Treatment of bleeding and perioperative prophylaxis MedDRA version: 20.0 Level: LLT Classification code 10005103 Term: Bleeding System Organ Class: 100000004866 MedDRA version: 21.0 Level: PT Classification code 10036898 Term: Prophylaxis System Organ Class: 10042613 - Surgical and medical procedures
Conditions
Interventions
Trade Name: Human prothrombin complex concentrate (PCC) (Cofact)
Product Name: Cofact
Product Code: N/A
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: N/A
CAS Number: 37224-63-8
Curre
Sponsors
Prothya Biosolutions BV
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Sex : Male or female of nonchildbearing potential. 2. Age : 18 to 55 years, inclusive, at screening. 3. Body mass index (BMI) : 18.0 to 30.0 kg/m2, inclusive, at screening. Body weight is not less than 50 kg and not more than 100 kg. 4. Status : Healthy subjects. 5. Female subjects will be included if they are of nonchildbearing potential. Female subjects should have a documented history of tubal ligation more than 6 months prior to the onset of the study, or with a documented hysterectomy. Postmenopausal women will be included in the study if the postmenopausal status is confirmed with a history of 12 months uninterrupted spontaneous amenorrhea, or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels >40 mIU/ml, or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy. 6. Male subjects, if not surgically sterilized, must agree to use adequate contraception and not donate sperm from first admission to the clinical research center until 90 days after the EOS visit. Adequate contraception for the male subject (and his female partner, if she is of childbearing potential) is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, a cervical cap, or a condom. Total abstinence from heterosexual intercourse, in accordance with the lifestyle of the subject, is also acceptable. 7. Subjects should not be taking any prescribed medication for at least 14 days prior to first admission to the clinical research center. 8. All over-the-counter medication, vitamin preparations and other food supplements, or herbal medications (eg, St. John’s wort) must have been stopped at least 14 days prior to first admission to the clinical research center. 9. Ability and willingness to abstain from alcohol from 48 hours (2 days) prior to each admission into the clinical research center. 10. Ability and willingness to abstain from methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, energy drinks) and grapefruit (juice) from 48 hours (2 days) prior to the first admission to the clinical research center on Day -11 up to admission to the clinical research center on Day 1. 11. Good physical and mental health on the basis of medical history, physical examination, clinical laboratory, electrocardiogram (ECG), and vital signs, as judged by the Investigator. 12. Computerized 12-lead ECG recording without signs of clinically relevant pathology or showing no clinically relevant deviations as judged by the Investigator. The ECG may be repeated if in the judgment of the Investigator there is a reason to believe the initial result is inaccurate. 13. All values for clinical laboratory tests of blood and urine within the normal range or showing no clinically relevant deviations as judged by the Investigator. Clinical laboratory tests may be repeated if they are just out of range, or there is a reason to believe the initial results are inaccurate (eg, clumped platelets). 14. Willing and able to sign the ICF. 15. The INR is 2.0 to 3.0 (inclusive) at least in one of the two INR measurements taken on Day 1 after acenocoumarol has been administered for 10 days. The INR is measured twice predose on Day 1, one via the blood draw and the other via the device. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 120
Exclusion criteria
Exclusion criteria: 1. Employee of PRA or the Sponsor. 2. History of relevant drug and/or food allergies. 3. Any of the following laboratory results outside of the ranges, at screening: lupus anticoagulants (LA screen) and/or anti-beta2-glycoprotein I, low levels of protein C (activity), low levels of protein S (activity), or low levels of antithrombin. 4. Abnormal aPTT or PT levels, or Fe or ferritin levels. 5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and total bilirubin are not more than about 1.2 times the upper limit of normal at screening (per the Investigator’s discretion). 6. Participants with thyroid disorders as evidenced by assessment of thyroid stimulating hormone (TSH) levels outside the normal reference range at screening. 7. Prior history of thromboembolic complications including those in first degree relatives. 8. Glomerular filtration rate (GFR) is lower than estimated GFR 62 mL/min/1.73 m2 using the Modification of Diet in Renal Disease Study equation. 9. Anaphylactic or systemic reactions to human plasma, plasma products, or blood products. 10. History of hypersensitivity to active or inactive excipients of acenocoumarol or drugs with a similar chemical structure or class. 11. Gastrointestinal disease that may impair acenocoumarol absorption.. 12. On medication that may affect acenocoumarol activity, such as aspirin, acetaminophen (with prolonged use [longer than 4 days] and in high doses (4 g per day), antibiotics, antifungals, or allergy medication. 13. Any regular medication involving hepatic metabolism, increasing risk for thrombosis, or otherwise affecting hemostasis. 14. Significant psychiatric illness that could interfere with the ability to comprehend and comply with study procedures and ability to tolerate treatment as outlined in the protocol. 15. Participation in another clinical study 100 beats per minute (bpm); systolic blood pressure 140 mmHg; diastolic blood pressure 90 mmHg (to be confirmed by a second measurement, after subject has been resting in supine position for 5 min). If initial results do not meet these criteria, blood pressure and/or pulse may be repeated if in the judgment of the Investigator there is a reason to believe the initial result is inaccurate (eg, white coat hypertension). 19. Whole blood or plasma donation of more than 100 mL within 30 days prior to administration of study medication or intended donation during the study. 20. Judgment by the Investigator that the subject should not participate in the study because the subject is unlikely to comply with all study procedures and treatment. 21. Unsuitable veins for infusion or blood sampling. 22. Subjects who have not reached an INR of 2.0 to 3.0 (inclusive) on at least 1 of the measurements on Day -1Day 1, after receiving
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Establish dose-response relationship for Cofact in vitamine K antagonist (VKA) reversal with respect to thrombin generation in subjects anticoagulated with warfarin therapy;Secondary Objective: Kinetics of thrombin generation Assessment of global parameters of coagulation over 14 days To evaluate the effects of Cofact in healthy subjects receiving warfarin on biomarkers reflective of coagulation activation To assess the safety and tolerability of Cofact in healthy subjects receiving warfarin;Primary end point(s): Peak thrombin generation at 30 minutes after the end of the Cofact infusion (EOI) ;Timepoint(s) of evaluation of this end point: Throughout the study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Change in ETP over 24 hours after the EOI (ETP measured at predose, at the EOI, and at 30 minutes, 1, 3, 6, 12, and 24 hours after the EOI), including lag time, time to peak thrombin, peak thrombin Changes in global assays of the blood coagulation markers: activated partial thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR) Concentration over time of clotting factors: Factor II, Factor VII, Factor IX, Factor X, Protein C and Protein S Activation of blood coagulation, as indicated by markers prothrombin fragment 1+2, D-Dimer, and thrombin–antithrombin complexes (TATs) Changes in safety laboratory parameters Incidence of clinical adverse events (AEs) particularly related to thrombic complications ;Timepoint(s) of evaluation of this end point: Throughout the study | — |
Countries
Netherlands
Contacts
Public ContactIlona Kleine Budde
Prothya Biosolutions BV
Outcome results
None listed