Study of Ciraparantag for Reversal of Anticoagulation Induced by Edoxaban, Apixaban or Rivaroxaban in Healthy Adults

Study Overview
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Brief Summary
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A randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of ciraparantag for reversal of anticoagulation induced by different anticoagulant drugs in generally healthy adults as measured primarily by an automated coagulometer device.

Detailed Description
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This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of ciraparantag for reversal of anticoagulation induced by different anticoagulant drugs (edoxaban, apixaban or rivaroxaban) in generally healthy adults. Throughout the study, coagulation status will be determined by whole blood clotting time (WBCT), which will be measured primarily by the Perosphere Technologies' PoC Coagulometer and at selected timepoints using a manual testing method. The study will be conducted in three separate cohorts; each cohort will evaluate the reversal of a different anticoagulant drug. Within each cohort, an initial group of subjects (Group 1) will be enrolled for evaluation of a target dose of ciraparantag. Depending on the efficacy and safety results from Group 1, a second group (Group 2) may be enrolled to evaluate a different dose of ciraparantag for that cohort.

Official Title
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A Phase 2 Randomized, Double-blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Ciraparantag for Reversal of Anticoagulation in Healthy Adults

Conditions
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Healthy

Intervention / Treatment
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* Drug: Ciraparantag
* Drug: Placebo
* Device: Point-of-Care Coagulometer (investigational device)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent. 18 to 75 years of age. Be in generally good health with BMI 18 to 32 kg/m2. If female, be surgically sterile or post-menopausal, or using an acceptable method of contraception (other than a combination estrogen/progestin hormonal contraceptive). If male, be surgically sterile, or agree to use appropriate contraception. Have suitable venous access for multiple venipunctures. Exclusion Criteria: Have any of the following findings at Screening: Hemoglobin , hematocrit, platelets, PT, aPTT, fibrinogen, triglycerides, or bilirubin Serum creatinine >1.5 mg/dL or known renal disease Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x the upper limit of normal, or known liver disease Positive viral screen for HBV, HCV, or HIV Positive pregnancy test (females) Positive drug, tobacco or alcohol screen Any clinically significant findings on 12-lead ECG or urinalysis Have a personal or family history of clotting disorder or hematologic abnormality. Have a history of unexplained syncope. Have a history within 6 months prior to Screening of major bleeding, trauma, surgical procedure, vaginal delivery, peptic ulcer or GI bleeding. Have received any blood product or anticoagulant, or donated any blood, within 3 months prior to Screening. Have a history of recurrent minor bleeding episodes. If female, have a history of excessive or dysfunctional uterine bleeding (unless the subject had a subsequent hysterectomy). Have used any tobacco or nicotine-containing products within 3 months prior to Screening. Have used any systemic prescription or non-prescription drugs within 14 days prior to Day 1. If female, be pregnant, breastfeeding, or planning to become pregnant during the study. Have received ciraparantag in any prior clinical study. Have received another investigational drug within 5 half-lives or 30 days, whichever is longer, prior to Day 1. Known allergy to apixaban or rivaroxaban.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study will be conducted in separate cohorts; each cohort will evaluate the reversal of a different anticoagulant drug. Within each cohort, an initial group of subjects (Group 1) will be enrolled for evaluation of a target dose of ciraparantag. Depending on the efficacy and safety results from Group 1, a second group (Group 2) may be enrolled to evaluate a different dose of ciraparantag for that cohort.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Subjects receive 60 mg edoxaban orally once daily in the morning on Days 1 to 4. On Day 4, approximately 3 hours after administering edoxaban, study drug (ciraparantag or placebo) will be intravenously administered. | Drug: Ciraparantag<br>* Ciraparantag: 180 mg, intravenous<br>* Other names: AMAG 977;Drug: Placebo<br>* Placebo: 0.9% sodium chloride, intravenous<br>* Other names: PBO;Device: Point-of-Care Coagulometer (investigational device)<br>* Perosphere Technologies' Point of Care (POC) Coagulometer Device will be used to measure whole blood clotting time.<br>* Other names: Coagulometer;|
