Contact Activation Inhibitor, AB023, in Heparin-Free Hemodialysis: Results of a Randomized Phase 2 Clinical Trial

Blood ◽  
2021 ◽  
Author(s):  
Christina U. Lorentz ◽  
Erik I. Tucker ◽  
Norah G. Verbout ◽  
Joseph J Shatzel ◽  
Sven R Olson ◽  
...  
Keyword(s):  
Small Sample Size ◽  
Chronic Hemodialysis ◽  
Small Sample ◽  
Phase 2 ◽  
Contact Activation ◽  
Dialysis Dose ◽  
Double Blind ◽  
Phase 2 Clinical Trial ◽  
Stage Renal Disease ◽  
End Stage

End-stage renal disease (ESRD) patients on chronic hemodialysis have repeated blood exposure to artificial surfaces that can trigger clot formation within the hemodialysis circuit. Dialyzer clotting can lead to anemia despite erythropoietin and iron supplementation. Unfractionated heparin prevents clotting during hemodialysis, but it is not tolerated by all patients. Although heparin-free dialysis is performed, intradialytic blood entrapment can be problematic. To address this issue, we performed a randomized, double-blind, phase 2 study comparing AB023, a unique antibody that binds factor (F) XI and blocks its activation by factor XIIa but not by thrombin, to placebo in 24 patients with ESRD undergoing heparin-free hemodialysis (www.clinicaltrials.gov #NCT03612856). Patients were randomized to receive a single pre-dialysis dose of AB023 (0.25 or 0.5 mg/kg) or placebo in a 2:1 ratio and safety and preliminary efficacy were compared to placebo and to observations made prior to dosing within each treatment arm. AB023 administration was not associated with impaired hemostasis or other drug-related adverse events. Occlusive events requiring hemodialysis circuit exchange were less frequent and levels of thrombin-antithrombin complexes and C-reactive protein were lower after AB023 administration compared with data collected prior to dosing. AB023 also reduced potassium and iron entrapment in the dialyzers, consistent with less blood accumulation within the dialyzers. We conclude that despite the small sample size, inhibition of contact activation-induced coagulation with AB023 was well tolerated and reduced clotting within the dialyzer.

Safety and Efficacy of the Contact Activation Inhibitor AB023 in Patients with End-Stage Renal Disease on Chronic Hemodialysis: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Christina U Lorentz ◽  
Norah G Verbout ◽  
Joseph J Shatzel ◽  
Michael Wallisch ◽  
Brandon D Markway ◽  
...  
Keyword(s):  
Chronic Hemodialysis ◽  
Contact System ◽  
Clot Formation ◽  
Phase 2 ◽  
Access Site ◽  
Post Dose ◽  
Double Blind ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients

Background: End stage renal disease (ESRD) patients on chronic hemodialysis (HD) repeatedly have their blood exposed to artificial surfaces within the hemodialysis circuit, which triggers contact system-initiated coagulation. Clot formation within the HD circuit results in blood loss, decreased HD efficiency, and device circuit failure. Heparin reduces circuit clotting but it is not tolerated by all patients. Mounting experimental data suggest that contact system inhibition is antithrombotic without significantly compromising hemostasis. AB023 is a unique recombinant anti-factor (F) XI antibody that interferes with the interactions of FXI and FXII without inhibiting FXI activation by thrombin or the activation of FIX by activated FXI. This study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of AB023 in patients with ESRD on chronic HD. Methods: In this phase 2, randomized, double-blind, placebo-controlled, single-administration study, AB023 (0.25 or 0.5 mg/kg) or placebo was injected into the HD circuit of 24 ESRD patients at the start of heparin-free HD (NCT03612856). All patients underwent three pre-dose HD procedures and four monitored post-dose HD sessions. In total, the study encompassed 168 individual HD sessions, 72 of which occurred pre-dose and 96 of which occurred post-dose. Safety parameters, including time to hemostasis at HD access site, prothrombin time, physical examinations, vital signs, electrocardiograms, clinical chemistry, immunogenicity and other adverse events (AEs), were recorded. Clotting within the hemodialyzer circuit was assessed using a visual clotting scale by investigators who were blinded to treatment. The frequency of circuit clot obstructions requiring dialyzer exchange was also recorded. Pharmacokinetic and pharmacodynamic parameters, including activated partial thromboplastin times, were also assessed. The study was approved by an ethics review board and all subjects provided written informed consent. Results: AB023 demonstrated a favorable safety profile in ESRD patients. No drug-related AEs were noted. Clinically relevant bleeding did not occur in any patient, and the time to hemostasis at the HD access site was unchanged after AB023 administration. As expected, the aPTT was prolonged after AB023 administration, reaching saturation at both dose levels (about 2-fold prolongation) immediately after dosing, and remaining prolonged for up to 9 days with the high dose. Compared with pretreatment, the frequency of occlusive events requiring circuit exchange decreased by 68% and 50% in subjects given the 0.25 and 0.5 mg/kg AB023 respectively, while the number of occlusive events was numerically unchanged in the placebo arm. Likewise, the number of saline flushes required to maintain circuit patency decreased by 44% and 85%, and the incidence of high-grade clotting in the hemodialyzer as assessed by visual scoring decreased by 15% and 43% on day 1, 8% and 35% by day 3, and 0% and 19% by day 5 in the 0.25 and 0.5 mg/kg cohorts, respectively. Conclusions: Anticoagulation with AB023 was well-tolerated and reduced clot formation within the HD circuit of ESRD patients. These findings suggest that inhibiting contact system activation could reduce medical device-initiated blood clot formation in patients. Disclosures Lorentz: Aronora, Inc.: Current Employment. Verbout:Aronora, Inc.: Current Employment. Shatzel:Aronora, Inc.: Consultancy. Wallisch:Aronora, Inc.: Current Employment. Markway:Aronora, Inc.: Current Employment. Tucker:Aronora, Inc.: Current Employment. Gruber:Aronora, Inc.: Current Employment, Current equity holder in private company.

scholarly journals Usefulness of mycophenolate mofetil in Indian patients with C3 glomerulopathy

2018 ◽  
Vol 12 (4) ◽  
pp. 483-487 ◽  
Author(s):  
Joyita Bharati ◽  
Karalanglin Tiewsoh ◽  
Ashwani Kumar ◽  
Ritambhra Nada ◽  
Manish Rathi ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Small Sample Size ◽  
Initial Response ◽  
Immunosuppressive Agent ◽  
Small Sample ◽  
C3 Glomerulopathy ◽  
Standardized Treatment ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background C3 glomerulopathy (C3G) is a heterogeneous disease caused by alternative complement pathway abnormalities without any standardized treatment. An immunosuppressive agent, mycophenolate mofetil (MMF), has been recently shown to be useful in treating C3G, mainly in studies from the west. We report the clinical outcome of 17 Indian C3G patients treated with MMF with or without steroids. Methods The clinical and histology details of the C3G patients treated with MMF for at least 6 months with a follow-up of at least 12 months were retrieved from the medical records of our center. Results The median serum creatinine and proteinuria at presentation were 0.8 mg/dL and 3.7 g/day, respectively, with the majority (88.2%) presenting as nephrotic syndrome. The mean dose of MMF was 1.65 (±0.56) g/day, and the median duration of MMF therapy was 18 months. Two-thirds (64%) of the patients responded to the treatment, with complete remission in 4 (23%) and partial remission in 7 (41%) (median time: 9 months). Three patients progressed to end-stage renal disease (ESRD) on follow-up. Of the three patients, one (33%) had an initial response in proteinuria to MMF but did not respond after a relapse and subsequently progressed to ESRD and two (67%) other patients were nonresponsive to MMF from the start of the therapy. Conclusion Despite a small sample size and lack of a control arm, this study describes the effectiveness of MMF in treating C3G patients from Asia and forms a basis for future randomized trials.

