BACKGROUND: Daptomycin stands as a key IV antibiotic in treating MRSA infections. However, patients facing challenges with difficult venous access require alternative administration routes. This study aimed to evaluate the pharmacokinetic (PK) profile and safety of subcutaneous (SC) daptomycin. PATIENTS AND METHODS: In a two-period, two-treatment, single-blind crossover Phase I trial (ClinicalTrials.gov NCT04434300), participants with no medical history received daptomycin (10 mg/kg) both IV and SC in a random order, with a minimum 2 week washout period together with matched placebo (NaCl 0.9%). Blood samples collected over 24 h facilitated PK comparison. Monte Carlo simulations assessed the PTA for various dosing regimens. Adverse events were graded according to Common Terminology Criteria for Adverse Events(CTCAE) v5.0. RESULTS: Twelve participants (aged 30.9 ± 24.4 years; 9 male,75%) were included. SC daptomycin exhibited delayed (median Tmax 0.5 h for IV versus 4 h for SC) and lower peak concentration than IV (Cmax = 132.2 ± 16.0 μg/mL for IV versus 57.3 ± 8.6 μg/mL for SC; P < 0.001). SC AUC0-24 (937.3 ± 102.5 μg·h/mL) was significantly lower (P = 0.005) than IV AUC0-24 (1056.3 ± 123.5 μg·h/mL) but was deemed bioequivalent. PTA demonstrated target AUC0-24 attainment for 100% of simulated individuals, for both 8 and 10 mg/kg/24 h SC regimens. Adverse events (AEs) related to SC daptomycin were more frequent than for SC placebo (25 versus 13, P = 0.016). No serious AEs were reported. CONCLUSIONS: Single-dose SC daptomycin infusion proved to be safe, exhibiting a bioequivalent AUC0-24 compared with the IV route. The SC route emerges as a potential and effective alternative when IV administration is not possible.

INTRODUCTION: Several randomised controlled trials have demonstrated that novel oral anticoagulants are safer compared with vitamin K antagonists for the management of non-valvular atrial fibrillation (NVAF) to prevent thromboembolic events in the general population. There is a growing interest in the use of apixaban in patients with end-stage renal disease (ESRD) undergoing peritoneal dialysis (PD) but there is a lack of randomised data in this population. METHODS AND ANALYSIS: APIDP2 is a prospective parallel, randomised, open-label, blinded endpoint trial involving patients with ESRD undergoing chronic PD who have NVAF. A total of 178 participants will be recruited from 20 French PD centres. Eligible patients will be randomly assigned to receive either apixaban at a reduced dose of 2.5 mg two times per day (dose determined with the previous pharmacokinetic study APIDP1) or dose-adjusted to international normalised ratio (INR) target (2-3) coumadin therapy. Anticoagulation to prevent thromboembolic events will be initiated or changed according to the randomisation for a duration of 1 year. The primary outcome is a major or clinically relevant non-major bleeding from randomisation up to month 12, assessed according to the International Society on Thrombosis and Haemostasis Score. Secondary outcomes encompass an efficacy composite criterion combining stroke or transient ischaemic attack (TIA), cardiovascular death and thrombosis including myocardial infarction cumulated at 12 months. Bleeding events will be also classified according to Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) and Thrombolysis In Myocardial Infarction (TIMI) criteria and pharmacodynamics outcomes will evaluate the time within the INR target range of 2-3 in the warfarin arm over 1 year, and anti-Xa apixaban activity in case of bleeding events and at 1 month, 6 months and 12 months of follow-up in the apixaban arm. To demonstrate that apixaban is safer than warfarin at 1 year, assuming two interim analyses after 60 and 118 patients, a bilateral alpha risk of 5% and a power of 80%, 178 patients are needed in this randomised trial (effect size found from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Study among patients with creatinine clearance 25-30 ml/min), that is, 89 patients per group. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee Comité de Protection des Personnes Sud Est III - Lyon - FRANCE, CT number 2023-507544-37-00. Written informed consent is required for each participant. Findings will be presented at scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06045858; European Clinical Trial System, CT number 2023-507544-37-00.

BACKGROUND: Postoperative atrial fibrillation (PoAF) after cardiac surgery has a high incidence of 30%, but its management is controversial. Two strategies are recommended without evidence of a superiority of one against the other: rate control with beta-blocker or rhythm control with amiodarone. Landiolol is a new-generation beta-blocker with fast onset and short half-life. One retrospective, single-center study compared landiolol to amiodarone for PoAF after cardiac surgery with a better hemodynamic stability and a higher rate of reduction to sinus rhythm with landiolol, justifying the need for a multicenter randomized controlled trial. Our aim is to compare landiolol to amiodarone in the setting of PoAF after cardiac surgery with the hypothesis of a higher rate of reduction to sinus rhythm with landiolol during the 48 h after the first episode of POAF. METHODS: The FAAC trial is a multicenter single-blind two parallel-arm randomized study, which planned to include 350 patients with a first episode of PoAF following cardiac surgery. The duration of the study is 2 years. The patients are randomized in two arms: a landiolol group and an amiodarone group. Randomization (Ennov Clinical®) is performed by the anesthesiologist in charge of the patient if PoAF is persistent for at least 30 min after correction of hypovolemia, dyskalemia, and absence of pericardial effusion on a transthoracic echocardiography done at bedside. Our hypothesis is an increase of the percentage of patients in sinus rhythm from 70 to 85% with landiolol in less than 48 h after onset of PoAF (alpha risk = 5%, power = 90%, bilateral test). DISCUSSION: The FAAC trial was approved by the Ethics Committee of EST III with approval number 19.05.08. The FAAC trial is the first randomized controlled trial comparing landiolol to amiodarone for PoAF after cardiac surgery. In case of higher rate of reduction with landiolol, this beta-blocker could be the drug of choice used in this context as to reduce the need for anticoagulant therapy and reduce the risk of complications of anticoagulant therapy for patients with a first episode of postoperative atrial fibrillation after cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT04223739. Registered on January 10, 2020.

BACKGROUND: According to European clinical research legislation, no undue influence, including financial incentives, should be used to encourage participation in clinical trials. Financial compensation should be based on the inconvenience experienced by patients and is determined by the sponsor. OBJECTIVES: The objective of this study was to assess the adequacy of patients' financial compensation by obtaining an external ethical opinion compared to the actual compensation provided. METHODS: We randomly selected and reviewed 50 clinical drug trials, including 25 academic and 25 industry-sponsored studies. An external ethics group consisting of three members from French ethics committees, blinded to the actual compensation and the sponsor, retrospectively reviewed the study characteristics and assessed whether financial compensation was appropriate. Cohen's Kappa test measured agreement between actual compensation and the ethics group's opinion, and the McNemar test measured discrepancies. RESULTS: There was no agreement between the actual financial compensation and the ethics group's opinion (K = -.07; 95% CI = [-.16-.02]). More discrepancies were found in favour of financial compensation according to the ethics group than provided by sponsors (12 vs. 2, p = .016). The ethics group recommended financial compensation in 12 out of 50 studies (24%), which were studies with a higher number of additional visits (p = .004) and were more frequently sponsored by industry (p = .008). Sponsors only provided financial compensation in 2 out of 50 studies (4%). CONCLUSION: Patients are rarely compensated despite the perceived inconvenience. Both sponsors and ethics members struggle to determine the need for financial compensation, indicating a need for more precise recommendations for both parties.

8054 Background: Frailty is associated with inferior outcome in older myeloma patients, especially in the relapse setting. 1,2 This adverse prognosis is mainly related to a high discontinuation rate for treatment (Tx) related adverse events (AE). Dexamethasone is responsible of a high rate of infections and metabolic AE. We present here the updated results from the phase 2 study I-Dara evaluating efficacy and tolerability of Ixazomib-Daratumumab without Dexamethasone in elderly frail patients with relapsed myeloma (RRMM) (NCT03757221). Methods: Ixa-Dara naïve RRMM patients received oral Ixazomib (4 mg: days 1, 8, 15), IV Daratumumab (16 mg/kg; days 1, 8, 15, 22, cycles 1-2; days 1, 15, cycles 3-6; days 1, cycles 7+) and IV Methylprednisolone before Daratumumab (100 mg at day 1, 8, cycle 1 and then 60 mg). They were enrolled after 1 or 2 prior therapy if their frailty score was ≥ 2 by IMWG score. The primary endpoint was ≥ very good partial response rate (VGPR) at one year. Secondary endpoints included ORR, PFS, OS & toxicity according to NCI-CTCAE version 5. Results: Sixty-three patients were screened and 55 enrolled between 03/2018 and 09/2021. Patient were at first (n = 36) or second relapse (n = 19). Thirty-five patients (64%) were previously exposed to bortezomib, 37 (67%) were previously exposed to lenalidomide (Len) and 23 (42 %) were refractory to Len. Median age was 82 (72-93). All patients had a frailty score ≥2 and 13 (24 %) had a 3 or 4 frailty score. In 41 patients ISS at diagnosis was stage I (n = 11), II (n = 18) or III (n = 12). Seventeen (36%) patients harbored high-risk (HR) cytogenetic, including t(4;14) (n = 8) or del17p (n = 10). The median duration of Tx (DOT) in 14 pts with ongoing Tx was 22 mos [min-max: 16-40] at data cutoff (January, 19)]. The median DOT in 41 pts who stopped Tx was 10 mos [min-max: 0-31]: 28 had progressive disease (PD). Fourteen patients died during the study: Daratumumab-related bronchospasm (D1C1); Ixazomib-related overdose (C2), sepsis (n = 3), pneumonia (n = 2), PD (n = 7). Regarding toxicity, 31 pts had a ≥grade 3 AE (55%). The most common grade 3-4 AE were thrombocytopenia (n = 10), other cytopenias (n = 5), anemia (n = 3), infection (n = 6), gastrointestinal disorders (n = 5) and hypertension (n = 3). The ≥VGPR rate is 32 % @ 1 year (34 % overall) with an ORR of 70% @ 1 year (74 % overall). In Len refractory patients the ≥VGPR rate is 40% @ 1 y and the ORR 70 %, in HR patients the ≥VGPR rate is 60 % and ORR 80%. With a median follow-up of 23.0 mos median PFS is 18.5 mos and median OS NR (75% OS estimated at 27.9 mos). Conclusions: In this elderly frail population Ixa-Dara is a feasible combination with favorable efficacy profile even in Len refractory and HR cytogenetic patients. Early toxicity remains a concern in this population eventhough more manageable with Dara SC. Late benefit is consistent with one third of patients still on treatment. Clinical trial information: NCT03757221 .

