Michael K. Woodward

Grifols (Spain)

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Antonio Páez

Grifols (Spain)

Miquel Barceló

Grifols (Spain)

Mauro Salizzoni

Azienda Ospedaliera Citta' della Salute e della Scienza di Torino

Toshko Lissitchkov

National Specialized Hospital for Active Treatment of Hematologic Diseases

Paolo De Simone

University of Pisa

PŁ

Paweł Łaguna

Medical University of Warsaw

Michał Matysiak

Medical University of Warsaw

José A. Aznar

Instituto de Investigación Sanitaria La Fe

Marco Ranucci

IRCCS Policlinico San Donato

Liana Gercheva

University Hospital St. Marina

Cooperative Institutions

Grifols (Spain)

Bellvitge University Hospital

Institut d'Investigació Biomédica de Bellvitge

Instituto de Salud Carlos III

IRCCS Policlinico San Donato

University of Turin

Mon Health Medical Center

Dartmouth College

Hospital Universitari i Politècnic La Fe

Sociedad Española de Trombosis y Hemostasia

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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Preoperative Antithrombin Supplementation in Patients at Risk for Antithrombin Deficiency After Cardiac Surgery

Anesthesia & Analgesia (2022)

Michael G. Moront Michael K. Woodward Michael Essandoh Edwin G. Avery T. Brett Reece

BACKGROUND: Antithrombin (AT) activity is reduced during cardiac operations with cardiopulmonary bypass (CPB), which is associated with adverse outcomes. Preoperative AT supplementation, to achieve >58% and <100% AT activity, may potentially reduce postoperative morbidity and mortality in cardiac operations with CPB. This prospective, multicenter, randomized, double-blind, placebo-controlled study was designed to evaluate the safety and efficacy of preoperative treatment with AT supplementation in patients at risk for low AT activity after undergoing cardiac surgery with CPB. METHODS: A total of 425 adult patients were randomized (1:1) to receive either a single dose of AT (n = 213) to achieve an absolute increase of 20% above pretreatment AT activity or placebo (n = 212) before surgery. The study duration was approximately 7 weeks. The primary efficacy end point was the percentage of patients with any component of a major morbidity composite (postoperative mortality, stroke, acute kidney injury [AKI], surgical reexploration, arterial or venous thromboembolic events, prolonged mechanical ventilation, and infection) in the 2 groups. Secondary end points included AT activity, blood loss, transfusion requirements, duration of intensive care unit (ICU), and hospital stays. Safety was also assessed. RESULTS: Overall, 399 patients (men, n = 300, 75.2%) with a mean (standard deviation [SD]) age of 66.1 (11.7) years, with the majority undergoing complex surgical procedures (n = 266, 67.9%), were analyzed. No differences in the percentage of patients experiencing morbidity composite outcomes between groups were observed (AT-treated 68/198 [34.3%] versus placebo 58/194 [29.9%]; P = .332; relative risk, 1.15). After AT infusion, AT activity was significantly higher in the AT group (108% [42–143]) versus placebo group (76% [40–110]), and lasted up to postoperative day 2. At ICU, the frequency of patients with AT activity ≥58% in the AT group (81.5%) was significantly higher ( P < .001) versus placebo group (43.2%). Secondary end point analysis did not show any advantage of AT over placebo group. There were significantly more patients with AKI ( P < .001) in the AT group (23/198; 11.6%) than in the placebo group (5/194, 2.6%). Safety results showed no differences in treatment-emergent adverse events nor bleeding events between groups. CONCLUSIONS: AT supplementation did not attenuate adverse postoperative outcomes in our cohort of patients undergoing cardiac surgery with CPB.

Multicenter trial

Stroke

Clinical endpoint

10.1213/ane.0000000000006145

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Citations (7)

Head‐to‐head comparison of the pharmacokinetic profiles of a high‐purity factor IX concentrate (AlphaNine^®) and a recombinant factor IX (BeneFIX^®) in patients with severe haemophilia B

Haemophilia (2013)

Toshko Lissitchkov Michał Matysiak K. Zavilska Paweł Łaguna Liana Gercheva

Summary Head‐on comparative studies of factor IX (FIX) concentrates performed under standardized conditions are rarely conducted regardless of being a valuable instrument guiding health care providers towards better informed and cost‐effective decisions. This study is an extension of a multicentre study that assessed the efficacy, safety and pharmacokinetics ( PK ) of AlphaNine ® in 25 previously treated patients with severe haemophilia B (FIX:C ≤ 2%). After a washout period ≥7 days following the last PK performed with AlphaNine ® after a dose of 65–75 IU kg −1 , an identical PK study was performed with BeneFIX ® on 22 of the same patients. Venous blood samples for analysis were taken at baseline and at 0.25, 0.5, 1, 3, 6, 9, 24, 48, 72 and 74 h post infusion. The outcomes of the comparison of the PK parameters were as follows: Mean (± SD ) in vivo recovery ( IVR ) was 1.3 ± 0.4 IU dL −1 per IU kg −1 for AlphaNine ® and 1.0 ± 0.3 IU dL −1 per IU kg −1 for BeneFIX ® ( P < 0.01). Mean terminal half‐life, mean residence time, area under the curve, clearance and volume of distribution of BeneFIX ® were 36.0 ± 12.8 h, 39.3 ± 13.9 h, 1631 ± 467 IU h dL −1 , 0.046 ± 0.01 dL kg −1 min −1 and 1.75 ± 0.52 mL kg −1 respectively. These values were not significantly different to those observed in AlphaNine ® , although BeneFIX ® displayed higher than expected IVR values and lower than expected clearance values. In conclusion, AlphaNine ® showed a comparable half‐life, but an IVR significantly higher than that of BeneFIX ® . This dissimilarity may have implications on dosing requirements for on‐demand treatment regimes affecting optimal resource allocation.

