Ignite Creation Date:
2024-05-05 @ 11:42 AM
Last Modification Date:
2024-10-26 @ 9:12 AM
Study NCT ID:
NCT00113997
Status:
COMPLETED
Last Update Posted:
2008-03-04
First Post:
2005-06-11
Brief Title:
Safety and Dosing Evaluation of REG1 Anticoagulation System
Sponsor:
National Heart Lung and Blood Institute NHLBI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
The Healthy Volunteer Evaluation of an Aptamer-RNA Target to Factor IXa
Status:
COMPLETED
Status Verified Date:
2005-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This 1-week study will test the safety and dosing of an anticoagulation system called REG1 that is designed to improve control of blood thinning Patients with heart attack and other conditions require treatment with an anticoagulant blood thinner to prevent the formation of blood clots However anticoagulation therapy can increase the risk of bleeding The REG1 system is designed to minimize this risk One part of the system stops the activity of factor IX a protein that helps blood clot while the other part of the system the antidote inactivates the drug and stops the thinning process This study will examine in normal healthy subjects how the REG1 system works in the body and how it leaves the body
Healthy normal volunteers between 12 and 65 years of age who weigh 50-120 kilograms 110-264 pounds and have no history of bleeding problems or significant bleeding may be eligible for this study Candidates are screened with a medical history physical examination and blood tests
Participants must avoid foods that may alter the bloods clotting ability and must not take any medications the week of the study They undergo the following tests and procedures
Day 1
Subjects are admitted to the NIH Clinical Center for an overnight stay Two catheters plastic tubes are placed in the subjects arm veins one for drawing blood samples and the other for injecting one of the following REG1 drug REG1 antidote REG1 drug and antidote or placebo Two injections of study medication are given spaced 3 hours apart each over a 1-minute period After each injection blood is collected at specific times to measure levels of the drug or antidote in the body and the bloods ability to clot Subjects also provide a 24-hour urine collection and stool sample
Day 2
A blood sample is drawn 24 hours after the drug or antidote injection from the previous day If the blood test result is normal subjects are discharged home with instructions to follow They return to the Clinical Center at 36 hours and 48 hours for additional blood samples
Days 3 and 7
A blood sample is collected at the end of day 3 and day 7 Urine and stool samples are also collected
Healthy normal volunteers between 12 and 65 years of age who weigh 50-120 kilograms 110-264 pounds and have no history of bleeding problems or significant bleeding may be eligible for this study Candidates are screened with a medical history physical examination and blood tests
Participants must avoid foods that may alter the bloods clotting ability and must not take any medications the week of the study They undergo the following tests and procedures
Day 1
Subjects are admitted to the NIH Clinical Center for an overnight stay Two catheters plastic tubes are placed in the subjects arm veins one for drawing blood samples and the other for injecting one of the following REG1 drug REG1 antidote REG1 drug and antidote or placebo Two injections of study medication are given spaced 3 hours apart each over a 1-minute period After each injection blood is collected at specific times to measure levels of the drug or antidote in the body and the bloods ability to clot Subjects also provide a 24-hour urine collection and stool sample
Day 2
A blood sample is drawn 24 hours after the drug or antidote injection from the previous day If the blood test result is normal subjects are discharged home with instructions to follow They return to the Clinical Center at 36 hours and 48 hours for additional blood samples
Days 3 and 7
A blood sample is collected at the end of day 3 and day 7 Urine and stool samples are also collected
Detailed Description:
Given the central role of thrombosis in the pathobiology of acute ischemic heart disease injectable intravenous or subcutaneous anticoagulants have become the foundation of medical treatment for patients presenting with acute coronary syndromes unstable angina and myocardial infarction ACS and for those undergoing coronary revascularization procedures either percutaneously or surgically Harrington et al 2004 Popma et al 2004 Currently available anticoagulants include unfractionated heparin UFH the low molecular weight heparins LMWH and the direct thrombin inhibitors DTI eg recombinant hirudin bivalirudin and argatroban The present paradigm both for anticoagulant use and for continued antithrombotic drug development is to establish a balance between efficacy reducing the risk of ischemic events and safety minimizing the risk of bleeding Harrington et al 2004 Each of the available agents carries an increased risk of bleeding relative to placebo
