In this phase 1 study, a chemically modified RNA interference therapy designed to target antithrombin was administered to participants with hemophilia A or B. Antithrombin levels decreased and the ...generation of thrombin increased.
In recent decades, economic activity has sharply increased in the Pechora Sea, one of the most hydrologically unique areas of the Barents Sea. Hence, the information about the current state of its ...ecosystems is quite important for assessing their possible changes in the future. The aim of the present study was to analyze the distribution of macrobenthos and assess its ecological quality in the southeastern part of the Pechora Sea at the beginning of the 21st century (based on data collected in 2012–2013). The results showed that since 1920s there have been no serious changes in the macrobenthos in the studied area. The weak shifts detected in the benthic fauna were either within the natural range of fluctuations in population of common species, or may be associated with differences in the methodological approaches of different researches. Heterogeneity in the macrobenthos distribution, the most significant abiotic factors identified in relation to it, quantitative indicators of biota, and species dominating in communities were similar to those revealed in previous studies. As of 2013, the characteristics of benthic communities in the southeastern part of the Pechora Sea, including their ecological quality, allow us to refer them as undisturbed biosystems.
•In 2012–2013 the detailed studies of macrobenthos in the south-eastern part of the Pechora-Sea were carried out.•No serious changes in the macrobenthos structure since the 1920s had registered.•The ecological status of benthic communities is assessed as undisturbed.•The obtained data can be used as a reference point when tracking future ecosystem changes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hemostatic management is essential for ensuring the safety of patients with hemophilia during surgery. This phase 3, prospective, uncontrolled trial, evaluated hemostatic efficacy, consumption, and ...safety of a recombinant factor IX concentrate, nonacog gamma (BAX 326, Rixubis® Baxalta US Inc., a Takeda company, Lexington, MA, USA), in intraoperative and postoperative settings in previously treated patients (PTPs) with severe or moderately severe hemophilia B undergoing elective surgery (N = 38 surgeries; 21 major, 17 minor). Predefined preoperative hemostatic factor IX levels (80-100% of normal for major and 30-60% for minor surgeries) were maintained for each patient. Intraoperative efficacy was rated as “excellent” or “good” for all surgeries. Postoperative hemostatic efficacy on day of discharge was rated as “excellent,” “good,” and “fair,” respectively, for 29 (76.3%), 7 (18.4%), and 2 (5.3%) surgical procedures. All adverse events were considered unrelated to study drug; most frequently reported was mild procedural pain (9 patients). No thrombotic events, severe allergic reactions, or inhibitor formation were observed. Nonacog gamma was well tolerated and effective for intraoperative and postoperative hemostatic management of PTPs with hemophilia B.
NCT01507896, EudraCT: 2011-000413-39
To date, tuberculosis (TB) remains the primary cause of mortality in human immunodeficiency virus (HIV) patients in Russia. Since the beginning of 2000, a sharp change in the HIV patients’ structure, ...to the main known risk factors for HIV infection has taken place in Russia. The transmission of HIV through injectable drug use has begun to decline significantly, giving way to the prevalence of sexual HIV transmission today. These changes may require adjustments to organizational approaches to anti-TB care and the treatment of HIV-positive patients. Our study is aimed at identifying changes in TB-HIV coinfection patients’ structures in 2019 compared to 2000. Based on the results obtained, our goal was to point out the parameters that need to be taken into account when developing approaches to improve the organization of TB control care for people with HIV infection. We have carried out a cross-sectional, retrospective, epidemiological study using government TB registry data from four regions in two federal districts of Russia in 2019. The case histories of 2265 patients from two regions with high HIV prevalence, which are part of the Siberian Federal District of Russia, and 89 patient histories from two regions of low HIV prevalence, which are part of the Central Federal District of Russia, were analyzed. We found that parenteral transmission (69.4%) remains the primary route of HIV transmission among the TB-HIV coinfected. The unemployed of working age without disability account for 80.2% of all coinfected people, while the formerly incarcerated account for 53.7% and the homeless account for 4.1%. Those with primary multidrug-resistant TB (MDR-TB) comprise 56.2% of HIV-TB patients. When comparing the incidence of coinfection with HIV among TB patients, statistically significant differences were obtained. Thus, the chances of coinfection increased by 4.33 times among people with active TB (95% CI: 2.31; 8.12), by 2.97 times among people with MDR-TB (95% CI: 1.66; 5.32), by 5.2 times in people with advanced processes in the lungs, including destruction, (95% CI: 2.78; 9.7), as well as by 10.3 times in the case of death within the first year after the TB diagnosis (95% CI: 2.99; 35.5). The absence of data for the presence of TB during preventive examination was accompanied by a decrease in the chances of detecting coinfection (OR 0.36; 95% CI: 0.2; 0.64). We have identified the probable causes of the high incidence of TB among HIV-infected: HIV-patient social maladaptation usually results in delayed medical care, leading to TB treatment regimen violations. Furthermore, self-administration of drugs triggers MDR-TB within this group. Healthcare providers should clearly explain to patients the critical importance of immediately seeking medical care when initial TB symptoms appear.
