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.

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.

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.