Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Tranexamic Acid for the Prevention of Blood Loss after Cesarean Delivery.

BACKGROUND: Prophylactic administration of tranexamic acid has been associated with reduced postpartum blood loss after cesarean delivery in several small trials, but evidence of its benefit in this clinical context remains inconclusive. METHODS: In a multicenter, double-blind, randomized, controlled trial, we assigned women undergoing cesarean delivery before or during labor at 34 or more gestational weeks to receive an intravenously administered prophylactic uterotonic agent and either tranexamic acid (1 g) or placebo. The primary outcome was postpartum hemorrhage, defined as a calculated estimated blood loss greater than 1000 ml or receipt of a red-cell transfusion within 2 days after delivery. Secondary outcomes included gravimetrically estimated blood loss, provider-assessed clinically significant postpartum hemorrhage, use of additional uterotonic agents, and postpartum blood transfusion. RESULTS: Of the 4551 women who underwent randomization, 4431 underwent cesarean delivery, 4153 (93.7%) of whom had primary outcome data available. The primary outcome occurred in 556 of 2086 women (26.7%) in the tranexamic acid group and in 653 of 2067 (31.6%) in the placebo group (adjusted risk ratio, 0.84; 95% confidence interval [CI], 0.75 to 0.94; P = 0.003). There were no significant between-group differences in mean gravimetrically estimated blood loss or in the percentage of women with provider-assessed clinically significant postpartum hemorrhage, use of additional uterotonic agents, or postpartum blood transfusion. Thromboembolic events in the 3 months after delivery occurred in 0.4% of women (8 of 2049) who received tranexamic acid and in 0.1% of women (2 of 2056) who received placebo (adjusted risk ratio, 4.01; 95% CI, 0.85 to 18.92; P = 0.08). CONCLUSIONS: Among women who underwent cesarean delivery and received prophylactic uterotonic agents, tranexamic acid treatment resulted in a significantly lower incidence of calculated estimated blood loss greater than 1000 ml or red-cell transfusion by day 2 than placebo, but it did not result in a lower incidence of hemorrhage-related secondary clinical outcomes. (Funded by the French Ministry of Health; TRAAP2 ClinicalTrials.gov number, NCT03431805.).

Standardized technique for ejaculation preservation during prostatic endoscopic ablative surgery.

PURPOSE: Ejaculatory dysfunction is the most common side effect of benign prostatic hyperplasia surgery. Modified techniques have emerged with the aim of preserving antegrade ejaculation without compromising obstruction relief. None are standardized or validated. The PARTURP study is a randomized study investigating partial versus complete prostate resection. We conducted an investigator consensus meeting to define the ideal surgical technique to achieve both correct obstruction relief with ejaculation preservation. METHODS: An expert consensus meeting involving all investigators of the PARTURP study took place to define a common technique using the nominal group methodology. The objectives were to define the areas to be resected and the areas to be preserved; to define the criteria for proper obstruction relief; to define the criteria for proper ejaculation preservation. RESULTS: All investigators (n = 15) attended the consensus meeting, and agreement between all the participants was obtained. The anatomical landmarks to be preserved are located around the verumontanum and along the posterior part of the prostatic urethra. These structures must be preserved up to 2 cm from the verumontanum. The participants agreed on the need to preserve the urethral mucosa in all the areas to be preserved and to reach the enucleation plane in the areas of resection. CONCLUSIONS: Anatomical landmarks for ejaculation-sparing surgery have been defined by the investigators of the PARTURP randomized study. These landmarks will be used during the study, and the clinical outcomes of this ejaculation-sparing technique will be compared with complete resection with up to 3 years follow-up.

Early non-invasive ventilation and high-flow nasal oxygen therapy for preventing endotracheal intubation in hypoxemic blunt chest trauma patients: the OptiTHO randomized trial.