The major adverse event associated with anticoagulant and antithrombotic drugs is bleeding which can cause permanent disability and death Ebbesen et al 2001 Levine et al 2004 Generally cardiovascular clinicians have been willing to trade off an increased risk of bleeding when a drug can reduce the ischemic complications of either the acute coronary syndromes or of coronary revascularization procedures However recent data have suggested that bleeding events particularly those that require blood transfusion have a significant impact on the outcome and cost of treatment of patients with ACS Transfusion rates in patients undergoing elective coronary artery bypass graft CABG surgery range from 30-60 and transfusion in these patients is associated with increased short medium and long-term mortality Bracey et al 1999 Engoren et al 2002 Hebert et al 1999 Bleeding is also the most frequent and costly complication associated with percutaneous coronary interventions PCI with transfusions being performed in 5-10 of patients at an incremental cost of 8000-12000 Moscucci 2002 In addition the frequency of significant bleeding in patients undergoing treatment for ACS is high as well ranging from 5 to 10 excluding patients who undergo CABG with bleeding and transfusion independently associated with a significant increase in short-term mortality Moscucci et al 2003 Rao et al 2004 Therefore despite the continued development of novel antithrombotics a significant clinical need exists for safer anticoagulant agents
For hospitalized patients with acute ischemic heart disease the ideal anticoagulant would be deliverable by intravenous or subcutaneous injection immediately effective easily dosed so as not to require frequent monitoring and immediately and predictably reversible
UFH is the only antidote-reversible anticoagulant currently approved for use However UFH has significant limitations First heparin has complex pharmacokinetics that make the predictability of its use challenging Granger et al 1996 Second the dose predictability of its antidote protamine is challenging and there are serious side effects associated with its use Carr and Silverman 1999 Welsby et al 2005 Finally heparin can induce thrombocytopenia HIT and thrombocytopenia with thrombosis HITT Warkentin 2005 Warkentin and Greinacher 2004
Despite these limitations heparin remains the most commonly used anticoagulant for hospitalized patients primarily because it is reversible Newer-generation anticoagulants such as the LMWHs have improved upon the predictability of UFH dosing and do not require lab-based monitoring as part of their routine use HIT and HITT are observed less frequently with the LMWHs relative to UFH but they have not eliminated this risk Two of the three commercially available DTIs lepirudin and argatroban are specifically approved for use in patients who have developed or have a history of HIT Bivalirudin is approved for use as an anticoagulant during PCI and therefore provides an attractive alternative to UFH in patients who have HIT However there are no direct and clear antidotes to reverse the anticoagulant effects of the LMWHs nor of the DTIs which presents a particular risk to their use in patients undergoing surgical or percutaneous coronary revascularization procedures Jones et al 2002 Bleeding in patients treated with LMWHs or DTIs is managed by administering blood products including clotting factor
Rapid reversal of drug activity can be achieved by formulation of a drug as an infusible agent with a short half-life or via administration of a second agent an antidote that can neutralize the activity of the drug Short-acting direct thrombin inhibitors such as bivalirudin which can be reversed simply by cessation of infusion are being developed as infusible anticoagulants for use in CABG surgery Merry et al 2004 However the co-morbidities such as renal dysfunction present in a large percentage of patients undergoing CABG or PCI procedures Al Suwaidi et al 2002 may preclude rapid clearance of the drug and thus delay reversal of activity andor the relatively large quantity of drug required to sustain anticoagulation ie necessary to achieve effective steady state levels of a short-half-life agent may significantly interact with underlying renal impairment to compound the problem Therefore it remains to be seen if these drugs will indeed achieve rapid reversal of anticoagulation following stoppage of infusion in the target patient populations and whether the clearance of the drug itself may exacerbate renal dysfunction
An alternative approach to providing controlled anticoagulation embraced by Regado Biosciences is the utilization of an anticoagulating agent with medium-term duration of action 12 hours that can achieve clinically appropriate activity at relatively low doses in combination with a second agent capable of specifically binding to and neutralizing the primary anticoagulant Such a drug-antidote combination can ensure predictable and safe neutralization and reversal of the anticoagulant activity of the drug Rusconi et al 2004 Rusconi et al 2002
