French Health Ministry Research Articles

Presentation and Outcome of Severe Staphylococcal Pneumonia Depends Strongly on Age and the Presence of Panton-Valentine Leucocidin: A Prospective Multicenter Cohort Study

Background: The first characterisation of Panton-Valentine Leucocidin (PVL)-associated staphylococcal necrotizing pneumonia (SNP) was published in 2002. A major controversy regarding the role played by PVL in the severity of community-acquired pneumonia (CAP) ensued. To address this issue, all French intensive care units (ICU) were asked to prospectively include their cases of staphylococcal CAP between January 2011 and December 2016. Method: Patients with CAP who fulfilled the following criteria were included: clinical and radiological signs of lung infection, at least one assessment of S. aureus involvement (positive culture from blood/pleural fluid, respiratory sample), and admission to ICU. At the time of data collection, clinicians were not aware of PVL status. Patterns in patient age distribution were detected using a clustering procedure. Risk factors for mortality were identified using multivariate Cox regression. Findings: One-hundred and sixty-three patients, aged from one month to 87 years, were included; 52.1% were PVL-positive. Unexpectedly, PVL-positive cases distributed into two independent clusters, with a cut-off of around 3 years of age, whereas PVL-negative cases were only observed in adolescents and adults. Features of the <3 year-old patients matched with the historical description of staphylococcal pleuropneumonia (SPP) in toddlers with round-shaped infiltrates and mild severity. In older patients, PVL was associated with an enhanced severity and a higher case-fatality rate despite its occurrence in more favourable underlying conditions. Interpretation: This study demonstrates the association of PVL with two distinct facets of staphylococcal CAP with marked differences between toddlers and adolescents/adults regarding clinical presentation and outcome. The strong link between SPP and PVL was found and the association of PVL with severity of SNP in adults is confirmed. This dichotomy between SPP and SNP elucidates the conflicting results of previous studies assessing the role of PVL in staphylococcal pneumonia. Trial Registration: The study is registered with ClinicalTrials.gov, number NCT02798497. Funding Statement: Funded by the French Ministry of Health, PHRC 2010-A01132-37. Declaration of Interests: FV have received a grant from the French Ministry of Research for the submitted work, has received grants from bioMerieux, and has been a consultant for Pfizer and Acccelerate Diagnosis. YG has been a consultant for Pfizer vaccine, GSK Vaccines and Sanofi-Pasteur MSD vaccines. AT has received a grant from bioMerieux and R-biopharm. JPR has received a grant from bioMerieux; and honoraria for lecturing from Pfizer, MSD and Procter&Gamble. CB has received a grant from bioMerieux and Pathoquest. GL has received a grant from Pfizer, Novartis, Basilea, Diadenode and Pierre Fabre, and has been consultant for Eumedica, GenMark and Beckton Dickinson. OD has received a grant from the French Ministry of Research and from Pfizer. CD has received honoraria for lecturing from Correvi. PV has received personnal fees for expertise and consulting from GSK, Astellas, Pfizer and bioMerieux, and received research grant from Sanofi, MSD and ANIOS. The other authors declare no competing interests. Ethics Approval Statement: The regional ethics committee (Comite de Protection des Personnes Sud-Est IV) approved the study (number: A11-39). Written informed consent was obtained from all patients, and patient records were anonymised prior to analysis.

An exoskeleton controlled by an epidural wireless brain–machine interface in a tetraplegic patient: a proof-of-concept demonstration

Approximately 20% of traumatic cervical spinal cord injuries result in tetraplegia. Neuroprosthetics are being developed to manage this condition and thus improve the lives of patients. We aimed to test the feasibility of a semi-invasive technique that uses brain signals to drive an exoskeleton. We recruited two participants at Clinatec research centre, associated with Grenoble University Hospital, Grenoble, France, into our ongoing clinical trial. Inclusion criteria were age 18-45 years, stability of neurological deficits, a need for additional mobility expressed by the patient, ambulatory or hospitalised monitoring, registration in the French social security system, and signed informed consent. The exclusion criteria were previous brain surgery, anticoagulant treatments, neuropsychological sequelae, depression, substance dependence or misuse, and contraindications to magnetoencephalography (MEG), EEG, or MRI. One participant was excluded because of a technical problem with the implants. The remaining participant was a 28-year-old man, who had tetraplegia following a C4-C5 spinal cord injury. Two bilateral wireless epidural recorders, each with 64 electrodes, were implanted over the upper limb sensorimotor areas of the brain. Epidural electrocorticographic (ECoG) signals were processed online by an adaptive decoding algorithm to send commands to effectors (virtual avatar or exoskeleton). Throughout the 24 months of the study, the patient did various mental tasks to progressively increase the number of degrees of freedom. Between June 12, 2017, and July 21, 2019, the patient cortically controlled a programme that simulated walking and made bimanual, multi-joint, upper-limb movements with eight degrees of freedom during various reach-and-touch tasks and wrist rotations, using a virtual avatar at home (64·0% [SD 5·1] success) or an exoskeleton in the laboratory (70·9% [11·6] success). Compared with microelectrodes, epidural ECoG is semi-invasive and has similar efficiency. The decoding models were reusable for up to approximately 7 weeks without recalibration. These results showed long-term (24-month) activation of a four-limb neuroprosthetic exoskeleton by a complete brain-machine interface system using continuous, online epidural ECoG to decode brain activity in a tetraplegic patient. Up to eight degrees of freedom could be simultaneously controlled using a unique model, which was reusable without recalibration for up to about 7 weeks. French Atomic Energy Commission, French Ministry of Health, Edmond J Safra Philanthropic Foundation, Fondation Motrice, Fondation Nanosciences, Institut Carnot, Fonds de Dotation Clinatec.