BACKGROUND: The benefit-risk ratio of prophylactic non-invasive ventilation (NIV) and high-flow nasal oxygen therapy (HFNC-O2) during the early stage of blunt chest trauma remains controversial because of limited data. The main objective of this study was to compare the rate of endotracheal intubation between two NIV strategies in high-risk blunt chest trauma patients. METHODS: The OptiTHO trial was a randomized, open-label, multicenter trial over a two-year period. Every adult patients admitted in intensive care unit within 48 h after a high-risk blunt chest trauma (Thoracic Trauma Severity Score ≥ 8), an estimated PaO2/FiO2 ratio < 300 and no evidence of acute respiratory failure were eligible for study enrollment (Clinical Trial Registration: NCT03943914). The primary objective was to compare the rate of endotracheal intubation for delayed respiratory failure between two NIV strategies: i) a prompt association of HFNC-O2 and "early" NIV in every patient for at least 48 h with vs. ii) the standard of care associating COT and "late" NIV, indicated in patients with respiratory deterioration and/or PaO2/FiO2 ratio ≤ 200 mmHg. Secondary outcomes were the occurrence of chest trauma-related complications (pulmonary infection, delayed hemothorax or moderate-to-severe ARDS). RESULTS: Study enrollment was stopped for futility after a 2-year study period and randomization of 141 patients. Overall, 11 patients (7.8%) required endotracheal intubation for delayed respiratory failure. The rate of endotracheal intubation was not significantly lower in patients treated with the experimental strategy (7% [5/71]) when compared to the control group (8.6% [6/70]), with an adjusted OR = 0.72 (95%IC: 0.20-2.43), p = 0.60. The occurrence of pulmonary infection, delayed hemothorax or delayed ARDS was not significantly lower in patients treated by the experimental strategy (adjusted OR = 1.99 [95%IC: 0.73-5.89], p = 0.18, 0.85 [95%IC: 0.33-2.20], p = 0.74 and 2.14 [95%IC: 0.36-20.77], p = 0.41, respectively). CONCLUSION: A prompt association of HFNC-O2 with preventive NIV did not reduce the rate of endotracheal intubation or secondary respiratory complications when compared to COT and late NIV in high-risk blunt chest trauma patients with non-severe hypoxemia and no sign of acute respiratory failure. CLINICAL TRIAL REGISTRATION: NCT03943914, Registered 7 May 2019.

Tranexamic acid for reduction of blood loss after Caesarean delivery: a cost-effectiveness analysis of the TRAAP2 trial.

BACKGROUND: Prophylactic administration of tranexamic acid is associated with a reduction of blood loss after Caesarean delivery, but cost-effectiveness for this indication has not been assessed. METHODS: We used data from the TRAAP2 trial, a multicentre, double-blinded, RCT aimed at estimating the efficacy of tranexamic acid for preventing postpartum haemorrhage among women undergoing Caesarean delivery. Women recruited at 27 French maternity hospitals from 2018 to 2020 were enrolled before the procedure if they had a Caesarean delivery before or during labour at 34 or more weeks of gestation. The main outcomes were the cost of hospital stay for delivery and the incremental cost per delivery without complication within 90 days after delivery with tranexamic acid compared with placebo. Differences in costs and the incremental net monetary benefit (INMB) were estimated using linear regression models, and the cost-effectiveness probability of tranexamic acid compared with placebo was estimated through the parametric distribution of the INMB. RESULTS: The proportion of women without complications at day 90 was 70.7% in the tranexamic acid group and 66.0% in the placebo group. Mean total costs until occurrence of a complication of interest were €3321 in the tranexamic acid group and €3260 in the placebo group, resulting in a difference between the two groups of 7.2% and €55 after multiple imputation. The adjusted incremental cost-effectiveness ratio was €762 per additional Caesarean delivery without a complication at 90 days after delivery. At a cost-effectiveness threshold of €10,000, the cost-effectiveness probability of tranexamic acid compared with placebo was 99.9%, varying from 5.8% to 100.0% for thresholds from €0 to €10,000 per additional delivery without a complication at day 90. CONCLUSION: Tranexamic acid for the prevention of blood loss is cost-effective in reducing complications after Caesarean delivery at day 90 postpartum. However, the effect size (in cost and effectiveness) is very low. CLINICAL TRIAL REGISTRATION: NCT03431805.

A phase III randomized trial evaluating the quality of life impact of a tailored versus systematic use of defunctioning ileostomy following total mesorectal excision for rectal cancer-GRECCAR 17 trial protocol.