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Frailty is associated with inferior outcome in elderly myeloma patients, especially in the relapse setting.1,2 This adverse prognosis is mainly related to a high discontinuation rate for treatment (Tx) related adverse events (AE). Dexamethasone is responsible of a high rate of infections and metabolic AE. Aims: To evaluate efficacy and tolerability of Ixazomib and Daratumumab without Dexamethasone in elderly frail patients with relapsed myeloma (RRMM) (NCT03757221). We present here the updated results from the phase 2 study I-Dara Methods: Ixa-Dara naïve RRMM patients received oral Ixazomib (4 mg: days 1, 8, 15), IV Daratumumab (16 mg/kg; days 1, 8, 15, 22, cycles 1-2; days 1, 15, cycles 3-6; days 1, cycles 7+) and IV Methylprednisolone before Daratumumab (100 mg at day 1, 8, cycle 1 and then 60 mg). They were enrolled after 1 or 2 prior therapy if their frailty score was ≥ 2 by IMWG score. The primary endpoint was ≥ very good partial response rate (VGPR) at one year. Secondary endpoints included ORR, PFS, OS & toxicity according to NCI-CTCAE version 5 Results: Sixty-three patients were screened and 55 enrolled between 03/2018 and 09/2021. Patient were at first (n = 36) or second relapse (n = 19). Thirty-five patients (64 %) were previously exposed to bortezomib, 37 (67%) were previously exposed to lenalidomide (Len) and 23 (42 %) were refractory to Len. Median age was 82 (72-93). All patients had a frailty score ≥2 and 13 (24 %) had a 3 or 4 frailty score. In 41 patients ISS at diagnosis was stage I (n = 11), II (n = 18) or III (n = 12). Seventeen (36%) patients harbored high-risk (HR) cytogenetic, including t(4;14) (n = 8) or del17p (n = 10). The median duration of Tx (DOT) in 14 pts with ongoing Tx was 22 mos [min-max: 16-40] at data cutoff (January, 19)]. The median DOT in 41 pts who stopped Tx was 10 mos [min-max: 0-31]: 28 had progressive disease (PD). Fourteen patients died during the study: Daratumumab-related bronchospasm (D1C1); Ixazomib-related overdose (C2), sepsis (n = 3), pneumonia (n = 2), PD (n = 7). Regarding toxicity, 31 pts had a ≥grade 3 AE (55%). The most common grade 3-4 AE were thrombocytopenia (n = 10), other cytopenias (n = 5), anemia (n = 3), infection (n = 6), gastrointestinal disorders (n = 5) and hypertension (n = 3). The ≥VGPR rate is 32 % @ 1 year (34 % overall) with an ORR of 70% @ 1 year (74 % overall). In Len refractory patients the ≥VGPR rate is 40 % @ 1 y and the ORR 70 %, in HR patients the ≥VGPR rate is 60 % and ORR 80 %. With a median follow-up of 23.0 mos median PFS is 18.5 mos and median OS NR (75% OS estimated at 27.9 mos). Summary/Conclusion: In this elderly frail population Ixa-Dara is a feasible combination with favorable efficacy profile even in Len refractory and HR cytogenetic patients. Early toxicity remains a concern in this population eventhough more manageable with Dara SC. Late benefit is consistent with one third of patients still on treatment. 1Palumbo et al. JCO 2015, 2Facon et al. Leukemia 2020Keywords: dexamethasone, Myeloma, Elderly, Relapse

BACKGROUND: Crushing or dissolving bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) tablets is not recommended because there are no data supporting this practice. METHODS: A crossover, randomized trial in healthy adults (NCT04244448) investigated the bioavailability of two off-label uses of BIC/TAF/FTC (50/200/25 mg), dissolved in water or crushed in apple compote, compared with the solid tablet. Pharmacokinetic (PK) parameters were estimated from sequential intensive plasma antiretroviral concentrations over a 72 h period post dose. Bioequivalence was met if the 90% CIs of the geometric least-squares means ratios comparing BIC/TAF/FTC exposures (AUC and Cmax) from the experimental phases were within 80%-125% of the reference. RESULTS: Eighteen subjects participated in each of the three phases. Dissolved tablet Cmax geometric mean ratio (90% CI) for BIC/TAF/FTC was 105% (93-119)/97% (87-108)/96% (74-124), respectively. Dissolved tablet AUC geometric mean ratio (90% CI) for BIC/TAF/FTC was 111% (100-122)/100% (94 to 105)/99% (81 to 120), respectively. Crushed tablet Cmax geometric mean ratio (90%) CI for BIC/TAF/FTC was 110% (97 to 124)/70% (63-78)/66% (51-85), respectively. Crushed tablet AUC geometric mean ratio (90%) CI for BIC/TAF/FTC was 107% (96-118)/86% (82-91)/84% (69-103), respectively. CONCLUSIONS: Crushing BIC/TAF/FTC tablets may lead to suboptimal emtricitabine and tenofovir alafenamide drug exposures. Dissolving BIC/TAF/FTC in water may be acceptable if the tablet cannot be swallowed whole.