1095P - RUBIH2 - Use of NGS in haematological malignancies: From real world data to national recommendations, an innovative program to evaluate the impact of healthcare technology on patient care

BackgroundKnowledge of molecular abnormalities in haematological malignancies led to better understanding of their role in disease development, progression and resistance to treatments. However, effective impact of NGS analyses need to be evaluated. RuBIH2 programme aims to determine appropriate prescription, clinical utility and validity, cost and territorial organisation of NGS under a governmental funded “Programme de Recherche Médico-Economique” (Health Economics Research Program). MethodsWe considered 5 haematological malignancies: myelodysplasia, acute lymphoid leukaemia, acute myeloid leukaemia, lymphoma and lymphoproliferative disorders and myeloproliferative disorders. 26 French biomolecular platforms are involved. The program is split into 4 work packages (WP). WP1: micro-costing, WP2: appropriate prescribing guidelines, WP3: evaluation of clinical validity, WP4: recommendations on national organization. ResultsWP1: is a micro-costing of NGS on 5 biomolecular platforms to assess production cost depending on the volume of analyses performed, type of pathology and panel size. Based on a bottom-up approach and onsite observations, we calculated an average mean cost. WP2: is to define recommended diagnostic tests according to pathologies and patients’ characteristics. National key opinion leaders (clinicians and biologists) defined a NGS minimal panel depending on therapeutic possibilities. Biological analyses performed at diagnosis, relapse or during follow-up will be classified as mandatory, recommended, under evaluation or obsolete. WP3: is a real-world data study of NGS analyses carried out by 26 biomolecular platforms. Biological and clinical information are collected in an eCRF. Analysis will describe the impact of NGS on patients’ pathways. WP4: will integrate data collected during WP 1-3 to define an optimal national organization and bundled payment scheme. ConclusionsFinal objective is to improve patient care and access to NGS based on better stratification and definition of analyses to perform at each stage of patient’s care pathways: diagnostic, relapse and follow-up. Clinical trial identificationNCT03750994. Legal entity responsible for the studyAssistance Publique Hôpitaux de Paris. FundingDirection Générale de l’Offre de Soins (DGOS) - French Ministry of Health. DisclosureAll authors have declared no conflicts of interest.

LBA15_PR - A phase III trial of empiric chemotherapy with cisplatin and gemcitabine or systemic treatment tailored by molecular gene expression analysis in patients with carcinomas of an unknown primary (CUP) site (GEFCAPI 04)

BackgroundCUP are heterogeneous tumors that share the unique characteristic of metastases with no identifiable origin. The outcome of patients (pts) with CUP is poor despite empiric chemotherapy that has activity against a wide variety of neoplasms such as the cisplatin-gemcitabine combination (Culine S, JCO 2002). Molecular tests may identify primary sites in up to 80% of pts, and results suggest that at least 1/3 of identified primaries may not be sensitive to empiric chemotherapy used in CUPs (Gross-Goupil G 2012). In the GEFCAPI 04 phase III trial, we hypothesized that tailored treatment will improve outcomes. MethodsEligible pts had pathologically-confirmed metastatic CUPs and were treatment naïve. Pts belonging to pre-defined favorable subsets were excluded. After relevant workup had identified no primary site, pts were randomized 1:1 to either Arm A (Cisplatin 100mg/m² d1+ Gemcitabine 1250mg/m², day 1 and 8, q3w) or Arm B (gene expression test followed by à la carte treatment according to the suspected primary). The test consisted of the Tissue Of Origin (Pathwork, n=21) or CancerTYPE ID (Biotheranostics, n=222). The primary endpoint was PFS (HR=0.625, power=80%, 5% bilateral test). Stratification was on site, PS and LDH level. Secondary endpoints were PFS in pts with pre-defined cancers likely insensitive to cisplatin-gemcitabine and OS. ResultsFrom 03/12 to 02/18, 243 pts from 4 EU countries were randomized (Arm A: 120, Arm B: 123). Primary cancers most often reported by tests were pancreatico-biliary cancer (19%), squamous cell carcinoma (11%, kidney cancer (8%), and lung cancer (8%). Treatment was tailored by molecular test results in 91/123 arm B pts (74%). PFS by central review was similar: HR=0.95 (0.72-1.25); p=0.7; medians: 5.3 m arm A vs 4.6 m arm B. PFS by local review also showed no significant difference: HR=0.80 (0.60-1.06); p=0.12; medians 5.8 vs 6.4 m. OS was also similar in the overall population (HR: 0.92 (0.69-1.23), medians: 10 vs 10.7 m) and in 60 pts with suspected cancers likely insensitive to GC. ConclusionsIn GEFCAPI 04, using a molecular test followed by tailored systemic treatment did not improve outcomes of pts with CUP. Clinical trial identification2011-A01202-39. Legal entity responsible for the studyInstitut Gustave Roussy. FundingProgramme Hospitalier de Recherche Clinique (PHRC) from the French Ministry of Health. DisclosureK. Fizazi: Advisory / Consultancy: Astellas; Advisory / Consultancy: AAA; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis; Advisory / Consultancy: Curevac; Advisory / Consultancy: Incyte; Advisory / Consultancy: Janssen; Advisory / Consultancy: MSD; Advisory / Consultancy: Orion; Advisory / Consultancy: Sanofi. R. Morales Barrera: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Astrazeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Asofarma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Johnson and Jonhson; Honoraria (self), Advisory / Consultancy: Roche. C.A. Schnabel: Full / Part-time employment: bioTheranostics. All other authors have declared no conflicts of interest.

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials.

SummaryBackgroundHeterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response.MethodsWe did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab.FindingsIn the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo.InterpretationStratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases.FundingUK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology.Video Symptom-based stratification of patients with Sjögren's syndrome

Personalised mechanical ventilation tailored to lung morphology versus low positive end-expiratory pressure for patients with acute respiratory distress syndrome in France (the LIVE study): a multicentre, single-blind, randomised controlled trial

The effect of personalised mechanical ventilation on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remains uncertain and needs to be evaluated. We aimed to test whether a mechanical ventilation strategy that was personalised to individual patients' lung morphology would improve the survival of patients with ARDS when compared with standard of care. We designed a multicentre, single-blind, stratified, parallel-group, randomised controlled trial enrolling patients with moderate-to-severe ARDS in 20 university or non-university intensive care units in France. Patients older than 18 years with early ARDS for less than 12 h were randomly assigned (1:1) to either the control group or the personalised group using a minimisation algorithm and stratified according to the study site, lung morphology, and duration of mechanical ventilation. Only the patients were masked to allocation. In the control group, patients received a tidal volume of 6 mL/kg per predicted bodyweight and positive end-expiratory pressure (PEEP) was selected according to a low PEEP and fraction of inspired oxygen table, and early prone position was encouraged. In the personalised group, the treatment approach was based on lung morphology; patients with focal ARDS received a tidal volume of 8 mL/kg, low PEEP, and prone position. Patients with non-focal ARDS received a tidal volume of 6 mL/kg, along with recruitment manoeuvres and high PEEP. The primary outcome was 90-day mortality as established by intention-to-treat analysis. This study is registered online with ClinicalTrials.gov, NCT02149589. From June 12, 2014, to Feb 2, 2017, 420 patients were randomly assigned to treatment. 11 patients were excluded in the personalised group and nine patients were excluded in the control group; 196 patients in the personalised group and 204 in the control group were included in the analysis. In a multivariate analysis, there was no difference in 90-day mortality between the group treated with personalised ventilation and the control group in the intention-to-treat analysis (hazard ratio [HR] 1·01; 95% CI 0·61-1·66; p=0·98). However, misclassification of patients as having focal or non-focal ARDS by the investigators was observed in 85 (21%) of 400 patients. We found a significant interaction between misclassification and randomised group allocation with respect to the primary outcome (p<0·001). In the subgroup analysis, the 90-day mortality of the misclassified patients was higher in the personalised group (26 [65%] of 40 patients) than in the control group (18 [32%] of 57 patients; HR 2·8; 95% CI 1·5-5·1; p=0·012. Personalisation of mechanical ventilation did not decrease mortality in patients with ARDS, possibly because of the misclassification of 21% of patients. A ventilator strategy misaligned with lung morphology substantially increases mortality. Whether improvement in ARDS phenotyping can decrease mortality should be assessed in a future clinical trial. French Ministry of Health (Programme Hospitalier de Recherche Clinique InterRégional 2013).