AIM: The systematic use of a defunctioning ileostomy for 2-3 months postoperatively to protect low colorectal anastomosis (<7 cm from the anal verge) has been the standard practice after total mesorectal excision (TME). However, stoma-related complications can occur in 20%-60% of cases, which may lead to prolonged inpatient care, urgent reoperation and long-term definitive stoma. A negative impact on quality of life (QoL) and increased healthcare expenses are also observed. Conversely, it has been reported that patients without a defunctioning stoma or following early stoma closure (days 8-12 after TME) have a better functional outcome than patients with systematic defunctioning stoma in situ for 2-3 months. METHOD: The main objective of this trial is to compare the QoL impact of a tailored versus systematic use of a defunctioning stoma after TME for rectal cancer. The primary outcome is QoL at 12 months postoperatively using the European Organization for. Research and Treatment of Cancer QoL questionnaire QLQ-C30. Among 29 centres of the French GRECCAR network, 200 patients will be recruited over 18 months, with follow-up at 1, 4, 8 and 12 months postoperatively, in an open-label, randomized, two-parallel arm, phase III superiority clinical trial. The experimental arm (arm A) will undergo a tailored use of defunctioning stoma after TME based on a two-step process: (i) to perform or not a defunctioning stoma according to the personalized risk of anastomotic leak (defunctioning stoma only if modified anastomotic failure observed risk score ≥2) and (ii) if a stoma is fashioned, whether to perform an early stoma closure at days 8-12, according to clinical (fever), biochemical (C-reactive protein level on days 2 and 4 postoperatively) and radiological postoperative assessment (CT scan with retrograde contrast enema at days 7-8 postoperatively). The control arm (arm B) will undergo systematic use of a defunctioning stoma for 2-3 months after TME for all patients, in keeping with French national and international guidelines. Secondary outcomes will include comprehensive analysis of functional outcomes (including bowel, urinary and sexual function) again up to 12 months postoperatively and a cost analysis. Regular assessments of anastomotic leak rates in both arms (every 50 randomized patients) will be performed and an independent data monitoring committee will recommend trial cessation if this rate is excessive in arm A compared to arm B. CONCLUSION: The GRECCAR 17 trial is the first randomized trial to assess a tailored, patient-specific approach to decisions regarding defunctioning stoma use and closure after TME according to personalized risk of anastomotic leak. The results of this trial will describe, for the first time, the QoL and morbidity impact of selective use of a defunctioning ileostomy and the potential health economic effect of such an approach.

Factors associated with the time from the first call to emergency medical services to puncture for mechanical thrombectomy for ischaemic stroke patients in Gironde, France, in 2017 and 2018.

BACKGROUND AND PURPOSE: When an ischaemic stroke due to a large vessel occlusion occurs, the sooner Mechanical Thrombectomy (MT) is performed, the better the functional prognosis. However, the organisation of care does not systematically allow rapid access to MT. The aim of our study was to determine the clinical and organisational factors associated with the time to access to MT. METHODS: We conducted a cohort study in Gironde County, France. Patients admitted for MT and regulated by the Gironde Emergency Medical Services (EMS) between 01/01/2017 and 31/12/2018 were included. The time to access to MT was the difference between the first call to EMS and groin puncture for MT. The main explanatory variables were: type of pathway (mothership (MS), drip and ship (DS) with cerebral imaging performed in the local hospital centre (LHC), and DS without imaging in the LHC); NIHSS score; driving distance to MT; time of stroke onset (weekend or holiday, school holidays, other); age and sex. Linear regression models were used to explain time to access to MT. Missing data were handled using a multiple imputation procedure (Full conditional specification, Mice R-Package) carried out in our multivariable linear regression model. A quantitative bias analysis was performed by weighing the imputed time to access to MT and identifying the weight changing the conclusions of our analysis. RESULTS: Among the 314 included patients, 152 were women (48.4%), and the mean NIHSS score was 16.4. Two hundred and two (64.3%) patients were managed through the MS pathway. The average time from onset to femoral puncture was 251 minutes. In the multivariate analysis, the time to MT was longer when patients were managed DS with imaging in the LHC pathway (+106 min, p = 0.03), and even longer in the DS without imaging in the LHC pathway (+197 min, p = 0.002), compared with MS. Time from onset to MT decreased with increasing NIHSS score (-6 min per NIHSS point, p <.0001). In our quantitative bias analysis, we multiplied the imputed time in access to MT in the DS pathways only (with or without imaging in the LHC) by weights varying from 0.9 to 0.2 (imputed delays reduced from 10% to 80%). With reduction of 40% or more, there was no longer any difference in time to access to MT between the three studied pathways. CONCLUSIONS: The DS pathway can be shortened by generalizing access to cerebral imaging in LHCs. Optimizing pre-admission orientation toward MT is a major issue in LVOS management.

Tranexamic acid for the prevention of blood loss after cesarean among women with twins: a secondary analysis of the TRAnexamic Acid for Preventing Postpartum Hemorrhage Following a Cesarean Delivery randomized clinical trial.

BACKGROUND: Although prophylactic tranexamic acid administration after cesarean delivery resulted in a lower incidence of calculated estimated blood loss of >1000 mL or red cell transfusion by day 2, its failure to reduce the incidence of hemorrhage-related secondary clinical outcomes (TRAnexamic Acid for Preventing Postpartum Hemorrhage Following a Cesarean Delivery trial) makes its use questionable. The magnitude of its effect may differ in women at higher risk of blood loss, including those with multiple pregnancies. OBJECTIVE: This study aimed to compare the effect of tranexamic acid vs placebo to prevent blood loss after cesarean delivery among women with multiple pregnancies. STUDY DESIGN: This was a secondary analysis of the TRAnexamic Acid for Preventing Postpartum Hemorrhage Following a Cesarean Delivery trial data, a double-blind, randomized controlled trial from March 2018 to January 2020 in 27 French maternity hospitals, that included 319 women with multiple pregnancies. Women with a cesarean delivery before or during labor at ≥34 weeks of gestation were randomized to receive intravenously 1 g of tranexamic acid (n=160) or placebo (n=159), both with prophylactic uterotonics. The primary outcome was a calculated estimated blood loss of >1000 mL or a red blood cell transfusion by 2 days after delivery. The secondary outcomes included clinical and laboratory blood loss measurements. RESULTS: Of the 4551 women randomized in this trial, 319 had a multiple pregnancy and cesarean delivery, and 298 (93.4%) had primary outcome data available. This outcome occurred in 62 of 147 women (42.2%) in the tranexamic acid group and 67 of 152 (44.1%) receiving placebo (adjusted risk ratio, 0.97; 95% confidence interval, 0.68-1.38; P=.86). No significant between-group differences occurred for any hemorrhage-related clinical outcomes: gravimetrically estimated blood loss, provider-assessed clinically significant hemorrhage, additional uterotonics, postpartum blood transfusion, arterial embolization, and emergency surgery (P>.05 for all comparisons). CONCLUSION: Among women with a multiple pregnancy and cesarean delivery, prophylactic tranexamic acid did not reduce the incidence of any blood loss-related outcomes.

Day-case robotic-assisted partial nephrectomy: feasibility and preliminary results of a prospective evaluation (UroCCR-25 AMBU-REIN study).

PURPOSE: Robotic partial nephrectomy (RPN) is a minimally-invasive technique used to treat renal tumors. A clinical pathway and prospective research protocol (AMBU-REIN) were specifically set up to establish and assess the routine use of day-case RPN. METHODS: The AMBU-REIN study was conducted in the framework of the French research network on kidney cancer UroCCR (NCT03293563). We present our initial experience of patients treated using day-case RPN and released from our hospital on the same day, focusing on patient selection, safety and patient satisfaction using the EVAN-G validated questionnaire. RESULTS: Between September 2016 and September 2019, 429 RPN were performed and 82 patients were consecutively selected for day-case RPN. Patients were managed using transperitoneal RPN with off-clamp tumorectomy for 66/82 cases. Mean tumor size was 2.7 ± 1.2 cm. There were no immediate severe postoperative complications; 7/82 patients were kept under observation overnight and discharged the following day. The follow-up at day 30 indicated postoperative complications, readmissions, and mortality rates of 1.2, 1.2, and 0%, respectively. Next-day patient satisfaction questionnaires indicated that patients were generally highly satisfied, with a mean ± standard deviation global score of 83.6 ± 10.3%. "Attention" was rated the highest overall (mean 94.8 ± 10.5%), while "pain management" scored the lowest (61.2 ± 20.5%). CONCLUSIONS: This prospective case series is the first to demonstrate the safety and feasibility of day-case RPN. For selected patients and through a dedicated, nurse-led clinical pathway, it provided a high level of patient satisfaction. Expected benefits on healthcare cost savings warrant further investigation.

Early multidisciplinary prevention program of post-stroke shoulder pain: A randomized clinical trial.

OBJECTIVE: To evaluate if positioning the upper-limb promoting abduction, external rotation and flexion of the shoulder reduces the intensity of post-stroke shoulder pain at day-7 compared to usual clinical practice. DESIGN & SETTING: Prospective single-center randomized clinical trial using a superiority design comparing two preventive strategies of post-stroke shoulder pain in a stroke unit. SUBJECTS: Patients were included within 2 days from a first symptomatic ischemic stroke affecting shoulder motor function. INTERVENTIONS: Intervention group included specific positioning of the shoulder in abduction, external rotation and flexion in bed, chair and during mobilization. Control group referred to usual practice i.e. positioning using a standard support scarf. MAIN MEASURES: Primary outcome was the intensity of shoulder pain assessed by the visual analog scale (VAS) (0-100) at day-7 post-stroke. Other outcomes measured at day-7 and 2 months post-stroke were the VAS, motor function, spasticity, depression, functional independence and rates of complex regional Pain syndrome (CRPS). RESULTS: 76 patients (49 males; mean age = 68.3) were randomized. The shoulder pain at day-7 was not different between the control group (16.1, SD = 27.4) and the intervention group (10.3, SD = 21.5, p = 0.18) as well as at 2 months (p = 0.12). A lower rate of depression was observed in the intervention group at 2 months 36.7% (CI95% 19.9;56.1) vs 52.9% (CI95% 35.1;70.2). No between-group difference in other outcomes was observed at 2 months. CONCLUSIONS: This study failed to demonstrate the benefit of a specific positioning tool in reducing the intensity of post-stroke shoulder pain which was lower than previously reported in the literature.