8000 Background: Frail patients with multiple myeloma have an inferior outcome, especially in the relapse setting. This adverse prognosis is mainly related to a high discontinuation rate due to treatment (Tx) related adverse events. The aim of this phase 2 study is to evaluate efficacy and tolerability of Ixazomib-Daratumumab (I-Dara) without Dexamethasone in elderly frail patients with relapsed myeloma (RRMM) (NCT03757221). Methods: Ixa-Dara naïve RRMM patients received oral Ixazomib (4 mg: days 1, 8, 15), IV Daratumumab (16 mg/kg; days 1, 8, 15, 22, cycles 1-2; days 1, 15, cycles 3-6; days 1, cycles 7+) and IV Methylprednisolone before Daratumumab (100 mg at day 1, 8, cycle 1 and then 60 mg). They were enrolled after 1 or 2 prior therapy if their frailty score was ≥ 2 by IMWG score. The primary endpoint was ≥ very good partial response rate (VGPR) at one year. Secondary endpoints included ORR, PFS, OS & toxicity according to NCI-CTCAE version 5. Results: Sixty-three patients were screened and 55 enrolled between 03/2018 and 09/2021. Patient were at first (n = 36) or second relapse (n = 19). Thirty-three patients (60%) were previously exposed to bortezomib, 37 (67%) were previously exposed to lenalidomide (Len) and 20 (36 %) were refractory to Len. Median age was 82 (72-93). All patients had a frailty score ≥2 and 13 (24 %) had a 3 or 4 frailty score. In 41 patients ISS at diagnosis was stage I (n = 11), II (n = 18) or III (n = 12). Seventeen (36%) patients harbored high-risk (HR) cytogenetic, including t(4;14) (n = 8) or del17p (n = 10). The median duration of Tx among 28 pts with ongoing Tx was 10 months [5-32] at data cutoff (February, 2)]. The median duration of Tx among 27 pts who stopped Tx was 6 months [0-18]: 18 had progressive disease. Nine patients died during the study: Daratumumab-related bronchospasm (D1C1); Ixazomib-related overdose (C2); sepsis (n = 4), progressive disease (n = 3). Regarding toxicity, 27 pts had a ≥grade 3 AE (49%). The most common grade 3-4 toxicities were thrombocytopenia (n = 9), other cytopenias (n = 4), infection (n = 8), hypertension (n = 3) and gastrointestinal disorders (n = 3). Fourteen out of 28 were SAE including 5 infections, 1 bronchospasm, 1 acute respiratory failure and 2 ixazomib overdoses. Overall response rate, including minimal response, was 86 % with a ≥VGPR rate of 32 % in the whole group. In Len refractory patients the ORR was 82 % and ≥VGPR 41%, in HR cytogenetic patients ORR was 85 % and ≥VGPR 46%. With a median follow-up of 11.6 months median PFS is 16 months and median OS NR (76% estimated at one year). Conclusions: In this elderly frail population Ixa-Dara is a feasible combination with favorable efficacy profile even in Len refractory and HR cytogenetic patients. Early toxicity remains a concern in this population eventhough more manageable with Dara SC. Clinical trial information: NCT03757221.

BackgroundTenofovir and emtricitabine interfere with the SARS CoV-2 ribonucleic acid (RNA)-dependent RNA polymerase (RdRp). Several cohorts reported that people treated by tenofovir disoproxil fumarate and emtricitabine are less likely to develop SARS CoV-2 infection and related severe COVID-19.MethodsWe conducted a pilot randomized, open-label, controlled, phase 2 trial at two hospitals in France. Eligible patients were consecutive outpatients (aged ≥18 years) with RT-PCR-confirmed SARS-CoV-2 infection and an interval from symptom onset to enrolment of 7 days or less. Patients were randomly assigned in a 1:1 ratio to receive oral tenofovir disoproxil fumarate and emtricitabine (2 pills on day 1 followed by 1 pill per day on days 2–7) or the standard of care. The primary and secondary endpoints were SARS-CoV-2 viral clearance from baseline assessed by cycle threshold (Ct) RT-PCR on nasopharyngeal swab collected at day 4 and day 7, respectively. A higher Ct corresponds to a lower SARS CoV-2 viral burden. Other endpoints were the time to recovery and the number of adverse events. This trial is registered with ClinicalTrials.gov, NCT04685512.FindingsFrom November, 20th 2020 to March, 19th 2021, 60 patients were enrolled and randomly assigned to a treatment group (30 to tenofovir disoproxil fumarate and emtricitabine and 30 to standard of care). The median number of days from symptom onset to inclusion was 4 days (IQR 3–5) in both groups. Amongst patients who received tenofovir disoproxil fumarate, the difference from standard of care in the increase in Ct RT-PCR from baseline was 2.3 (95% confidence interval [-0.6 to 5.2], p = 0.13) at day 4 and 2.9 (95% CI [0.1 to 5.2], p = 0.044) at day 7. At day 7, 6/30 in the tenofovir disoproxil fumarate and emtricitabine group and 3/30 in the standard of care group reported no COVID-related symptoms. Adverse events included 11 cases of gastrointestinal side effects (grade ≤ 2), three of which leaded to drug discontinuation. Three patients had COVID-19 related hospitalisation, no participant died.InterpretationIn this pilot study of outpatients adult with recent non-severe COVID-19, tenofovir disoproxil fumarate plus emtricitabine appeared to accelerate the natural clearance of nasopharyngeal SARS-CoV-2 viral burden. These findings support the conduct of larger trials of tenofovir-based therapies for the prevention and early treatment of COVID-19.FundingNo external funding.