MO136RELATIONSHIP BETWEEN UPCR AND EGFR IN C3 GLOMERULOPATHY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Carla Nester ◽  
Patrick Breheny ◽  
Monica Hall ◽  
Alan Charney ◽  
Martin Lefkowitz ◽  
...  
Keyword(s):  
Natural History ◽  
Small Sample Size ◽  
Continuous Variable ◽  
Small Sample ◽  
C3 Glomerulopathy ◽  
University Of Iowa ◽  
History Of ◽  
Stage Renal Disease ◽  
End Stage ◽  
The Relationship

Abstract Background and Aims Considerable knowledge gaps exist in our understanding of the natural history of C3 glomerulopathy (C3G). Disease rarity, multiple nomenclature changes, and the inclusion of dissimilar cases in historical cohorts have precluded retrospective studies to define the natural course of C3G and identify risks for progression to kidney failure (end stage renal disease/ESRD). In the present analysis, we focus on C3G patients with native kidneys and examine the relationship between reductions in UPCR and disease progression as indicated by changes in eGFR. Method Patients included in this study were consented and enrolled in the University of Iowa C3G ReCom Registry, which was created in 2013. Beginning in 2017, complement activity and renal function data were collected prospectively at approximately 6-month intervals to define the natural history of C3G. Analyses were performed across 1-year periods of time (“spans”). To be included in a span, a patient had to meet the following criteria at the start of the 1-year period: native C3G, eGFR ≥30 mL/min/1.73 m2, UPCR ≥1 g/g and ≥12 years of age. An individual patient could be included in more than one span. Results Analyses were performed using 34 one-year spans for 24 patients who met inclusion criteria at the beginning of the 1-year span. Baseline characteristics for the 34 spans were: male, 59%; mean age, 22.7 years; mean eGFR, 83.1 ml/min/1.73m2; mean UPCR, 2.86 g/g; mean plasma C3, 75.1 mg/dL. Similar analyses using only the first 1-year span for each of the 24 patients produced results that were consistent with those generated using all 1-year spans. Limitations of this study include its small sample size and data variability due to its observational nature. Conclusion The findings of this observational study support the premise that reductions in proteinuria are associated with a more stable eGFR in native kidney C3G. Regression analyses using UPCR as a continuous variable demonstrate the relationship between reduction in UPCR and preservation of eGFR. This association was also observed using both change in eGFR by UPCR reduction subgroup and UPCR-eGFR categorical analyses.

scholarly journals A Phase 2 Trial of the Protein C Activator AB002 in End-Stage Renal Disease Patients on Chronic Hemodialysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 669-669
Author(s):  
Norah G Verbout ◽  
Christina U Lorentz ◽  
Brandon D Markway ◽  
Michael Wallisch ◽  
Joseph J Shatzel ◽  
...  
Keyword(s):  
End Stage Renal Disease ◽  
Protein C ◽  
Drug Exposure ◽  
Bleeding Risk ◽  
Chronic Hemodialysis ◽  
Phase 2 ◽  
Stage Renal Disease ◽  
End Stage ◽  
Dose Levels ◽  
Esrd Patients

