Clinical trial NCT04543383: A Study to Assess the Reversal of the Anticoagulant Effects of Milvexian by 4-Factor Prothrombin Complex Concentrate (4F-PCC) (Part 1) and Recombinant Human Factor VIIa (rFVIIa) (Part 2) in Healthy Participants
Official title: A Two-Part, Open-Label, Randomized, Placebo-Controlled Crossover Study to Assess the Reversal of the Anticoagulant Effects of Milvexian by 4-Factor Prothrombin Complex Concentrate (4F-PCC) (Part 1) and Recombinant Human Factor VIIa (rFVIIa) (Part 2) in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2020-09-10
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Maximum age (years): 54
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The primary purpose of this study is to evaluate the reversal of the anticoagulant effects of milvexian by 4-Factor Prothrombin Complex Concentrate (4F-PCC) and Recombinant Human Factor VIIa (rFVIIa) in healthy participants as measured by changes from baselines of the coagulation testing parameters (activated partial thromboplastin time \[aPTT\] and thrombin generation assay \[TGA\]).


Eligibility criteria: Inclusion Criteria:

* Participants must be healthy on the basis of medical history, physical examination, vital signs, electrocardiogram (ECG), and laboratory test results, including serum chemistry, lipid profiles (low-density lipoprotein \[LDL\], high-density lipoprotein \[HDL\], apolipoprotein B and lipoprotein a), levels of protein C, protein S and antithrombin, fibrinogen, factors VIIIc, IXc, Xc, XIc and blood coagulation (activated partial thromboplastin time \[aPTT\], prothrombin time \[PT\]) measured at local laboratory, hematology and urinalysis performed at screening. If abnormalities or deviations from normal are observed, they must be of no clinical significance in the opinion of the investigator
* Before randomization, a woman must either be: Not of childbearing potential defined as: Postmenopausal-A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level greater than (\>) 40 International Units Per Liter (IU/L) or milli-international units per milliliter (mIU/mL) in the postmenopausal range may be used to confirm a postmenopausal state in women, however, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient; Permanently sterile- Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Of childbearing potential, a woman must have an intrauterine device without estrogen- and or progestogen-containing system, or have vasectomized partner or practice sexual abstinence, agrees to remain on the above highly effective contraceptive method throughout the study and for at least 90 days after the last dose of study intervention
* A male participant must wear a condom when engaging in any activity with a woman of childbearing potential during the study and for the duration of treatment with milvexian plus 5 half-lives of the study intervention for a total of 94 days after the completion of treatment. Male participants should also be advised of the benefit for a female partner to use a highly effective method of contraception because condom may break or leak
* If a woman, must have a negative highly sensitive serum (Beta-human chorionic gonadotropin \[Beta-hCG\]) pregnancy test at screening and urine (Beta-hCG) pregnancy test on Day -1 of each study period (Part 1) or on Day -1 of Period 1 (Part 2)
* Women must have no history of excessive menstrual bleeding or hemorrhage following pregnancy delivery
* A male participant must agree not to donate sperm for the purpose of reproduction during the study and for 94 days after receiving the last dose of study intervention
* Body mass index (weight \[kilogram {kg}/height\^2 \[meter {m\^2}\]) more than equal to 18.0 and less than equal to 29.9 kg/m\^2 body weight not less than 50 kg and not more than 100 kg.

Exclusion Criteria:

* History or family history of any known illness that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study intervention to the participant or that could prevent, limit or confound the protocol specified assessments. This may include but is not limited to any known bleeding or clotting disorder, cardiolipin antibody and anti-beta2-glycoprotein I, abnormal levels of fibrinogen, factors VIIIc, IXc, Xc, XIc, inherited or acquired thrombophilia, bleeding diathesis or coagulopathy, excessive bruising, bleeding from nose or gums or known disorders with increased bleeding risk, serious bleeding including gastrointestinal bleeding requiring hospitalization, intracranial bleeding of any type, or uncontrollable postoperative bleeding, a history of arterial or venous thrombosis, phlebitis, inherited or acquired thrombophilia, known family history of unexplained thrombotic disorders, known intracranial or intraabdominal tumor, hemorrhage, or aneurysm, liver or renal dysfunction, clinically significant cardiac, vascular disorders, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, neoplastic abnormalities, or metabolic disturbances, or poor venous access
* History of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental Disorders criteria within 1 year before screening or positive test result(s) for alcohol and/or drugs of abuse (such as hallucinogens (lysergic acid diethylamide \[LSD\]), barbiturates, opiates, opioids, cocaine, cannabinoids, amphetamines, and benzodiazepines) at screening and/or on Day -1 of Period 1
* Have laboratory values at screening or Day -1 of Period 1 above or below limits of normal that in the investigator's judgment may affect the safety of the participants
* Any of the following laboratory results outside of the ranges specified below at screening or on Day -1 of Period 1, confirmed by repeat: Hemoglobin or hematocrit \< lower limit of normal, Platelet count less than (\<) lower limit of normal, aPTT, or PT \> upper limit of normal (ULN), LDL, HDL, apolipoprotein B, or lipoprotein a, outside the normal reference ranges, Factor II gene mutation or Factor V Leiden mutation assessed by polymerase chain reaction (PCR) tests, positive for Lupus Anticoagulants (LA screen, confirm and Silica Clotting Time \[SCT\]), cardiolipin antibody and anti-beta2-glycoprotein I, abnormal levels of protein C, protein S, antithrombin, fibrinogen, factors VIIIc, IXc, Xc, XIc
* Any of the following on 12-lead ECG based on an average of triplicate measurements at screening or Day -1 of Period 1: PR greater than or equal to (\>=) 210 millisecond (msec), QRS \>=120 msec, QTcF\>=450 msec for male and \>=470 msec for female, Heart Rate (HR) \>= 100 beats per minute (bpm)
* History of any significant drug allergy (such as anaphylaxis or hepatotoxicity) and known allergy to the study interventions or any of the excipients of the formulations. History of allergy to or unwillingness to consume any component of high-fat breakfast menu to be provided in this study