Although biofield therapy is unexplained by scientific evidence, it has been practised for many years in numerous cultures for a variety of medical conditions. This study aimed to determine whether one session of biofield therapy with an experienced practitioner could treat warts on the hands and feet in adults. A single-blind, assessor-blind, placebo-controlled, randomized trial was performed between April 2016 and November 2018. The enrolled participants had at least one wart on the hand or foot that had been present for at least 90 days and they were not using any other therapy for the wart. The primary outcome of this trial was the disappearance of the original wart 3 weeks after session of proximal nontouch biofield therapy vs. a sham session. No original wart had disappeared 3 weeks after intervention (0/64), which made the study impossible to conclude on the primary objective. There were no significant differences between the two groups concerning wart disappearance 3 weeks (P = 0.49) or 6 weeks (P = 0.40) after the intervention. Reduction in wart size at Week 3 tended towards a better result for biofield therapy but this was not significant (P = 0.27). No related adverse effects were observed. The major limitation of this trial was the short follow-up time for measurement of clinical outcome, which did not allow verification of the hypothesis. However, this study shows that 3 weeks after a session of proximal nontouch biofield therapy is an insufficient length of time to assess biofield therapy in comparison with a sham session. Based on this study, biofield therapy cannot be recommended to treat warts within 3 weeks.

Abstract Introduction Anemia is a common complication of hematological chemotherapy for acute leukemia and following hematopoietic stem cell transplantation (HSCT). Exposure to allogeneic blood transfusions has been associated with unfavorable outcome in several studies in a non-surgical settings. Retrospective studies in hematological intensive unit have suggested that single red blood cell (RBC) unit transfusion policy may reduce the number of RBC used in comparison with a classical double RBC unit transfusion policy, without clinical impact. The aim of the study was to demonstrate that single RBC transfusion was non inferior to the standard double RBC transfusion arm in terms of severe complication or mortality for inpatient with hematological malignancies. Key secondary endpoint, was the comparison of the numbers of RBC units transfused in each arm. Method In a phase 3 multicenter randomized trial, 245 adults' patients with acute leukemia requiring intensive chemotherapy or patients receiving autologous or allogeneic HSCT were randomly assigned (1:1) to receive either single RBC unit (1 RBC arm, n=125) per transfusion or double RBC (2 RBC arm, n=120) per transfusion when hemoglobin level was below 8g/dL. The primary composite endpoint was the percentage of patients who developed a grade ≥3 complications defined as stroke, transient ischemic attack, acute coronary syndrome, heart failure, elevated troponin level, intensive care unit transfer, death, new pulmonary infiltrates, and/or transfusion-related infections during hospital stays. The secondary endpoint was the number of red cell units transfused per patient per hospital stay. The primary endpoint was compared between groups by non-inferiority analysis for the proportion risk difference using Farrington-Manning method with a non-inferiority margin of 0.1, in ITT dataset. Results Hematological disease were as followed: AML (59%), ALL (13.1%), Lymphoma (16.4%), others (11.5%). The median age was 55 years. Baseline characteristics were well balanced between the 2 arms (Figure 1A). A total of 981 and 592 transfusions have been necessary in the 1 RBC arm and 2 RBC arm, respectively. The median of RBC unit per transfusion was 1(1-1) and 2(2-2) in the 1 RBC and 2 RBC arm, respectively. The mean pre transfusion hemoglobin level was 7.49 +/- 0.83 g/dL in the 1 RBC arm and 7.46 +/- 0.67 g/dL in the 2 RBC arm (p=0.275). Hemoglobin level at discharge was 9.35 +/-1.14 g/dL in the 1 RBC arm and 9.58 +/-1.13 g/dL in the 2 RBC arm (p=0.118). The median (IQR) of red-cell units transfused per patient was 7 (4-12) in the single arm and 8 (4-12) in the double arm (p=0.65). The median number of platelet transfusion event was 7 (3.5-11.5) in the 1 RBC arm and 7 (3-13) in the 2 RBC arm (p=0.69). The median (IQR) number of red cell unit transfused per cycle and per day was 7 (3-9) and 0.28 (0.17-0.37) in the 1RBC arm and 6 (4-10) and 0.27 (0.20-0.38) in the 2 RBC arm (p=0.61 and p=0.47). The predefined non-inferiority criteria was achieved with 28 patients developing a serious complication in the 1 CGR arm (22.4%) and 28 patients in the 2 RBC arm (23.3%) (Risk difference 0.009; 95% Confidence interval [-0.0791- 0.0978] (Figure 1B). Conclusion: Single RBC transfusion policy is non inferior to double RBC transfusion policy in hematological intensive care unit for patient receiving a bone marrow transplant or intensive chemotherapy. Single RBC unit transfusion can be used safely in daily clinical practice. The single RBC transfusion policy does not reduce the number of RBC transfusion. Figure 1 Figure 1. Disclosures Jardin: Genexpath: Patents & Royalties: The author is a potential inventor on a patent application for the LymphoSign, which has been licensed for by Genexpath Patents & Royalties. .