Abstract CT140: Circulating tumor cells as a tool to guide first line therapy in metastatic breast cancer: subgroup analyses of the STIC CTC Phase III utility trial

Abstract Background: Endocrine therapy (ET) is the preferred 1st line therapy in ER+ HER2- metastatic breast cancer (MBC) patients, but not all benefit from such strategy for which predictive biomarkers are lacking. Prior studies showed that circulating tumor cells (CTC) count is the strongest prognostic factor beyond PS in that population. The STIC CTC trial (NCT01710605) assessed whether CTC count could drive the choice between frontline ET or chemotherapy (CT, with or without ET maintenance). Methods: For this multicenter phase 3 non-inferiority trial, main inclusion criteria were: ER+ HER2- MBC with no prior therapy, PS≤2, no contra-indication to ET or CT, informed consent. Patients were randomized 1:1 between clinically-driven choice (single agent ET if clinicallow, CT if clinicalhigh, as decided by physician based on clinical factors, blinded to CTC results) or a CTC-driven choice [ET if CTClow (&amp;lt;5 CTCs/7.5mL), CT if CTChigh (≥5 CTCs/7.5mL)]. The primary objective was treatment efficacy ([PFS hazard ratio (HR)], non-inferiority being established if the upper bound of the PFS HR 2-sided 90%CI is &amp;lt;1.25; secondary objectives included subgroup analyses (CTC status, patient characteristics) and OS. Results: In this trial, 778 patients were randomized between both strategies. Of all patients, 71.0%, 26.6% and 2.4% were considered as endocrine-sensitive, with secondary or with primary endocrine resistance, respectively. In both arms (clinically- and CTC-driven), prognostic evaluation by physician/CTCs and allocated treatments were as follows: (i) clinicallow/CTClow 46.5% and 48.6% of patients, all treated with ET. (ii) clinicalhigh/CTChigh 14.0% and 13.0%, all treated with CT. (iii) clinicallow/CTChigh 26.1% and 24.2%, treated with ET or CT respectively. (iv) clinicalhigh/CTClow 13.4% and 14.0%, treated with CT or ET respectively. CTC-driven strategy met the primary endpoint, yielding a non-inferior PFS (median: 17 months; 95%CI [15.4-20.3] vs 18 months 95%CI[13.9-23.3]). In the 2 discordant subgroups, preplanned analyses showed the following results: in the clinicallow/CTChigh subgroup, patients treated with CT had a significantly longer PFS than those treated with ET (15.6 months, 95%CI [12.2-22.7] vs 10.5 months, 95%CI [7.3-15.4], log rank p=0.002). In the clinicalhigh/CTClow subgroup, patients treated with CT had a non-significant PFS advantage over patients treated with ET. Pooling these two subgroups of patients (N=292) with discordant treatment recommendations (depending on clinician or CTC count standpoint), an exploratory analysis showed that patients treated with CT frontline had significantly longer PFS (HR=0.66; 95%CI [0.51-0.85]) and OS (HR=0.65; 95%CI [0.43-0.98]); 2-year OS were 82.9% versus 74.7% in patients treated with CT (±maintenance ET) or ET, respectively. Conclusion: This trial demonstrates the utility of CTC count to select 1st line therapy in ER+ HER2- MBC patients, especially in those for whom single agent ET is the recommended therapy based on clinical factors. With this modern prognostic biomarker, the STIC CTC trial is the first one to identify potential ER+ HER2- MBC patients who might derive more benefit from frontline CT followed by maintenance ET than from frontline ET, challenging current standards. Funding: French Ministry of Health (PSTIC 2011); Menarini SB; Institut Curie. Citation Format: Francois-Clement Bidard, William Jacot, Sylvain Dureau, Etienne Brain, Thomas Bachelot, Hugues Bourgeois, Anthony Goncalves, Sylvain Ladoire, Herve Naman, Florence Dalenc, Joseph Gligorov, Marc Espie, Christelle Levy, Jean-Marc Ferrero, Delphine Loirat, Paul Cottu, Veronique Dieras, Marie-Emmanuelle Legrier, Frederique Berger, Catherine Alix-Panabieres, Jean-Yves Pierga. Circulating tumor cells as a tool to guide first line therapy in metastatic breast cancer: subgroup analyses of the STIC CTC Phase III utility trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT140.

Diagnosis of Heparin-Induced Thrombocytopenia: Development and Validation of a Predictive Clinical Score Based on Objective Features Identified by a Multivariate Analysis of a Multinational Prospective Study

