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Factor VIII (FVIII) circulates in a noncovalent complex with von Willebrand Factor (VWF), the latter determining FVIII half-life. The VWF-binding aptamer rondaptivon pegol (BT200) increases plasma levels of VWF/FVIII in healthy volunteers. This trial assessed its safety, pharmacokinetics, and pharmacodynamics in hemophilia A. Nineteen adult patients (ages 20-62 years, 4 women) with hemophilia A (8 mild, 2 moderate, and 9 severe) received subcutaneous injections of rondaptivon pegol. After an initial fixed dose of 3 mg on days 0 and 4, patients received weekly doses of 2 to 9 mg until day 28. Severe hemophilia A patients underwent sparse-sampling population pharmacokinetics individual profiling after the final dose of rondaptivon pegol. Adverse events, pharmacokinetics, and pharmacodynamics were assessed. FVIII activity and VWF levels were measured. All patients tolerated rondaptivon pegol well. The geometric mean half-life of rondaptivon pegol was 5.4 days and rondaptivon pegol significantly increased VWF levels. In severe hemophilia A, 6 doses of rondaptivon pegol increased the half-lives of 5 different FVIII products from a median of 10.4 hours to 31.1 hours (range, 20.8-56.0 hours). Median FVIII increased from 22% to 48% in mild hemophilia A and from 3% to 7.5% in moderate hemophilia A. Rondaptivon pegol is a first-in-class prohemostatic molecule that extended the half-life of substituted FVIII approximately 3-fold and increased endogenous FVIII levels approximately 2-fold in hemophilia patients. This trial was registered at www.clinicaltrials.gov as #NCT04677803.

BackgroundAn understanding vaccine-dependent effects on protective and sustained humoral immune response is crucial to planning future vaccination strategies against coronavirus disease 2019 (COVID-19).MethodsIn this multicenter, population-based, cohort study including 4601 individuals after primary vaccination against COVID-19 ≥ 4 months earlier we compared factors associated with residual antibody levels against severe acute respiratory syndrome coronavirus-2 receptor-binding domain (RBD) across different vaccination strategies (BNT162b2, mRNA-1273, or ChAdOx1).ResultsOur main model including 3787 individuals (2 × BNT162b2, n = 2271; 2 × mRNA-1273, n = 251; 2 × ChAdOx1, n = 1265), predicted significantly lower levels of anti-RBD antibodies after 6 months in individuals vaccinated with ChAdOx1 (392.7 binding antibody units per milliliter [BAU/mL]) compared with those vaccinated with BNT162b2 (1179.5 BAU/mL) or mRNA-1273 (2098.2 BAU/mL). Vaccine-dependent association of antibody levels was found for age with a significant predicted difference in BAU/ml per year for BNT162b2 (−21.5; 95% confidence interval [CI], −24.7 to −18.3) and no significant association for mRNA-1273 (−4.0; 95% CI, −20.0 to 12.1) or ChAdOx1 (1.7; 95% CI, .2 to 3.1). The predicted decrease over time since full immunization was highest in mRNA-1273 (−23.4; 95% CI, −31.4 to −15.4) compared with BNT162b2 (−5.9; 95% CI, −7 to −4.8).ConclusionsOur study revealed population-based evidence of vaccine-dependent effects of age and time since full immunization on humoral immune response. Findings underline the importance of individualized vaccine selection, especially in elderly individuals.

Von Willebrand factor (VWF) and factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary hemostasis and clotting, respectively. A new VWF A1-domain binding aptamer, BT200, demonstrated good subcutaneous bioavailability and a long half-life in non-human primates. This first-in-human, randomized, placebo-controlled, doubleblind trial tested the hypothesis that BT200 is well tolerated and has favorable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: a single ascending dose of BT200 (0.18-48 mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterized, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin-induced aggregation, platelet function under high shear rates, and thrombin generation. The mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dose-dependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagen-adenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (P

To investigate immunogenicity and safety of BNT162b2 booster vaccination with and without a tetravalent influenza vaccine.A prospective, open-label cohort study on immunogenicity and safety of COVID-19 booster vaccination with or without a tetravalent influenza vaccine was performed. 838 health care workers were included in the following study arms: BNT162b2 booster-only, influenza-vaccine-only or combination of both. Levels of antibodies against SARS-CoV-2 spike receptor binding domain (RBD), and haemagglutinine inhibition (HAI) tested for four different influenza strains (A(H1N1)pdm09, A(H3N2), B/Victoria, B/Yamagata) were measured at time of vaccination and four weeks later.After four weeks, median [IQR] anti-RBD antibody levels and relative change from baseline were higher in individuals who received BNTb162b2 booster vaccination only (absolute: 16,600 [10,980-24,360] vs. 12,630 [8,198-18,750] BAU/mL (p0·0001); relative increase: 49% [23·6-95·3] vs. 40% [21·9-80·6](p = 0·048); booster-only n=521 vs. combination-arm n=229 respectively). Results were confirmed after matching for sex, age, BMI, baseline antibody levels and vaccine compound received for primary immunization (absolute: 13,930 [10,610 - 22,760] vs. 12,520 [8,710 - 17,940]; p = 0·031); relative increase: 55·7% [27·8-98·5] vs. 42·2% [22·9-74·5]; p = 0·045). Adverse events were almost identical in the booster-only and the combination-arm, but numerically lower in the influenza arm (525/536[97·9] % vs.235/240 [97·9%] vs. 26/33 [78·8 %]).While no safety concerns occurred, our study provides evidence on reduced immunogenicity of a BNT162b2 booster vaccination in combination with a tetravalent influenza vaccine. Further studies investigating new influenza variants as well as potential differences vaccine effectiveness are needed.

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Understanding vaccine-dependent effects on protective and sustained humoral immune response are crucial to plan further vaccination strategies against COVID-19. Population-based data comparing different vaccination strategies are lacking.This multicenter, population-based cohort study included 4,601 individuals ≥18 years of age after primary vaccination against COVID-19 at least four months ago (full immunization). We compared factors associated with residual antibody levels against SARS-CoV-2 receptor binding domain (RBD) across different vaccination strategies (BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 [ChAdOx1]).Our main model including 3,787 individuals (2xBNT162b2 n = 2,271, 2xmRNA-1273 n = 251, 2xChAdOx1 n = 1,265) predicted significantly lower levels of anti-RBD-antibodies after 6 months in individuals vaccinated with ChAdOx1 (392.7 BAU/ml) compared to those vaccinated with BNT162b2 (1179.5 BAU/ml) or mRNA-1273 (2098.2 BAU/ml). Vaccine-dependent association of antibody levels was found for age with a significant predicted difference in BAU/ml per year for BNT162b2 (-21.5 [95%CI -24.7 to -18.3]) and no significant association for mRNA-1273 (-4.0 [95%CI -20.0 to 12.1]) or ChAdOx1 (1.7 [95%CI 0.2 to 3.1]). The predicted decrease over time since full immunization was highest in mRNA-1273 (-23.4 [95%CI -31.4 to -15.4]) compared to BNT162b2 -5.9 [95%CI -7 to -4.8]). Higher antibody levels were observed for individuals with systemic adverse events upon vaccination and current smoking (BNT162b2), for days between first and second vaccination (BNT162b2 and ChAdOx1) and for absence of comorbidities (all).Our study revealed population-based evidence of vaccine-dependent effects of age and time since full immunization on humoral immune response. Findings underline the importance of an individualized vaccine selection, especially in elderly individuals.

