Randomized Study of Rivaroxaban vs Placebo on Disease Progression and Symptoms Resolution in High-Risk Adults With Mild Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection may be associated with a prothrombotic state, predisposing patients for a progressive disease course. We investigated whether rivaroxaban, a direct oral anticoagulant factor Xa inhibitor, would reduce coronavirus disease 2019 (COVID-19) progression. METHODS: Adults (N = 497) with mild COVID-19 symptoms and at high risk for COVID-19 progression based on age, body mass index, or comorbidity were randomized 1:1 to either daily oral rivaroxaban 10 mg (N = 246) or placebo equivalent (N = 251) for 21 days and followed to day 35. Primary end points were safety and progression. Absolute difference in progression risk was assessed using a stratified Miettinen and Nurminen method. RESULTS: The study was terminated after 497 of the target 600 participants were enrolled due to a prespecified interim analysis of the first 200 participants that crossed the futility boundary for the primary efficacy end point in the intent-to-treat population. Enrollees were 85% aged <65 years; 60% female; 27% Hispanic, Black, or other minorities; and 69% with ≥2 comorbidities. Rivaroxaban was well tolerated. Disease progression rates were 46 of 222 (20.7%) in rivaroxaban vs 44 of 222 (19.8%) in placebo groups, with a risk difference of -1.0 (95% confidence interval, -6.4 to 8.4; P = .78). CONCLUSIONS: We did not demonstrate an impact of rivaroxaban on disease progression in high-risk adults with mild COVID-19. There remains a critical public health gap in identifying scalable effective therapies for high-risk people in the outpatient setting to prevent COVID-19 progression.

A Phase II Trial of Lutikizumab, an Anti-Interleukin-1α/ß Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis.

OBJECTIVE: To assess the efficacy and safety of the anti-interleukin-1α/ß (anti-IL-1α/ß) dual variable domain immunoglobulin lutikizumab (ABT-981) in patients with knee osteoarthritis (OA) and evidence of synovitis. METHODS: Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2-3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI-assessed synovitis at week 26. RESULTS: The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab-treated and placebo-treated patients. Changes from baseline in MRI-assessed synovitis at week 26 and other key symptom- and most structure-related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high-sensitivity C-reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations. CONCLUSION: The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL-1 inhibitors, suggest that IL-1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis.

Phase IIa, placebo-controlled, randomised study of lutikizumab, an anti-interleukin-1α and anti-interleukin-1ß dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis.

OBJECTIVE: To assess the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1α/ß dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand osteoarthritis (HOA). METHODS: Patients with ≥1 erosive and ≥3 tender and/or swollen hand joints were randomised to placebo or lutikizumab 200 mg subcutaneously every 2 weeks for 24 weeks. The primary endpoint was change in Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain score from baseline to 16 weeks. At baseline and week 26, subjects had bilateral hand radiographs and MRI of the hand with the greatest number of baseline tender and/or swollen joints. Continuous endpoints were assessed using analysis of covariance models, with treatment and country as main factors and baseline measurements as covariates. RESULTS: Of 132 randomised subjects, 1 received no study drug and 110 completed the study (placebo, 61/67 (91%); lutikizumab, 49/64 (77%)). AUSCAN pain was not different among subjects treated with lutikizumab versus placebo at week 16 (least squares mean difference, 1.5 (95% CI -1.9 to 5.0)). Other clinical and imaging endpoints were not different between lutikizumab and placebo. Lutikizumab significantly decreased serum high-sensitivity C reactive protein levels, IL-1α and IL-1ß levels, and blood neutrophils. Lutikizumab pharmacokinetics were consistent with phase I studies and not affected by antidrug antibodies. Injection site reactions and neutropaenia were more common in the lutikizumab group; discontinuations because of adverse events occurred more frequently with lutikizumab (4/64) versus placebo (1/67). CONCLUSION: Despite adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive HOA compared with placebo.

Longitudinal Reliability of the OMERACT Thumb Base Osteoarthritis Magnetic Resonance Imaging Scoring System (TOMS).

OBJECTIVE: To assess the longitudinal reliability of the Outcome Measures in Rheumatology (OMERACT) Thumb base Osteoarthritis Magnetic resonance imaging (MRI) Scoring system (TOMS). METHODS: Paired MRI of patients with hand osteoarthritis were scored in 2 exercises (6-mo and 2-yr followup) for synovitis, subchondral bone defects (SBD), osteophytes, cartilage assessment, bone marrow lesions (BML), and subluxation. Interreader reliability of delta scores was assessed. RESULTS: Little change occurred. Average-measure intraclass correlation coefficients were good-excellent (≥ 0.71), except synovitis (0.55-0.83) and carpometacarpal-1 osteophytes/cartilage assessment (0.47/0.39). Percentage exact/close agreement was 52-92%/68-100%, except BML in 2 years (28%/64-76%). Smallest detectable change was below the scoring increment, except in SBD and BML. CONCLUSION: TOMS longitudinal reliability was moderate-good. Limited change hampered assessment.

Pharmacokinetics of the B-Cell Lymphoma 2 (Bcl-2) Inhibitor Venetoclax in Female Subjects with Systemic Lupus Erythematosus.

BACKGROUND AND OBJECTIVE: Venetoclax is an oral selective Bcl-2 inhibitor approved for the treatment of patients with chronic lymphocytic leukemia with 17p deletion. Mechanistic and preclinical evidence warranted evaluation of venetoclax for the treatment of systemic lupus erythematosus (SLE). This work characterized the pharmacokinetics of venetoclax in female subjects with SLE. METHODS: Single (10-500 mg) and multiple (30-600 mg) escalating doses of venetoclax or matching placebo were evaluated using randomized, double-blind, placebo-controlled designs (6 active and 2 placebo per dose with 73 unique SLE patients enrolled, 25 of whom enrolled twice). The multiple-dose evaluation consisted of two cycles, each with once-daily dosing for 7 days followed by a 21-day washout. Non-compartmental and population pharmacokinetic analyses of venetoclax serial plasma concentrations were conducted. RESULTS: Venetoclax exhibited approximately dose-proportional exposures, with peak concentrations observed 4-8 h post-dose. Venetoclax steady-state exposures were achieved by day 4 of dosing, and the median area under the plasma concentration-time curve (AUC) accumulation ratio ranged from 1.1 to 1.5. A two-compartment model with first-order absorption and elimination described venetoclax pharmacokinetics. The estimates (95% bootstrap confidence interval) for venetoclax apparent clearance, central and peripheral volumes of distribution, intercompartmental clearance, absorption rate constant, and lag time were 16.3 L/h (14.6-17.9), 37 L (26-57), 122 L (98-183), 3.7 L/h (2.6-5.0), 0.13 h-1 (0.11-0.17), and 1.6 h (1.6-1.7), respectively. The population estimate for venetoclax terminal-phase elimination half-life was approximately 28 h. CONCLUSIONS: In female subjects with SLE, venetoclax displayed pharmacokinetic characteristics consistent with previous observations in subjects with hematologic malignancies. CLINICALTRIALS. GOV IDENTIFIER: NCT01686555.

Healthcare resource utilization and costs by age and joint location among osteoarthritis patients in a privately insured population.

AIMS: To compare healthcare resource utilization and costs between patients aged 18-64 years with osteoarthritis (OA) and matched controls without OA in a privately insured population. METHODS: Patients with OA were selected from de-identified US-based employer claims (Q1:1999-Q3:2011). The index date was defined as the first OA diagnosis indicated by ICD-9-CM codes. One year before and after the index date were defined as the baseline and study periods, respectively. A second OA diagnosis during the study period was also required. Patients with OA were matched one-to-one on age, gender, index date, and minimum length of follow-up to controls without OA. Baseline characteristics and study period resource utilization and costs (2016 USD) were compared between cohorts. RESULTS: This study identified 199,539 patients with OA (knee: 87,271, hip: 19,953, hand: 15,670, spine: 12,496). The average age was 54 years, and 58% were female. OA patients had higher healthcare resource utilization than matched controls in inpatient, emergency room, and outpatient settings (p < .001 for all). Further, patients with OA had 4-times the excess total medical costs of their matched controls ($14,521 vs $3,629; p < .001). Patients with hip OA had the highest medical costs among all joint locations. Outpatient and pharmacy costs were similar among patients with knee, hip, and hand OA, but higher in patients with spine OA. In sub-group analyses, older patients (45-64 years old) had higher costs. LIMITATIONS: This sample, obtained using claims data, only includes patients who were actively seeking care for OA and were likely symptomatic. Asymptomatic patients would likely not be captured in this analysis. CONCLUSIONS: Patients with OA incur greater healthcare resource utilization and costs than patients without OA, with substantial variation by joint location.