Femtosecond laser-assisted versus phacoemulsification cataract surgery (FEMCAT): a multicentre participant-masked randomised superiority and cost-effectiveness trial.

BACKGROUND: Cataract surgery is one of the most common operations in health care. Femtosecond laser-assisted cataract surgery (FLACS) enables more precise ocular incisions and lens fragmentation than does phacoemulsification cataract surgery (PCS). We hypothesised that FLACS might improve outcomes in cataract surgery compared with PCS despite having higher costs. METHODS: We did a participant-masked randomised superiority clinical trial comparing FLACS and PCS in two parallel groups (permuted block randomisation stratified on centres via a centralised web-based application, allocation ratio 1:1, block size of 2 or 4 for unilateral cases and 2 or 6 for bilateral cases). Five French University Hospitals enrolled consecutive patients aged 22 years or older who were eligible for unilateral or bilateral cataract surgery. Participants, outcome assessors, and technicians carrying out examinations were masked to the surgical treatment allocation until the last follow-up visit and a sham laser procedure was set up for participants randomly assigned to the PCS arm. The primary clinical endpoint was the success rate of surgery, defined as a composite of four outcomes at a 3-month postoperative visit: absence of severe perioperative complication, a best-corrected visual acuity (BCVA) of 0·0 LogMAR (logarithm of the minimum angle of resolution) or better, an absolute refractive error of 0·75 dioptres or less, and unchanged postoperative corneal astigmatism power (≤0·5 dioptres) and axis (≤20°). The primary economic endpoint was the incremental cost per additional patient who had treatment success at 3 months. Primary outcomes were assessed in all randomly assigned patients who met all eligibility criteria (missing data considered as failure). We used mixed logistic regression models or mixed linear regression models for statistical comparisons, adjusted on centres and whether cataract surgery was bilateral or unilateral. The study is registered with ClinicalTrials.gov, NCT01982006. FINDINGS: Of the 907 patients (1476 eyes) randomly assigned between Oct 9, 2013, and Oct 30, 2015, 870 (704 eyes in FLACS group and 685 eyes in the PCS group) were analysed. We identified no significant difference in the success rate of surgery between the FLACS and PCS groups (FLACS: 41·1% [289 eyes]; PCS: 43·6% [299 eyes]); adjusted odds ratio 0·85, 95% CI 0·64-1·12, p=0·250). The incremental cost-effectiveness ratio was €10 703 saved per additional patient who had treatment success with PCS compared with FLACS. We observed no severe adverse events during the femtosecond laser procedure, and most of the complications in the FLACS group related to the primary outcome measures occurred during the phacoemulsification phase or postoperatively. INTERPRETATION: Despite its advanced technology, femtosecond laser was not superior to phacoemulsification in cataract surgery and, with higher costs, did not provide an additional benefit over phacoemulsification for patients or health-care systems. FUNDING: French Ministry of Social Affairs and Health.

Cost-effectiveness of screening of coronary artery disease in patients with type 2 DIABetes at a very high cardiovascular risk (SCADIAB study) rational and design.

BACKGROUND: Screening for coronary artery disease (CAD) remains broadly performed in patients with type 2 diabetes (T2DM), although the lack of evidence. We conduct a real-world evidence (RWE) study to assess the risk of major clinical outcomes and economic impact of routine CAD screening in T2DM individuals at a very high cardiovascular risk. METHODS: SCADIAB is a comparative nationwide cohort study using data from the French National Health Data System. The main inclusion criteria are: age ≥ 40 years, DT2 diagnosed for ≥ 7 years, with ≥ 2 additional cardiovascular risk factors plus a history of microvascular or macrovascular disease, except CAD. We estimated ≥ 90,000 eligible participants for our study. Data will be extracted from 01/01/2008 to 31/12/2019. Eligible participants will be identified during a first 7-year selection period (2008-2015). Each participant will be assigned either in experimental (CAD screening procedure during the selection period) or control group (no CAD screening) on 01/01/2015, and followed for 5 years. The primary endpoint is the incremental cost per life year saved over 5 years in CAD screening group versus no CAD screening. The main secondary endpoints are: total 5-year direct costs of each strategy; incidence of major cardiovascular (acute coronary syndrome, hospitalization for heart failure, coronary revascularization or all-cause death), cerebrovascular (hospitalization for transient ischemic attack, stroke, or carotid revascularization) and lower-limb events (peripheral artery disease, ischemic diabetic foot, lower-limb revascularization or amputation); and the budget impact for the French Insurance system to promote the cost-effective strategy. Analyses will be adjusted for a high-dimension propensity score taking into account known and unknown confounders. SCADIAB has been funded by the French Ministry of Health and the protocol has been approved by the French ethic authorities. Data management and analyses will start in the second half of 2021. DISCUSSION: SCADIAB is a large and contemporary RWE study that will assess the economic and clinical impacts of routine CAD screening in T2DM people at a very high cardiovascular risk. It will also evaluate the clinical practice regarding CAD screening and help to make future recommendations and optimize the use of health care resources. Trial registration ClinicalTrials.gov Identifier: NCT04534530 ( https://clinicaltrials.gov/ct2/show/NCT04534530 ).

