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| ID | Type | Description | Link |
|---|---|---|---|
| 2020-000180-24 | EudraCT Number | ||
| 70033093EDI1001 | Other Identifier | Janssen Research & Development, LLC |
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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]).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part 1 | Experimental | Participants will receive two oral doses of milvexian (on Days 1 to 3), one in the morning and one in the evening. On Day 4, participants will only receive the morning dose of milvexian. On Day 4, four hours after the morning dosing of milvexian, each participant will receive an intravenous (IV) infusion of 4-Factor Prothrombin Complex Concentrate (4F-PCC) or matching placebo as per the treatment sequence AB and BA; in treatment period 1 and treatment period 2 where Treatment A=Dose 2 of milvexian + Dose 1 of 4F-PCC; Treatment B=Dose 2 milvexian + Placebo. A washout period of 14 days to 21 days will be maintained between each treatment period 1 and 2. |
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| Part 2 (Group 1) | Experimental | Participants will receive an oral dose of milvexian in morning in fed state on Day 1 and IV injection of Recombinant Human Factor VIIa (rFVIIa) or placebo matching to rFVIIa on Day 1 after 4 hours post morning milvexian dose in the following treatment sequence: DEF1, EF1D, F1DE, EDF1, F1ED and DF1E; in treatment period 1, treatment period 2 and treatment period 3 respectively where Treatment D=Dose 1 of milvexian +Dose 1 of rFVIIa; Treatment E=Dose 3 of milvexian+Dose 1 of rFVIIa; Treatment F1=Dose 3 of milvexian+Placebo; Treatment F2=Dose 1 of milvexian+Placebo. A washout period of 4 days will be maintained between each treatment period 1, 2 and 3. |
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| Part 2 (Group 2) | Experimental | Participants will receive an oral dose of milvexian in morning in fed state on Day 1 and IV injection of rFVIIa or placebo matching to rFVIIa on Day 1 after 4 hours post morning milvexian dose in the following treatment sequence: DEF2, EF2D, F2DE, EDF2, F2ED and DF2E; in treatment period 1, treatment period 2 and treatment period 3 respectively where Treatment D=Dose 1 of milvexian+Dose 1 of rFVIIa; Treatment E=Dose 3 of milvexian+Dose 1 of rFVIIa; Treatment F1=Dose 3 of milvexian+Placebo; Treatment F2=Dose 1 of milvexian+Placebo. A washout period of 4 days will be maintained between each treatment period 1, 2 and 3. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Milvexian | Drug | Milvexian will be administered orally. |
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| Measure | Description | Time Frame |
|---|---|---|
| Part 1: Change from Baseline in Activated Partial Thromboplastin Time (aPTT) | The aPTT measures the time it takes plasma to clot when exposed to substances that activate the contact factors, which assesses the intrinsic and common pathways of coagulation. | Baseline, Day 4 |
| Part 2: Change from Baseline in aPTT | The aPTT measures the time it takes plasma to clot when exposed to substances that activate the contact factors, which assesses the intrinsic and common pathways of coagulation. | Baseline, Day 1 |
| Part 1: Change from Baseline in Endogenous Thrombin Potential (ETP) (Thrombin Generation Assay [TGA] Parameter) | The TGA measures the thrombin generation that is indicative of an overall coagulating capacity. A calibrated automated thrombography is used to monitor the concentration of thrombin in clotting plasma with a fluorogenic substrate. The data derived from the thrombography can be used to determine the ETP (TGA parameter). The ETP assesses the amount of thrombin which can be generated after the in vitro activation of coagulation and represents the balance between pro and anti-coagulant forces in plasma. | Baseline, Day 4 |
| Part 1: Change from Baseline in Lag Time (TGA Parameter) | The TGA measures the thrombin generation that is indicative of an overall coagulating capacity. A calibrated automated thrombography is used to monitor the concentration of thrombin in clotting plasma with a fluorogenic substrate. The data derived from the thrombography can be used to determine the lag time (TGA parameter). The lag time is defined as the time needed until thrombin is generated. | Baseline, Day 4 |
| Part 1: Change from Baseline in Peak Thrombin (TGA Parameter) | The TGA measures the thrombin generation that is indicative of an overall coagulating capacity. A calibrated automated thrombography is used to monitor the concentration of thrombin in clotting plasma with a fluorogenic substrate. The data derived from the thrombography can be used to determine the peak thrombin (TGA parameter). The peak thrombin is defined as the maximal effect on thrombin generation. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants with Treatment-Emergent Adverse Events (TEAE) as a Measure of Safety and Tolerability | Treatment-emergent adverse events (TEAEs) are defined as adverse events (AEs) with onset or worsening on or after date of first dose of study treatment. | Part 1: Up to 74 Days; Part 2: Up to 25 Days |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Janssen Research & Development, LLC Clinical Trial | Janssen Research & Development, LLC | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| PRA Health Sciences | Groningen | NZ 9728 | Netherlands |