Background: von Willebrand disease (VWD) is characterized by a deficiency or reduction of activity in von Willebrand factor (VWF). As VWF has a role in stabilizing coagulation factor VIII (FVIII), ...VWD patients often suffer from secondary FVIII deficiency. Current guidelines recommend that VWD patients with a history of severe and frequent bleeds should use long-term prophylaxis with factor replacement therapy. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII concentrate containing VWF and FVIII in a 1:1 activity ratio (pdVWF/FVIII; wilate ®) in adults and children with VWD. The primary endpoint was met, showing a decrease of 84% in the mean total annualized bleeding rate (ABR). As elevated levels of FVIII are associated with an increased risk for thrombosis, it is important to determine whether repeated dosing with pdVWF/FVIII leads to accumulation of FVIII over time.
Aims: To investigate the activity levels of VWF and FVIII in patients with VWD receiving regular prophylaxis with pdVWF/FVIII.
Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients, aged ≥6 years old with VWD type 1 (VWF:RCo <30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a pdVWF/FVIII concentrate during a 6-month, prospective, observational, run-in study (WIL-29). Patients in WIL-31 received regular pdVWF/FVIII prophylaxis 2-3 times per week at a dose of 20-40 IU/kg for 12 months. VWF activity (VWF:RCo) and FVIII activity (measured by the chromogenic Chr and one-stage OS assays) were performed at baseline and throughout the study. Full pharmacokinetic (PK) analyses were performed in all patients aged 6-16 years, a single dose of 60 ± 10 IU/kg pdVWF/FVIII was administered. Samples were collected at up to 1 hour prior to injection and then at multiple time points post-injection (1-72 hours). Safety, including the occurrence of thrombotic events, was monitored throughout the study.
Results: The overall study population included 33 patients, with a median age of 18 years consisting of 9 (27.3%) patients aged 6-11 years, 6 (18.2%) patients aged 12-16 years, and 18 (54.5%) patients aged ≥17 years. Six (18.2%) patients had severe type 1 VWD, 5 (15.2%) patients had type 2, and 22 (66.7%) patients had type 3. Baseline FVIII and VWF activities in WIL-31 were similar regardless of age group, and as expected were lower in patients with type 3 VWD compared with severe type 1 and type 2 (Figure 1). There was a negative correlation of baseline FVIII and VWF activity with the number of spontaneous bleeding episodes (BEs) during prophylaxis. Patients who had no spontaneous BEs during prophylaxis had higher baseline FVIII and VWF levels compared with those who had spontaneous BEs. Mean peak and trough FVIII and VWF activity levels remained consistent during the study and there was no accumulation of either factor over the 12-month prophylaxis period (Figure 2). Full PK assessments were performed according to protocol in 13 patients aged 6-16 years. The mean ± standard deviation in vivo half-life was 16.1±6.7, 16.2±7.7, and 9.8±7.7 hours, for FVIII Chr, FVIII OS, and VWF:RCo, respectively. No thrombotic events were observed.
Conclusion: No accumulation of FVIII or VWF in the plasma was reported in 33 patients who received regular prophylaxis with pdVWF/FVIII for 12 months, regardless of VWD type and age.
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IJS, IMTLJ, NUK, PNG, SAZU, UL, UM, UPUK, ZRSKP
Background: FVIII replacement therapy is ineffective for severe haemophilia A (HA) patients who develop inhibitors to FVIII. Patients with intractable inhibitors currently require FVIII mimetics ...and/or bypassing agents to prevent bleeding. PEGylated liposomes (PEGLip) have been shown to protect FVIII from anti-FVIII antibodies in ex-vivo human studies and in combination with FVIII may present an option for the prophylactic treatment of inhibitor patients.
Aims: To (a) demonstrate that PEGLip-FVIII administered intravenously (IV) to severe HA patients with history of inhibitors to FVIII enhances their clotting activity, (b) compare the number of bleeding episodes before and after PEG-Lip treatment, and (c) demonstrate that PEGLip-FVIII is well tolerated with no increase in inhibitor titres.
Methods: Stage A: Four patients with a history of inhibitors were given single IV injections of PEGLip-FVIII (simoctocog alfa) at a dose of 22mg/kg PEGLip + 35 IU/kg FVIII and assessed for clotting activity at 0 hours (pre-injection) and at 20min, 1, 2, 4, 8, 24 hours, and daily thereafter up to 7 days using Rotational Thromboelastometry. Stage B: Patients received IV injections of PEGLip-FVIII for 6-weeks at a frequency determined by the investigator based on results obtained during Stage A. Inhibitor titres were monitored throughout.
Results: Results are shown below.