Background: Diagnosis of heparin-induced thrombocytopenia (HIT) is based on a composite of clinical likelihood and laboratory testing. We aimed to develop a diagnostic score derived from multivariate analysis of clinical features, including platelet count changes, prospectively recorded in patients with suspected HIT. Methods: This multinational observational study (ClinicalTrials.gov no. NCT00748839) included 2280 adult patients with suspected HIT: 1597 (derivation cohort) formed the basis for developing the scoring system, subsequently validated in 683 additional randomly selected patients (validation cohort). HIT was diagnosed by two independent adjudicators based on clinical features, local laboratory data, and the results of a centrally performed serotonin release assay (SRA). Findings: Overall, 56.7% of the patients were treated in an intensive care unit of whom 57.4% received unfractionated heparin; thromboembolism occurred in 12.3%. In the derivation and validation cohorts, 234 (14.7%) and 99 (14.5%) patients, respectively, were diagnosed with HIT. Eight features were positively associated with HIT diagnosis in a multivariate model (in brackets the value assigned for score calculation): unfractionated heparin use (1); therapeutic-dose heparin use (1); cardiac surgery with cardiopulmonary bypass (2); major trauma (3); 5- to 21-day interval from anticoagulant treatment initiation to suspicion of HIT (4); ≥ 40% decrease in platelet count over ≤ 6 days during the last 10 days of anticoagulation exposure (3); thrombotic event, either arterial (3) or venous (3). The C statistic of the model was 0.791 [0.76; 0.82] (p-value 0.70, Hosmer-Lemeshow test). In the validation cohort, the area under the ROC curve was 0.77 [95% CI 0.74-0.80], and HIT prevalence was 2.6% for a score ≤2; 6% for a score of 3–8; and 28.8% for a score >8: Interpretation: This study distinguishes validated clinical features of HIT, permitting improved estimation of its likelihood. Trial Registration: (ClinicalTrials.gov no. NCT00748839) Funding Statement: Programme Hospitalier de Recherche Clinique (French Health Ministry), Sanofi, LFB, Organon SA. Declaration of Interests: Dr. Mullier reports personal fees from Aspen, personal fees from Stago, grants from Werfen, outside the submitted work; Dr. Gruel reports personal fees from Sanofi, personal fees from LFB, other from Stago, personal fees from Aspen, outside the submitted work; . All other authors declare no conflict of interests. Ethics Approval Statement: The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki, Good Clinical Practice, and relevant French, Swiss and Belgian legal and regulatory requirements regarding data protection. The protocol was approved by French, Swiss and Belgian independent ethics committees. All patients received written information about the study, emphasizing their right to refuse participation or to withdraw at any time. As no experimental interventions were induced from the protocol, no written informed consent was required for inclusion.

Low-level laser therapy in treatment of chemoradiotherapy-induced mucositis in head and neck cancer: results of a randomised, triple blind, multicentre phase III trial

BackgroundLow-level laser therapy (LLLT) also called Photobiomodulation therapy (PBMT) could reduce oral mucositis (OM) incidence and severity in head and neck cancer patients treated by chemoradiotherapy, however randomised data about efficacy and safety are missing with curative dose 4 J/cm2.MethodsThis phase III trial was conducted in patients with oral cavity, or oro/hypopharyngeal cancers (stage III or IV). Patients were treated by lasertherapy on OM lesions grade ≥ 2 (4 J/cm2 or placebo), during chemoradiotherapy and until recovery. Severity of OM (incidence and duration of grades ≥3) was used as primary endpoint and blindly assessed.ResultsAmong 97 randomised patients, 83 patients (85.6%) could be assessed finally (erroneous inclusions, chemoradiotherapy interruptions) and 32 patients had no lasertherapy because of unreachable OM lesions. Randomisation and population characteristics (sex ratio, age, chemoradiotherapy procedures, toxicities incidence) were still comparable between the two LLLT/PBMT groups. An acute OM (grade ≥ 3) was observed in 41 patients (49.4%): 23 patients (54.8%) of the active laser group versus 18 (43.9%) in the control group (modified intend to treat, p = 0.32). Median time before occurrence of OM ≥ grade 3 in half of the patients was 8 weeks in active laser group (vs. 9 weeks in control group). However, 95% of patients exhibited a very good tolerance of LLLT/PBMT.ConclusionsThis study assessed LLLT/PBMT according to the Multinational Association of Supportive care in Cancer recommendations but lacked power. LLLT/PBMT was well tolerated with a good safety profile, which promotes its use in clinical routine for severe OM treatment.Trial registrationClinicalTrials.gov Identifier: NCT01772706.Title: Laser Mucite ORL: Effectiveness of Laser Therapy for Mucositis Induced by a Radio-chemotherapy in Head and Neck Cancer (LaserMucite).Study Start Date: October 2008.Primary Completion Date: October 2016.Responsible Party: Institut de Cancérologie de l’Ouest – Paul Papin.Principal Investigator: Eric Jadaud, M.D., Institut de Cancérologie de l’Ouest – Paul Papin.Funding: French Ministry of Health, French national funding scheme (PHRC 2008).

EMouvoir: Randomized study estimating the impact of a personalized and remote support centered on physical activity (PA) for patients (pts) after breast cancer (BC).

TPS11631 Background: BC pts can reduce their health-related quality of life (HRQoL) encompassing physical, psychological and social components due to cancer and treatments (trts). Despite the strong evidence of the beneficial effects of EPA for BC pts on HRQoL, the cancer pts’ EPA levels most often decline after diagnosis and trts due to physical and psychological components, accessibility to exercise programs, time constraints. Connected watches can now contribute to pts’ deeper commitment to their program by providing reliable trends of their EPA metrics. Notwithstanding this recent progress, cancer pts keep facing challenges to maintain a regular EPA. We aim at evaluating a holistic intervention including a physical activity educator, coaching pts remotely for 4 months (mo), to improve HRQoL after BC. Methods: eMouvoir is a multicenter randomized, controlled phase 3 trial started 4-6 mo after the end of trt among non-metastatic BC pts. It assesses the benefit of a personalized remote EPA coaching, including a connected watch, access to a digital platform, personalized objectives, ≥2 messages per week, weekly lessons, for a 4-mo duration, compared to the standard supportive approach (recommendations for EPA made during visits with the oncologist) in terms of HRQoL. The randomization is balanced 1:1 and controlled for HRQoL at inclusion, trts, exercise practice, age, access to the Internet and center. Main eligibility criteria are: age ≥18; adjuvant or neoadjuvant trt for non-metastatic BC; medical certificate for sports practice. Patients without a connected device are eligible. HRQoL is evaluated using the SF-36 questionnaire, at 4, 8 and 12 mo. Both components (physical and mental summary) at 12 mo are used as co-primary endpoints. The study includes a health-economics evaluation, using EQ-5D and EQ VAS, to estimate the incremental cost-utility ratio. Based on the following assumptions: expected mean difference for each SF-36 component at 12 mo =3 points, standard deviation=15, power=90%, 2-sided alpha=2.5%, 10% drop-outs, 1242 evaluable pts are required, leading to 1380 pts. The trial is funded by the French ministry of health and should open enrollment soon.