Molecular profiling of advanced soft-tissue sarcomas: the MULTISARC randomized trial.

BACKGROUND: Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumors including more than 70 different histological subtypes. High throughput molecular analysis (next generation sequencing exome [NGS]) is a unique opportunity to identify driver mutations that can change the usual one-size-fits-all treatment paradigm to a patient-driven therapeutic strategy. The primary objective of the MULTISARC trial is to assess whether NGS can be conducted for a large proportion of metastatic STS participants within a reasonable time, and, secondarily to determine whether a NGS-guided therapeutic strategy improves participant's outcome. METHODS: This is a randomized, multicentre, phase II/III trial inspired by the design of umbrella and biomarker-driven trials. The setting plans up to 17 investigational centres across France and the recruitment of 960 participants. Participants aged at least 18 years, with unresectable locally advanced and/or metastatic STS confirmed by the French sarcoma pathological reference network, are randomized according to 1:1 allocation ratio between the experimental arm "NGS" and the standard "No NGS". NGS will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a multidisciplinary tumor board is provided to investigators within 7 weeks from reception of the samples on the biopathological platform. A feasibility rate of more than 70% is expected (null hypothesis: 70% versus alternative hypothesis: 80%). In terms of care, participants randomized in "No NGS" arm and who fail treatment will be able to switch to the NGS arm at the request of the investigator. DISCUSSION: The MULTISARC trial is a prospective study designed to provide high-level evidence to support the implementation of NGS in routine clinical practice for advanced STS participants, on a large scale. TRIAL REGISTRATION: clinicaltrial.gov NCT03784014 .

Budget Impact of Tyrosine Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia With Sustained Deep Molecular Response.

OBJECTIVES: Tyrosine kinase inhibitors (TKIs) account for the vast majority of healthcare expenditure on patients with chronic myeloid leukemia (CML), and it has been demonstrated that TKI discontinuation in patients in long-term deep molecular remission (DMR) is safe and improves quality of life. Our objective was to estimate the budget impact of TKI discontinuation in CML patients in long-term DMR from the perspective of the French healthcare system. METHODS: This analysis was conducted over a 5-year time horizon using a Markov model with cycles of 6 months. Transition probabilities were estimated through systematic reviews and meta-analyses. Costs were estimated from the French National Claims Database. Monte Carlo simulations were performed to take into account the uncertainty surrounding model parameters. Sensitivity analyses were carried out by varying the size of the target population and the cost of TKIs. RESULTS: Over a 5-year period and for a target population of 100 patients each year eligible and agreeing to stop TKI, the TKI discontinuation strategy would save €25.5 million (95% confidence interval -39.3 to 70.0). In this model, the probability that TKI discontinuation would be more expensive than TKI continuation was 12.0%. In sensitivity analyses, mean savings ranged from €14.9 million to €62.9 million. CONCLUSIONS: This study provides transparent, reproducible, and interpretable results for healthcare professionals and policy makers. Our results clearly show that innovative healthcare strategies can benefit both the healthcare system and patients. Savings from generalizing TKI discontinuation in CML patients in sustained DMR should yield health gains for other patients.

A Phase 2 Randomized Trial of Asleep versus Awake Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVE: Asleep deep brain stimulation (DBS) for Parkinson's disease (PD) is being performed more frequently; however, motor outcomes and safety of asleep DBS have never been assessed in a prospective randomized trial. METHODS: We conducted a prospective, randomized, noncomparative trial to assess the motor outcomes of asleep DBS. Leads were implanted in the subthalamic nucleus (STN) according to probabilistic stereotactic coordinates with a surgical robot under O-arm© imaging guidance under either general anesthesia without microelectrode recordings (MER) (20 patients, asleep group) or local anesthesia with MER and clinical testing (9 patients, awake group). RESULTS: The mean motor improvement rates on the Unified Parkinson's Disease Rating Scale Part III (UPDRS-3) between OFF and ON stimulation without medication were 52.3% (95% CI: 45.4-59.2%) in the asleep group and 47.0% (95% CI: 23.8-70.2%) in the awake group, 6 months after surgery. Except for a subcutaneous hematoma, we did not observe any complications related to the surgery. Three patients (33%) in the awake group and 8 in the asleep group (40%) had at least one side effect potentially linked with neurostimulation. CONCLUSIONS: Owing to its randomized design, our study supports the hypothesis that motor outcomes after asleep STN-DBS in PD may be noninferior to the standard awake procedure.