The cell-based model of coagulation Hoffman et al 1995 Kjalke et al 1998 Monroe et al 1996 Figure 1 provides the clearest explanation to date of how physiologic coagulation occurs in vivo The advance of this model over prior descriptions of the coagulation reaction is that it incorporates the cellular surfaces upon which the specific coagulation factors accumulate and react and thereby more accurately explains the phenotypes observed in individuals lacking or deficient in the various coagulation factors and platelet receptors
According to this model the procoagulant reaction occurs in three distinct steps initiation amplification and propagation Initiation of coagulation takes place on tissue factor-bearing cells eg activated monocytes macrophages and endothelial cells Coagulation factor VIIa which forms a complex with tissue factor catalyzes the activation of coagulation factors IX FIX and X FX which in turn generates a small amount of thrombin from prothrombin In the amplification phase also referred to as the priming phase the small amount of thrombin generated in the initiation phase activates coagulation factors V VIII and XI and also activates platelets which supplies a surface upon which further procoagulant reactions occur In vivo the small amounts of thrombin generated during the amplification phase are not sufficient to convert fibrinogen to fibrin due to the presence of endogenous thrombin inhibitors termed serpins such as anti-thrombin III -2-macroglobulin and heparin cofactor II The final phase of the procoagulant reaction propagation occurs exclusively on the surface of activated platelets During propagation significant amounts of FIXa are generated by the FXIa-catalyzed activation of FIX FIXa forms a complex with its requisite cofactor FVIIIa which activates FX Subsequently FXa forms a complex with its requisite cofactor FVa The FXa-FVa complex activates prothrombin which leads to a burst of thrombin generation and fibrin deposition The end result is the formation of a stable clot
Based upon this model FIXa play two roles in coagulation In the initiation phase FIXa plays an important role in generating small amounts of thrombin via activation of FX to FXa and subsequent prothrombin activation However this role of FIXa is at least partially redundant with the tissue factor FVIIa-catalyzed conversion of FX to FXa The more critical role of FIXa occurs in the propagation phase in which the FVIIIaFIXa enzyme complex serves as the sole catalyst of FXa generation on the activated platelet surface Therefore a reduction in FIXa activity either due to genetic deficiency in FIX ie hemophilia B or pharmacologic inhibition of FIXIXa is expected to have several effects on coagulation First inhibition or loss of FIXa activity should partially dampen the initiation of coagulation Second inhibition or loss of FIXa activity should have a profound effect on the propagation phase of coagulation resulting in a significant reduction or elimination of thrombin production Finally limitation of thrombin generation during the propagation phase will at least partially quell feedback amplification of coagulation by reducing activation of platelets and upstream coagulation factors such as factors V VIII and XI
Inhibitors of FIX activity such as active site-inactivated factor IXa FIXai or monoclonal antibodies against FIX eg the antibody BC2 have exhibited potent anticoagulant and antithrombotic activity in multiple animal models including various animal models of arterial thrombosis and stroke Benedict et al 1991 Choudhri et al 1999 Feuerstein et al 1999 Spanier et al 1998a Spanier et al 1997 Spanier et al 1998b Toomey et al 2000 In general these studies have shown that FIXa inhibitors have a higher ratio of antithrombotic activity to bleeding risk than unfractionated heparin in animals However in these studies at doses marginally higher than the effective dose animals treated with these agents have exhibited bleeding profiles no different than heparin Such an experience in well-controlled animal studies suggests that in the clinical setting the ability to control the activity of a FIXa inhibitor would enhance its safety and facilitate its medical use In addition FIXai has been shown to be safe and effective as a heparin replacement in multiple animal surgical models requiring anticoagulant therapy including rabbit models of synthetic patch vascular repair as well as canine and non-human primate models of CABG with cardiopulmonary bypass Spanier et al 1998a Spanier et al 1997 Spanier et al 1998b FIXai has also been used successfully for several critically ill patients requiring cardiopulmonary bypass and in the setting of other extracorporeal circuits such as extracorporeal membrane oxygenation Spanier et al 1998a by physicians at the Columbia College of Physicians and Surgeons on a compassionate care basis Thus FIXa is a validated target for anticoagulant therapy in coronary revascularization procedures both CABG and PCI and for the treatment and prevention of thrombosis in patients suffering from acute coronary syndromes