Non-invasive ventilation versus high-flow nasal cannula oxygen therapy with apnoeic oxygenation for preoxygenation before intubation of patients with acute hypoxaemic respiratory failure: a randomised, multicentre, open-label trial

Non-invasive ventilation has never been compared with high-flow oxygen to determine whether it reduces the risk of severe hypoxaemia during intubation. We aimed to determine if preoxygenation with non-invasive ventilation was more efficient than high-flow oxygen in reducing the risk of severe hypoxaemia during intubation. The FLORALI-2 multicentre, open-label trial was done in 28 intensive care units in France. Adult patients undergoing tracheal intubation for acute hypoxaemic respiratory failure (a partial pressure of arterial oxygen [PaO2] to fraction of inspired oxygen [FiO2] ratio of ≤300 mm Hg) were randomly assigned (1:1; block size, four participants) to non-invasive ventilation or high-flow oxygen during preoxygenation, with stratification by PaO2/FiO2 ratio (≤200 mm Hg vs >200 mm Hg). Key exclusion criteria were intubation for cardiac arrest, altered consciousness (defined as a Glasgow coma score of less than eight points), other contraindications to non-invasive ventilation (recent laryngeal, oesophageal, or gastric surgery, and substantial facial fractures), pulse oximetry not available, pregnant or breastfeeding women, and refusal to participate. The primary outcome was the occurrence of severe hypoxaemia (pulse oximetry <80%) during the procedure, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02668458. Between April 15, 2016, and Jan 8, 2017, 2079 patients were intubated in the 28 participating units, and 322 were enrolled. We excluded five patients with no recorded data, two who withdrew consent or were under legal protection, one who was not intubated, and one who had a cardiac arrest. Of the 313 patients included in the intention-to-treat analysis, 142 were assigned to non-invasive ventilation and 171 to high-flow oxygen therapy. Severe hypoxaemia occurred in 33 (23%) of 142 patients after preoxygenation with non-invasive ventilation and 47 (27%) of 171 with high-flow oxygen (absolute difference -4·2%, 95% CI -13·7 to 5·5; p=0·39). In the 242 patients with moderate-to-severe hypoxaemia (PaO2/FiO2 ≤200 mm Hg), severe hypoxaemia occurred less frequently after preoxygenation with non-invasive ventilation than with high-flow oxygen (28 [24%] of 117 patients vs 44 [35%] of 125; adjusted odds ratio 0·56, 0·32 to 0·99, p=0·0459). Serious adverse events did not differ between treatment groups, with the most common immediate complications being systolic arterial hypotension (70 [49%] patients in the non-invasive ventilation group vs 86 [50%] patients in the high-flow oxygen group) and chest infiltrate on x-ray (28 [20%] vs 33 [19%]), and the most common late complications being death at day 28 (53 [37%] vs 58 [34%]) and ventilator-associated pneumonia during ICU stay (31 [22%] vs 35 [20%]). In patients with acute hypoxaemic respiratory failure, preoxygenation with non-invasive ventilation or high-flow oxygen therapy did not change the risk of severe hypoxaemia. Future research should explore the effect of preoxygenation method in patients with moderate-to-severe hypoxaemia at baseline. French Ministry of Health.

Efficacy and safety of one anastomosis gastric bypass versus Roux-en-Y gastric bypass for obesity (YOMEGA): a multicentre, randomised, open-label, non-inferiority trial

One anastomosis gastric bypass (OAGB) is increasingly used in the treatment of morbid obesity. However, the efficacy and safety outcomes of this procedure remain debated. We report the results of a randomised trial (YOMEGA) comparing the outcomes of OAGB versus standard Roux-en-Y gastric bypass (RYGB). This prospective, multicentre, randomised non-inferiority trial, was held in nine obesity centres in France. Patients were eligible for inclusion if their body-mass index (BMI) was 40 kg/m2 or higher, or 35 kg/m2 or higher with the presence of at least one comorbidity (type 2 diabetes, high blood pressure, obstructive sleep apnoea, dyslipidaemia, or arthritis), and were aged 18-65 years. Key exclusion criteria were a history of oesophagitis, Barrett's oesophagus, severe gastro-oesophageal reflux disease resistant to proton-pump inhibitors, and previous bariatric surgery. Participants were randomly assigned (1:1) to OAGB or RYGB, stratified by centre with blocks of variable size; the study was open-label, with no masking required. RYGB consisted of a 150 cm alimentary limb and a 50 cm biliary limb and OAGB of a single gastrojejunal anastomosis with a 200 cm biliopancreatic limb. The primary endpoint was percentage excess BMI loss at 2 years. The primary endpoint was assessed in the per-protocol population and safety was assessed in all randomised participants. This study is registered with ClinicalTrials.gov, number NCT02139813, and is now completed. From May 13, 2014, to March 2, 2016, of 261 patients screened for eligibility, 253 (97%) were randomly assigned to OAGB (n=129) or RYGB (n=124). Five patients did not undergo their assigned surgery, and after undergoing their surgery 14 were excluded from the per-protocol analysis (seven due to pregnancy, two deaths, one withdrawal, and four revisions from OAGB to RYGB) In the per-protocol population (n=117 OAGB, n=117 RYGB), mean age was 43·5 years (SD 10·8), mean BMI was 43·9 kg/m2 (SD 5·6), 176 (75%) of 234 participants were female, and 58 (27%) of 211 with available data had type 2 diabetes. After 2 years, mean percentage excess BMI loss was -87·9% (SD 23·6) in the OAGB group and -85·8% (SD 23·1) in the RYGB group, confirming non-inferiority of OAGB (mean difference -3·3%, 95% CI -9·1 to 2·6). 66 serious adverse events associated with surgery were reported (24 in the RYGB group vs 42 in the OAGB group; p=0·042), of which nine (21·4%) in the OAGB group were nutritional complications versus none in the RYGB group (p=0·0034). OAGB is not inferior to RYGB regarding weight loss and metabolic improvement at 2 years. Higher incidences of diarrhoea, steatorrhoea, and nutritional adverse events were observed with a 200 cm biliopancreatic limb OAGB, suggesting a malabsorptive effect. French Ministry of Health.