Haemophilia B

Factor IX

10.1111/hae.12148

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Citations (27)

Efficacy and safety of Niuliva^® immune globulin to prevent hepatitis B reinfection in de novo orthotopic liver transplant

Future Virology (2019)

Paolo De Simone Mauro Salizzoni Umberto Cillo Fabrizio Di Benedetto Michael K. Woodward

Aims: To determine efficacy and safety of intravenous hepatitis B immune globulin (Niuliva®, Grifols) to prevent reinfection in de novo orthotopic liver transplantation. Patients & methods: In a nonrandomized, noncontrolled and Phase III clinical trial, 15 adult patients (12 men) were treated with Niuliva from the anhepatic phase (10,000 IU/daily 1 week postsurgery) up to 6 or 12 months (5000 IU/weekly 1 month; 5000 IU/monthly thereafter). Results: No patients showed reinfection throughout the study. Niuliva was effective in maintaining antibody titers above the thresholds recommended by the European Medicines Agency (EMA) to prevent reinfection (100–150 IU/l). Four serious adverse events were reported in three patients (none related to the study product). There were no seroconversions and no deaths. Conclusion: Long-term, high-dose Niuliva administration was safe and effective to prevent graft reinfection in the tested patients.

Hepatitis B

Hepatitis C

10.2217/fvl-2018-0139

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Absence of Inhibitor Development in the Routine Clinical Use of Alphanate® in Patients with Severe Hemophilia A: Results From a Long-Term Post-Marketing Surveillance Study.

Blood (2009)

Charles L. Sexauer Yasmin Ayob Madeline Cantini Miguel A. Escobar Tamiko Fukuda

Tolerability

Clinical endpoint

Postmarketing surveillance

Factor IX

10.1182/blood.v114.22.3141.3141

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Citations (1)

Plasma exchange with albumin replacement and disease progression in amyotrophic lateral sclerosis: a pilot study

Neurological Sciences (2021)

Mónica Povedano Andrés Paipa Miquel Barceló Michael K. Woodward Sandra Ortega

Abstract Background Plasma exchange (PE) is used to treat a range of neurological disorders. Based on results demonstrated in Alzheimer’s disease, we theorized that PE with albumin replacement (PE-A) might alter the metabolic profile of plasma and cerebrospinal fluid in patients with amyotrophic lateral sclerosis (ALS) by removing disease-inducing molecules. The aim of this study was to evaluate the effect of PE-A on disease progression in ALS. Methods In this open-label, non-controlled, single-arm, prospective pilot study, 13 adults with ALS had 6 months’ treatment with PE-A 5% and 6 months’ follow-up. Primary endpoints were changes from baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score and forced vital capacity (FVC) through 48 weeks. A post hoc analysis compared individual patient data with the expected ALSFRS-R progression slope. Results The median ALSFRS-R score declined throughout the study, although the rate of decline was slower than expected in seven patients at treatment end and in five patients at study end. Six patients remained in the same baseline slope progression category, and four patients improved their slope category at treatment end. Median FVC decreased significantly during the study. Treatment was well tolerated. Of 330 PE-A procedures, 0.9% were associated with potentially related adverse events. Conclusion Although functional impairment progressed, about two-thirds of patients showed a slower than expected rate of decline at treatment end. Most patients had unaltered (54.5%) or reduced (36.4%) ALSFRS-R slope progression at treatment end. Further evaluation of PE-A in controlled studies involving more patients is warranted. EudraCT number 2013-004842-40. Trial registration ClinicalTrials.gov identifier: NCT02479802.

Post-hoc analysis

Vital capacity

10.1007/s10072-021-05723-z

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Citations (3)

Efficacy, safety, and pharmacokinetics of intramuscular hepatitis B immune globulin, Igantibe®, for the prophylaxis of viral B hepatitis after liver transplantation

Digestive and Liver Disease (2009)

Franco Filipponi A Franchello Paola Carrai Renato Romagnoli Paolo De Simone

Tolerability

Hepatitis B

Intramuscular injection

Liver disease

10.1016/j.dld.2009.09.005

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Citations (13)

Efficacy and Safety of Plasma Exchange with Albumin Replacement as a Therapy for Amyotrophic Lateral Sclerosis

Plasmatology (2022)

