Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Milvexian · 7 trials · 5 indications
Time to the first occurrence of composite endpoint of stroke and non-CNS systemic embolism will be reported.
Time to first occurrence of any component of MACE will be reported. MACE is a composite of cardiovascular (CV) death, myocardial infarction (MI), and ischemic stroke.
Time to first occurrence of ischemic stroke will be reported.
Cmax is defined as the maximum observed plasma concentration of midazolam and 1-hydroxymidzolam.
AUC(0-last) is defined as area under the plasma concentration-time curve from time 0 to time of the last observed quantifiable concentration of midazolam and 1-hydroxymidzolam.
AUC(0-infinity) is defined as the area under the plasma concentration-time curve from time 0 to infinite time of midazolam and 1-hydroxymidzolam.
Cmax is defined as the maximum observed plasma concentration of ethinylestradiol and drospirenone.
AUC(0-last) is defined as area under the plasma concentration-time curve from time 0 to time of the last observed quantifiable concentration of ethinylestradiol and drospirenone.
AUC(0-infinity) is defined as the area under the plasma concentration-time curve of from time 0 to infinite time ethinylestradiol and drospirenone.
Cmax is the maximum observed plasma concentration of milvexian at Steady State.
AUC(0-24 hours) is the area under the plasma concentration-time curve from time zero to 24 hours of milvexian at Steady State.
Cmax is the maximum observed plasma concentration of Atorvastatin at Steady State.
AUC(0-24 hours) is the area under the plasma concentration-time curve from time zero to 24 hours of Atorvastatin at Steady State.
AUC (0-infinity) is defined as area under the plasma concentration-time curve of milvexian from time zero to infinity after administration.
AUC (0-last) is defined as area under the plasma concentration-time curve of milvexian from time zero to time of last quantifiable concentration after administration.
Cmax is defined as maximum observed analyte concentration of milvexian.
AUC (0-infinity) is defined as area under the plasma concentration-time curve of milvexian from time zero to infinity after administration.
AUC (0-last) is defined as area under the plasma concentration-time curve of milvexian from time zero to time of last quantifiable concentration after administration.
Cmax is defined as maximum observed analyte concentration of milvexian.
Tmax is defined as the actual sampling time to reach the maximum observed analyte concentration of milvexian.
Tmax is defined as the actual sampling time to reach the maximum observed analyte concentration of milvexian.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
| Arm | Type | Description |
|---|---|---|
| Milvexian | EXPERIMENTAL | Participants will receive milvexian 100 milligrams (mg) orally, twice daily and placebo that matches apixaban beginning on Day 1 through end of treatment (EOT). Participants after the EOT visit may have an option to receive open-label apixaban at the appropriate dose (5 mg or 2.5 mg, twice daily), for which the sponsor provides a 30-day supply. |
| Apixaban | ACTIVE_COMPARATOR | Participants will receive a placebo that matches milvexian and a capsule containing apixaban 5 mg or 2.5 mg orally, twice daily. Participants after the EOT visit may have an option to receive open-label apixaban (5 mg or 2.5 mg, twice daily) at the appropriate dose, for which the sponsor provides a 30-day supply. |
| Placebo | PLACEBO_COMPARATOR | Participants enrolled within 7 days of an ACS, who have undergone cardiac catheterization with PCI or who are being managed conservatively with or without catheterization, and who are receiving antiplatelet therapy standard-of-care (SAPT or DAPT) as determined by the investigator will receive placebo orally, twice daily. |
| Milvexian + Midazolam + Ethinylestradiol/Drospirenone | EXPERIMENTAL | Participants will receive midazolam on Day 1 and Day 19; ethinylestradiol and drospirenone on Day 2 and Day 20; and milvexian from Day 7 to Day 24. |
| Treatment Sequence ABC | EXPERIMENTAL | Participants will receive milvexian capsule once daily (qd) for 5 days (Treatment A) in Period 1 followed by Atorvastatin tablets qd for 5 days (Treatment B) in Period 2 followed by milvexian capsules qd and atorvastatin tablets qd for 5 days (Treatment C) in Period 3. Each period is separated by a washout period of 7 days. |
| Treatment Sequence BCA | EXPERIMENTAL | Participants will receive Treatment B in Period 1 followed by Treatment C in Period 2 and Treatment A in Period 3. Each Period is separated by a washout period of 7 days. |