| Experimental: Cohort 2<br>Subjects receive 10 mg apixaban orally every 12 hours on Days 1 to 3, with a final dose in the morning on Day 4. On Day 4, approximately 4 hours after administering apixaban, study drug (ciraparantag or placebo) will be intravenously administered. | Drug: Ciraparantag<br>* Ciraparantag: 180 mg, intravenous<br>* Other names: AMAG 977;Drug: Placebo<br>* Placebo: 0.9% sodium chloride, intravenous<br>* Other names: PBO;Device: Point-of-Care Coagulometer (investigational device)<br>* Perosphere Technologies' Point of Care (POC) Coagulometer Device will be used to measure whole blood clotting time.<br>* Other names: Coagulometer;|
| Experimental: Cohort 3<br>Subjects receive 20 mg rivaroxaban orally once daily in the morning on Days 1 to 4. On Day 4, approximately 4 hours after administering rivaroxaban, study drug (ciraparantag or placebo) will be intravenously administered. | Drug: Ciraparantag<br>* Ciraparantag: 180 mg, intravenous<br>* Other names: AMAG 977;Drug: Placebo<br>* Placebo: 0.9% sodium chloride, intravenous<br>* Other names: PBO;Device: Point-of-Care Coagulometer (investigational device)<br>* Perosphere Technologies' Point of Care (POC) Coagulometer Device will be used to measure whole blood clotting time.<br>* Other names: Coagulometer;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of subjects achieving WBCT ≤120% of baseline within 1 hour after administration of ciraparantag or placebo and sustained after 1 hour through at least 6 hours after ciraparantag/placebo dosing. |  | 6 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of subjects achieving WBCT ≤115% of baseline within 1 hour after administration of ciraparantag or placebo and sustained after 1 hour through at least 6 hours after ciraparantag/placebo dosing. |  | 6 Hours | 
| The number of subjects achieving WBCT ≤110% of baseline within 1 hour after administration of ciraparantag or placebo and sustained after 1 hour through at least 6 hours after ciraparantag/placebo dosing. |  | 6 Hours | 
| The number of subjects achieving WBCT ≤120% of baseline within 30 minutes after administration of ciraparantag or placebo and sustained after 30 minutes through at least 6 hours after ciraparantag/placebo dosing. |  | 6 Hours | 
| The number of subjects achieving WBCT ≤115% of baseline within 30 minutes after administration of ciraparantag or placebo and sustained after 30 minutes through at least 6 hours after ciraparantag/placebo dosing. |  | 6 Hours | 
| The number of subjects achieving WBCT ≤110% of baseline within 30 minutes after administration of ciraparantag or placebo and sustained after 30 minutes through at least 6 hours after ciraparantag/placebo dosing. |  | 6 Hours | 
| The number of subjects achieving WBCT ≤120% of baseline within 15 minutes after administration of ciraparantag or placebo and sustained after 15 minutes through at least 6 hours after ciraparantag/placebo dosing. |  | 6 Hours | 
| The number of subjects achieving WBCT ≤115% of baseline within 15 minutes after administration of ciraparantag or placebo and sustained after 15 minutes through at least 6 hours after ciraparantag/placebo dosing. |  | 6 Hours | 
| The number of subjects achieving WBCT ≤110% of baseline within 15 minutes after administration of ciraparantag or placebo and sustained after 15 minutes through at least 6 hours after ciraparantag/placebo dosing. |  | 6 Hours | 
| Correlation between WBCT measured with Perosphere Technologies' POC Coagulometer and with a manual testing method | Correlation will be analyzed by a linear regression model. | 24 Hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ciraparantag, PER977, Apixaban, Rivaroxaban, Whole Blood Clotting Time (WBCT), Coagulometer, AMAG 977, Edoxaban