Primary outcomes:
measure: Part 1: Change from Baseline in Activated Partial Thromboplastin Time (aPTT)
timeFrame: Baseline, Day 4
measure: Part 2: Change from Baseline in aPTT
timeFrame: Baseline, Day 1
measure: Part 1: Change from Baseline in Endogenous Thrombin Potential (ETP) (Thrombin Generation Assay [TGA] Parameter)
timeFrame: Baseline, Day 4
measure: Part 1: Change from Baseline in Lag Time (TGA Parameter)
timeFrame: Baseline, Day 4
measure: Part 1: Change from Baseline in Peak Thrombin (TGA Parameter)
timeFrame: Baseline, Day 4
measure: Part 1: Change from Baseline in Time to Peak Thrombin (TGA Parameter)
timeFrame: Baseline, Day 4
measure: Part 2: Change from Baseline in ETP (TGA Parameter)
timeFrame: Baseline, Day 1
measure: Part 2: Change from Baseline in Lag Time (TGA Parameter)
timeFrame: Baseline, Day 1
measure: Part 2: Change from Baseline in Peak Thrombin (TGA Parameter)
timeFrame: Baseline, Day 1
measure: Part 2: Change from Baseline in Time to Peak Thrombin (TGA Parameter)
timeFrame: Baseline, Day 1
Secondary outcomes:
measure: Number of Participants with Treatment-Emergent Adverse Events (TEAE) as a Measure of Safety and Tolerability
timeFrame: Part 1: Up to 74 Days; Part 2: Up to 25 Days
measure: Number of Participants with TEAEs of interest
timeFrame: Part 1: Up to 74 Days; Part 2: Up to 25 Days
measure: Parts 1 and 2: Change From Baseline in Pulse Rate
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in QTc Interval
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change from Baseline in Heart Rate (HR)
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change from Baseline in QRS Interval
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change from Baseline in PR Interval
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in QT Interval
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in Hematology Parameter: Platelet Count
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in Hematology Parameter: Red Blood Cell (RBC) count
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in Hematology Parameter: Hemoglobin (Hb)
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in Hematology Parameter: Hematocrit
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in Hematology Parameter: Mean Corpuscular Volume (MCV)
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin (MCH)
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in Hematology Parameter: Percentage of Reticulocytes
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in Hematology Parameters: Neutrophils, Lymphocytes, Monocytes, Eosinophils and Basophils
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in Coagulation Parameter: Activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT)
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change from Baseline in Serum Chemistry Parameters: Bicarbonate, Calcium, Glucose, Chloride, Magnesium, Phosphate, Sodium, BUN, Cholesterol, HDL, LDL, Triglycerides
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change from Baseline in Serum Chemistry Parameters: ALT, AST, GGT, LDH, Alkaline phosphatase, CPK
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change from Baseline in Serum Chemistry Parameters: Amylase
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change from Baseline in Serum Chemistry Parameters: Lipase
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change from Baseline in Serum Chemistry Parameters: Total Bilirubin, Creatinine and Uric Acid
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change from Baseline in Serum Chemistry Parameters: Total Protein and Albumin
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in Urinalysis Parameter: Specific Gravity
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Parts 1 and 2: Change From Baseline in Urinalysis Parameter: pH
timeFrame: Part 1: Up to 77 Days; Part 2: Up to 59 Days
measure: Part 1: Mean Trough Plasma Concentration of Milvexian at Steady State (Ctrough)
timeFrame: Part 1: Predose, 2, 4, 4.75, 5, 6, 8, 12, 24, 48, and 72 hours Postdose
measure: Part 1 and Part 2: Maximum Observed Analyte Concentration (Cmax) of Milvexian
timeFrame: Part 1: Predose, 2, 4, 4.75, 5, 6, 8, 12, 24, 48, and 72 hours Postdose; Part 2: 0.25, 2, 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose
measure: Part 1 and Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of milvexian
timeFrame: Part 1: Predose, 2, 4, 4.75, 5, 6, 8, 12, 24, 48, and 72 hours Postdose; Part 2: 0.25, 2, 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose
measure: Parts 1 and Part 2: Elimination Half-Life (t1/2) of Milvexian
timeFrame: Part 1: Predose, 2, 4, 4.75, 5, 6, 8, 12, 24, 48, and 72 hours Postdose; Part 2: 0.25, 2, 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose
measure: Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Dosing Interval (AUC [0-t]) of Milvexian
timeFrame: Part 1: Predose, 2, 4, 4.75, 5, 6, 8, 12, 24, 48, and 72 hours Postdose
measure: Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of Milvexian
timeFrame: Part 2: 0.25, 2, 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose
measure: Part 1 and Part 2: Area Under Plasma Concentration From Time Zero to the Last Quantifiable Concentration (AUC [0-last]) of Milvexian
timeFrame: Part 1: Predose, 2, 4, 4.75, 5, 6, 8, 12, 24, 48, and 72 hours Postdose; Part 2: 0.25, 2, 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose
measure: Part 2: Maximum Observed Analyte Concentration (Cmax) of rFVIIa
timeFrame: Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose
measure: Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of rFVIIa
timeFrame: Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose
measure: Part 2: Elimination Half-Life (t1/2) of rFVIIa
timeFrame: Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose
measure: Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of rFVIIa
timeFrame: Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose
measure: Part 2: Area Under Plasma Concentration From Time Zero to the Last Quantifiable Concentration (AUC [0-last]) of rFVIIa
timeFrame: Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose
measure: Part 2: Systemic Clearance (CL) of rFVIIa
timeFrame: Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose
measure: Part 2: Volume of distribution (Vz) of rFVIIa
timeFrame: Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose
measure: Part 1 and Part 2: Change from Baseline in aPTT
timeFrame: Part 1: Baseline, Day 1, Day 4, Day 5, Day 6 and Day 7; Part 2: Baseline, Day 1 and Day 2
measure: Part 1 and Part 2: Change from Baseline in ETP (TGA Parameter)
timeFrame: Part 1: Baseline, Day 1, Day 4, Day 5, Day 6 and Day 7; Part 2: Baseline, Day 1 and Day 2
measure: Part 1 and Part 2: Change from Baseline in Lag Time (TGA Parameter)
timeFrame: Part 1: Baseline, Day 1, Day 4, Day 5, Day 6 and Day 7; Part 2: Baseline, Day 1 and Day 2
measure: Part 1 and Part 2: Change from Baseline in Peak Thrombin (TGA Parameter)
timeFrame: Part 1: Baseline, Day 1, Day 4, Day 5, Day 6 and Day 7; Part 2: Baseline, Day 1 and Day 2
measure: Part 1 and Part 2: Change from Baseline in Time to Peak Thrombin (TGA Parameter)
timeFrame: Part 1: Baseline, Day 1, Day 4, Day 5, Day 6 and Day 7; Part 2: Baseline, Day 1 and Day 2
measure: Percent Change from Baselines in aPTT
timeFrame: Part 1: Baseline, Day 1, Day 4, Day 5, Day 6 and Day 7; Part 2: Baseline, Day 1 and Day 2
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: PRA Health Sciences
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References: