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

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.

• Ciraparantag (Drug), also known as PER977, AMAG 977: Ciraparantag: 180 mg, intravenous
• Placebo (Drug), also known as PBO: Placebo: 0.9% sodium chloride, intravenous
• Point-of-Care Coagulometer (investigational device) (Device), also known as Coagulometer: Perosphere Technologies' Point of Care (POC) Coagulometer Device will be used to measure whole blood clotting time.

Primary outcomes

• Subjects Achieving WBCT ≤120% of Baseline [Within 1 hour and sustained through 6 hours]: The primary efficacy endpoint is achieving a WBCT (measured by PoC coagulometer) ≤ 120% of baseline within 1 hour after administration of ciraparantag/PBO, which is subsequently sustained after 1 hour through at least 6 hours after ciraparantag/PBO dosing (Responder).

Sex: All, ages: 18 Years to 75 Years, accepts healthy volunteers

Inclusion Criteria:

1. Provide written informed consent.
2. 18 to 75 years of age.
3. Be in generally good health
4. BMI 18 to 32 kg/m2, inclusive, at Screening.
5. If female, be surgically sterile or post-menopausal or if of child-bearing potential, using an acceptable method of contraception (other than a combination estrogen/progestin hormonal contraceptive) for at least 1 month prior to Day 1.
6. If male, be surgically sterile, or agree to use appropriate contraception.
7. Have suitable venous access for multiple venipunctures.

Exclusion Criteria:

1. Have any of the following findings at Screening:

   1. Hemoglobin or hematocrit value outside the normal range
   2. Platelet count outside the normal range
   3. PT or aPTT outside the normal range
   4. Plasma fibrinogen outside the normal range
   5. Serum triglycerides or total cholesterol outside the normal range
   6. Serum creatinine >1.5 mg/dL (133 μmol/L) or known renal disease
   7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x the upper limit of normal, or known liver disease
   8. Total bilirubin outside the normal range
   9. Positive viral screen for hepatitis B virus, hepatitis C virus (HCV), or human immunodeficiency virus (HIV)
   10. Positive pregnancy test (females)
   11. Positive drug, tobacco or alcohol screen
   12. Any clinically significant findings on 12-lead ECG or urinalysis
2. Have a personal or family history of clotting disorder or hematologic abnormality.
3. Have a history of unexplained syncope.
4. Have a history within 6 months prior to Screening of major bleeding, trauma, surgical procedure of any type, or vaginal delivery
5. Have a history within 6 months prior to Screening of peptic ulcer or gastrointestinal bleeding.
6. Have received any blood product or anticoagulant within 3 months prior to Screening.
7. Have donated blood or blood products within 3 months prior to Screening
8. Have a history of minor bleeding episodes within 1 month prior to Screening, or a long-standing history of such bleeding.
9. If female, have a history of excessive or dysfunctional uterine bleeding (unless the subject had a subsequent hysterectomy).
10. Have used any tobacco or nicotine-containing products within 3 months prior to Screening.
11. Have used any systemic prescription or non-prescription drugs within 14 days prior to Day 1 (except for permitted contraceptives).
12. If female, be pregnant, breastfeeding, or planning to become pregnant during the study.
13. Have received ciraparantag in any prior clinical study.
14. Have received another investigational drug within 5 half-lives or 30 days, whichever is longer, prior to Day 1.
15. Known allergy to edoxaban, apixaban or rivaroxaban.
16. Have any other condition that, in the opinion of the Investigator, would interfere with a subject's ability to adhere to the protocol, interfere with assessment of the investigational product, or compromise the safety of the subject or the quality of the data.

Participant flow

Outcome results

• Subjects Achieving WBCT ≤120% of Baseline (Primary), Count of participants, Participants: Cohort 1 (Edox) Cira 180 mg 0; Cohort 1 (Edox) PBO 1; Cohort 3 (Riva) Cira 180 mg 0; Cohort 3 (Riva) PBO 0 (p 0.248)

Adverse events

Time frame: Adverse events were monitored from the time the informed consent was signed through the last study visit / study completion which occurred five days after IP-dosing. Serious Adverse Events were reported through 30 days after the last dose of ciraparantag/placebo.

Other adverse events by term

• Study Protocol (PDF, 2022-10-14)
• Statistical Analysis Plan (PDF, 2024-07-31)

• Advisor, Study director, Apollo Investment Management