The major adverse event associated with anticoagulant and antithrombotic drugs is bleeding which can cause permanent disability and death Ebbesen et al 2001 Levine et al 2004 Generally cardiovascular clinicians have been willing to trade off an increased risk of bleeding when a drug can reduce the ischemic complications of either the acute coronary syndromes or of coronary revascularization procedures However recent data have suggested that bleeding events particularly those that require blood transfusion have a significant impact on the outcome and cost of treatment of patients with ACS Transfusion rates in patients undergoing elective coronary artery bypass graft CABG surgery range from 30-60 and transfusion in these patients is associated with increased short medium and long-term mortality Bracey et al 1999 Engoren et al 2002 Hebert et al 1999 Bleeding is also the most frequent and costly complication associated with percutaneous coronary interventions PCI with transfusions being performed in 5-10 of patients at an incremental cost of 8000-12000 Moscucci 2002 In addition the frequency of significant bleeding in patients undergoing treatment for ACS is high as well ranging from 5 to 10 excluding patients who undergo CABG with bleeding and transfusion independently associated with a significant increase in short-term mortality Moscucci et al 2003 Rao et al 2004 Therefore despite the continued development of novel antithrombotics a significant clinical need exists for safer anticoagulant agents
For hospitalized patients with acute ischemic heart disease the ideal anticoagulant would be deliverable by intravenous or subcutaneous injection immediately effective easily dosed so as not to require frequent monitoring and immediately and predictably reversible
UFH is the only antidote-reversible anticoagulant currently approved for use However UFH has significant limitations First heparin has complex pharmacokinetics that make the predictability of its use challenging Granger et al 1996 Second the dose predictability of its antidote protamine is challenging and there are serious side effects associated with its use Carr and Silverman 1999 Welsby et al 2005 Finally heparin can induce thrombocytopenia HIT and thrombocytopenia with thrombosis HITT Warkentin 2005 Warkentin and Greinacher 2004
Despite these limitations heparin remains the most commonly used anticoagulant for hospitalized patients primarily because it is reversible Newer-generation anticoagulants such as the LMWHs have improved upon the predictability of UFH dosing and do not require lab-based monitoring as part of their routine use HIT and HITT are observed less frequently with the LMWHs relative to UFH but they have not eliminated this risk Two of the three commercially available DTIs lepirudin and argatroban are specifically approved for use in patients who have developed or have a history of HIT Bivalirudin is approved for use as an anticoagulant during PCI and therefore provides an attractive alternative to UFH in patients who have HIT However there are no direct and clear antidotes to reverse the anticoagulant effects of the LMWHs nor of the DTIs which presents a particular risk to their use in patients undergoing surgical or percutaneous coronary revascularization procedures Jones et al 2002 Bleeding in patients treated with LMWHs or DTIs is managed by administering blood products including clotting factor
Rapid reversal of drug activity can be achieved by formulation of a drug as an infusible agent with a short half-life or via administration of a second agent an antidote that can neutralize the activity of the drug Short-acting direct thrombin inhibitors such as bivalirudin which can be reversed simply by cessation of infusion are being developed as infusible anticoagulants for use in CABG surgery Merry et al 2004 However the co-morbidities such as renal dysfunction present in a large percentage of patients undergoing CABG or PCI procedures Al Suwaidi et al 2002 may preclude rapid clearance of the drug and thus delay reversal of activity andor the relatively large quantity of drug required to sustain anticoagulation ie necessary to achieve effective steady state levels of a short-half-life agent may significantly interact with underlying renal impairment to compound the problem Therefore it remains to be seen if these drugs will indeed achieve rapid reversal of anticoagulation following stoppage of infusion in the target patient populations and whether the clearance of the drug itself may exacerbate renal dysfunction
An alternative approach to providing controlled anticoagulation embraced by Regado Biosciences is the utilization of an anticoagulating agent with medium-term duration of action 12 hours that can achieve clinically appropriate activity at relatively low doses in combination with a second agent capable of specifically binding to and neutralizing the primary anticoagulant Such a drug-antidote combination can ensure predictable and safe neutralization and reversal of the anticoagulant activity of the drug Rusconi et al 2004 Rusconi et al 2002