BACKGROUND/AIMS: The Clinical Trials Coordination and Facilitation Group has issued recommendations on contraception and pregnancy testing to help sponsors meet regulatory expectations and harmonize practices to limit embryofetal risks in clinical trials. Our objective was to assess the compliance of French academic clinical trials with these recommendations and to describe the mitigation measures required by sponsors in their trials. METHODS: A cross-sectional study was performed on the French academic drug trials authorized by the national competent authority between January 2015 and June 2018. We included trials which tested systemic administration of drugs and enrolled men or women of childbearing potential. RESULTS: Data from 97 trials included were compiled. One-third of the trials (23.8%-43.3%, 95% confidence interval) complied with the Clinical Trial Facilitation and Coordination Group recommendations. No improvement over time or according to embryofetotoxic status or drug duration exposure was found. Contraception was required in 56.7% of trials and was more often required in case of potentially embryofetotoxic drugs (68.5% vs 41.9%, p = 0.013) or exposure over 1 month (71.7% vs 43.8%, p = 0.006). Pregnancy testing at inclusion was required in 59.1% of trials and additional testing in 17.2%. Pregnancy testing at inclusion was more often required in trials with drug exposure above 1 month (67.4% vs 45.8%, p = 0.035). CONCLUSION: French academic sponsors barely met the recommendations on contraception and pregnancy testing potentially leading to potential embryofetal risks in case of pregnancy. They need to implement these recommendations quickly.

Abstract Aim To assess the safety and efficacy of the short‐acting glucagon‐like peptide‐1 receptor agonist exenatide on a population of patients with type 2 diabetes (T2D) mostly treated with continuous subcutaneous insulin injection (CSII). Materials and Methods A phase 2/3, multicentre, randomized, parallel‐group, double‐blind, placebo‐controlled, 6‐month trial was conducted. Patients were randomized to receive subcutaneous (SC) injections of exenatide (10 μg BID) or matched placebo. Results A total of 46 patients with T2D and elevated HbA1c were randomized (42% of the planned sample size): exenatide (n = 28) and placebo (n = 18). CSII treatment was used by 75% and 89% of patients of the exenatide and placebo groups, respectively. At 6 months, the change in HbA1c was −0.62% ± 0.94% and 0.08% ± 0.81% in the exenatide and placebo groups, respectively (difference, −0.70%; 95% CI [−1.24%; −0.15%], P = .014); body weight and body mass index decreased in the exenatide group (−2.55 ± 3.25 kg and −1.00 ± 1.31 kg/m 2 ) and increased in the placebo group (1.29 ± 2.82 kg and 0.46 ± 1.16 kg/m 2 ) (observed difference, −3.85 and −1.45, respectively, both P < .001); the postdinner capillary blood glucose value was lower in the exenatide group compared with the placebo group (162.4 ± 80.5 vs. 259.1 ± 94.4 mg/dL, respectively; observed difference, −96.7, P < .01). Hypoglycaemic risk, quality of life and overall safety were not different between the groups, apart from the expected occurrence of digestive effects in the exenatide group. Conclusions Although we failed to reach our planned sample size, the addition of exenatide treatment 10 μg BID SC in T2D patients with uncontrolled HbA1c despite an intensified insulin regimen, resulted in a significant reduction of HbA1c and body weight with a good overall safety profile and acceptance.

BACKGROUND: Among palliative care (PC) patients who are administered paracetamol, the subcutaneous (SC) route is often an alternative to the intravenous (IV) route. Yet pharmacological and clinical data on whether these are equivalent pharmacokinetically are lacking. Many French palliative teams are now empirically using paracetamol by the SC route, but there are no data to support this practice. This trial aims to compare the pharmacokinetic (PK) parameters of paracetomol between the IV and SC routes in PC patients. METHODS/DESIGN: This is a randomized, open, crossover study in two PC centers. The primary endpoints are AUC0-t, AUC0-∞, Cmax, Vd, and t1/2. All adverse events will be reported for a safety analysis. Twenty adult PC patients with an IV device having spontaneous pain not related to care, with a numeric pain rate scale > 3/10, or having a systematic prescription of paracetamol as the usual treatment will be included. All patients also have to meet all eligibility criteria. CONCLUSION: This is the first study comparing PK parameters for IV paracetamol versus SC paracetamol in PC patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03944044. Registered on 4 June 2019. Committee for the protection of persons (CPP) 18.09.05.58206 approval 4 October 2018. National Drug Safety Agency (ANSM; Agence Nationale de Sécurité Médicament) MEDAECNAT-2018-09-00009 approval 29 November 2018.