Risk of molecular recurrence after tyrosine kinase inhibitor discontinuation in chronic myeloid leukaemia patients: a systematic review of literature with a meta-analysis of studies over the last ten years.

More than 10 years ago, the first pilot observational study of imatinib discontinuation was reported in chronic myeloid leukaemia (CML) patients in deep molecular response (DMR). Several studies have been published since then, in patients treated with frontline imatinib, or second-generation tyrosine kinase inhibitors (TKI) in first or second line but also on second attempt of TKI discontinuation. Our objective was to estimate, through meta-analyses of the literature data, the probability of molecular recurrence (MolRec) in the time periods of 0-6, 6-12, 12-18 and 18-24 months after a first and second TKI discontinuation and the probability of re-acquisition of DMR after MolRec. The Medline and Scopus databases were searched up to April 2019. The studies were selected by three independent reviewers. Random-effect meta-analyses were conducted using the MetaXL software. The probability of MolRec in the time periods 0-6, 6-12, 12-18 and 18-24 months after the first attempt was respectively 35%, 8%, 3% and 3%, whereas the probability of MolRec in the time periods 0-6, 6-12 and 12-18 after the second attempt was 48%, 27% and 12% respectively. Re-acquisition of a DMR was observed in 90% of patients. Most of the MolRec occur during the first six months in case of a first attempt, whereas the second MolRec occurs over a larger window of time.

No Improvement of Hepatitis B Vaccination Response in Patients Dialysed with a Polymethylmethacrylate Membrane Compared to High-Flux Polysulfone: Results of the HEPADIAL Study.

BACKGROUND: An altered immune response and decreased vaccine response are observed in patients with chronic renal failure. A preliminary study of 15 non-immunised patients, despite appropriate previous hepatitis B vaccination, showed a 60% seroconversion rate after 3 months of dialysis with a polymethylmethacrylate (PMMA) membrane. This response was associated with circulating soluble CD40 (CD40s) decrease, a natural inhibitor of the humoral immune response. The aim of the study is to confirm these results in a randomised study. METHODS: We conducted a multicentre randomised intention-to-treat superiority clinical trial comparing polysulfone and a PMMA membrane in 2 parallel patient groups. The primary end point was the vaccine response rate, as defined by an anti-HBs antibodies titre of >10 IU/L, 1 month after the last vaccination with a double dose of Engerix B20®, performed at weeks 12, 16, 20, and 36. RESULTS: Twenty-five patients were randomised and included in an intention-to-treat analysis. They were dialysed on polysulfone (n = 11) or PMMA (n = 14) for 40 weeks. Fifty percent of the PMMA patients versus 54.5% of the polysulfone patients achieved seroconversion (p = 1.00). The median anti-HBs antibody titre in responders at week 40 was 496 (92-750) versus 395 (43-572) UI/mL for PMMA and polysulfone, respectively (p = 0.46). The median CD40s titre at week 12 was 306 (193-448) versus 491 (281-515) pg/mL (p = 0.21). The CD40s median variation between week 0 and week 12 was 5 (-105 to 90) versus 64 (-63 to 123) pg/mL (p = 0.55). The CD40s level at week 12 in non-responders was slightly inferior to that of the responders: median 193 (168-331) versus 413 (281-512) pg/mL (p = 0.08). CONCLUSION: We did not observe a better vaccine response with the PMMA membrane compared to high-flux polysulfone. The PMMA membrane did not decrease the CD40s more than the polysulfone membrane probably because the titre was previously low in the 2 groups.

Decrease in pregnancy rate after endometrial scratch in women undergoing a first or second in vitro fertilization. A multicenter randomized controlled trial.