The cell-based model of coagulation Hoffman et al 1995 Kjalke et al 1998 Monroe et al 1996 Figure 1 provides the clearest explanation to date of how physiologic coagulation occurs in vivo The advance of this model over prior descriptions of the coagulation reaction is that it incorporates the cellular surfaces upon which the specific coagulation factors accumulate and react and thereby more accurately explains the phenotypes observed in individuals lacking or deficient in the various coagulation factors and platelet receptors
According to this model the procoagulant reaction occurs in three distinct steps initiation amplification and propagation Initiation of coagulation takes place on tissue factor-bearing cells eg activated monocytes macrophages and endothelial cells Coagulation factor VIIa which forms a complex with tissue factor catalyzes the activation of coagulation factors IX FIX and X FX which in turn generates a small amount of thrombin from prothrombin In the amplification phase also referred to as the priming phase the small amount of thrombin generated in the initiation phase activates coagulation factors V VIII and XI and also activates platelets which supplies a surface upon which further procoagulant reactions occur In vivo the small amounts of thrombin generated during the amplification phase are not sufficient to convert fibrinogen to fibrin due to the presence of endogenous thrombin inhibitors termed serpins such as anti-thrombin III -2-macroglobulin and heparin cofactor II The final phase of the procoagulant reaction propagation occurs exclusively on the surface of activated platelets During propagation significant amounts of FIXa are generated by the FXIa-catalyzed activation of FIX FIXa forms a complex with its requisite cofactor FVIIIa which activates FX Subsequently FXa forms a complex with its requisite cofactor FVa The FXa-FVa complex activates prothrombin which leads to a burst of thrombin generation and fibrin deposition The end result is the formation of a stable clot
Based upon this model FIXa play two roles in coagulation In the initiation phase FIXa plays an important role in generating small amounts of thrombin via activation of FX to FXa and subsequent prothrombin activation However this role of FIXa is at least partially redundant with the tissue factor FVIIa-catalyzed conversion of FX to FXa The more critical role of FIXa occurs in the propagation phase in which the FVIIIaFIXa enzyme complex serves as the sole catalyst of FXa generation on the activated platelet surface Therefore a reduction in FIXa activity either due to genetic deficiency in FIX ie hemophilia B or pharmacologic inhibition of FIXIXa is expected to have several effects on coagulation First inhibition or loss of FIXa activity should partially dampen the initiation of coagulation Second inhibition or loss of FIXa activity should have a profound effect on the propagation phase of coagulation resulting in a significant reduction or elimination of thrombin production Finally limitation of thrombin generation during the propagation phase will at least partially quell feedback amplification of coagulation by reducing activation of platelets and upstream coagulation factors such as factors V VIII and XI
Inhibitors of FIX activity such as active site-inactivated factor IXa FIXai or monoclonal antibodies against FIX eg the antibody BC2 have exhibited potent anticoagulant and antithrombotic activity in multiple animal models including various animal models of arterial thrombosis and stroke Benedict et al 1991 Choudhri et al 1999 Feuerstein et al 1999 Spanier et al 1998a Spanier et al 1997 Spanier et al 1998b Toomey et al 2000 In general these studies have shown that FIXa inhibitors have a higher ratio of antithrombotic activity to bleeding risk than unfractionated heparin in animals However in these studies at doses marginally higher than the effective dose animals treated with these agents have exhibited bleeding profiles no different than heparin Such an experience in well-controlled animal studies suggests that in the clinical setting the ability to control the activity of a FIXa inhibitor would enhance its safety and facilitate its medical use In addition FIXai has been shown to be safe and effective as a heparin replacement in multiple animal surgical models requiring anticoagulant therapy including rabbit models of synthetic patch vascular repair as well as canine and non-human primate models of CABG with cardiopulmonary bypass Spanier et al 1998a Spanier et al 1997 Spanier et al 1998b FIXai has also been used successfully for several critically ill patients requiring cardiopulmonary bypass and in the setting of other extracorporeal circuits such as extracorporeal membrane oxygenation Spanier et al 1998a by physicians at the Columbia College of Physicians and Surgeons on a compassionate care basis Thus FIXa is a validated target for anticoagulant therapy in coronary revascularization procedures both CABG and PCI and for the treatment and prevention of thrombosis in patients suffering from acute coronary syndromes
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 05-H-0164 | None | None | None |