Osteoprotegerin (OPG) regulates bone metabolism by reducing the activation of osteoclasts, but may also be involved in blood vessel calcification and atherosclerosis. Within endothelial cells OPG is stored in Weibel–Palade bodies (WPBs). Blood kinetics of OPG are essentially unknown. We aimed to assess these using two distinct in vivo models; one after stimulation with desmopressin (DDAVP) and another after stimulation with lipopolysaccharide (LPS). Both clinical trials were conducted at the Department of Clinical Pharmacology at the Medical University of Vienna, Austria. Participants received desmopressin (0.3 µg/kg), LPS (2 ng/kg), or placebo (sodium chloride 0.9%) with subsequent blood sampling at time points up to 24 hours after administration. The primary objective of this study was to investigate the plasma kinetics of OPG after stimulation with desmopressin and LPS. Secondary analyses included the release of other WPB contents including von Willebrand factor (vWF). This analysis included 31 healthy volunteers (n = 16 for desmopressin and placebo, n = 15 for LPS). Infusion of desmopressin did not increase OPG concentrations compared with placebo, while LPS infusion significantly increased OPG levels, both compared with desmopressin (p

Aims Oral opioid preparations combined with naloxone are intended to induce a transient acute withdrawal syndrome to avoid intravenous misuse. This trial aimed to establish an appropriate morphine–naloxone dose ratio for an abuse‐deterrent oral opioid formulation. Methods In a randomized, double‐blinded, 2 × 2 cross‐over trial, 43 patients with opioid use disorder were challenged with intravenous morphine HCl Ph.Eur. (75 mg; [morphine mono]) or morphine HCl Ph.Eur. and naloxone HCl Ph.Eur. at ratios of 100:1 (75 mg: 0.75 mg; [morphine–naloxone 100:1]) or 200:1 (75 mg: 0.375 mg; [morphine–naloxone 200:1]). Acute naloxone‐induced opioid withdrawal was evaluated using subjective (Short Opiate Withdrawal Scale–German [SOWS‐G]) and observer‐rated (Objective Opiate Withdrawal Scale [OOWS], Wang scale) questionnaires, and physiological parameters. For statistical analysis, the area under the curve between baseline and 20 minutes after drug administration of the outcome variables was calculated. Results Intravenous morphine–naloxone caused rapid withdrawal symptoms. Coadministration of naloxone dose‐dependently (morphine–naloxone 100:1 > morphine–naloxone 200:1) increased SOWS‐G, OOWS and Wang Scale area under the curve when compared to morphine mono, respectively (all P < .0001). A similar response was detectable for changes of pupil diameter. Blood pressure and respiratory rate changed heterogeneously, and heart rate was unaltered by morphine without or with naloxone. Conclusion Morphine–naloxone 100:1 effectively suppresses the pleasurable effects of intravenous morphine and results in an aversive withdrawal reaction. A lower naloxone concentration as used in morphine–naloxone 200:1 does not appear to be appropriate to prevent intravenous morphine misuse.

Aims Animal studies suggest that inhibition of dipeptidyl peptidase 4 (DPP‐IV) may improve heart function and survival after myocardial infarction by increasing cardiac myocytes’ regenerative capacity. Parenterally administered dutogliptin may provide continuous strong DPP‐IV inhibition to translate these results into humans. This trial investigated the safety and tolerability, as well as pharmacokinetics and pharmacodynamics, of parenterally administered dutogliptin after single and repeated doses. Methods In an open‐label trial, volunteers received dutogliptin at increasing doses of 30–120 mg subcutaneously or 30 mg intravenously in the single‐dose cohorts. Subjects in the multiple‐dose cohort received 60, 90 or 120 mg dutogliptin subcutaneously once daily on 7 consecutive days. Results Forty healthy males were included in the trial. No related serious adverse events occurred. Mild local injection site reactions with no requirement for intervention comprised 147 of 153 (96%) related adverse events. Subcutaneous bioavailability was approximately 100%. Multiple injections at daily intervals did not lead to the accumulation of the study drug. The accumulation ratios based on AUC0‐24h range from 0.90 to 1.03, supporting this argument. All subjects receiving ≥60 mg dutogliptin yielded a maximum DPP‐IV inhibition >90%. The duration of DPP‐IV inhibition over time increased in a dose‐dependent manner and was highest in the 120‐mg multiple‐dosing cohort with a maximum AUEC0‐24h of 342 h % (standard deviation: 73), translating into 86% DPP‐IV inhibition 24 hours after dosing. Conclusion Parenteral injection of dutogliptin was safe and subcutaneous bioavailability is excellent. DPP‐IV inhibition increased dose dependently to >86% over 24 hours after multiple doses of 120 mg dutogliptin.

Aims Anticoagulation was associated with improved survival of hospitalized coronavirus disease 2019 (COVID-19) patients in large-scale studies. Yet, the development of COVID-19-associated coagulopathy (CAC) and the mechanism responsible for improved survival of anticoagulated patients with COVID-19 remain largely elusive. This investigation aimed to explore the effects of anticoagulation and low-molecular-weight heparin (LMWH) in particular on patient outcome, CAC development, thromboinflammation, cell death, and viral persistence. Methods and results Data of 586 hospitalized COVID-19 patients from three different regions of Austria were evaluated retrospectively. Of these, 419 (71.5%) patients received LMWH and 62 (10.5%) received non-vitamin-K oral anticoagulants (NOACs) during hospitalization. Plasma was collected at different time points in a subset of 106 patients in order to evaluate markers of thromboinflammation (H3Cit-DNA) and the cell death marker cell-free DNA (cfDNA). Use of LMWH was associated with improved survival upon multivariable Cox regression (hazard ratio = 0.561, 95% confidence interval: 0.348–0.906). Interestingly, neither LMWH nor NOAC was associated with attenuation of D-dimer increase over time, or thromboinflammation. In contrast, anticoagulation was associated with a decrease in cfDNA during hospitalization, and curtailed viral persistence was observed in patients using LMWH leading to a 4-day reduction of virus positivity upon quantitative polymerase chain reaction [13 (interquartile range: 6–24) vs. 9 (interquartile range: 5–16) days, P = 0.009]. Conclusion Time courses of haemostatic and thromboinflammatory biomarkers were similar in patients with and without LMWH, indicating either no effects of LMWH on haemostasis or that LMWH reduced hypercoagulability to levels of patients without LMWH. Nonetheless, anticoagulation with LMWH was associated with reduced mortality, improved markers of cell death, and curtailed viral persistence, indicating potential beneficial effects of LMWH beyond haemostasis, which encourages use of LMWH in COVID-19 patients without contraindications., Graphical Abstract Graphical Abstract

We report the case of a 19-year-old male who complained of myalgia, muscle weakness, and darkened urine two days after receiving his Ad26.COV2.S (Johnson & Johnson, New Brunswick, New Jersey, United States) COVID-19 vaccination. Blood examination revealed an increased creatine kinase (CK) level, and his urinary dipstick tested positive for blood, indicative of acute rhabdomyolysis. Serum creatinine levels were normal. Rhabdomyolysis due to strenuous physical activity was ruled out and further diagnostics excluded an autoimmune cause. Under repeated treatment with intravenous fluid resuscitation (outpatient treatment), his symptoms resolved and peak CK levels of 44,180 U/L returned to almost normal levels within two weeks. Rhabdomyolysis is a rare, potentially fatal vaccine-induced reaction. Further research is needed to better understand the underlying pathomechanism and to investigate whether subcutaneous injection of vaccines may be able to prevent rhabdomyolysis.