Treatment with PEGLip-FVIII was highly tolerated with no clinically significant changes in inhibitor titres. No Adverse Drug Reactions were reported. The mean frequency of administration of PEGLip-FVIII was every 5.7±1.4 days. The mean number of bleeding episodes reported during Stage B was 0.5±0.9 per month (due to 1 patient) compared with 0.9±0.4 per month recorded during the 24 weeks prior to enrollment.
Conclusion: PEGLip-FVIII in inhibitor patients demonstrated efficacy in preventing spontaneous bleeds without increasing inhibitor titres, indicating a novel FVIII-based treatment for this cohort. Planned studies in a larger cohort may confirm our findings.
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No relevant conflicts of interest to declare.
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IJS, IMTLJ, NUK, PNG, SAZU, UL, UM, UPUK, ZRSKP
Background
Fitusiran, an investigational small interfering RNA therapy, reduces antithrombin production to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors.
...Objectives
To evaluate the safety and efficacy of fitusiran treatment for people with moderate/severe hemophilia A or B with inhibitors.
Patients/Methods
In this open‐label phase 1, part D study, 17 males with hemophilia A or B with inhibitors received three once‐monthly subcutaneous injections of fitusiran 50 mg (n = 6) or 80 mg (n = 11); followed for up to 112 days. Endpoints included safety (primary), pharmacokinetics/pharmacodynamics (secondary), annualized bleeding rate, and patient‐reported outcomes (exploratory).
Results
The most common adverse event was injection site erythema (n = 8). No thrombotic events were reported. At nadir, mean (standard error of the mean SEM) antithrombin activity decreased from baseline by 82.0% (2.2) and 87.4% (0.7) in the 50 mg and 80 mg groups, respectively. Antithrombin reduction was associated with increased thrombin generation. 11/17 (64.7%) participants had no bleeds during the observation period (mean standard deviation 69.4 16.3 days). Mean (SEM) changes from baseline in Haemophilia Quality of Life Questionnaire for Adults total (−9.2 2.9) and physical health (−12.3 3.9) domain scores suggested clinically meaningful improvement.
Conclusions
Monthly fitusiran was generally well tolerated, lowered antithrombin levels from baseline, and resulted in improved thrombin generation. These preliminary results suggest that monthly fitusiran treatment may reduce bleeding episodes and improve quality of life in participants with hemophilia A or B with inhibitors.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The novel coronavirus (COVID-19) outbreak is a public health emergency of international concern, and this emergency led to postponing elective dental care procedures. The postponing aimed to protect ...the public from an unknown risk caused by COVID-19. At the beginning of the outbreak, for public health authorities, the aerosol-generating procedures and the close proximity between dental care workers and patients in dentistry represented sufficient justification for the delay of dental visits. Dental care is a priority, and for many years, studies have proven that the lack and delay of dental care can cause severe consequences for the oral health of the general population, which can cause a high global burden of oral diseases. Safety is necessary while resuming dental activities, and risk assessment is an efficient method for understanding and preventing the COVID-19 infectious threats facing the dental industry and affecting dental care workers and patients. In this study, for safe dental care delivery, we adapted risk assessment criteria and an approach and an occupational classification system. Based on those tools, we also recommend measures that can help to minimize infectious risk in dental settings.
Introduction
SHP656 is the first factor VIII (FVIII) product developed using polysialylation (PSA) technology, in which full‐length recombinant (r) FVIII (anti‐haemophilic factor recombinant) is ...conjugated with a 20 kDa PSA polymer.
Aim
To compare the safety, immunogenicity and pharmacokinetics of SHP656 vs the parent rFVIII (octocog alfa) after single infusions of 25‐75 IU/kg in patients with severe haemophilia A (FVIII activity <1%).
Methods
Multinational, phase 1, prospective, open‐label, two‐period, fixed‐sequence, dose‐escalation trial (clinicaltrials.gov NCT02716194). Patients received single doses of rFVIII and then SHP656 sequentially at the same dose: 25 ± 3 IU/kg (Cohort 1), 50 ± 5 IU/kg (Cohort 2) and 75 ± 5 IU/kg (Cohort 3).
Results
Forty patients received rFVIII: 11 in Cohort 1, 16 in Cohort 2 and 13 in Cohort 3. Two patients withdrew before receiving SHP656, leaving 38 patients who completed the study and received both treatments. No treatment‐related adverse events (AEs), serious AEs, deaths, study withdrawals, thrombotic events or allergic reactions were reported; and no significant treatment‐related changes in laboratory parameters or vital signs. No patients developed FVIII inhibitors or antibodies to PSA. FVIII activity was significantly prolonged following SHP656 administration vs rFVIII with an approximately 1.5‐fold extension in mean residence time (P < .05). Exposure increased proportional to the SHP656 dose over the 25‐75 IU/kg dose range.
Conclusion
Polysialylation of rFVIII confers a half‐life extension similar to that of approved extended half‐life products that use either PEGylation or Fc fusion technology and was not associated with any treatment‐related adverse events.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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