Abstract Background: During hemodialysis of patients with renal failure, thrombi that form within the dialyzer circuit cause blood entrapment, blood loss, reduced dialysis efficiency and may require dialyzer changeouts. Anticoagulation with heparin is effective in preventing clot formation within the circuit, but is contraindicated in a subset of end-stage renal disease (ESRD) patients on chronic hemodialysis due to bleeding risk or heparin intolerance. A safe, short-acting alternative to heparin is an unmet need for this patient population, and for others suffering from or at risk of thrombosis. AB002 is a first-in-class protein C activator thrombin analog that targets to the thrombus interface and generates endogenous activated protein C (APC) without cleaving prothrombotic substrates. In a preclinical baboon thrombosis model, AB002 rapidly interrupted thrombus development with no observable hemostasis impairment, and was similar in antithrombotic efficacy to high-dose enoxaparin while appearing superior to interventional tissue-plasminogen activator. This proof-of-concept phase 2 clinical trial was designed to evaluate the safety, tolerability, efficacy, and pharmacodynamics of AB002 as a heparin alternative for ESRD patients. Methods: In this phase 2, randomized, double-blind, placebo-controlled study, a single dose of AB002 (1.5 µg/kg or 3 µg/kg) or placebo was infused into the hemodialysis line over four hours in 36 ESRD patients undergoing heparin-free hemodialysis (NCT03963895). Patients underwent five sequential heparin-free hemodialysis sessions over a period of 10 days, with three occurring prior to dosing, one on the day of dosing, and one after dosing. A total of 179 hemodialysis sessions were evaluated. Safety parameters were recorded throughout the study and immunogenicity to AB002 or thrombin was monitored by validated assays. Clotting within the dialyzer circuit was visually assessed and the number of occlusive events requiring a changeout of the circuit recorded. Circulating plasma APC-protein C inhibitor complexes (APC-PCI) and thrombin-antithrombin (TAT) complexes, markers of drug exposure and thrombin generation, respectively, were quantified by ELISA. This study was approved by the local ethics review board and all patients provided informed consent. Results: AB002 demonstrated a favorable safety profile, with no treatment-related adverse events. Clinically relevant bleeding did not occur in any patient and the time to hemostasis at the vascular access site was not affected by AB002. There was no evidence of AB002-induced anti-drug or anti-thrombin antibodies at 14 days post-dose. The frequency of occlusive events requiring circuit changeouts was 13.9% (21/155) on days in which AB002 was not administered, compared to 0% (0/12) and 8.3% (1/12) at the 1.5 µg/kg and 3 µg/kg dose levels, respectively. Compared to placebo, the incidence of high-grade clotting in the hemodialyzer decreased by 49% and 62% at the 1.5 µg/kg and 3 µg/kg AB002 dose levels, respectively. Hemodialysis increased TAT levels measured at the end of hemodialysis approximately 12-fold over baseline in patients given placebo. By contrast, AB002 attenuated TAT generation to 4-fold and 2-fold over baseline at the 1.5 µg/kg and 3 µg/kg dose levels, respectively. Hemodialysis-induced TAT generation was not different across groups on non-dosing days. Drug exposure was confirmed by a transient, dose-dependent elevation of circulating APC-PCI complexes following AB002 administration. Conclusions: In ESRD patients undergoing heparin-free hemodialysis, AB002 was well-tolerated and reduced thrombus accumulation in the hemodialysis circuit without observable hemostasis impairment. The results of this study support further clinical evaluation of AB002 as a novel drug candidate to limit thrombus development or device-initiated clotting in patients with elevated bleeding risk, including ESRD patients on chronic heparin-free hemodialysis. Disclosures Verbout: Aronora, Inc.: Current Employment. Lorentz: Aronora, Inc.: Current Employment. Markway: Aronora, Inc.: Current Employment. Wallisch: Aronora Inc,: Current Employment. Shatzel: Aronora Inc,: Consultancy. Gruber: Aronora Inc.: Current Employment, Current equity holder in publicly-traded company; Oregon Health and Science University: Current Employment.

Treatment with Cinacalcet in Hemodialysis Patients with Severe Secondary Hyperparathyroidism, Influences Bone Mineral Metabolism and Anemia Parameters

2020 ◽  
Vol 15 (3) ◽  
pp. 249-263
Author(s):  
Maria Aktsiali ◽  
Theodora Papachrysanthou ◽  
Ioannis Griveas ◽  
Christos Andriopoulos ◽  
Panagiotis Sitaras ◽  
...  
Keyword(s):  
Bone Mineral ◽  
Mineral Metabolism ◽  
Treatment Options ◽  
Dry Weight ◽  
Chronic Hemodialysis ◽  
Protective Agent ◽  
Positive Correlation ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients

Background: Due to the premium rate of Chronic Kidney Disease, we have increased our knowledge with respect to diagnosis and treatment of Bone Mineral Disease (BMD) in End- Stage Renal Disease (ESRD). Currently, various treatment options are available. The medication used for Secondary Hyper-Parathyroidism gives promising results in the regulation of Ca, P and Parathormone levels, improving the quality of life. The aim of the present study was to investigate the relation of cinacalcet administration to not only parathormone, Ca and P but also to anemia parameters such as hematocrit and hemoglobin. Materials and Methods: retrospective observational study was conducted in a Chronic Hemodialysis Unit. One-hundred ESRD patients were recruited for twenty-four months and were evaluated on a monthly rate. Biochemical parameters were related to medication prescribed and the prognostic value was estimated. Cinacalcet was administered to 43 out of 100 patients in a dose of 30-120 mg. Results: Significant differences were observed in PTH, Ca and P levels with respect to Cinacalcet administration. Ca levels appeared to be higher at 30mg as compared to 60mg cinacalcet. Furthermore, a decreasing age-dependent pattern was observed with respect to cinacalcet dosage. A positive correlation was observed between Dry Weight (DW) and cinacalcet dose. Finally, a positive correlation between Hematocrit and Hemoglobin and cinacalcet was manifested. Conclusions: Cinacalcet, is a potential cardiovascular and bone protective agent, which is approved for use in ESRD patients to assist SHPT. A novel information was obtained from this study, regarding the improvement of the control of anemia.