Lead exposure can cause substantial organ damage. Enteral lead absorption may be reduced by concomitant intake of clinoptilolite tuff, a zeolite from natural sources. This study aimed to assess the effect of purified clinoptilolite tuff (G-PUR) on enteral lead uptake in adults using stable lead isotope 204Pb as a tracer. In this randomized, placebo-controlled, double-blind, parallel-group study, 42 healthy participants were randomized to receive oral G-PUR 2.0 g, 2 * 2.0 g, or placebo, together with 2.5 µg of 204Pb in water. The enrichment of 204Pb caused by the tracer in blood and urine was measured by mass spectrometry. G-PUR was well tolerated. The mean maximum 204Pb enrichment of 0.505% of total blood lead was significantly higher (p 204Pb AUC0-192 was 86.5, 11.9, and 8.5% * h without and with G-PUR 2.0 g, and G-PUR 2 * 2.0 g, respectively (p 204Pb exposure was paralleled by a reduced urinary excretion in subjects receiving G-PUR. Concomitant oral intake of purified clinoptilolite tuff reduced enteral uptake of 204Pb in healthy humans by approximately 90%. The reduced bioavailability is demonstrable by a decrease of 204Pb tracer enrichment in blood and urine.Trial registration: clinicaltrials.gov identifier: NCT04138693, registered 24/10/2019.

Defibrotide is approved for the treatment of sinusoidal obstruction syndrome after allogeneic stem cell transplantation. The exact mode of action of defibrotide is unclear and human in vivo data are scarce. In this randomized, double blind, crossover trial we included 20 healthy volunteers. Four were randomized to receive placebo, while 16 received a 2 ng/kg bodyweight bolus of lipopolysaccharide (LPS). Infusion of 6.25 mg/kg defibrotide or placebo was started one hour before the injection of the LPS bolus. Plasma levels of prothrombin fragments F1 + 2, thrombin-antithrombin complexes, von Willebrand factor, E-selectin, tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), plasmin-antiplasmin complexes (PAP), tumor necrosis factor-α, interleukin 6, and C-reactive protein were measured. Thromboelastometry was performed. Infusion of defibrotide did not reduce the LPS-induced activation of coagulation, the endothelium or the release of pro-inflammatory cytokines. However, defibrotide increased t-PA antigen levels by 31% (Quartiles: 2–49%, p = 0.026) and PAP concentrations by 13% (−4–41%, p = 0.039), while PAI-1 levels remained unaffected. Moreover, defibrotide reduced C-reactive protein levels by 13% (0–17%, p = 0.002). A transient increase in the clotting time in thromboelastometry and a decrease in F1 + 2 prothrombin fragments suggests modest anticoagulant properties. In conclusion, defibrotide infusion enhanced fibrinolysis and reduced C-reactive protein levels during experimental endotoxemia.

Background Late antibody-mediated rejection (ABMR) triggered by donor-specific antibodies (DSA) is a cardinal cause of kidney allograft dysfunction and loss. Diagnostic criteria for this rejection type are well established, but effective treatment remains a major challenge. Recent randomized controlled trials (RCT) have failed to demonstrate the efficacy of widely used therapies, such as rituximab plus intravenous immunoglobulin or proteasome inhibition (bortezomib), reinforcing a great need for new therapeutic concepts. One promising target in this context may be interleukin-6 (IL-6), a pleiotropic cytokine known to play an important role in inflammation and adaptive immunity. Methods This investigator-driven RCT was designed to assess the safety and efficacy of clazakizumab, a genetically engineered humanized monoclonal antibody directed against IL-6. The study will include 20 DSA-positive kidney allograft recipients diagnosed with ABMR ≥ 365 days after transplantation. Participants will be recruited at two study sites in Austria and Germany (Medical University of Vienna; Charité University Medicine Berlin). First, patients will enter a three-month double-blind RCT (1,1 randomization, stratification according to ABMR phenotype and study site) and will receive either clazakizumab (subcutaneous administration of 25 mg in monthly intervals) or placebo. In a second open-label part of the trial (months 4–12), all patients will receive clazakizumab at 25 mg every month. The primary endpoint is safety and tolerability. Secondary endpoints are the pharmacokinetics and pharmacodynamics of clazakizumab, its effect on drug metabolism in the liver, DSA characteristics, morphological ABMR lesions and molecular gene expression patterns in three- and 12-month protocol biopsies, serum/urinary biomarkers of inflammation and endothelial activation/injury, Torque Teno viral load as a measure of overall immunosuppression, kidney function, urinary protein excretion, as well as transplant and patient survival. Discussion Currently, there is no treatment proven to be effective in halting the progression of late ABMR. Based on the hypothesis that antagonizing the effects of IL-6 improves the outcome of DSA-positive late ABMR by counteracting DSA-triggered inflammation and B cell/plasma cell-driven alloimmunity, we suggest that our trial has the potential to provide proof of concept of a novel treatment of this type of rejection. Trial registration ClinicalTrials.gov, NCT03444103. Registered on 23 February 2018 (retrospective registration). Electronic supplementary material The online version of this article (10.1186/s13063-018-3158-6) contains supplementary material, which is available to authorized users.

BackgroundThe Covid-19 pandemic has become a global public health crisis and providing optimal patient care while preventing a collapse of the health care system is a principal objective worldwide.ObjectiveTo develop and validate a prognostic model based on routine hematological parameters to predict uncomplicated disease progression to support the decision for an earlier discharge.DesignDevelopment and refinement of a multivariable logistic regression model with subsequent external validation. The time course of several hematological variables until four days after admission were used as predictors. Variables were first selected based on subject matter knowledge; their number was further reduced using likelihood ratio-based backward elimination in random bootstrap samples.SettingModel development based on three Austrian hospitals, validation cohorts from two Austrian and one Swedish hospital.ParticipantsModel development based on 363 survivors and 78 non-survivors of Covid-19 hospitalized in Austria. External validation based on 492 survivors and 61 non-survivors hospitalized in Austria and Sweden.OutcomeIn-hospital death.Main ResultsThe final model includes age, fever upon admission, parameters derived from C-reactive protein (CRP) concentration, platelet count and creatinine concentration, approximating their baseline values (CRP, creatinine) and change over time (CRP, platelet count). In Austrian validation cohorts both discrimination and calibration of this model were good, with c indices of 0.93 (95% CI 0.90 - 0.96) in a cohort from Vienna and 0.93 (0.88 - 0.98) in one from Linz. The model performance seems independent of how long symptoms persisted before admission. In a small Swedish validation cohort, the model performance was poorer (p = 0.008) compared with Austrian cohorts with a c index of 0.77 (0.67 - 0.88), potentially due to substantial differences in patient demographics and clinical routine.ConclusionsHere we describe a formula, requiring only variables routinely acquired in hospitals, which allows to estimate death probabilities of hospitalized patients with Covid-19. The model could be used as a decision support for earlier discharge of low-risk patients to reduce the burden on the health care system. The model could further be used to monitor whether patients should be admitted to hospital in countries with health care systems with emphasis on outpatient care (e.g. Sweden).