Dennis Obat Mirjana Stevanovic Catherine Andrews Elsa Mondou Zbigniew M. Szczepiorkowski

Background: Neuroinflammation is being increasingly recognized as a key factor in the pathogenesis of amyotrophic lateral sclerosis (ALS). A therapeutic approach for ALS using plasma exchange with albumin replacement (PE-A) has been proposed to remove antibody complexes, inflammatory mediators, and toxins to decrease neuronal damage caused by inflammation. Methods: In this pilot study, 15 patients underwent 24 weeks of PE-A with 5% albumin and their revised ALS Functional Rating Scale (ALSFRS-R) scores and Forced Vital Capacity (FVC) were tracked for 48 weeks to evaluate the efficacy of PE-A as a therapy for ALS. Results: There was a statistically significant decline of ALSFRS-R scores as well as FVC (%) throughout the study. A post hoc comparison with clinically matched control patients showed no statistically significant difference. Likewise, no significant differences were found when the rate of ALSFRS-R decline in the PE-A-treated patients was compared to the European Medicines Agency (EMA) guideline estimate of a −1 point/month decrease in untreated patients. However, 50% of the PE-A-treated patients showed a slow rate of decline of < −0.8 points/month. PE was safe and well tolerated in ALS patients. Conclusion: In conclusion, results of this study indicated that PE-A performed in this manner was safe but showed a considerable heterogeneity in the response to treatment when it comes to slowing the ALS deterioration, with no overall clinical benefit. Further investigation focused on the characterization of ALS patients suitable for PE-A therapy is warranted. Registration: ClinicalTrials.gov ID: NCT02872142.

Post-hoc analysis

Post hoc

Vital capacity

10.1177/26348535221114460

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Citations (0)

Preoperative antithrombin supplementation in cardiac surgery: A randomized controlled trial

Journal of Thoracic and Cardiovascular Surgery (2012)

Marco Ranucci Ekaterina Baryshnikova Giulia Beatrice Crapelli Michael K. Woodward Antonio Páez

10.1016/j.jtcvs.2012.09.061

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Citations (38)

An analysis of the impact of offset requirements on the U.S. and defense industry

Michael K. Woodward

Abstract : The purpose of this thesis is to determine if offset agreements, as a condition of sale of military articles, have an adverse effect on the U. S. national security and the defense industrial base. The effects of offset agreements are measured from the context of their implications for defense preparedness, competitiveness of U.S. defense companies in the world's arms market, levels of foreign dependence in U. S. weapon systems and the transfer of technology to foreign countries and competitors. Additionally, offset agreements are analyzed as a contributory factor to the globalization of the arms industry and its consequences on the existing defense industrial base evaluated. It is concluded that the future arms market will consist of increased transnational cooperation , requiring the U.S. defense industry to establish strong relationships with foreign counterparts to retain access to their markets. Additionally, the increase in arms producers in the world will challenge arms control efforts and require continued technological innovation to prevent the U.S. lead from eroding further.

Defense industry

Competitor analysis

Defence industry

Preparedness

Source

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Citations (1)

A clinical study assessing the pharmacokinetics, efficacy and safety of AlphaNine®, a high-purity factor IX concentrate, in patients with severe haemophilia B

Haemophilia (2011)

Toshko Lissitchkov Michał Matysiak K. Zavilska Paweł Łaguna Liana Gercheva

Summary. Effective treatment with factor IX (FIX) requires a thorough consideration of the properties of the concentrate to be used as replacement therapy, to date, the only available treatment for haemophilia B. The aim of the study was to determine the pharmacokinetics, clinical efficacy and safety in routine clinical use of AlphaNine®, a high-purity human FIX concentrate. This open, single-arm, multicentre, non-randomized trial included 25 subjects (age ≥ 12) with moderate/severe haemophilia B. Pharmacokinetics was assessed at baseline and after a 6-month follow-up. The degree of haemostasis control achieved was evaluated during a 12-month follow-up. Safety was evaluated in terms of tolerance, thrombogenicity, immunogenicity and viral safety. Mean recovery was 1.01 ± 0.19 IU dL−1 per IU kg−1 at baseline and 1.23 ± 0.34 IU dL−1 per IU kg−1 6 months later. Terminal half-life was 34.5 ± 6.2 h and 33.7 ± 5.4 h, respectively. Ratios of each parameter between the two pharmacokinetic studies were all close to 1. A total of 1,576,890 IU AlphaNine® were administered in 889 infusions (mean dose per infusion: 1774 IU; 3.2 infusions per month per patient). The main reasons for infusion were mild/moderate bleeding (62.3%) and prophylaxis (20.5% continuous, 15.6% intermittent). Overall, 93.0% of the efficacy assessments were rated as excellent/good and 88.8% of bleedings resolved after the first infusion. Twenty-one adverse events were reported in eight patients, none of which was considered related to the study medication. AlphaNine® showed a pharmacokinetic profile in agreement with that of other plasma-derived FIX concentrates and provides safe and clinically effective substitution therapy for patients with haemophilia B.

Haemophilia B

Factor IX

10.1111/j.1365-2516.2010.02470.x

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Citations (21)