OBJECTIVES: To explore the frequent interaction between antiretroviral-boosting agents and corticosteroids causing Cushing's syndrome (CS) in the French Pharmacovigilance Database (FPVD). METHODS: We conducted a retrospective case-control study describing CS recorded in the FPVD between 1996 and 2018. Case was defined as CS occurring in people living with HIV (PLWH) and control was defined as CS in uninfected individuals. Drug-drug interaction (DDI) was defined as an interaction between corticosteroids and CYP3A4 inhibitors. Data concerning the DDI, corticosteroids involved, route of administration and seriousness of the CS were described. RESULTS: Among the 139 instances of CS identified, 34/35 cases (97%) had DDIs (31 with ritonavir and 3 with cobicistat) and 7/104 controls (7%) had DDIs (6 with itraconazole and 1 with verapamil). The main corticosteroid involved was inhaled fluticasone (28/35, 80%) among the cases and oral prednisone (38/104, 37%) among the controls. More CS cases (30/35, 86%) than CS controls (62/104, 60%) were serious (OR = 4.0, 95% CI = 1.4-14.4; P = 0.007). CONCLUSIONS: Antiretroviral-boosting agents were responsible for one out of four iatrogenic CS cases in a French national database. Prescribers should be aware of the risk of potentially serious DDIs between antiretroviral-boosting agents and corticosteroids, including single-tablet regimens containing cobicistat.

Abstract Background We aimed to describe the frequency, risk factors, and costs attributable to drug–drug interactions (DDIs) among an aging French HIV population. Methods We conducted a retrospective cohort study using French nationwide health care e-records: the SNIIRAM database. People living with HIV (PLWH) aged &gt;65 years and receiving combined antiretroviral treatment (cART) during 2016 were included. A DDI was defined as “These drugs should not be co-administered,” represented by a red symbol on the University of Liverpool website. Attributable DDIs’ cost was defined as the difference between individuals with and without DDIs regarding all reimbursed health care acts. Results Overall, 9076 PLWH met the study criteria. Their baseline characteristics were: mean age, 71.3 ± 4.9 years; 25% female; median HIV duration (interquartile range [IQR]), 16.2 (9.5–20.3) years; median comorbidities (IQR), 2 (1–3). During 2016, they received a median (IQR) of 14 (9–21) comedications (non-cART), and 1529 individuals had at least 1 DDI (16.8%; 95% confidence interval [CI], 16.1–17.6). In multivariate analysis, raltegravir or dolutegravir plus 2 nucleoside reverse-transcriptase inhibitors (NRTIs) significantly and independently reduced the risk of DDIs (adjusted odds ratio [aOR], 0.02; 95% CI, 0.005–0.050; P &lt; .0001) compared with non-nucleoside reverse-transcriptase inhibitor plus 2 NRTIs, whereas cART with boosted agents (protease inhibitors or elvitegravir) significantly increased the risk (aOR, 4.12; 95% CI, 3.34–5.10; P &lt; .0001). Compared with propensity score–matched PLWH without DDIs, the presence of DDIs was associated with a $2693 additional cost per year (P &lt; .0001). Conclusions The presence of DDIs is frequent and significantly increases health care costs in the aging population of PLWH.

BACKGROUND: The reporting of adverse drug reactions (ADR) by patients represents an interesting challenge in the field of pharmacovigilance, but the reporting system is not adequately implemented in France. In 2015, only 20 MS patients in France reported ADR due to first-line disease-modifying drugs (DMD), while more than 3000 patients were initiated on DMD. The aim of this study is to validate a proof-of-concept as to whether the use of a mobile application (App) increases ADR reporting among patients with relapsing-remitting multiple sclerosis (RR-MS) receiving DMD. METHODS/DESIGN: We designed a multi-centric, open cluster-randomized controlled trial, called the Vigip-SEP study (NCT03029897), using the App My eReport France® to report ADR to the appropriate authorities in E2B language, in accordance with European regulations. RR-MS patients who were initiated on, or switched, first-line DMD will be included. In the experimental arm, a neurologist will introduce the patient to the App to report ADR to the appropriate French authorities. In the control arm, the patient will be informed of the existence of the App but will not be introduced to its use and will then report ADR according to the usual reporting procedures. Primary assessment criteria are defined as the average number of ADR per patient and per center. We assume that the App will increase patient reporting by 10-fold. Therefore, we will require 24 centers (12 per arm: 6 MS academic expert centers, 3 general hospitals, 3 private practice neurologists), allowing for an expected enrollment of 180 patients (alpha risk 5%, power 90% and standard deviation 4%). DISCUSSION: Increasing patient reporting of ADR in a real-life setting is extremely important for therapeutic management of RR-MS, particularly for monitoring newly approved DMD to gain better knowledge of their safety profiles. To increase patient involvement, teaching patients to use tools, such as mobile applications, should be encouraged, and these tools should be tested rigorously. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT03029897 . Registered on 20 January 2017.