Background Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. Methods We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. Results Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. Conclusions Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.

Aberrant activation of the classical complement pathway is the common underlying pathophysiology of orphan diseases such as bullous pemphigoid, antibody‐mediated rejection of organ transplants, cold agglutinin disease, and warm autoimmune hemolytic anemia. Therapeutic options for these complement‐mediated disorders are limited and sutimlimab, a humanized monoclonal antibody directed against complement factor C1s, may be potentially useful for inhibition of the classical complement pathway. A phase I, first‐in‐human, double‐blind, randomized, placebo‐controlled, dose‐escalation trial of single and multiple doses of sutimlimab or placebo was conducted in 64 volunteers to evaluate safety, tolerability, pharmacokinetic, and pharmacodynamic profiles. Single and multiple infusions of sutimlimab were well tolerated without any safety concerns. sutimlimab exhibited a steep concentration–effect relationship with a Hill coefficient of 2.4, and an IC90 of 15.5 μg/mL. This study establishes the foundation for using sutimlimab as a highly selective inhibitor of the classical complement pathway in different diseases.

There are no dose-finding trials available for rituximab that could guide dosing in non-malignant diseases. We hypothesized that currently used doses (≥375 mg/m2) exceed several hundred-fold the half-maximal effective dose, which is most sensitive for detecting putative differences between biosimilars and important for dose finding. In an open label, exploratory trial healthy volunteers received single infusions of rituximab at doses of 0.1, 0.3 or 1.0 mg/m2. Subsequently, in a double-blind, randomized trial healthy volunteers received single infusions of two rituximab products at doses of 0.1 and 0.3 mg/m2. In the exploratory trial rituximab transiently depleted CD20+ cells by a mean 68% (range: 57–95%), 74% (55–82%) and 97% (94–100%) immediately after the infusion of 0.1 (n = 4), 0.3 (n = 4) and 1 mg/m2 (n = 8), respectively. In the randomized trial CD20+ cells decreased by a mean 48% (25–84%) − 55% (26–85%) and 81 (67–89%) – 87% (77–96%) after infusion of 0.1 mg/m2 (n = 12) or 0.3 mg/m2 (n = 8 proposed biosimilar, n = 4 reference product) of the proposed biosimilar or the reference product, respectively. It is important to understand that in healthy volunteers

ASN100 is a novel antibody combination of two fully human IgG1(κ) monoclonal antibodies (MAbs), ASN-1 and ASN-2, which neutralize six Staphylococcus aureus cytotoxins, alpha-hemolysin (Hla) and five bicomponent leukocidins. We assessed the safety, tolerability, and serum and lung pharmacokinetics of ASN100 in a randomized, double-blind, placebo-controlled single-dose-escalation first-in-human study., ASN100 is a novel antibody combination of two fully human IgG1(κ) monoclonal antibodies (MAbs), ASN-1 and ASN-2, which neutralize six Staphylococcus aureus cytotoxins, alpha-hemolysin (Hla) and five bicomponent leukocidins. We assessed the safety, tolerability, and serum and lung pharmacokinetics of ASN100 in a randomized, double-blind, placebo-controlled single-dose-escalation first-in-human study. Fifty-two healthy volunteers were enrolled and randomized to receive either ASN-1, ASN-2, a combination of both MAbs (ASN100), or a corresponding placebo. Thirty-two subjects in the double-blind dose escalation portion of the study received ASN-1 or ASN-2 at a 200-, 600-, 1,800-, or 4,000-mg dose, or placebo. Eight subjects received both MAbs simultaneously in a 1:1 ratio (ASN100) at 3,600 or 8,000 mg, or they received placebos. Twelve additional subjects received open-label ASN100 at 3,600 or 8,000 mg to assess the pharmacokinetics of ASN-1 and ASN-2 in epithelial lining fluid (ELF) by bronchoalveolar lavage fluid sampling. Subjects were monitored for 98 days (double-blind cohorts) or 30 days (open-label cohorts) for safety assessment. No dose-limiting toxicities were observed, and all adverse events were mild and transient, with only two adverse events considered possibly related to the investigational product. ASN100 exhibited linear serum pharmacokinetics with a half-life of approximately 3 weeks and showed detectable penetration into the ELF. No treatment-emergent anti-drug antibody responses were detected. The toxin neutralizing potency of ASN100 in human serum was confirmed up to 58 days postdosing. The favorable safety profile, ELF penetration, and maintained functional activity in serum supported the further clinical development of ASN100.

Deposition of autoantibodies (α-BP180 and BP230) and complement along the dermal-epidermal-junction is a hallmark of bullous pemphigoid and was shown to be important for pathogenesis. Given the adverse effects of standard treatment (glucocorticoids, immunosuppressants), there is an unmet need for safe and effective therapies. In this phase 1 trial, we evaluated the safety and activity of BIVV009 (sutimlimab, previously TNT009), a targeted C1s inhibitor, in 10 subjects with active or past bullous pemphigoid (NCT02502903). Four weekly 60 mg/kg infusions of BIVV009 proved sufficient for inhibition of the classical complement pathway in all patients, as measured by CH50. C3c deposition along the dermal-epidermal junction was partially or completely abrogated in 4 of 5 patients, where it was present at baseline. BIVV009 was found to be safe and tolerable in this elderly population, with only mild to moderate adverse events reported (e.g., headache, fatigue). One serious adverse event (i.e., fatal cardiac decompensation) occurred at the end of the post-treatment observation period in an 84-year-old patient with a history of diabetes and heart failure, but was deemed unlikely to be related to the study drug. This trial provides the first results with a complement-targeting therapy in bullous pemphigoid, to our knowledge, and supports further studies on BIVV009's efficacy and safety in this population.

Summary Background Chikungunya fever is an emerging viral disease and substantial threat to public health. We aimed to assess the safety, tolerability, and immunogenicity of a live-attenuated, measles-vectored chikungunya vaccine (MV-CHIK). Methods In this double-blind, randomised, placebo-controlled and active-controlled phase 2 trial, we enrolled healthy volunteers aged 18–55 years at four study sites in Austria and Germany. Participants were randomly assigned to receive intramuscular injections with MV-CHIK (5 × 10 4 or 5 × 10 5 50% tissue culture infectious dose), control vaccine, or measles prime and MV-CHIK, in two different administration regimens. Randomisation was done by use of three-digit randomisation codes in envelopes provided by a data management service. The participants and investigators were masked to treatment assignment, which was maintained by use of sterile saline as a placebo injection. The primary endpoint was immunogenicity, defined as the presence of neutralising antibodies against chikungunya virus, at day 56, which is 28 days after one or two immunisations. The primary endpoint was assessed in all participants who completed the study without major protocol deviations (per-protocol population) and in all randomised participants who received at least one study treatment (modified intention-to-treat population). The safety analysis included all participants who received at least one study treatment. This trial is registered with ClinicalTrials.gov (NCT02861586) and EudraCT (2015-004037-26) and is completed. Findings Between Aug 17, 2016, and May 31, 2017, we randomly assigned 263 participants to receive control vaccine (n=34), MV-CHIK (n=195), or measles prime and MV-CHIK (n=34). 247 participants were included in the per-protocol population. Neutralising antibodies against chikungunya virus were detected in all MV-CHIK treatment groups after one or two immunisations, with geometric mean titres ranging from 12·87 (95% CI 8·75–18·93) to 174·80 (119·10–256·50) and seroconversion rates ranging from 50·0% to 95·9% depending on the dose and administration schedule. Adverse events were similar between groups, with solicited adverse events reported in 168 (73%) of 229 participants assigned to MV-CHIK and 24 (71%) of 34 assigned to control vaccine (p=0·84) and unsolicited adverse events in 116 (51%) participants assigned to MV-CHIK and 17 (50%) assigned to control vaccine (p=1·00). No serious adverse events related to the vaccine were reported. Interpretation MV-CHIK showed excellent safety and tolerability and good immunogenicity, independent of pre-existing immunity against the vector. MV-CHIK is a promising candidate vaccine for the prevention of chikungunya fever, an emerging disease of global concern. Funding Themis.