447-P: The Efficacy and Safety Trial of ENERGI-F703 in Diabetic Wound Healing: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Clinical Trial

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 447-P
Author(s):  
GUANG-HUAR YOUNG ◽  
JIUN-TSAI LIN ◽  
YI-FANG CHENG ◽  
HAN-MIN CHEN ◽  
CHUN-FANG HUANG
Keyword(s):  
Clinical Trial ◽  
Wound Healing ◽  
Diabetic Wound ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Phase 2 Clinical Trial ◽  
Diabetic Wound Healing

L-Carnitine Consecutively Administered to Patients on Hemodialysis Improves Beta-Cell Response

2003 ◽  
Vol 26 (4) ◽  
pp. 304-307 ◽  
Author(s):  
E. Vazelov ◽  
A-M. Borissova ◽  
G. Kirilov ◽  
B. Assenova ◽  
M. Tchetirska ◽  
...  
Keyword(s):  
Beta Cell ◽  
Chronic Hemodialysis ◽  
Dialysis Session ◽  
Carnitine Level ◽  
Peripheral Tissues ◽  
Before And After ◽  
Oxidative Processes ◽  
Stage Renal Disease ◽  
End Stage ◽  
Beta Cell Response

Eight patients with end stage renal disease (ESRD) on chronic hemodialysis (CHD) treatment were supplemented with 1 g L-carnitine intravenously (i.v.) after each dialysis session for one month. A Tolbutamide test was done and blood sugar (BS), serum C-peptide (CP) were measured at 0, 20 and 60 minutes, as well as the plasma L-carnitine level before and after treatment. Delta CP and the area under CP curve were ascertained. After L-carnitine application delta CP was significantly increased (1.33 ± 0.63 vs. 2.24 ± 1.0 nmol/L; p <0.05) and also the area of the stimulated secretion under the CP curve (14.93 ± 11.11 vs. 36.88 ± 25.36 nmol/L × 60 min.; p <0.05). The fasting BS-level was significantly lower after the treatment - 3.85 ± 0.43 vs. 4.76 ± 1.02 mmol/L; p <0.05 and plasma L-carnitine level significantly increased (72.8 ± 43.2 vs. 35.2 ± 18.3 mcmol/L; p <0.05) Improving the oxidative processes in peripheral tissues, L-carnitine increases the peripheral effectiveness of insulin and relieves the overstretched beta-cell apparatus.

scholarly journals Outcomes of Chronic Hemodialysis Patients in the Intensive Care Unit

2013 ◽  
Vol 2013 ◽  
pp. 1-7
Author(s):  
Melanie Chan ◽  
Marlies Ostermann
Keyword(s):  
Intensive Care Unit ◽  
Renal Function ◽  
Intensive Care ◽  
Kidney Injury ◽  
Chronic Hemodialysis ◽  
Current Evidence ◽  
Icu Outcome ◽  
Stage Renal Disease ◽  
End Stage

Patients with end-stage renal disease (ESRD) experience higher rates of hospitalisation, cardiovascular events, and all-cause mortality and are more likely to require admission to the intensive care unit (ICU) than patients with normal renal function. Sepsis and cardiovascular diseases are the most common reasons for ICU admission. ICU mortality rates in patients requiring chronic hemodialysis are significantly higher than for patients without ESRD; however, dialysis patients have a better ICU outcome than those with acute kidney injury (AKI) requiring renal replacement therapy suggesting that factors other than loss of renal function contribute to their prognosis. Current evidence suggests, the longer-term outcomes after discharge from ICU may be favourable and that long-term dependence on dialysis should not prejudice against prompt referral or admission to ICU.

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