The DaptoDP (NCT 2012-005699-33) study aimed to evaluate the pharmacokinetic parameters of daptomycin (DAP) in peritoneal dialysis-related peritonitis (PDRP) patients following intraperitoneal (IP) administration. The authors have already reported the findings on the 200-mg dosing and present here the follow-up results of the 300-mg dosing. The primary endpoint was a dialysate concentration of DAP above the effective concentration in situ during 6 hours of dwell time i.e., 16 mg/L. Secondary endpoints were to avoid the toxic threshold of 120 mg/L DAP and to be above 16 mg/L DAP for 2 hours in plasma. Pharmacokinetic parameters were evaluated on days 1 and 5. Safety data were evaluated on days 1 to 14 based on clinical and biological parameters. Daptomycin was administered in Nutrineal during 6 hours of dwell time for 14 days plus the usual antibiotic therapy in a separate dwell. Because the 200-mg dosing objectives were not reached, a higher DAP dose of 300 mg was tested in the next 3 patients. Effective dialysate and plasma concentrations were achieved at the 300-mg DAP dose with the plasma concentration well below the toxic threshold, even at steady state, during which the accumulation factor never exceeded 3. The optimal DAP dose of 300 mg daily by the IP route, as determined by the pharmacokinetic data, needs to be clinically confirmed prior to routine use. The peritoneal bioavailability of DAP supports using the IP route as an alternative to the intravenous route for peritonitis and systemic infections.

Validate a proof-of-concept study: is the use of a mobile application (App) increase adverse drug reaction (ADR) reporting in patients with relapsing remitting multiple sclerosis (RR-MS) receiving disease modifying drugs (DMDs).

BACKGROUND: Despite the lack of scientific studies on biofield therapies, they are widely acclaimed by patients. The mechanisms of action are not explained by current allopathic medical approaches. Warts are common and contagious viral lesions that may be refractory to standard dermatologic treatments such as cryotherapy, laser therapy, and keratolytic ointments. Biofield therapies are efficient in various pathologies. Their ability to treat warts has never been demonstrated in a scientific study with a robust methodology. Patients with refractory warts often place their trust in these alternative therapies because of the poor results obtained from traditional medicine. We propose a prospective, randomized, single-blind, assessor-blind trial to evaluate the efficacy of treatment of warts by biofield therapy. METHODS/DESIGN: Subjects with warts on their feet or hands will be randomized into two groups: real biofield therapy versus sham therapy. The diagnosis will be made at the time of inclusion, and follow-up will take place in week 3. Comparison of pictures of the warts at baseline and after 3 weeks will be used as the primary outcome measure. The hypothesis is that the extent of the disappearance of the original wart in the group treated by real biofield therapy will be 70% and that it will be 30% in the group treated by sham therapy. Using 90% power and an alpha risk of 5%, 31 subjects are required in each group for a two-tailed proportion comparison test. DISCUSSION: To our knowledge, this is the first study to evaluate the efficacy of biofield therapy on warts. Therefore, the aim of this study is to extend knowledge of biofield therapy to another area of medicine such as dermatology and to propose complementary or alternative practices to improve patient well-being. The main strength of the study is that it is a randomized, single-blind, assessor-blind, placebo-controlled study. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02773719 . Registered on 22 April 2016.

WHAT IS KNOWN AND OBJECTIVE: A randomized phase III study was designed to assess the efficacy and safety of second-line platinum-based chemotherapy with or without erlotinib in non-small cell lung cancer (NSCLC) with EGFR-activating mutation after secondary resistance to EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors). CASE SUMMARY: We report herein two of the first three patients who presented with major gastrointestinal toxicities in the experimental arm of the trial. WHAT IS NEW AND CONCLUSION: Pending further data, it would seem safer to administer EGFR-TKIs and chemotherapy sequentially rather than concomitantly.

♦ BACKGROUND: Antibiotics are preferentially delivered via the peritoneal route to treat peritoneal dialysis-related peritonitis (PDRP) to ensure that maximal concentrations are delivered to the site of infection. Our study focused on the pharmacokinetics of daptomycin (DAP) administered via the intraperitoneal (IP) route in patients with PDRP. ♦ METHODS: According to the DaptoDP protocol (Clinical Trial No. 2012-005699-33), IP DAP was administered daily, i.e., during the 6-h Nutrineal (Baxter Healthcare Corporation, Deerfield, IL, USA) dwell time period, for 14 days, in addition to administration of the antibiotics used for the usual care of patients with PDRP. The plasma and IP levels of DAP were measured on days 1 and 5. The tested dose was 200 mg/day. The principal endpoint was the dialysate concentration after 6 hours of dwell time > 16 mg/L (corresponding to 4 x minimum inhibitory concentration [MIC] for E. faecalis). ♦ RESULTS: Three participants were evaluated. On day 5, the IP concentrations after 6 hours of dwell time were between 6.3 and 23.4 mg/L, and the peak plasma concentrations were between 13.0 and 15.3 mg/L. ♦ CONCLUSION: The results suggest that 200 mg/day is very likely sufficient for the treatment of PDRP by Staphylococci or Streptococci whereas it could be insufficient to treat PRDP by Enterococci. The good peritoneal bioavailability of DAP was quantitatively established, suggesting that IP administration could also be used as an alternate route for patients with damaged venous access. No DAP accumulation that could lead to toxic concentrations after repeated administration is expected, even in anuric patients. The protocol will further continue to assess whether a higher dose achieves the pharmacokinetic objectives.