Pharmacokinetics and Tolerability of a Dual Variable Domain Immunoglobulin ABT-981 Against IL-1α and IL-1ß in Healthy Subjects and Patients With Osteoarthritis of the Knee.

The interleukin (IL)-1 family of proinflammatory cytokines are thought to play a significant role in the structural progression of osteoarthritis and its associated symptoms. IL-1α and IL-1ß are 2 distinct cytokines found in the cartilage, synovial membrane, and synovial fluid of patients with osteoarthritis. The aim of these studies was to evaluate the pharmacokinetics of ABT-981, a dual variable domain immunoglobulin (DVD-Ig) capable of simultaneously binding IL-1α and IL-1ß, in healthy subjects and patients with osteoarthritis of the knee. Fifty-six healthy adult subjects were randomized to receive single doses of ABT-981 intravenously (0.3, 1, 3, or 10 mg/kg), subcutaneously (0.3, 1, 3 mg/kg), or matching placebo in a 3:1 ratio. Thirty-six patients with osteoarthritis of the knee were randomized to receive 4 subcutaneous ABT-981 doses of 0.3, 1, or 3 mg/kg administered every 2 weeks, 3 subcutaneous doses of ABT-981 3 mg/kg every 4 weeks, or matching placebo in a 7:2 active:placebo ratio. ABT-981 behaved similarly to conventional monoclonal antibodies following single or multiple doses with mean maximum serum concentrations 2 to 9 days after subcutaneous doses, mean terminal half-lives of 10 to 14 days, and an absolute subcutaneous bioavailability of 46%. Exposure of ABT-981 was approximately linear following single or multiple doses every 2 weeks with monoexponential decline of terminal-phase concentrations. The most common adverse events associated with ABT-981 were diarrhea and headache in healthy subjects and injection site erythema in subjects with osteoarthritis of the knee. Decreased absolute neutrophil counts were observed in response to ABT-981 administration.

Pharmacological modulation of brain activity in a preclinical model of osteoarthritis.

The earliest stages of osteoarthritis are characterized by peripheral pathology; however, during disease progression chronic pain emerges-a major symptom of osteoarthritis linked to neuroplasticity. Recent clinical imaging studies involving chronic pain patients, including osteoarthritis patients, have demonstrated that functional properties of the brain are altered, and these functional changes are correlated with subjective behavioral pain measures. Currently, preclinical osteoarthritis studies have not assessed if functional properties of supraspinal pain circuitry are altered, and if these functional properties can be modulated by pharmacological therapy either by direct or indirect action on brain systems. In the current study, functional connectivity was first assessed in order to characterize the functional neuroplasticity occurring in the rodent medial meniscus tear (MMT) model of osteoarthritis-a surgical model of osteoarthritis possessing peripheral joint trauma and a hypersensitive pain state. In addition to knee joint trauma at week 3 post-MMT surgery, we observed that supraspinal networks have increased functional connectivity relative to sham animals. Importantly, we observed that early and sustained treatment with a novel, peripherally acting broad-spectrum matrix metalloproteinase (MMP) inhibitor (MMPi) significantly attenuates knee joint trauma (cartilage degradation) as well as supraspinal functional connectivity increases in MMT animals. At week 5 post-MMT surgery, the acute pharmacodynamic effects of celecoxib (selective cyclooxygenase-2 inhibitor) on brain function were evaluated using pharmacological magnetic resonance imaging (phMRI) and functional connectivity analysis. Celecoxib was chosen as a comparator, given its clinical efficacy for alleviating pain in osteoarthritis patients and its peripheral and central pharmacological action. Relative to the vehicle condition, acute celecoxib treatment in MMT animals yielded decreased phMRI infusion responses and decreased functional connectivity, the latter observation being similar to what was detected following chronic MMPi treatment. These findings demonstrate that an assessment of brain function may provide an objective means by which to further evaluate the pathology of an osteoarthritis state as well as measure the pharmacodynamic effects of therapies with peripheral or peripheral and central pharmacological action.