Acyclovir for Mechanically Ventilated Patients with Herpes Simplex Virus Oropharyngeal Reactivation

Background: The role of herpes simplex virus (HSV) reactivation on morbidity/mortality in intensive care unit patients requiring mechanical ventilation remains controversial. Methods: In this multicentre study, non-immunosuppressed adults >18 years old, mechanically ventilated for at least 96 hours and expected to remain on mechanical ventilation for ≥48 hours, with HSV oropharyngeal reactivation, were double-blindly randomized to receive intravenous acyclovir (5 mg/kg tid, for 14 days) or a matching placebo (controls). Randomisation (1:1) was stratified by study site, pre-randomisation mechanical ventilation duration and number of organ failure, and performed using a secure web-based system. The primary endpoint was ventilator-free days from randomisation to day 60. Findings: The 16 participating centres randomised 238 patients: 119 to receive acyclovir and 119 the placebo. On day 60, for acyclovir recipients and controls, respectively, the median (IQR) numbers of ventilator-free days were 35 (0-53) and 36 (0-50) (p=0.17 for between-group comparison); 26 (22%) and 39 (33%) patients had died (risk difference, 0.11, 95% CI, - 0.004 to 0.22, p=0.059). The adverse-event frequency was similar for both groups (28% in the acyclovir group and 23% in the placebo group, p= 0.4), particularly with acute renal failure post-randomisation affecting three acyclovir recipients and two controls. Four patients in the acyclovir group (vs. none in the placebo group) stopped the study drug for treatment-related adverse event. Interpretation: In non-immunosuppressed patients mechanically ventilated for ≥96 hours with HSV reactivation in the throat, intravenous acyclovir use (5 mg/kg tid) did not increase the number of ventilator-free days on day 60, compared to a placebo. Trial Registration: The trial is registered on ClinicalTrials.gov, number NCT02152358. Funding Statement: Direction de la Recherche Clinique et du Developpement and the French Ministry of Health (Programme Hospitalier de Recherche Clinique 2011). Declaration of Interests: No potential conflict of interest relevant to this article was reported. The following conflicts of interest are outside the area of the article. Dr Luyt reports receiving lecture fees from ThermoFischer Brahms, Biomerieux, Merck Sharp & Dohme and Aerogen, and consulting fees from Bayer Healthcare, Carmat and Faron. Dr Jaber reports receiving consulting fees from Drager, Fisher-Paykel, Xenios-Fresenius Medical and Medtronic. Dr Rimmele reports receiving consulting or lecture fees from Fresenius Medical Care, Baxter, Medtronic, Biomerieux, BBraun. Dr Lu reports receiving lectures fees from Aerogen. Dr Combes reports receiving grant support and lectures fees from Maquet and Baxter and consulting fees from Hemovent. Dr Wolff reports receiving consulting fees from Merck Sharp & Dohme, Inotrem, Correvio, Menarini and Pfizer. Dr Chastre reports receiving lecture and consulting fees from Bayer Healthcare, Pfizer, Merck Sharp & Dohme, Aridis, the Medicines Company, Astra Zenecca, Tigenix, Accelerate Diagnotics, Inotrem and Glaxo Smith Kline Ethics Approval Statement: An independent Ethics Committee (Comite de Protection des Personnes Sud Mediterranee 5) approved its protocol.

Diagnosis Value of &lt;sup&gt;18&lt;/sup&gt;F-FDG PET/CT versus Whole Body CT Scan in Management of Patients with Fever of Unknown Origin, Inflammatory Syndrome of Unknown Origin or Episodic Fever of Unknown Origin: A Comparative Multicentre Prospective Clinical Trial

Background: 18F-fluorodesoxyglucose positron emission tomography (PET/CT) takes an increasing part in the management of patients with fever of unknown origin (FUO), inflammation of unknown origin (IUO) and episodic fever of unknown origin (EFUO). However, its costs keep on substantial and may have accessibility issues. Studies regarding the place of Whole Body Computed Tomography (WBCT) in this condition are outstanding. Methods: A prospective, multicentre study was driven to test the diagnosis value of PET/CT compared to WBCT in patients with FUO, IUO or EFUO. Diagnostic orientation (DO), diagnostic contribution (DC) and time to diagnosis of both imaging resources were evaluated. Logistic regression was used to define diagnostic's predictive parameters and to delimit a patient profile displaying the highest DC of PET/CT. Findings: 103 patients were included, 35 FUO, 35 IUO and 33 EFUO. Diagnosis, performed in 58 patients (56·3%), was mostly represented by non-infectious inflammatory diseases (n=35/58, 60·3%) in patients with FUO and IUO, while patients with EFUO had mainly miscellaneous diseases (n=6/14, 42.8%). PET/CT both showed higher DO (28·2% vs 7·8%, p 30 mg/L (p=0·03) were associated with obtaining a diagnosis. PET/CT was more relevant in patients over 60 years (p=0·003) and in those with a duration of symptoms shorter than 35 months (p=0·004). Interpretation: PET/CT performs better DO and DC than WBCT, especially in patients with FUO and IUO, and reduces the time to diagnosis in these populations. Elderly patients and those with a duration of symptoms shorter than 3 years are the ones who most benefit from PET/CT. Trial Registration: NCT01200771. Funding Statement: The study was sponsored by public grants from the French Ministry of Health. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The trial was approved by all local ethical committees. All patients provided written informed consent before entering the study.

Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation

BackgroundIn patients who have chronic heart failure with reduced left ventricular ejection fraction, severe secondary mitral-valve regurgitation is associated with a poor prognosis. Whether percutaneous mitral-valve repair improves clinical outcomes in this patient population is unknown.MethodsWe randomly assigned patients who had severe secondary mitral regurgitation (defined as an effective regurgitant orifice area of >20 mm2 or a regurgitant volume of >30 ml per beat), a left ventricular ejection fraction between 15 and 40%, and symptomatic heart failure, in a 1:1 ratio, to undergo percutaneous mitral-valve repair in addition to receiving medical therapy (intervention group; 152 patients) or to receive medical therapy alone (control group; 152 patients). The primary efficacy outcome was a composite of death from any cause or unplanned hospitalization for heart failure at 12 months.ResultsAt 12 months, the rate of the primary outcome was 54.6% (83 of 152 patients) in the intervention group and 51.3% (78 of 152 patients) in the control group (odds ratio, 1.16; 95% confidence interval [CI], 0.73 to 1.84; P=0.53). The rate of death from any cause was 24.3% (37 of 152 patients) in the intervention group and 22.4% (34 of 152 patients) in the control group (hazard ratio, 1.11; 95% CI, 0.69 to 1.77). The rate of unplanned hospitalization for heart failure was 48.7% (74 of 152 patients) in the intervention group and 47.4% (72 of 152 patients) in the control group (hazard ratio, 1.13; 95% CI, 0.81 to 1.56).ConclusionsAmong patients with severe secondary mitral regurgitation, the rate of death or unplanned hospitalization for heart failure at 1 year did not differ significantly between patients who underwent percutaneous mitral-valve repair in addition to receiving medical therapy and those who received medical therapy alone. (Funded by the French Ministry of Health and Research National Program and Abbott Vascular; MITRA-FR ClinicalTrials.gov number, NCT01920698.)

