scholarly journals Peak Thrombin and D-Dimer Levels in Subjects with Severe Hemophilia Receiving Acute Treatment for Bleeding Episodes Experienced during Prophylactic Marstacimab Treatment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Satyaprakash Nayak ◽  
Sangeeta Raje ◽  
John Teeter ◽  
Lutz Harnisch ◽  
Steven Arkin
Keyword(s):  
Bleeding Episode ◽  
Phase 2 ◽  
Bleeding Events ◽  
Post Hoc Analysis ◽  
On Demand ◽  
Increased Risk ◽  
Phase 2 Study ◽  
Bleeding Episodes ◽  
Post Hoc ◽  
D Dimer

Introduction: Marstacimab is a fully humanized monoclonal immunoglobulin G1 that targets the shared K2 domains of tissue factor pathway inhibitor (TFPI)α and (TFPI)β and is currently in phase 3 development. The intended indication is routine prophylaxis treatment to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B (with or without inhibitors). Factor replacement or bypass treatment for bleeding events may lead to increased levels of peak thrombin and D-dimer associated with an increased risk of thrombosis . In this post hoc analysis of data from a phase 2 study in patients with hemophilia with and without bleeding episodes, receiving prophylactic marstacimab treatment, peak thrombin and D-dimer levels were investigated to assess the changes in these biomarker levels observed after bleeding episodes. Methods: Individual subject data from the phase 2 study (clinicaltrials.gov identifier: NCT02974855)were used for this analysis. Biomarker data for healthy volunteers who received single doses of marstacimab in a phase 1 dose escalation study (clinicaltrials.gov identifier: NCT02531815) were used as control data, as these subjects represent an intact and uncompromised coagulation system. Study subjects in the phase 2 study received subcutaneous (SC) marstacimab at doses of (1) 150 mg once weekly (QW), with a loading dose of 300 mg, (2) 300 mg QW, and (3) 450 mg QW. All subjects with bleeding episodes were identified, along with on-demand treatment administered for each bleeding episode. Treatments permitted for bleeding episodes included activated coagulation factor VIIa, factor VIII, or factor IX; use of activated prothrombin complex concentrate was prohibited. D-dimer and peak thrombin data collected within 3 days after each bleeding episode were used for this analysis. Time profiles of peak thrombin and D-dimer levels were analyzed to assess the effect of bleed treatment. Biomarker profiles were compared between subjects with and without bleeding episodes, as well as with the data from healthy volunteers (n=41). Results: A total of 15 bleeding episodes were reported in 8 of 26 subjects during the study (excluding screening and follow-up). No subject participating in the study showed any relevant increases in D-dimer levels after receiving on-demand treatment for a bleeding episode while receiving regular prophylaxis with marstacimab, compared with levels seen in subjects who did not experience a bleeding episode. Based on the peak thrombin data (see Figure), 150 nM was observed as the upper limit for 18 of 26 subjects who did not experience any bleeding episodes, which was approximately 50% of the 300 nM observed in healthy volunteer controls treated with 450 mg intravenous marstacimab. Transient increases in peak thrombin of >150 nM were observed at several time points in 3 of 8 subjects who experienced bleeding episodes. The highest peak thrombin level reported was approximately 211 nM in one subject receiving marstacimab 300 mg SC QW and factor VIII concentrate on demand during the study. Conclusions: No transient increases in D-dimer could be attributed to the administration of bleeding episode treatment. The transient increases in peak thrombin levels following on-demand treatment for bleeding episodes did not exceed peak thrombin levels seen in subjects without bleeding events or the levels seen in healthy volunteer controls receiving single doses of marstacimab. Based on peak thrombin and D-dimer levels observed in this post hoc analysis, there does not appear to be any indication of an increased risk of thrombosis post administration of acute on-demand bleeding episode treatment while on prophylactic marstacimab therapy at the doses studied. Disclosures Nayak: Pfizer Inc.: Current Employment, Other. Raje:Pfizer Inc.: Current Employment, Other. Teeter:Pfizer Inc.: Current Employment. Harnisch:Pfizer Inc.: Current Employment, Other. Arkin:Pfizer: Current Employment, Current equity holder in publicly-traded company, Other: own stock/options in the company.

scholarly journals Thromboprophylaxis for Patients with Newly Diagnosed Vs. Recurrent Cancers: A Post-Hoc Analysis of the Avert Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3660-3660
Author(s):  
Marina Atalla ◽  
James Zhang ◽  
Ranjeeta Mallick ◽  
Philip S. Wells ◽  
Marc Carrier
Keyword(s):  
Major Bleeding ◽  
Research Funding ◽  
Bleeding Complications ◽  
Primary Efficacy ◽  
Newly Diagnosed ◽  
Recurrent Cancer ◽  
Post Hoc Analysis ◽  
Increased Risk ◽  
Bleeding Episodes ◽  
Post Hoc

Background: The risk of venous thromboembolism (VTE) is increased in cancer patients, which can result in significant increases in mortality, morbidity and healthcare expenditures. The recent AVERT trial (N Engl J Med 2019 Feb 21;380(8):711-719), showed that prophylactic apixaban lowered the rate of VTE when compared to placebo in cancer patients starting chemotherapy. However, the risk-benefit ratio of primary thromboprophylaxis in patients initiating chemotherapy for recurrent disease compared to those with newly diagnosed patients who are chemotherapy naïve is unknown. Methods: This is a post-hoc analysis of the AVERT trial. The AVERT trial assessed apixaban therapy vs. placebo for prophylaxis among patients with cancer who were intermediate-to-high risk for VTE (Khorana score ≥2; the Khorana score is ranged from 0 to 6 with higher scores reflecting an increased risk of VTE) and were initiating chemotherapy. It was a randomized, placebo-controlled, double-blind clinical trial. The primary efficacy outcome was VTE and the main safety outcomes were major bleeding episodes. Secondary outcome measures included clinically relevant non-major bleeding (CRNMB). The severity of major bleeding was stratified from category 1 to 4, with category 4 being the most severe type. We performed time-to-event analysis on the primary efficacy and main safety end-points in patients with recurrent and new diagnosed cancers. The hazard ratio (HR) for the outcomes were estimated using a Cox regression model controlling for age, gender, and center. Results: A total of 574 patients were randomized in the AVERT trial. 563 were included in the modified intention-to-treat analysis. 237 and 232 patients with newly diagnosed cancer were allocated to the apixaban and placebo groups, respectively. Similarly, 51 and 43 patients with recurrent cancer were allocated to the apixaban and placebo groups, respectively. Baseline demographics and clinical characteristics are depicted in Table 1A and Table 1B. In patients with newly diagnosed cancers, the use of apixaban was associated with a significantly lower risk of VTE (HR: 0.45; 95% CI: 0.27-0.76; p = 0.002) and a higher rate of major bleeding complications (HR: 2.10; 95% CI: 1.09-4.08; p = 0.028) but not of CRNMB (HR: 1.06; 95% CI: 0.61-1.82) (Table 2A). A majority of the major bleeding complications were of category 2. In patients with recurrent cancer, apixaban was associated with a significant lower rate of VTE (HR: 0.26; 95% CI: 0.13-0.53; p < 0.001) without an associated significant increased risk of major bleeding complication (HR: 1.82; 95% CI: 0.36-9.15; p = 0.466) but with a significant increase rate of CRNMB (HR: 2.78; 95% CI: 0.58-1.34; p = 0.006) (Table 2B). Major bleeding episodes were split evenly between severity category 1 and 2. Conclusion: The risk-benefit ratio of primary thromboprophylaxis with apixaban might differ between patients with recurrent or newly diagnosed cancers. Apixaban was associated with a lower rate of VTE compared to placebo in both groups. Patients with recurrent cancer initiating chemotherapy may potentially have a more favorable risk benefit profile, as shown through the HR and the prevalence of major bleeding episodes. However, more trials are required to confirm these findings to help tailor thromboprophylaxis in this patient population. (AVERT ClinicalTrials.gov number, NCT02048865.) Disclosures Wells: BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Honoraria. Carrier:Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Servier: Honoraria; Bayer: Honoraria; Pfizer: Honoraria, Research Funding. OffLabel Disclosure: Apixaban can be used as postoperative prophylaxis of DVT/PE and for treatment of DVT/PE. This study will show whether the prophylactic effects of apixaban will be more effective when used with patients with recurrent cancer or patients with newly diagnosed cancer.

scholarly journals Estimation of the correlates of protection of the rVSVΔG-ZEBOV-GP Zaire ebolavirus vaccine: a post-hoc analysis of data from phase 2/3 clinical trials

2021 ◽  
Vol 2 (2) ◽  
pp. e70-e78 ◽  
Author(s):  
Rebecca F Grais ◽  
Stephen B Kennedy ◽  
Barbara E Mahon ◽  
Sheri A Dubey ◽  
Rebecca J Grant-Klein ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase 2 ◽  
Post Hoc Analysis ◽  
Correlates Of Protection ◽  
Zaire Ebolavirus ◽  
Post Hoc

scholarly journals The “Gender Factor” in Wearing-Off among Patients with Parkinson’s Disease: A Post Hoc Analysis of DEEP Study