Current challenges in implementing cell-derived influenza vaccines: implications for production and regulation, July 2007, NIBSC, Potters Bar, UK.

A meeting was held at NIBSC, UK in July 2007 to discuss the implications of progress in the use of cell culture systems for the manufacture of vaccines against influenza. Issues discussed included the effect of using eggs and different cell types in strain selection, development of seed viruses to be used in production and the nature of the reagents to be used in determining vaccine potency. Future studies to progress the field were reviewed.

Alum boosts TH2-type antibody responses to whole-inactivated virus influenza vaccine in mice but does not confer superior protection.

Clinical trials with pandemic influenza vaccine candidates have focused on aluminium hydroxide as an adjuvant to boost humoral immune responses. In this study we investigated the effect of aluminium hydroxide on the magnitude and type of immune response induced by whole-inactivated virus (WIV) vaccine. Balb/c mice were immunized once with a range of antigen doses (0.04-5 microg) of WIV produced from A/PR/8 virus, either alone or in combination with aluminium hydroxide. The hemagglutination inhibition (HI) titers of mice receiving WIV+aluminium hydroxide were 4-16-fold higher than HI titers in mice receiving the same dose of WIV alone, indicating the boosting effect of aluminium hydroxide. WIV induced a TH1 skewed humoral and cellular immune response, characterized by strong influenza-specific IgG2a responses and a high number of IFNgamma-secreting T cells. In contrast, immunization with WIV adsorbed to aluminium hydroxide resulted in skewing of this response to a TH2 phenotype (high IgG1 levels and a low number of IFNgamma-producing T cells). To assess the effect of the observed immune response skewing on viral clearance from the lungs mice immunized once with 1 microg WIV without or with aluminium hydroxide were challenged with A/PR/8 virus 4 weeks later. The immunized mice showed a significant decrease in viral lung titers compared to control mice receiving buffer. However, despite higher antibody titers, mice immunized with WIV adsorbed to aluminium hydroxide suffered from more severe weight loss and had significantly higher virus loads in their lung tissue than mice receiving WIV alone. Major difference between these groups of mice was the type of immune response induced, TH2 instead of TH1, indicating that a TH1 response plays a major role in viral clearance.

Establishing the health and economic impact of influenza vaccination within the European Union 25 countries.

BACKGROUND: In 2003, the World Health Assembly (WHA) issued a resolution for prevention and control of influenza pandemics and annual epidemics, which urges the European Union 25 (EU-25) Member States to (1) establish and implement strategies to increase vaccination coverage of all people at high risk, including the elderly and people with underlying disease, with the goal of attaining vaccination coverage of the elderly population of at least 50% by 2006 and 75% by 2010; (2) to assess the disease burden and economic impact of annual influenza epidemics as a basis for framing and implementing influenza prevention policies. This resolution was reinforced by the European Union (EU), where Member States agreed to make additional efforts to improve uptake on their territory in accordance with their own recommendations and to achieve the World Health Organisation (WHO) target of 75% in high risk groups before 2010. It was also noted that the changing demographic profile of the EU population would result in an increasing number of elderly people falling within the current target groups. OBJECTIVES: To establish the number of people who may be eligible for influenza vaccination in the EU, and estimate the costs and consequences of not vaccinating this population for five EU Member States, France, Germany, Italy, Spain, and the UK. METHODS: A mathematical model has previously been developed, in which vaccine distribution data are combined with demographic and health economics data to model the public health consequences of influenza and possible intervention strategies. We have extended that model using specific EU-25 demographic data on populations at risk of influenza during the inter-pandemic period. For each country, the total population and age breakdown was calculated to estimate the percentage of the population that falls under the WHA recommendations. Other target groups for influenza vaccination were identified by analysing estimating the proportion of the population with respiratory or cardiovascular related diseases, diabetes, AIDS or transplantation, as well as health care professionals. Target population size and possible vaccination coverage rates across the EU-25 Member States, along with the potential cost and health consequence impact is estimated. RESULTS: For the EU-25, it was estimated that up to 49.1% of the population (or 223.4 million people) should be vaccinated against influenza. This ranged from 41.6% in Cyprus to 56.4% in the UK. There were, on average, 174 vaccine doses distributed per 1000 population within the EU-25, which leads to an average vaccination rate of the target population of 35.4% based on current supply constraints. As a consequence, up to 144.4 million people who could be considered "at risk" may not currently be vaccinated. Implementing a 100% vaccination rate programme for all risk groups across the EU-25 would lead to an estimated reduction of number of influenza cases of 7.22 million, 1.96 million reduced PCP visits for influenza treatment, 796,743 less hospital admissions and 68,537 fewer influenza related deaths for all EU-25 countries. The implementation of a 100% vaccination rate programme for all risk groups in France, Germany, Italy, Spain and UK would require an additional 1.52 billion Euro. This would result in estimated savings of 39.45 million Euro of reduced primary care visits and further savings of 1.59 billion Euro in reduced hospitalisations respectively in these countries. CONCLUSIONS: There is a gap between current vaccination coverage and the EU recommendations. The public health consequences of low vaccination coverage include increased morbidity, hospitalisations and mortality associated with influenza-related complications. This model is a powerful tool to: (1) support EU public health officials in implementing recommendations; (2) to visualize the need for increased vaccination rates for better influenza control; (3) the consequences of low vaccine coverage.