The classical pathway (CP) of complement may contribute to the pathogenesis of antibody-mediated rejection (ABMR). Selective CP blockade may be a promising strategy to counteract rejection. The objective of this first-in-patient phase 1b trial was to evaluate the safety/tolerability and CP-blocking potential of four weekly doses (60 mg/kg) of the anti-C1s antibody BIVV009 in complement-mediated disorders. Here we describe the results in a cohort of 10 stable kidney transplant recipients (median of 4.3 years post-transplantation) with late active ABMR and features of CP activation, such as capillary C4d or complement-fixing donor-specific antibodies (DSA). During seven weeks follow-up, no severe adverse events were reported, and BIVV009 profoundly inhibited overall and DSA-triggered CP activation in serum. Five of eight C4d-positive recipients turned C4d-negative in 5-week follow-up biopsies, while another two recipients showed a substantial decrease in C4d scores. There was, however, no change in microcirculation inflammation, gene expression patterns, DSA levels, or kidney function. In conclusion, we demonstrate that BIVV009 effectively blocks alloantibody-triggered CP activation, even though short-course treatment had no effect on indices of activity in late ABMR. This initial trial provides a valuable basis for future studies designed to clarify the therapeutic value of CP blockade in transplantation. ClinicalTrials. gov NCT#02502903 This article is protected by copyright. All rights reserved.

IC43 is a recombinant outer membrane protein-based vaccine against Pseudomonas aeruginosa (P. aeruginosa) consisting of OprF- and OprI- epitopes (Opr, outer membrane protein; OprF/I, OprF/OprI hybrid vaccine) with an N-terminal His 6 tag (Met-Ala-(His)6-OprF190-342-OprI21-83).The study aimed to confirm the optimal dose of IC43 in adults with regard to immunogenicity, safety, and tolerability after vaccination with three different dosages of IC43, compared with placebo, and to investigate a potential immune-enhancing effect of the adjuvant, aluminum hydroxide. Subjects were randomly allocated in a 1:1:1:1:1 ratio to one of five treatment groups: 50, 100, or 200 µg IC43 with adjuvant, 100 µg IC43 without adjuvant, or placebo (0.9% sodium chloride) and two intramuscular injections were given in the deltoid region 7 d apart.The primary immunogenicity analysis of OprF/I-specific IgG antibody titers on day 14 demonstrated statistically significant differences among treatment groups (P0.0001), with a significantly higher immune response detected in each IC43 treatment group compared with placebo. From day 0 to day 14, a ≥4-fold increase in OprF/I-specific immunoglobulin G (IgG) antibody titers were observed in90% of subjects in all IC43 treatment groups in the per-protocol (PP) and intention-to-treat (ITT) populations; a ≥50-fold titer increase was observed in 42.6% subjects including all IC43 treatment groups. On day 90, OprF/I-specific IgGs started to decline in all IC43 treatment groups but remained significantly higher until 6 mo compared with placebo. Assessment of functional antibody induction by opsonophagocytic assay (OPA) followed a similar pattern compared with OprF/I-specific IgG kinetics. At day 14, a ≥2-fold increase in OPA titer was observed in 54.5% subjects within all IC43 treatment groups. An increase in antibody avidity index was observed after the second vaccination. At day 14,96% of subjects in each IC43 treatment group had detectable OprF/I-specific IgG antibodies. Anti-histidine IgG antibody titers peaked on day 14 and were reduced on day 90 in all IC43 treatment groups. OprF/I-specific IgG secreted by antibody-secreting cell (ASC) was detected in all IC43 groups by B-cell ELIspot after the second vaccination and up to 6 mo. All vaccinations were safe and well tolerated up to the maximum cumulative dosage of 400 µg IC43.IC43 doses equal to or greater than 50 µg were sufficient to induce a plateau of IgG antibody responses in healthy volunteers. Higher doses, whether adjuvanted or non-adjuvanted, were not more effective.In this phase I, randomized, placebo-controlled, observer-blinded, multicenter clinical trial, 163 healthy volunteers (18-65 y) were randomly assigned to five treatment groups (1:1:1:1:1). Three groups received IC43 with adjuvant: 50 µg (n=32), 100 µg (n=33), or 200 µg (n=33). One group received IC43 100 µg without adjuvant (n=32), and one group received placebo (0.9% sodium chloride) (n=33). Each subject received two intramuscular vaccinations, separated by a 7-d interval (days 0 and 7) (Fig. 1). Humoral immune response was assessed by measurement of outer membrane protein F/I (OprF/I)-specific antibodies determined by enzyme-linked immunosorbent assay (ELISA), anti-histidine antibodies determined by ELISA, and functional antibody activity determined by opsonophagocytic assay (OPA), up to 6 mo post-vaccination. Antibody avidity was measured on days 7 and 14 from samples that had detectable vaccine antibody-specific immunoglobulin G (IgG) antibody titers. At the Austrian site only, the B-cell ELIspot assay was used to determine specific ASC responses. Safety was assessed using adverse event monitoring and clinical laboratory tests. Local and systemic tolerability was recorded in a subject diary for 7 d after each vaccination and by investigators up to 6 mo post-vaccination.

Summary Background Staphylococcal toxic shock syndrome is a superantigen-driven potentially life-threatening disease affecting mainly young and otherwise healthy individuals. Currently, no specific treatment or preventive measure is available. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant detoxified toxic shock syndrome toxin-1 variant (rTSST-1v) vaccine in adult volunteers. Methods In this randomised, double-blind, adjuvant-controlled, dose-escalation first-in-human trial, healthy adults aged 18–64 years were enrolled from the Medical University of Vienna, Austria. Participants were randomly assigned (2:1 and 3:1) by block randomisation (block sizes of three and 12) to receive increasing doses of rTSST-1v (100 ng to 30 μg) or the adjuvant comparator aluminium hydroxide (Al(OH) 3 ) (200 μg, 600 μg, or 1 mg). Investigators and participants were masked to group allocation. The per-protocol population received a booster immunisation 42 days after the first vaccination. The primary endpoint was safety and tolerability of rTSST-1v. The per-protocol population included all participants who had adhered to the study protocol without any major protocol deviations. The per-protocol population was the primary analysis population for immunogenicity. The trial is registered with EudraCT, number 2013-003716-50, and ClinicalTrials.gov, number NCT02340338. Findings Between Aug 19, 2014, and April 14, 2015, 46 participants were enrolled (safety population), of whom three were assigned to cohort 1 (two to receive 100 ng rTSST-1v and one to receive 200 μg Al(OH) 3 ), three to cohort 2 (two to receive 300 ng rTSST-1v and one to receive 600 μg Al(OH) 3 ), four to cohort 3 (three to receive 1 μg rTSST-1v and one to receive 1 mg Al(OH) 3 ), 12 to cohort 4 (nine to receive 3 μg rTSST-1v and three to receive 1 mg Al(OH) 3 ), 12 to cohort 5 (nine to receive 10 μg rTSST-1v and three to receive 1 mg Al(OH) 3 ), and 12 to cohort 6 (nine to receive 300 μg rTSST-1v and three to receive 1 mg Al(OH) 3 ). 45 participants (98%) were included in the per-protocol population. rTSST-1v had a good safety profile, and no vaccination-related severe or serious adverse events occurred. Adverse event rates were similar between participants who received rTSST-1v and those who received placebo (26 [76%] vs 10 [83%]; p=0·62) independent of pre-existing TSST-1 immunity. Interpretation rTSST-1v was safe, well-tolerated, and immunogenic. This study represents an important step in vaccine development to prevent or treat a potentially lethal disease. Funding Biomedizinische Forschungs GmbH.

Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhoea and colitis and the most common pathogen of health care-associated infections. In the US, CDI causes approximately half a million infections and close to 30,000 deaths. Despite antibiotic treatment of C. difficile associated diarrhoea, the disease is complicated by its recurrence in up to 30% of patients.An open-label, partially randomized, dose-escalation Phase I trial was performed in two parts. Sixty volunteers aged ≥18 to65 years were randomized into five treatment groups to receive three immunizations (Day 0, 7, 21) of VLA84 (20μg with Alum, 75μg with or without Alum, 200μg with or without Alum). Eighty-one volunteers aged ≥65 were randomized into four treatment groups (75μg with or without Alum, 200μg with or without Alum) and received four immunizations (Day 0, 7, 28 and 56). All subjects were followed for safety and immunogenicity for six months.VLA84 was safe and well tolerated. Fifty-one adult volunteers (85%) and 50 elderly (62%) experienced at least one solicited or unsolicited adverse event (AE). Forty-eight adult volunteers (80%) and 40 elderly (49%) experienced related AEs which were mostly mild or moderate. No related serious adverse event and no death occurred. The vaccine induced high antibody titres against Toxin A and Toxin B in both study populations.VLA84 was safe, well tolerated and highly immunogenic in adult volunteers aged ≥18 to65 years and elderly volunteers aged ≥65 years. This study is registered at ClinicalTrials.gov under registration number NCT01296386.

SummaryGranulocyte colony-stimulating factor (G-CSF) stimulates the bone marrow to produce granulocytes and stem cells and is widely used to accelerate neutrophil recovery after chemotherapy. Interestingly, specific G-CSF receptors have been demonstrated not only on myeloid cells, but also on platelets. Data on the effects of G-CSF on platelet function are limited and partly conflicting. The objective of this study was to determine the effect of G-CSF on platelet aggregation and in vivo platelet activation. Seventy-eight, healthy volunteers were enrolled into this randomised, placebo-controlled trial. Subjects received 5 μg/kg methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim) or placebo subcutaneously for four days. We determined platelet aggregation with a whole blood impedance aggregometer with various, clinically relevant platelet agonists (adenosine diphosphate [ADP], collagen, arachidonic acid [AA], ristocetin and thrombin receptor activating peptide 6 [TRAP]). Filgrastim injection significantly enhanced ADP (+40%), collagen (+60%) and AA (+75%) -induced platelet aggregation (all p

Atherothrombotic events, such as acute coronary syndrome or stroke, are the result of platelet activation. Von Willebrand factor (vWF), a multimeric glycoprotein, plays a key role in aggregation of platelets, especially under high-shear conditions. Acting as bridging element or ligand between damaged endothelial sites and the glycoprotein Ib (GPIb) receptor on platelets, vWF is responsible for platelet adhesion and aggregation. This vWF activation and further platelet aggregation mainly occurs under high shear stress present in small arterioles or during deficiency of the vWF-cleaving protease ADAMTS13. There are several substances targeting vWF itself or its binding receptor GPIb on platelets. Two antibodies are directed against vWF: AJW200, an IgG4 humanized monoclonal antibody, and 82D6A3, a monoclonal antibody of the collagen-binding A-3 domain of vWF. ALX-0081 and ALX-0681 are bivalent humanized nanobodies targeting the GPIb binding site of vWF. Aptamers are oligonucleotides with drug-like properties that share some of the attributes of monoclonal antibodies. ARC1779 is a second-generation, nuclease-resistant aptamer, binding to the activated vWF A1 domain and ARC15105 is a chemically advanced follower with an assumed higher affinity to vWF. Antibodies targeting GPIbα are h6B4-Fab, a murine monoclonal antibody; GPG-290, a recombinant, chimeric protein containing the amino-terminal 290 amino acids of GPIbα linked to human IgG1 Fc; and the monoclonal antibody SZ2. There are a number of promising preclinical results and development of some agents (AJW 200, ARC1779 and ALX-0081) has already reached Phase II trials.

Granulocyte colony-stimulating factor (G-CSF) has been associated with the induction of a hypercoagulable state in patients as well as peripheral blood stem donors. Interestingly, sparse data exist on the kinetics of platelet and coagulation activation in response to G-CSF and it is unknown if G-CSF augments shear-dependent platelet function. These two issues are addressed in the current trial. Thirty-six healthy volunteers were enrolled into this study. All subjects received a single-dose of 5 microg/kg filgrastim intravenously. The effects of recombinant G-CSF on platelet and coagulation function were assessed by the platelet function analyzer PFA-100 (collagen/epinephrine (CEPI-CT), collagen/ADP (CADP-CT) closure times), von Willebrand factor activity (vWF : RiCO) ELISA, tissue factor (TF)-mRNA expression on circulating leukocytes and rotation thrombelastography (ROTEM). G-CSF time-dependently enhanced shear dependent platelet function measured by the PFA-100: CEPI-CT declined by 48% and CADP-CT by 31% with nadir values after 24 h (p0.001 as compared to baseline) and returned to near-baseline values after 72 hours. In accordance, VWF : RiCO increased by 59% after 24 h (p0.001) and returned to baseline 48 h later. TF-mRNA peaked after 4 hours (6 fold increase p0.001) and reached near-baseline values after 24 hours. Nadir closure times were seen after 24 hours (-15%; p0.001). Single-dose administration of 5 microg/kg G-CSF significantly enhances shear-dependent platelet function and strongly induces leukocyte TF-mRNA, which translates into shortened clotting times ex vivo.

Background An effective vaccine would be a significant progress in the management of chronic HCV infections. This study was designed to examine whether different application schedules and injection routes may enhance the immunogenicity of the HCV peptide vaccine IC41. Methods In this randomized trial 54 healthy subjects received either subcutaneous (s.c.) or intradermal (i.d.) vaccinations weekly (16 injections) or every other week (8 injections). One group additionally received imiquimod, an activator of the toll-like receptor (TLR) 7. The T cell epitope-specific immune response to IC41 was assessed using [3H]-thymidine CD4+ T cell proliferation, interferon-gamma (IFN-γ) CD8+ and CD4+ ELIspot and HLA-A*0201 fluorescence-activated cell sorting (FACS) tetramer-binding assays. Results More than 60% of vaccinees responded in the CD4+ T cell proliferation assay in all groups. An HLA-A*0201 FACS tetramer-binding assay and IFN-γ CD8+ ELIspot class I response of more than 70% was induced in four and three groups, respectively. IC41 induced significant immunological responses in all groups with responder rates of up to 100%. Interestingly, topical imiquimod was not able to enhance immunogenicity but was associated with a lower immune response. Local injection site reactions were mostly transient. Intradermal injections caused more pronounced reactions compared to s.c., especially erythema and edema. Conclusion Compared to a previous study intensified dosing and/or i.d. injections enhanced the response rates to the vaccine IC41 in three assays measuring T cell function. Immunization with IC41 was generally safe in this study. These results justify testing IC41 in further clinical trials with HCV-infected individuals.

Monocyte chemoattractant protein-1 (MCP-1, CCL-2) binds to the Duffy antigen (DARC) on red blood cells, which act as a sink for several chemokines including MCP-1. In this study it is hypothesized that DARC may alter the pharmacokinetics of infused recombinant human MCP-1 (rhMCP-1). The primary aim of this first in man trial is to compare the pharmacokinetics of rhMCP-1 in Duffy positive and negative individuals. A randomized, double-blinded, placebo-controlled dose escalation trial was conducted on 36 healthy volunteers. Subjects received infusions of 0.02–2.0 μg/kg rhMCP-1 or placebo for one hour. RhMCP-1 displayed linear pharmacokinetics. Duffy negative individuals reached maximal plasma levels significantly earlier, but overall plasma concentration profiles were not altered. rhMCP-1 markedly increased monocyte counts, and estimated EC50 values were 10-fold higher in Duffy positive than in Duffy negative subjects. Increased monocyte counts were associated with decreased surface expression of intercellular adhesion molecule 1 (ICAM-1, CD54). In contrast, neither CCR-2 or CD11b expression, nor markers of platelet or endothelial activation, inflammation and coagulation were altered. RhMCP-1 is a highly selective chemoattractant for monocytes in humans. The Duffy antigen only minimally alters the pharmacokinetics of rhMCP-1 for doses up to 2 μg/kg.

Summary. Background: Racial differences in coagulation are poorly understood. While some studies suggest a ‘prothrombotic’ coagulation profile in blacks compared with whites, others report an increased bleeding risk for blacks in various clinical settings. Moreover, preclinical data suggest a link between the Duffy antigen (= DARC, Duffy antigen receptor of chemokines) and coagulation. Objectives: Based on our previous research in Duffy antigen negative Africans, we hypothesized that Africans have an attenuated procoagulant response compared with Caucasians in a model of lipopolysaccharide (LPS)-induced, tissue factor (TF)-triggered coagulation activation. Patients/methods: Healthy male volunteers (16 Duffy-negative Africans, 16 Duffy-positive Caucasians) received 2 ng kg−1 LPS, and outcome parameters were measured using enzyme immunoassays and real-time polymerase chain reaction (RT-PCR, Taqman). Results: LPS increased microparticle (MP)-associated TF procoagulant activity (PCA) less in Africans than Caucasians. Africans had reduced in vivo thrombin formation compared with Caucasians: they generated less thrombin–antithrombin (TAT) complexes (10.4 pg mL−1 vs. 23.0 pg mL−1, P

Objective: The aim of this study was to compare the efficacy of Lutrate® 3.75 and 7.5 mg depot to marketed references Lucrin® 3.75 mg and Procrin® 7.5 mg depot. Methods: 20 healthy male volunteers were randomly assigned to receive 1 of 4 active single dose treatments in this double-blind, parallel-group pilot study. Leuprolide acetate and testosterone levels were quantified by radioimmunoassays. Results: The pharmacokinetic profile of leuprolide could be well-described by a 4-step release curve. Leuprolide levels were detectable 14 days longer after injection of the test formulations as compared to the reference products. The total AUC observed with 3.75 and 7.5 mg of the test product were approximately 1.5- and 2.2-fold higher, compared to the reference products, respectively. After the expected testosterone "flare-up" effect, castration was achieved in 4 of 4 subjects with the test formulations, 4 of 5 subjects with Procrin and 2 of 5 subjects with Lucrin. On average, castration lasted more than 1 month with both test formulations compared to 2 weeks with the reference products. Conclusion: Sustained release of leuprolide from this new depot formulation suppressed testosterone levels at least as effectively and for a longer period of time than the reference products.

The Duffy receptor is a promiscuous receptor for chemokines and selectively binds CXC and CC chemokines with high affinity. Preclinical data show that presence of the Duffy receptor on red blood cells may influence plasma levels of proinflammatory cytokines and chemokines and be protective during inflammation. This trial was designed to investigate the influence of the Duffy antigen on human inflammation in vivo.Prospective, analyst-blinded clinical trial.A total of 32 healthy male volunteers: 16 Duffy-positive white subjects and 16 Duffy-negative subjects of African descent.All subjects received an intravenous bolus of 2 ng/kg endotoxin (lipopolysaccharide). Cytokines, chemokines, and their receptors were quantified by enzyme immunoassay, reverse transcriptase-polymerase chain reaction, and flow cytometry.Plasma levels of tumor necrosis factor, interleukin-6, interleukin-10, and whole blood growth-related oncogen-alpha, monocyte chemoattractant protein-1, and interleukin-8 messenger RNA increased similarly in both groups after lipopolysaccharide infusion. Monocyte chemoattractant protein-1 peak plasma levels were roughly two-fold higher in Duffy-positive subjects compared with Duffy-negative subjects (16 ng/mL vs. 7 ng/mL, p.0001). Similarly, growth-related oncogen-alpha levels were 2.5-fold higher in Duffy-positive subjects 2 hrs after lipopolysaccharide infusion (210 pg/mL vs. 85 pg/mL; p.001). Erythrocyte-bound monocyte chemoattractant protein-1, growth-related oncogen-alpha, and interleukin-8 increased 20- to 50-fold in Duffy-positive subjects (p.00001 vs. baseline).The Duffy antigen substantially alters chemokine concentrations in blood, but it does not have a protective effect during human endotoxemia.

BIBT986 is a dual inhibitor of factors Xa and IIa. The aim of this study was to compare with placebo the effect of three doses of BIBT986 on coagulation, platelet activation, and inflammation. This was a prospective, randomized, double-blind, placebo-controlled, parallel-group dose escalation trial in 48 healthy male volunteers. Participants received one of three doses of BIBT986 or placebo intravenously together with a bolus infusion of 2 ng/kg lipopolysaccharide (LPS). BIBT986 dose-dependently changed global coagulation parameters and in vivo markers of thrombin generation and action: BIBT986 doses, which prolonged activated partial thromboplastin time by 100%, completely suppressed the LPS-induced increases in prothrombin fragment, thrombin-antithrombin complexes, and D-dimer, which were 6.1-, 14.5, and 3.5-fold in the placebo group, respectively. BIBT986 did not influence inflammation, fibrinolysis, or platelet activation. Therefore, BIBT986 is a potent anticoagulant in the human endotoxemia model.

Ethnic neutropenia is common in people of African descent. As interleukin-8 (IL-8) and granulocyte colony stimulating factor (G-CSF) bind to receptors on neutrophils, ethnic differences in neutrophil counts are hypothesized to result in different plasma levels of these cytokines. A prospective study was conducted in 72 healthy young volunteers. Neutrophil counts were 60% higher in Caucasians (P0.00001). Average IL-8 and G-CSF levels were about 50% and 70% higher in African volunteers compared with Caucasian volunteers (P=0.0008 and P=0.00005, respectively). Additionally, oxidative burst capacity in stimulated neutrophils was significantly lower in volunteers of African descent (P=0.03 between both groups). In sum, lower neutrophil counts are associated with higher levels of IL-8 and G-CSF in Africans.

Reparixin antagonizes interleukin-8 (IL-8) on the level of signal transduction in vitro. We hypothesized that IL-8 mediates some of the reactions occurring during acute inflammation and specifically that IL-8 may be a mediator of endotoxin induced neutrophilia. We therefore tested the effects of reparixin on humoral and cellular parameters in LPS-induced acute systemic inflammation. The study is a randomized (3:2 active:placebo), double-blind, placebo-controlled parallel group trial. Twenty healthy male volunteers randomly received either reparixin (12) or placebo (8) intravenously. One hour after the start of reparixin/placebo infusion a bolus of 2 ng/kg endotoxin was infused over 1–2 min. Blood samples were obtained over 24 h. Reparixin, being metabolized to ibuprofen, suppressed serum thromboxane B2 levels by 78% compared to baseline and control at 8 h. LPS-induced neutrophilia was not significantly affected by reparixin in human volunteers. Consistently, reparixin did not alter the lymphocyte or monocyte counts and had no effect on LPS-induced systemic inflammation as measured by tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6) release. Regulation of IL-8 receptors CXCR1 and 2 and the degranulation marker CD11b showed the expected kinetics. Reparixin had no effect on thrombin formation as measured by prothrombin fragment (F1+2). In conclusion, our study showed that reparixin was safe but had no impact on endotoxin induced inflammation. In contrast to previous studies with its metabolite ibuprofen, reparixin does not enhance inflammation in this model.

Summary Background Chikungunya is an emerging arthropod-borne disease that has spread from tropical endemic areas to more temperate climates of the USA and Europe. However, no specific treatment or preventive measure is yet available. We aimed to investigate the immunogenicity and safety of a live recombinant measles-virus-based chikungunya vaccine. Methods We did a randomised, double-blind, placebo-controlled, active-comparator, phase 1, dose-escalation study at one centre in Vienna, Austria. Healthy men and women aged 18–45 years with no comorbidities were randomly assigned, by computer-generated block randomisation (block size of 14), to receive either one of three escalating doses of the measles-virus-based candidate vaccine (low dose [1·5 × 10 4 median tissue culture infection doses (TCID 50 ) per 0·05 mL], medium dose [7·5 × 10 4 TCID 50 per 0·25 mL], or high dose [3·0 × 10 5 TCID 50 per 1·0 mL]), or the active comparator—Priorix. Participants were additionally block-randomised to receive a booster injection on either day 28 or day 90 after the first vaccination. Participants and study investigators were masked to group allocation. The primary endpoint was the presence of neutralising anti-chikungunya antibodies on day 28, as assessed by 50% plaque reduction neutralisation test. Analysis was by intention to treat and per protocol. This trial is registered with EudraCT, number 2013-001084-23. Findings Between Nov 22, 2013, and Feb 25, 2014, we randomly assigned 42 participants to receive the low dose (n=12), the medium dose (n=12), or the high dose (n=12) of the measles-virus-based candidate vaccine, or Priorix (n=6), of whom 36 participants (86%; n=9, n=12, n=10, n=5, respectively) were included in the per-protocol population. The candidate vaccine raised neutralising antibodies in all dose cohorts after one immunisation, with seroconversion rates of 44% (n=4) in the low-dose group, 92% (n=11) in the medium-dose group, and 90% (n=10) in the high-dose group. The immunogenicity of the candidate vaccine was not affected by pre-existing anti-measles immunity. The second vaccination resulted in a 100% seroconversion for all participants in the candidate vaccine groups. The candidate vaccine had an overall good safety profile, and the rate of adverse events increased with vaccine dose and volume. No vaccination-related serious adverse events were recorded. Interpretation The live recombinant measles-virus-based chikungunya vaccine had good immunogenicity, even in the presence of anti-vector immunity, was safe, and had a generally acceptable tolerability profile. This vaccine is the first promising measles-virus-based candidate vaccine for use in human beings. Funding Themis Bioscience GmBH.

Japanese encephalitis virus, as the most important vaccine-preventable cause of viral encephalitis in Asia, is estimated to cause over 68,000 clinical cases yearly. In endemic areas, most Japanese encephalitis infections occur in children younger than 10 y and clinical manifestation of this disease is critical, because there is no effective treatment available. As JEV infections are regarded as one of the most serious viral causes of encephalitis and mass immunization programmes are generally recommended for residents in endemic areas, a safe and effective JEV vaccine was needed to protect them as well as others at risk. Due to the safety concerns with the mouse brain derived vaccine, second generation vaccines against JE produced in cell culture like Vero cells were developed. IXIARO® is a purified, inactivated aluminum-adjuvanted JE vaccine, based on the SA14-14-2 virus strain, and is available in North America, Europe, Canada, Switzerland, Singapore, Hong Kong and Israel as well as in Australia & New Zealand (as JESPECT®).The safety, tolerability and immunogenicity profile of IXIARO® is well established through a number of clinical studies comparing IXIARO® with placebo as well as mouse brain derived vaccine. Recent data show that the global incidence of JE remains substantial, especially young children in endemic areas are most susceptible. As vaccination is the most feasible, reliable and cost effective tool for JE control, IXIARO® with confirmed excellent safety profile is highly recommendable, in particular for vaccination of children at risk. The European Commission as well as the FDA approved the extension of indication of IXIARO® to the pediatric segment (2 months of age and older) based on these data.

Summary. Background: Thrombelastography (TEG) is a whole blood assay to evaluate the viscoelastic properties during blood clot formation and clot lysis. Rotation thrombelastography (e.g. ROTEM®) has overcome some of the limitations of classical TEG and is used as a point-of-care device in several clinical settings of coagulation disorders. Endotoxemia leads to systemic activation of the coagulation system and fibrinolysis in humans. Objectives: We validated whether ROTEM® is sensitive to endotoxin induced, tissue factor-triggered coagulation and fibrinolysis and if its measures correlate with biohumoral markers of coagulation and fibrinolysis. Patients and methods: Twenty healthy male volunteers participated in this randomized placebo-controlled trial. Volunteers received either 2 ng kg−1 National Reference Endotoxin or saline. Results: Endotoxemia significantly shortened ROTEM® clotting time (CT) by 36% (CI 0.26–0.46; P

We hypothesized that infusion of recombinant human antithrombin without concomitant heparin would have dose-dependent anticoagulant properties and potentially decrease endotoxin (lipopolysaccharide [LPS])–induced cytokine production. This was a randomized, double-blind, placebo-controlled study in parallel groups enrolling 30 healthy male volunteers. The active treatment groups received infusions of recombinant human antithrombin to increase antithrombin levels to 200% and 500% before infusion of 2 ng/kg endotoxin (LPS). Infusion of antithrombin dose-dependently decreased coagulation (P