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Delia Colombo ◽  
Giovanni Abbruzzese ◽  
Angelo Antonini ◽  
Paolo Barone ◽  
Gilberto Bellia ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cross Sectional Study ◽  
Motor Symptom ◽  
Cross Sectional ◽  
Post Hoc Analysis ◽  
Increased Risk ◽  
Wearing Off ◽  
Gender Factor ◽  
Post Hoc

Background. The early detection of wearing-off in Parkinson disease (DEEP) observational study demonstrated that women with Parkinson’s disease (PD) carry an increased risk (80.1%) for wearing-off (WO). This post hoc analysis of DEEP study evaluates gender differences on WO and associated phenomena.Methods. Patients on dopaminergic treatment for ≥1 year were included in this multicenter observational cross-sectional study. In a single visit, WO was diagnosed based on neurologist assessment as well as the use of the 19-item wearing-off questionnaire (WOQ-19); WO was defined for scores ≥2. Post hoc analyses were conducted to investigate gender difference for demographic and clinical features with respect to WO.Results. Of 617 patients enrolled, 236 were women and 381 were men. Prevalence of WO was higher among women, according to both neurologists’ judgment (61.9% versus 53.8%,P=0.045) and the WOQ-19 analysis (72.5% versus 64.0%,P=0.034). In patients with WO (WOQ-19), women experienced ≥1 motor symptom in 72.5% versus 64.0% in men and ≥1 nonmotor symptom in 44.5% versus 36.7%, in men.Conclusions. Our results suggest WO as more common among women, for both motor and nonmotor symptoms. Prospective studies are warranted to investigate this potential gender-effect.

Efficacy of Dual Antiplatelet Treatment in Minor stroke or TIA Patients with Multiple Acute Infarctions and Lower Level of Stress Hyperglycemic Marker – A Post-hoc Analysis of a Randomized Control Trial

2020 ◽  
Author(s):  
Yue Suo ◽  
Jing Jing ◽  
Anxin Wang ◽  
Yijun Zhang ◽  
Hongyu Zhou ◽  
...  
Keyword(s):  
Minor Stroke ◽  
Efficacy And Safety ◽  
Antiplatelet Treatment ◽  
Bleeding Events ◽  
Vascular Events ◽  
Stress Hyperglycemia ◽  
Post Hoc Analysis ◽  
Acute Infarction ◽  
Post Hoc ◽  
Dual Antiplatelet Treatment

Abstract Background We intended to investigate how the interaction between glycemic status and infarction pattern affected the efficacy and safety of dual antiplatelet treatment in minor stroke or transient ischemic attack (TIA) patients.Methods This post-hoc analysis of the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) study included 797 patients with complete data of stress hyperglycemia markers (fasting plasma glucose (FPG)/glycated albumin (GA) ratio) and Magnetic Resonance Imaging work-up. The primary outcome is a 90-day new stroke (ischemic or hemorrhagic). Other endpoints included combined vascular events and bleeding events at 90 days. We used multivariable Cox regression models to evaluate the influence of stress hyperglycemia status × infarction pattern (Multiple acute infarctions (MAI), Single acute infarction (SAI) and No acute infarction (NAI)) on the efficacy and safety of clopidogrel plus aspirin treatment.Results Among 797 patients, the median age was 63.1 years, and 64.9% of the patients were male. Within the 90-day after randomization, 73 (9.2%) new strokes 75 (9.4%) combined vascular events, and 17 (2.1%) bleeding events occurred. Dual antiplatelet treatment significantly reduced new stroke and combined vascular events in patients with lower FPG/GA ratio (lower than the median of FPG/GA ratio) and multiple acute infarctions, after adjusted for all potential confounders (11.9% vs. 23.3%, adjusted HR(95% confidence interval, CI): 0.240(0.080–0.713)). No significant reductions of recurrence or occurrence of combined vascular events were seen in the other three groups (NAI or SAI with lower FPG/GA ratio; NAI or SAI with higher FPG/GA ratio and MA with higher FPG/GA ratio). The proportion of bleeding events was similar among treatment groups regardless of the FPG/GA ratio or infarction pattern.Conclusions Clopidogrel plus aspirin treatment was associated with reduced 90-day new stroke or combined vascular events in patients with multiple acute infarctions and lower FPG/GA ratio, without increasing the risk of bleeding events.

scholarly journals Intra-articular CNTX-4975 for osteoarthritis knee pain: subgroup and post hoc analyses of a randomized phase 2 study

2019 ◽  
Vol 27 ◽  
pp. S499
Author(s):  
R.M. Stevens ◽  
J.N. Campbell ◽  
K. Guedes ◽  
V.H. Smith ◽  
P.D. Hanson ◽  
...  
Keyword(s):  
Knee Pain ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Osteoarthritis Knee ◽  
Post Hoc ◽  
Randomized Phase 2
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