The virosome concept for influenza vaccines.

There is a need for more efficacious inactivated influenza vaccines, since current formulations show suboptimal immunogenicity in at-risk populations, like the elderly. More effective vaccines are also urgently needed for an improved influenza pandemic preparedness. In this context, there is considerable interest in virosomes. Virosomes are virus-like particles, consisting of reconstituted influenza virus envelopes, lacking the genetic material of the native virus. Virosomes are produced from influenza virus through a detergent solubilization and removal procedure. Properly reconstituted virosomes retain the cell binding and membrane fusion properties of the native virus, mediated by the viral envelope glycoprotein haemagglutinin. These functional characteristics of virosomes form the basis for their enhanced immunogenicity. First, the repetitive arrangement of haemagglutinin molecules on the virosomal surface mediates a cooperative interaction of the antigen with Ig receptors on B lymphocytes, stimulating strong antibody responses. In addition, virosomes interact efficiently with antigen-presenting cells, such as dendritic cells, resulting in activation of T lymphocytes. In a murine model system, virosomes, as compared to conventional subunit vaccine, which consists of isolated influenza envelope glycoproteins, induce a more balanced T helper 1 versus T helper 2 response, virosomes in particular eliciting stronger T helper 1 responses than subunit vaccine. Also, as a result of fusion of the virosomes with the endosomal membrane, part of the virosomal antigen gains access to the major histocompatibility class I presentation pathway, thus priming cytotoxic T lymphocyte activity. Finally, virosomes represent an excellent platform for inclusion of lipophilic adjuvants for further stimulation of vaccine immunogenicity. By virtue of these characteristics, virosomes represent a promising novel class of inactivated influenza vaccines, which not only induce high virus-neutralizing antibody titres, but also prime the cellular arm of the immune system.

Modeling pandemic preparedness scenarios: health economic implications of enhanced pandemic vaccine supply.

Influenza pandemic planning is a complex, multifactorial process, which involves public health authorities, regulatory authorities, academia and industry. It is further complicated by the unpredictability of the time of emergence and severity of the next pandemic and the effectiveness of influenza epidemic interventions. The complexity and uncertainties surrounding pandemic preparedness have so far kept the various stakeholders from joining forces and tackling the problem from its roots. We developed a mathematical model, which shows the tangible consequences of conceptual plans by linking possible pandemic scenarios to health economic outcomes of possible intervention strategies. This model helps to structure the discussion on pandemic preparedness and facilitates the translation of pandemic planning concepts to concrete plans. The case study for which the model has been used shows the current level of global pandemic preparedness in an assumed pandemic scenario, the health economic implications of enhanced pandemic vaccine supply and the importance of cell culture-based influenza vaccine manufacturing technologies as a tool for pandemic control.