STUDY QUESTION: Does endometrial scratch in women undergoing a first or second IVF/ICSI attempt improve the clinical pregnancy rate (CPR)? SUMMARY ANSWER: Endometrial scratch (ES) in women undergoing their first or second IVF/ICSI attempt does not enhance the CPR under the technical conditions of our study. WHAT IS KNOWN ALREADY: Several studies have suggested that physical scratch of the endometrium before an IVF attempt could improve embryo implantation. STUDY DESIGN, SIZE, DURATION: This was a randomized controlled multi-center, two-arm, parallel trial. Inclusions started in February 2010 and stopped prematurely in July 2014 after an unplanned interim analysis. At the time of study closure, 191 of the planned 358 patients had been included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients included in the study were randomly assigned to either the ES arm or the non-ES arm. Local ES was performed between Day 20 and Day 24 of the cycle preceding ovarian stimulation using a device for endometrial biopsy. Ovarian stimulation used a combination of recombinant FSH and either an GnRH agonist protocol or a GnRH antagonist protocol without any estrogen pre-treatment. CPR was analyzed on an intent-to-treat basis. All comparisons between the two groups were done using a logistic regression model adjusted for age, BMI and infertility etiology. Differences between the two arms were considered statistically significant at P value of less than 0.0446 for the primary outcome only. MAIN RESULTS AND THE ROLE OF CHANCE: Sixty-eight embryo transfers were performed in the ES arm and sixty-four in the non-ES arm. CPR was 23.5% (16/68) in the ES arm and 35.9% (23/64) in the non-ES arm (hazard ratio (HR) = 0.43; 95% CI, 0.18-1.02; P = 0.0568). The implantation rate was 19.1% and 24.0% in the ES arm and in the non-ES arm, respectively. Two miscarriages and one ectopic pregnancy were reported in each arm. The multiple pregnancy rate was higher in the scratch arm (50.0% vs 20.0%), but the difference was not statistically significant (odds ratio (OR) = 4.54; 95% CI, 0.50-40.93; P = 0.1349). The endometrial biopsy procedure was well tolerated in most women. Of 50 patients in the ES arm having received the embryo transfer, 40 (80.0%) patients reported having felt pain during the procedure, the pain resolving quickly for 31 of them. LIMITATIONS, REASONS FOR CAUTION: An interim analysis of the primary endpoint was conducted and an independent data monitoring committee agreed on stopping the inclusions. This analysis was prompted by the tendency towards lower pregnancy rates observed in the ES arm. Consequently, the study suffered from a lower inclusion rate and failed to reach the planned sample size. WIDER IMPLICATIONS OF THE FINDINGS: Under the technical condition employed in this study, ES in the luteal phase of the cycle preceding the ovarian stimulation does not improve CPR in patients undergoing a first or second IVF/ICSI attempt. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a grant from Ministère de la Santé Français (Programme Hospitalier de Recherche Clinique 2009). There are no conflicts of interest. TRIAL REGISTRATION NUMBER: NCT01064193. TRIAL REGISTRATION DATE: 08-Feb-2010. DATE OF FIRST PATIENT'S ENROLMENT: 08-Feb-2010.

Cost-utility analysis of focal high-intensity focussed ultrasound vs active surveillance for low- to intermediate-risk prostate cancer using a Markov multi-state model.

OBJECTIVES: To estimate the relative cost-effectiveness of focal high-intensity focussed ultrasound (F-HIFU) compared to active surveillance (AS) in patients with low- to intermediate-risk prostate cancer, in France. PATIENTS AND METHODS: A Markov multi-state model was elaborated for this purpose. Our analyses were conducted from the French National Health Insurance perspective, with a time horizon of 10 years and a 4% discount rate for cost and effectiveness. A secondary analysis used a 30-year time horizon. Costs are presented in 2016 Euros (€), and effectiveness is expressed as quality-adjusted life years (QALYs). Model parameters' value (probabilities for transitions between health states, and cost and utility of health states) is supported by systematic literature reviews (PubMed) and random effect meta-analyses. The cost of F-HIFU in our model was the temporary tariff attributed by the French Ministry of Health to the overall treatment of prostate cancer by HIFU (€6047). Our model was analysed using Microsoft Excel 2010 (Microsoft Corp., Redmond, WA, USA). Uncertainty about the value of the model parameters was handled through probabilistic analyses. RESULTS: The five health states of our model were as follows: initial state (AS or F-HIFU), radical prostatectomy, radiation therapy, metastasis, and death. Transition probabilities from the initial F-HIFU state relied on four articles eligible for our meta-analyses. All were non-comparative studies. Utilities relied on a single cohort in San Diego, CA, USA. For a fictive cohort of 1000 individuals followed for 10 years, F-HIFU would be €207 520 more costly and would yield 382 less QALYs than AS, which means that AS is cost-effective when compared to F-HIFU. For a threshold value varying from €0 to 100 000/QALY, the probability of AS being cost-effective compared to F-HIFU varied from 56.5% to 60%. This level of uncertainty was in the same range with a 30-year time horizon. CONCLUSION: Given existing published data, our results suggest that AS is cost-effective compared to F-HIFU in patients with low- and intermediate-risk prostate cancer, but with high uncertainty. This uncertainty must be scaled down by continuing to supply the model with new published data and ideally through a randomised clinical trial that includes cost-effectiveness analyses.