT01572350 and EU Clinical Trial Registry as 2009-014654-15.Results:G2 was superior to G1 improving best corrected visual acuity (BCVA) with respect baseline (+8.0 vs + 3.0; p < 0.01). At month 12, a significantly greater proportion of patients had a BCVA letter score >15 and >73 in G2 (3 of 15 (20%) and 8 of 15 (53%), respectively) versus G1 (1 of 17 (6%) and 4 of 18 (23%), respectively). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire, at 12 months was statistically indistinguishable between both groups.Conclusion:G2 provided superior visual acuity gains over G1 in patients with visual impairment due to center-involving diffuse DME, associated with significant gains in VFQ-25 scores.

Implementation of the EU clinical trial regulation transforms the ethics committee systems and endangers ethical standards

The upcoming Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use (Regulation), which will replace the current Clinical Trial Directive at the end of 2021, has...

A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study

BackgroundThe peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19.MethodsIn this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily—or 75 IU anti-Xa twice daily for intensive care (ICU) patients—in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement.DiscussionIn this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome.Trial registrationThe EU Clinical Trials Register 2020-001739-28. Registered on April 10, 2020.

The Landscape of Emerging Randomized Clinical Trial Evidence for COVID-19 Disease Stages: A Systematic Review of Global Trial Registries.

PurposeA multitude of randomized controlled trials (RCTs) have emerged in response to the novel coronavirus disease (COVID-19) pandemic. Understanding the distribution of trials among various settings is important to guide future research priorities and efforts. The purpose of this review was to describe the emerging evidence base of COVID-19 RCTs by stages of disease progression, from pre-exposure to hospitalization.MethodsWe collated trial data across international registries: ClinicalTrials.gov; International Standard Randomised Controlled Trial Number Registry; Chinese Clinical Trial Registry; Clinical Research Information Service; EU Clinical Trials Register; Iranian Registry of Clinical Trials; Japan Primary Registries Network; German Clinical Trials Register (up to 7 October 2020). Active COVID-19 RCTs in international registries were eligible for inclusion. We extracted trial status, intervention(s), control, sample size, and clinical context to generate descriptive frequencies, network diagram illustrations, and statistical analyses including odds ratios and the Mann–Whitney U-test.ResultsOur search identified 11503 clinical trials registered for COVID-19 and identified 2388 RCTs. After excluding 45 suspended RCTs and 480 trials with unclear or unreported disease stages, 1863 active RCTs were included and categorized into four broad disease stages: pre-exposure (n=107); post-exposure (n=208); outpatient treatment (n=266); hospitalization, including the intensive care unit (n=1376). Across all disease stages, most trials had two arms (n=1500/1863, 80.52%), most often included (hydroxy)chloroquine (n=271/1863, 14.55%) and were US-based (n=408/1863, 21.90%). US-based trials had lower odds of including (hydroxy)chloroquine than trials in other countries (OR: 0.63, 95% CI: 0.45–0.90) and similar odds of having two arms compared to other geographic regions (OR: 1.05, 95% CI: 0.80–1.38).ConclusionThere is a marked difference in the number of trials across settings, with limited studies on non-hospitalized persons. Focus on pre- and post-exposure, and outpatients, is worthwhile as a means of reducing infections and lessening the health, social, and economic burden of COVID-19.

Rationale and description of a lifestyle intervention programme to achieve moderate weight loss in women with non-metastatic breast cancer: the lifestyle intervention part of the SUCCESS C Study

ObjectiveThere is growing evidence from observational studies that lifestyle factors such as obesity, an unhealthy diet and lack of physical activity are associated with poor long-term outcome in women with...

Measles-mumps-rubella vaccine at 6\u2009months of age, immunology, and childhood morbidity in a high-income setting: study protocol for a randomized controlled trial

BackgroundMeasles is a highly contagious and serious infection. Before the introduction of vaccination, measles caused yearly epidemics putting vulnerable children at risk of brain damage and death. Despite safe and cost-effective vaccines, measles remains a leading cause of death in children globally. Due to insufficient vaccine coverage and low levels of in utero transferred antibodies from vaccinated mothers, outbreaks of measles in Denmark and other high-income countries are observed at increasing frequency.The current vaccine was introduced in Denmark in 1987 as a one-shot measles-mumps-rubella vaccine at 15 months, a timing chosen to avoid inhibition of the infant’s immune response by maternal antibodies. One generation later, the MMR vaccinated mothers have lower antibody levels compared to the naturally infected, and their infants are already susceptible at 6 months of age or earlier, thus increasing the risk of epidemics.MethodsThe Danish MMR trial is a double-blind randomized clinical trial recruiting between March 2019 and December 2021 with last patient last visit in February 2022. Altogether N = 6500 infants aged 6 months will be randomly assigned to intramuscular vaccination with routine MMR (M-M-R VaxPro) or placebo (solvent only). According to the Danish Childhood vaccination program, all infants will receive a routine MMR vaccination at 15 months of age. At randomization, 1 month later, and 1 month after routine MMR vaccination at 15 months of age, a blood sample is drawn from app. 10% (N = 600) of the population. Additionally, hair, saliva, and urine are sampled at randomization. The co-primary study outcomes are immunogenicity 1 month after MMR vaccination at 6 months of age assessed as plaque-reduction neutralization test, and incidence of infectious disease hospitalizations from randomization to 12 months of age. Six weeks post randomization, all participants are interviewed regarding adverse events.Trial registrationThe trial is registered in the EU Clinical Trials Registry. EudraCT registration number: 2016-001901-18. Registered on 14 February 2017.

Effect of Cannabidiol and Δ9-Tetrahydrocannabinol on Driving Performance

Cannabis use has been associated with increased crash risk, but the effect of cannabidiol (CBD) on driving is unclear. To determine the driving impairment caused by vaporized cannabis containing Δ9-tetrahydrocannabinol (THC) and CBD. A double-blind, within-participants, randomized clinical trial was conducted at the Faculty of Psychology and Neuroscience at Maastricht University in the Netherlands between May 20, 2019, and March 27, 2020. Participants (N = 26) were healthy occasional users of cannabis. Participants vaporized THC-dominant, CBD-dominant, THC/CBD-equivalent, and placebo cannabis. THC and CBD doses were 13.75 mg. Order of conditions was randomized and balanced. The primary end point was standard deviation of lateral position (SDLP; a measure of lane weaving) during 100 km, on-road driving tests that commenced at 40 minutes and 240 minutes after cannabis consumption. At a calibrated blood alcohol concentration (BAC) of 0.02%, SDLP was increased relative to placebo by 1.12 cm, and at a calibrated BAC of 0.05%, SDLP was increased relative to placebo by 2.4 cm. Among 26 randomized participants (mean [SD] age, 23.2 [2.6] years; 16 women), 22 (85%) completed all 8 driving tests. At 40 to 100 minutes following consumption, the SDLP was 18.21 cm with CBD-dominant cannabis, 20.59 cm with THC-dominant cannabis, 21.09 cm with THC/CBD-equivalent cannabis, and 18.28 cm with placebo cannabis. SDLP was significantly increased by THC-dominant cannabis (+2.33 cm [95% CI, 0.80 to 3.86]; P < .001) and THC/CBD-equivalent cannabis (+2.83 cm [95% CI, 1.28 to 4.39]; P < .001) but not CBD-dominant cannabis (-0.05 cm [95% CI, -1.49 to 1.39]; P > .99), relative to placebo. At 240 to 300 minutes following consumption, the SDLP was 19.03 cm with CBD-dominant cannabis, 19.88 cm with THC-dominant cannabis, 20.59 cm with THC/CBD-equivalent cannabis, and 19.37 cm with placebo cannabis. The SDLP did not differ significantly in the CBD (-0.34 cm [95% CI, -1.77 to 1.10]; P > .99), THC (0.51 cm [95% CI, -1.01 to 2.02]; P > .99) or THC/CBD (1.22 cm [95% CI, -0.29 to 2.72]; P = .20) conditions, relative to placebo. Out of 188 test drives, 16 (8.5%) were terminated due to safety concerns. In a crossover clinical trial that assessed driving performance during on-road driving tests, the SDLP following vaporized THC-dominant and THC/CBD-equivalent cannabis compared with placebo was significantly greater at 40 to 100 minutes but not 240 to 300 minutes after vaporization; there were no significant differences between CBD-dominant cannabis and placebo. However, the effect size for CBD-dominant cannabis may not have excluded clinically important impairment, and the doses tested may not represent common usage. EU Clinical Trials Register: 2018-003945-40.

Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults

BackgroundTo study the pharmacokinetic and -dynamic behavior of landiolol in the presence of dobutamine in healthy subjects of European ancestry.MethodsWe conducted a single-center, prospective randomized study in 16 healthy subjects each receiving an infusion of dobutamine sufficient to increase heart rate by 30 bpm followed by a 60 min infusion of 10 μg/kg/min landiolol.ResultsDobutamine-induced increases in heart rate were stable for at least 20 min before a 60 min landiolol- infusion was started. The dobutamine effects were rapidly antagonized by landiolol within 16 min. A further slight decrease in heart rate during 20–60 min of the landiolol infusion occurred as well. Upon termination of landiolol infusion, heart rate and blood pressure recovered rapidly in response to the persisting dobutamine infusion but did not return to the maximum values before landiolol infusion. The pharmacokinetic parameters of landiolol in presence of dobutamine showed a short half-life (3.5 min) and a low distribution volume (0.3 l/kg). No serious adverse events were observed.ConclusionLandiolol can antagonize the dobutamine-induced increases in heart rate and blood pressure in a fast way. A rapid bradycardic effect until steady-state plasma levels is followed by a slow heart rate reduction. The latter can be attributed to an early desensitization to dobutamine. Consequently, after termination of landiolol, the heart rate did not achieve maximum pre-landiolol values. The pharmacokinetics of landiolol during dobutamine infusion are similar when compared to short- and long-term data in Caucasian subjects. Landiolol in the given dose can thus serve as an antagonist of dobutamine-induced cardiac effects.Trial registrationRegistration number 2010–023311-34 at the EU Clinical Trials Register, registration date 2010-12-21.

Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial

Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol. We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed. From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029-2052) and median on-treatment follow-up was 1324 days (IQR 870-1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70-1·03], p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group. Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol. Menarini, Ipsen, and Teijin Pharma Ltd.

A systematic review and meta-analysis of telephone vs in-person genetic counseling in BRCA1/BRCA2 genetic testing.

Pathogenic variants in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancer. Individuals with identified pathogenic variants in the BRCA1 or BRCA2 gene can benefit from cancer risk-reducing strategies. In the recent years, there has been an increase in the demand of genetic services. In light of the ongoing COVID19 pandemic, alternatives to face-to-face consultations have had to be considered and adopted, including telemedicine. Informed consent is necessary for genetic testing. Studies have suggested that increased levels of cancer-specific distress may impair the patient's ability to retain information, therefore, providing informed consent. This systematic review and meta-analysis aimed to answer if telephone genetic counseling for BRCA1 and BRCA2 genetic testing is non-inferior to in-person genetic counseling for the outcomes of cancer-specific distress and genetic knowledge. Databases of Medline, Embase, PsycINFO, CINAHL, SciELO, Web of Science, CENTRAL, ProQuest Dissertation & Theses Database, Clinicaltrials.gov, EU clinical trials register were accessed to identify any published or unpublished relevant literature. Random-effects models were used for the meta-analysis. Four studies were included in the qualitative synthesis of the results. Three studies were included in the quantitative synthesis of the results. Telephone genetic counseling was non-inferior compared to in-person genetic counseling for the outcomes of cancer-specific distress and genetic knowledge. Sensitivity analysis corroborated the main results. Telephone genetic counseling for BRCA1/BRCA2 genetic testing may be an alternative model of delivering genetic services in front of the increased demand/or when required by social context. However, the paucity of the evidence prevents from drawing strong conclusions regarding the generalizability of these results. Further research is needed to strengthen the conclusions.

Redundant trials can be prevented, if the EU clinical trial regulation is applied duly

The problem of wasteful clinical trials has been debated relentlessly in the medical community. To a significant extent, it is attributed to redundant trials – studies that are carried out to address questions, which can be answered satisfactorily on the basis of existing knowledge and accessible evidence from prior research. This article presents the first evaluation of the potential of the EU Clinical Trials Regulation 536/2014, which entered into force in 2014 but is expected to become applicable at the end of 2021, to prevent such trials. Having reviewed provisions related to the trial authorisation, we propose how certain regulatory requirements for the assessment of trial applications can and should be interpreted and applied by national research ethics committees and other relevant authorities in order to avoid redundant trials and, most importantly, preclude the unnecessary recruitment of trial participants and their unjustified exposure to health risks.

Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer\u2014results from the randomized phase III SUCCESS-A trial

BackgroundWhen chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients.MethodsA total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety.ResultsNo differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively.ConclusionAdding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting.Trial registrationClinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.

Conducting Non-COVID-19 Clinical Trials during the Pandemic: Can Today's Learning Impact Framework Efficiency?

The COVID-19 pandemic has severely disrupted non-coronavirus clinical trials. In the case of life-threatening diseases, such as cancer, this is particularly dangerous, as treatment cannot simply be stopped. In the EU, guidelines for the management of ongoing studies were issued; however, national coordination is still lacking. This article aims to raise awareness on the struggle of managing ongoing clinical trials in the EU during the pandemic. The goals are to bring attention, from a legal and regulatory point of view to the difficulties faced by those involved in clinical research, and to critically position the current hurdles against the backdrop of the existing legal and ethical framework. We investigated the EU guidance and the national approaches of all EU/EEA Member States, and critically discussed selected issues. We argue that the crisis may be an opportunity to foresee meaningful changes in the EU clinical trials framework post-COVID-19.