Nasal High-Flow Preoxygenation for Endotracheal Intubation in the Critically Ill Patient: A Randomized Clinical Trial

Background: Although performed daily, intubation in intensive care units (ICU) remains a critical procedure with life-threatening adverse events. High-flow therapy by nasal cannulae (HFNC) is now widespread in the operating room and in the ICU, especially for preoxygenation before intubation in non-hypoxemic patients. However, no large randomized study has assessed its relevance in this population. Methods: The PROTRACH study is a randomized, multicenter open-labelled, controlled trial, including non-severely hypoxemic patients requiring intubation in medical or surgical ICU. Patients were randomly allocated to receive 4-minute preoxygenation delivered by HFNC or standard high-flow face mask (HFFM) before intubation. HFNC was maintained throughout the intubation procedure whereas HFFM was removed to perform laryngoscopy. The primary outcome was the lowest pulse oximetry throughout the intubation procedure. Secondary outcomes included drop in pulse oximetry, adverse events related to intubation, and outcome in the ICU. Main Findings: A total of 192 patients were randomized. In the intent-to-treat analysis, 184 patients (HFNC n = 95; HFFM n = 89), the median [IQR] lowest pulse oximetry was 100% [97;100] for HFNC and 99 % [95;100] for the HFFM group (P = 0.30). Mild desaturation below 95% was more frequent with HFFM (23%) than with HFNC (12%) (relative risk 0.51, CI 95% [0.26 to 0.99], P = 0.045). There were fewer adverse events in the HFNC group (6%) than in the HFFM group (19%) (relative risk 0.31, CI 95% [0.13 to 0.76], P = 0.007), including significantly fewer severe adverse events, respectively 6 (6%) and 14 (16%) with HFNC and HFFM (relative risk 0.38, CI 95% [0.15 to 0.95], P = 0.03). There was no difference in the outcome in the ICU with a mortality rate of 27% in both groups (P = 0.90). Interpretation: Compared with HFFM, preoxygenation with HFNC in the ICU did not improve the lowest level of pulse oximetry during intubation in the non-severely hypoxemic patients but led to a reduction in severe and moderate intubation-related adverse events. Clinical Trial Number: Clinicaltrials.gov identifier: NCT02700321, Eudra CT: 2015-A00145-44 Funding Statement: The French Ministry of Health (Interregional French Clinical Hospital Research Program grant (PHRCi 2014 - API12/N/077), a grant for research & innovation missions (University Hospital of Nantes) and by Fisher & Paykel Healthcare. Declaration of Interests: Declaration of Interest: Christelle Volteau, Gwenael Colin, Adel Maamar, Vanessa Jean Michel, Pierre Joachim Mahe, Mickael Landais, Noelle Brule, Cedric Bretonniere, Olivier Zambon and Christophe Guitton declare no conflict of interest. Stephan Ehrmann declares receiving consultancy fees from Aerogen Ltd, La Diffusion Technique Francaise and Baxter healthcare and unrestricted research support from Fisher and Paykel, Aerogen Ltd and Hamilton medical. Mickael Vourc’h declares personal fees from MSD, Pfizer, Baxter, grants from Fisher Paykel, outside the submitted work. Ethics Approval Statement: Three methods of consent were available. When possible, capable patients were included after written informed consent. Most patients were included after the written informed consent of their next-of-kin or following an emergency inclusion procedure if not available at the time of inclusion. Then, consent was obtained from all patients as soon as possible after recovery. The appropriate ethics committee (Comite de Protection des Personnes, Rennes, France) approved this study protocol in September 2015 (15/13-975).

Early clindamycin for bacterial vaginosis in pregnancy (PREMEVA): a multicentre, double-blind, randomised controlled trial

Preterm delivery during pregnancy (<37 weeks' gestation) is a leading cause of perinatal mortality and morbidity. Treating bacterial vaginosis during pregnancy can reduce poor outcomes, such as preterm birth. We aimed to investigate whether treatment of bacterial vaginosis decreases late miscarriages or spontaneous very preterm birth. PREMEVA was a double-blind randomised controlled trial done in 40 French centres. Women aged 18 years or older with bacterial vaginosis and low-risk pregnancy were eligible for inclusion and were randomly assigned (2:1) to three parallel groups: single-course or triple-course 300 mg clindamycin twice-daily for 4 days, or placebo. Women with high-risk pregnancy outcomes were eligible for inclusion in a high-risk subtrial and were randomly assigned (1:1) to either single-course or triple-course clindamycin. The primary outcome was a composite of late miscarriage (16-21 weeks) or spontaneous very preterm birth (22-32 weeks), which we assessed in all patients with delivery data (modified intention to treat). Adverse events were systematically reported. This study is registered with ClinicalTrials.gov, number NCT00642980. Between April 1, 2006, and June 30, 2011, we screened 84 530 pregnant women before 14 weeks' gestation. 5630 had bacterial vaginosis, of whom 3105 were randomly assigned to groups in the low-risk trial (n=943 to receive single-course clindamycin, n=968 to receive triple-course clindamycin, and n=958 to receive placebo) or high-risk subtrial (n=122 to receive single-course clindamycin and n=114 to receive triple-course clindamycin). In 2869 low-risk pregnancies, the primary outcome occurred in 22 (1·2%) of 1904 participants receiving clindamycin and 10 (1·0%) of 956 participants receiving placebo (relative risk [RR] 1·10, 95% CI 0·53-2·32; p=0·82). In 236 high-risk pregnancies, the primary outcome occurred in 5 (4·4%) participants in the triple-course clindamycin group and 8 (6·0%) participants in the single-course clindamycin group (RR 0·67, 95% CI 0·23-2·00; p=0·47). In the low-risk trial, adverse events were more common in the clindamycin groups than in the placebo group (58 [3·0%] of 1904 vs 12 [1·3%] of 956; p=0·0035). The most commonly reported adverse event was diarrhoea (30 [1·6%] in the clindamycin groups vs 4 [0·4%] in the placebo group; p=0·0071); abdominal pain was also observed in the clindamycin groups (9 [0·6%] participants) versus none in the placebo group (p=0·034). No severe adverse event was reported in any group. Adverse fetal and neonatal outcomes did not differ significantly between groups in the high-risk subtrial. Systematic screening and subsequent treatment for bacterial vaginosis in women with low-risk pregnancies shows no evidence of risk reduction of late miscarriage or spontaneous very preterm birth. Use of antibiotics to prevent preterm delivery in this patient population should be reconsidered. French Ministry of Health.

Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis

BackgroundAcute kidney injury is the most frequent complication in patients with septic shock and is an independent risk factor for death. Although renal-replacement therapy is the standard of care for severe acute kidney injury, the ideal time for initiation remains controversial.MethodsIn a multicenter, randomized, controlled trial, we assigned patients with early-stage septic shock who had severe acute kidney injury at the failure stage of the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) classification system but without life-threatening complications related to acute kidney injury to receive renal-replacement therapy either within 12 hours after documentation of failure-stage acute kidney injury (early strategy) or after a delay of 48 hours if renal recovery had not occurred (delayed strategy). The failure stage of the RIFLE classification system is characterized by a serum creatinine level 3 times the baseline level (or ≥4 mg per deciliter with a rapid increase of ≥0.5 mg per deciliter), urine output less than 0.3 ml per kilogram of body weight per hour for 24 hours or longer, or anuria for at least 12 hours. The primary outcome was death at 90 days.ResultsThe trial was stopped early for futility after the second planned interim analysis. A total of 488 patients underwent randomization; there were no significant between-group differences in the characteristics at baseline. Among the 477 patients for whom follow-up data at 90 days were available, 58% of the patients in the early-strategy group (138 of 239 patients) and 54% in the delayed-strategy group (128 of 238 patients) had died (P=0.38). In the delayed-strategy group, 38% (93 patients) did not receive renal-replacement therapy. Criteria for emergency renal-replacement therapy were met in 17% of the patients in the delayed-strategy group (41 patients).ConclusionsAmong patients with septic shock who had severe acute kidney injury, there was no significant difference in overall mortality at 90 days between patients who were assigned to an early strategy for the initiation of renal-replacement therapy and those who were assigned to a delayed strategy. (Funded by the French Ministry of Health; IDEAL-ICU ClinicalTrials.gov number, NCT01682590.)

Lenalidomide in combination with R-CHOP (R2-CHOP) as first-line treatment of patients with high tumour burden follicular lymphoma: a single-arm, open-label, phase 2 study

Immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard front-line treatment for follicular lymphoma. The combination of lenalidomide and rituximab has shown high efficacy in relapsed or refractory and untreated follicular lymphoma. We aimed to evaluate the safety and activity of the combination of lenalidomide and R-CHOP (R2-CHOP) in previously untreated patients with high burden follicular lymphoma. This single-arm, open-label, multicentre, phase 2 trial was done in 16 hospitals in France, all of which were Lymphoma Study Association (LYSA) sites. Eligible patients were aged 18-70 years and had previously untreated CD20-positive follicular lymphoma of grade 1, 2, or 3a; at least one high tumour burden criterion according to Groupe d'Etude des Lymphomes Folliculaires criteria; an Eastern Cooperative Oncology Group performance status score of 2 or less; and a minimum life expectancy of more than 3 months. Patients received induction therapy with six cycles of R2-CHOP every 3 weeks (one cycle involved standard R-CHOP on days 1-5, and 25 mg oral lenalidomide per day on days 1-14), followed by two rituximab infusions at 3-week intervals. The total treatment schedule was 24 weeks. Patients who achieved a complete or partial response to induction therapy received maintenance therapy consisting of one rituximab infusion every 8 weeks for 2 years. The primary outcome was the proportion of patients who achieved a complete response (complete response and complete response unconfirmed), according to International Workshop to Standardize Response Criteria, at the end of induction treatment. Safety was assessed in all patients who completed treatment. This trial is registered with ClinicalTrials.gov, number NCT01393756, and is closed to accrual. Between Dec 21, 2010, and Jan 25, 2012, 80 patients were enrolled, and 68 (85%) completed six cycles of R2-CHOP. At the end of the induction phase, 59 patients achieved a complete response (74%, 95% CI 63-83). 55 patients achieved a complete response at 30 months from enrolment (69%, 57-78). The most frequent adverse event was grade 4 neutropenia in 52 (65%) patients. The most frequent non-haematological side-effects included grade 1-2 sensory neuropathy in 28 (35%) patients and grade 1-2 transient rash in 27 (34%) patients. Four patients died during the study period; none of these deaths were judged to be related to treatment. Lenalidomide in combination with R-CHOP had an acceptable safety profile and showed anti-cancer activity in patients with previously untreated high burden follicular lymphoma. A future comparative study showing evidence of a survival advantage would be necessary for this combination to be proposed as a treatment for follicular lymphoma. French Ministry of Health, Celgene Corporation, and Amgen France.

Tranexamic Acid for the Prevention of Blood Loss after Vaginal Delivery

BackgroundThe use of tranexamic acid reduces mortality due to postpartum hemorrhage. We investigated whether the prophylactic administration of tranexamic acid in addition to prophylactic oxytocin in women with vaginal delivery would decrease the incidence of postpartum hemorrhage.MethodsIn a multicenter, double-blind, randomized, controlled trial, we randomly assigned women in labor who had a planned vaginal delivery of a singleton live fetus at 35 or more weeks of gestation to receive 1 g of tranexamic acid or placebo, administered intravenously, in addition to prophylactic oxytocin after delivery. The primary outcome was postpartum hemorrhage, defined as blood loss of at least 500 ml, measured with a collector bag.ResultsOf the 4079 women who underwent randomization, 3891 had a vaginal delivery. The primary outcome occurred in 156 of 1921 women (8.1%) in the tranexamic acid group and in 188 of 1918 (9.8%) in the placebo group (relative risk, 0.83; 95% confidence interval [CI], 0.68 to 1.01; P=0.07). Women in the tranexamic acid group had a lower rate of provider-assessed clinically significant postpartum hemorrhage than those in the placebo group (7.8% vs. 10.4%; relative risk, 0.74; 95% CI, 0.61 to 0.91; P=0.004; P=0.04 after adjustment for multiple comparisons post hoc) and also received additional uterotonic agents less often (7.2% vs. 9.7%; relative risk, 0.75; 95% CI, 0.61 to 0.92; P=0.006; adjusted P=0.04). Other secondary outcomes did not differ significantly between the two groups. The incidence of thromboembolic events in the 3 months after delivery did not differ significantly between the tranexamic acid group and the placebo group (0.1% and 0.2%, respectively; relative risk, 0.25; 95% CI, 0.03 to 2.24).ConclusionsAmong women with vaginal delivery who received prophylactic oxytocin, the use of tranexamic acid did not result in a rate of postpartum hemorrhage of at least 500 ml that was significantly lower than the rate with placebo. (Funded by the French Ministry of Health; TRAAP ClinicalTrials.gov number, NCT02302456.)