The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu
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| 4-Factor Prothrombin Complex Concentrate (4F-PCC) | Biological | 4F-PCC will be administered intravenously. |
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| Recombinant Human Factor VIIa (rFVIIa) | Biological | rFVIIa will be administered intravenously. |
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| Placebo matching to 4F-PCC | Biological | Placebo matching to 4F-PCC will be administered intravenously. |
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| Placebo matching to rFVIIa | Biological | Placebo matching to rFVIIa will be administered intravenously. |
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| Baseline, Day 4 |
| Part 1: Change from Baseline in Time to Peak Thrombin (TGA Parameter) | The TGA measures the thrombin generation that is indicative of an overall coagulating capacity. A calibrated automated thrombography is used to monitor the concentration of thrombin in clotting plasma with a fluorogenic substrate. The data derived from the thrombography can be used to determine the time to peak thrombin (TGA parameter). The time to peak thrombin is defined as the time required to reach maximal effect on thrombin generation. | Baseline, Day 4 |
| Part 2: Change from Baseline in ETP (TGA Parameter) | The TGA measures the thrombin generation that is indicative of an overall coagulating capacity. A calibrated automated thrombography is used to monitor the concentration of thrombin in clotting plasma with a fluorogenic substrate. The data derived from the thrombography can be used to determine the ETP (TGA parameter). The ETP assesses the amount of thrombin which can be generated after the in vitro activation of coagulation and represents the balance between pro and anti-coagulant forces in plasma. | Baseline, Day 1 |
| Part 2: Change from Baseline in Lag Time (TGA Parameter) | The TGA measures the thrombin generation that is indicative of an overall coagulating capacity. A calibrated automated thrombography is used to monitor the concentration of thrombin in clotting plasma with a fluorogenic substrate. The data derived from the thrombography can be used to determine the lag time (TGA parameter). The lag time is defined as the time needed until thrombin is generated. | Baseline, Day 1 |
| Part 2: Change from Baseline in Peak Thrombin (TGA Parameter) | The TGA measures the thrombin generation that is indicative of an overall coagulating capacity. A calibrated automated thrombography is used to monitor the concentration of thrombin in clotting plasma with a fluorogenic substrate. The data derived from the thrombography can be used to determine the peak thrombin (TGA parameter). The peak thrombin is defined as the maximal effect on thrombin generation. | Baseline, Day 1 |
| Part 2: Change from Baseline in Time to Peak Thrombin (TGA Parameter) | The TGA measures the thrombin generation that is indicative of an overall coagulating capacity. A calibrated automated thrombography is used to monitor the concentration of thrombin in clotting plasma with a fluorogenic substrate. The data derived from the thrombography can be used to determine the time to peak thrombin (TGA parameter). The time to peak thrombin is defined as the time required to reach maximal effect on thrombin generation. | Baseline, Day 1 |
| Number of Participants with TEAEs of interest |
Number of participants with TEAEs of interest will be reported. TEAEs associated with the following situations are considered as TEAEs of interest: bleeding, thromboembolic events (TEs) and liver injury. |
| Part 1: Up to 74 Days; Part 2: Up to 25 Days |
| Parts 1 and 2: Change From Baseline in Pulse Rate | Changes from baseline in pulse rate will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Changes from baseline in SBP and DBP will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in QTc Interval | Change from baseline in QT interval corrected for heart rate (QTc interval) using Fridericia method will be measured by ECG. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change from Baseline in Heart Rate (HR) | Change from baseline in HR will be measured by ECG. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change from Baseline in QRS Interval | Change from baseline in QRS interval will be measured by ECG | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change from Baseline in PR Interval | Change from baseline in PR interval will be measured by ECG. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in QT Interval | Change from baseline in QT interval will be measured by ECG. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in Hematology Parameter: Platelet Count | Change from baseline in hematology parameter (platelet count) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in Hematology Parameter: Red Blood Cell (RBC) count | Change from baseline in hematology parameter (RBC count [Unit: Cells per liter]) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in Hematology Parameter: Hemoglobin (Hb) | Change from baseline in hematology parameter (Hb [Grams per deciliter]) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in Hematology Parameter: Hematocrit | Change from baseline in hematology parameter (Hematocrit) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in Hematology Parameter: Mean Corpuscular Volume (MCV) | Change from baseline in hematology parameter (MCV [Femtoliter]) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin (MCH) | Change from baseline in hematology parameter (MCH [Picogram]) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in Hematology Parameter: Percentage of Reticulocytes | Change from baseline in hematology parameter (Percentage of reticulocytes) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in Hematology Parameters: Neutrophils, Lymphocytes, Monocytes, Eosinophils and Basophils | Change from baseline in hematology parameters (Neutrophils, Lymphocytes, Monocytes, Eosinophils and Basophils [Unit: Giga cells per liter]) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in Coagulation Parameter: Activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) | Change from baseline in coagulation parameter (aPTT and PT [Unit: Seconds]) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change from Baseline in Serum Chemistry Parameters: Bicarbonate, Calcium, Glucose, Chloride, Magnesium, Phosphate, Sodium, BUN, Cholesterol, HDL, LDL, Triglycerides | Change from baseline in serum chemistry parameters (Bicarbonate, Calcium, Glucose, Chloride, Magnesium, Phosphate, Sodium, Blood urea nitrogen [BUN], Cholesterol, High density Lipoprotein [HDL], Low density lipoprotein [LDL], Triglycerides [Unit: Millimole per Liter]) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change from Baseline in Serum Chemistry Parameters: ALT, AST, GGT, LDH, Alkaline phosphatase, CPK | Change from baseline in serum chemistry parameters (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Gamma-glutamyl transferase [GGT], Lactic acid dehydrogenase [LDH], Alkaline phosphatase, Creatine phosphokinase [CPK] [Unit: International units per Liter]) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change from Baseline in Serum Chemistry Parameters: Amylase | Change from baseline in serum chemistry parameters (Amylase [Unit: Units per liter]) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change from Baseline in Serum Chemistry Parameters: Lipase | Change from baseline in serum chemistry parameters (Lipase [Unit: Units per liter]) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change from Baseline in Serum Chemistry Parameters: Total Bilirubin, Creatinine and Uric Acid | Change from baseline in serum chemistry parameters (Total bilirubin, Creatinine and Uric acid [Unit: Micromoles per Liter]) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change from Baseline in Serum Chemistry Parameters: Total Protein and Albumin | Change from baseline in serum chemistry parameters (Total protein and Albumin [Unit: Gram per Liter]) will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in Urinalysis Parameter: Specific Gravity | Change from baseline in urinalysis parameter (Specific gravity) tests will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Parts 1 and 2: Change From Baseline in Urinalysis Parameter: pH | Change from baseline in urinalysis parameter (pH) tests will be assessed. | Part 1: Up to 77 Days; Part 2: Up to 59 Days |
| Part 1: Mean Trough Plasma Concentration of Milvexian at Steady State (Ctrough) | Mean trough plasma concentration of milvexian at steady state will be reported. | Part 1: Predose, 2, 4, 4.75, 5, 6, 8, 12, 24, 48, and 72 hours Postdose |
| Part 1 and Part 2: Maximum Observed Analyte Concentration (Cmax) of Milvexian | Cmax is the maximum observed analyte concentration. | 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 |
| Part 1 and Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of milvexian | Tmax is defined as actual sampling time to reach the maximum observed analyte concentration. | 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 |
| Parts 1 and Part 2: Elimination Half-Life (t1/2) of Milvexian | t1/2 elimination half-life means time measured for the plasma concentration to decrease by 1 half to its original concentration of milvexian. | 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 |
| Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Dosing Interval (AUC [0-t]) of Milvexian | Area under the plasma concentration versus time curve from time zero to dosing interval of milvexian. | Part 1: Predose, 2, 4, 4.75, 5, 6, 8, 12, 24, 48, and 72 hours Postdose |
| Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of Milvexian | Area under the plasma concentration versus time curve from time zero to infinity with extrapolation of the terminal phase of milvexian. | Part 2: 0.25, 2, 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose |
| Part 1 and Part 2: Area Under Plasma Concentration From Time Zero to the Last Quantifiable Concentration (AUC [0-last]) of Milvexian | Area under the plasma concentration versus time curve from time zero to the time corresponding to the last quantifiable concentration of milvexian will be assessed. | 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 |
| Part 2: Maximum Observed Analyte Concentration (Cmax) of rFVIIa | Cmax is the maximum observed analyte concentration. | Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose |
| Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of rFVIIa | Tmax is defined as actual sampling time to reach the maximum observed analyte concentration. | Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose |
| Part 2: Elimination Half-Life (t1/2) of rFVIIa | t1/2 elimination half-life means time measured for the plasma concentration to decrease by 1 half to its original concentration of rFVIIa. | Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose |
| Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of rFVIIa | Area under the plasma concentration versus time curve from time zero to infinity with extrapolation of the terminal phase of rFVIIa. | Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose |
| Part 2: Area Under Plasma Concentration From Time Zero to the Last Quantifiable Concentration (AUC [0-last]) of rFVIIa | Area under the plasma concentration versus time curve from time zero to the time corresponding to the last quantifiable concentration of rFVIIa will be assessed. | Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose |
| Part 2: Systemic Clearance (CL) of rFVIIa | CL is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after intravenous dose will be estimated by dividing the total administered dose by the area under the plasma concentration-time curve from time zero to infinite time (AUC [0-infinity]). | Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose |
| Part 2: Volume of distribution (Vz) of rFVIIa | The Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. | Part 2: 4, 4.25, 4.5, 5, 6, 8, 12, 24 hours Postdose |
| Part 1 and Part 2: Change from Baseline in aPTT | Change from baseline in aPTT will be reported. | Part 1: Baseline, Day 1, Day 4, Day 5, Day 6 and Day 7; Part 2: Baseline, Day 1 and Day 2 |
| Part 1 and Part 2: Change from Baseline in ETP (TGA Parameter) | The TGA measures the thrombin generation that is indicative of an overall coagulating capacity. A calibrated automated thrombography is used to monitor the concentration of thrombin in clotting plasma with a fluorogenic substrate. The data derived from the thrombography can be used to determine the ETP (TGA parameter). The ETP assesses the amount of thrombin which can be generated after the in vitro activation of coagulation and represents the balance between pro and anti-coagulant forces in plasma. | Part 1: Baseline, Day 1, Day 4, Day 5, Day 6 and Day 7; Part 2: Baseline, Day 1 and Day 2 |
| Part 1 and Part 2: Change from Baseline in Lag Time (TGA Parameter) | The TGA measures the thrombin generation that is indicative of an overall coagulating capacity. A calibrated automated thrombography is used to monitor the concentration of thrombin in clotting plasma with a fluorogenic substrate. The data derived from the thrombography can be used to determine the lag time (TGA parameter). The lag time is defined as the time needed until thrombin is generated. | Part 1: Baseline, Day 1, Day 4, Day 5, Day 6 and Day 7; Part 2: Baseline, Day 1 and Day 2 |
| Part 1 and Part 2: Change from Baseline in Peak Thrombin (TGA Parameter) | The TGA measures the thrombin generation that is indicative of an overall coagulating capacity. A calibrated automated thrombography is used to monitor the concentration of thrombin in clotting plasma with a fluorogenic substrate. The data derived from the thrombography can be used to determine the peak thrombin (TGA parameter). The peak thrombin is defined as the maximal effect on thrombin generation. | Part 1: Baseline, Day 1, Day 4, Day 5, Day 6 and Day 7; Part 2: Baseline, Day 1 and Day 2 |
| Part 1 and Part 2: Change from Baseline in Time to Peak Thrombin (TGA Parameter) | The TGA measures the thrombin generation that is indicative of an overall coagulating capacity. A calibrated automated thrombography is used to monitor the concentration of thrombin in clotting plasma with a fluorogenic substrate. The data derived from the thrombography can be used to determine the time to peak thrombin (TGA parameter). The time to peak thrombin is defined as the time required to reach maximal effect on thrombin generation. | Part 1: Baseline, Day 1, Day 4, Day 5, Day 6 and Day 7; Part 2: Baseline, Day 1 and Day 2 |
| Percent Change from Baselines in aPTT | Percent change from baseline in aPTT will be reported. | Part 1: Baseline, Day 1, Day 4, Day 5, Day 6 and Day 7; Part 2: Baseline, Day 1 and Day 2 |
| ID | Term |
|---|---|
| C000720754 | milvexian |
| D005164 | Factor IX |
| C103587 | recombinant FVIIa |
| ID | Term |
|---|---|
| D004792 | Enzyme Precursors |
| D045762 | Enzymes and Coenzymes |
| D001779 | Blood Coagulation Factors |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011498 | Protein Precursors |
| D001685 | Biological Factors |
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