| Treatment Sequence CAB | EXPERIMENTAL | Participants will receive Treatment C in Period 1 followed by Treatment A in Period 2 and Treatment B in Period 3. Each Period is separated by a washout period of 7 days. |
| Treatment Sequence CBA | EXPERIMENTAL | Participants will receive Treatment C in Period 1 followed by Treatment B in Period 2 and Treatment A in Period 3. Each Period is separated by a washout period of 7 days. |
| Treatment Sequence ACB | EXPERIMENTAL | Participants will receive Treatment A in Period 1 followed by Treatment C in Period 2 and Treatment B in Period 3. Each Period is separated by a washout period of 7 days. |
| Treatment Sequence BAC | EXPERIMENTAL | Participants will receive Treatment B in Period 1 followed by Treatment A in Period 2 and Treatment C in Period 3. Each Period is separated by a washout period of 7 days. |
| Part 1A: Treatment Sequence ABC | EXPERIMENTAL | Participants will receive a single oral Dose 1 of milvexian as direct compression (DC) tablets under fasting conditions (Treatment A) in Treatment Period 1, followed by a single oral Dose 1 of milvexian as roller compacted (RC) tablets under fasting conditions (Treatment B) in Treatment Period 2 and then a single oral Dose 1 of milvexian Phase 2 oral capsules under fasting conditions (Treatment C) in Treatment Period 3 on Day 1 of each Treatment Period during Part 1A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 1A: Treatment Sequence BCA | EXPERIMENTAL | Participants will receive Treatment B in Treatment Period 1, followed by Treatment C in Treatment Period 2 and then Treatment A in Treatment Period 3 on Day 1 of each Treatment Period during Part 1A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 1A: Treatment Sequence CAB | EXPERIMENTAL | Participants will receive Treatment C in Treatment Period 1, followed by Treatment A in Treatment Period 2 and then Treatment B in Treatment Period 3 on Day 1 of each Treatment Period during Part 1A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 1A: Treatment Sequence ACB | EXPERIMENTAL | Participants will receive Treatment A in Treatment Period 1, followed by Treatment C in Treatment Period 2 and then Treatment B in Treatment Period 3 on Day 1 of each Treatment Period during Part 1A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 1A: Treatment Sequence BAC | EXPERIMENTAL | Participants will receive Treatment B in Treatment Period 1, followed by Treatment A in Treatment Period 2 and then Treatment C in Treatment Period 3 on Day 1 of each Treatment Period during Part 1A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 1A: Treatment Sequence CBA | EXPERIMENTAL | Participants will receive Treatment C in Treatment Period 1 followed by Treatment B in Treatment Period 2 and then Treatment A in Treatment Period 3 on Day 1 of each Treatment Period during Part 1A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 1B: Treatment Sequence DEF | EXPERIMENTAL | Participants will receive a single oral Dose 1 of milvexian as DC oral tablets under fed conditions (Treatment D) in Treatment Period 1, followed by a single oral Dose 1 of milvexian as RC oral tablets under fed conditions (Treatment E) in Treatment Period 2 and then a single oral Dose 1 of milvexian as Phase 2 oral capsules under fed conditions (Treatment F) in Treatment Period 3 on Day 1 of each Treatment Period during Part 1B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 1B: Treatment Sequence EFD | EXPERIMENTAL | Participants will receive Treatment E in Treatment Period 1, followed by Treatment F in Treatment Period 2 and then Treatment D in Treatment Period 3 on Day 1 of each Treatment Period during Part 1B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 1B: Treatment Sequence FDE | EXPERIMENTAL | Participants will receive Treatment F in Treatment Period 1, followed by Treatment D in Treatment Period 2 and then Treatment E in Treatment Period 3 on Day 1 of each Treatment Period during Part 1B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 1B: Treatment Sequence DFE | EXPERIMENTAL | Participants will receive Treatment D in Treatment Period 1, followed by Treatment F in Treatment Period 2 and then Treatment E in Treatment Period 3 on Day 1 of each Treatment Period during Part 1B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 1B: Treatment Sequence EDF | EXPERIMENTAL | Participants will receive Treatment E in Treatment Period 1, followed by Treatment D in Treatment Period 2 and then Treatment F in Treatment Period 3 on Day 1 of each Treatment Period during Part 1B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 1B: Treatment Sequence FED | EXPERIMENTAL | Participants will receive Treatment F in Treatment Period 1, followed by Treatment E in Treatment Period 2 and then Treatment D in Treatment Period 3 on Day 1 of each Treatment Period during Part 1B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 2A: Treatment Sequence GH | EXPERIMENTAL | Participants will receive twice daily (BID) oral Dose 1 of milvexian DC oral tablets (Treatment G) in Treatment Period 1, followed by BID oral Dose 1 of milvexian Phase 2 oral capsule (Treatment H) in Treatment Period 2 up to Day 5 in each Treatment Period during Part 2A. There will be a wash-out period of more than 5 days between the evening dose of Day 5 of Treatment Period 1 and the morning dose of Day 1 of Treatment Period 2. |
| Part 2A: Treatment Sequence HG | EXPERIMENTAL | Participants will receive Treatment H in Treatment Period 1, followed by Treatment G in Treatment Period 2 up to Day 5 in each Treatment Period during Part 2A. There will be a wash-out period of more than 5 days between the evening dose of Day 5 of Treatment Period 1 and the morning dose of Day 1 of Treatment Period 2. |
| Part 2B: Treatment Sequence IJ | EXPERIMENTAL | Participants will receive BID oral Dose 2 of milvexian DC oral tablet (Treatment I) in Treatment Period 1, followed by BID oral Dose 2 of milvexian Phase 2 oral capsule (Treatment J) in Treatment Period 2 up to Day 5 in each Treatment Period during Part 2B. There will be a wash-out period of more than 5 days between the evening dose of Day 5 of Treatment Period 1 and the morning dose of Day 1 of Treatment Period 2. |
| Part 2B: Treatment Sequence JI | EXPERIMENTAL | Participants will receive Treatment J in Treatment Period 1, followed by Treatment I in Treatment Period 2 up to Day 5 in each Treatment Period during Part 2B. There will be a wash-out period of more than 5 days between the evening dose of Day 5 of Treatment Period 1 and the morning dose of Day 1 of Treatment Period 2. |
| Part 3A: Treatment Sequence KLM | EXPERIMENTAL | Participants will receive single oral Dose 1 of milvexian as oral Tablet 1 under fasting conditions (Treatment K) in Treatment Period 1, followed by single oral Dose 1 of milvexian oral Tablet 2 under fasting conditions (Treatment L) in Treatment Period 2 and then single oral Dose 1 of milvexian as Phase 2 oral capsules under fasting conditions (Treatment M) in Treatment Period 3 on Day 1 in each Treatment Period during Part 3A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 3A: Treatment Sequence LMK | EXPERIMENTAL | Participants will receive Treatment L in Treatment Period 1, followed by Treatment M in Treatment Period 2 and then Treatment K in Treatment Period 3 on Day 1 of each Treatment Period during Part 3A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 3A: Treatment Sequence MKL | EXPERIMENTAL | Participants will receive Treatment M in Treatment Period 1, followed by Treatment K in Treatment Period 2 and then Treatment L in Treatment Period 3 on Day 1 in each Treatment Period during Part 3A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 3A: Treatment Sequence KML | EXPERIMENTAL | Participants will receive Treatment K in Treatment Period 1, followed by Treatment M in Treatment Period 2 and then Treatment L in Treatment Period 3 on Day 1 in each Treatment Period during Part 3A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 3A: Treatment Sequence LKM | EXPERIMENTAL | Participants will receive Treatment L in Treatment Period 1, followed by Treatment K in Treatment Period 2 and then Treatment M in Treatment Period 3 on Day 1 in each Treatment Period during Part 3A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 3A: Treatment Sequence MLK | EXPERIMENTAL | Participants will receive Treatment M in Treatment Period 1, followed by Treatment L in Treatment Period 2 and then Treatment K in Treatment Period 3 on Day 1 in each Treatment Period during Part 3A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 3B: Treatment Sequence NOP | EXPERIMENTAL | Participants will receive single oral Dose 1 of milvexian oral Tablet 1 under fed conditions (Treatment N) in Treatment Period 1, followed by single oral Dose 1 of milvexian oral Tablet 2 under fed conditions (Treatment O) in Treatment Period 2 and then single oral Dose 1 of milvexian Phase 2 oral capsule under fed conditions (Treatment P) in Treatment Period 3 on Day 1 in each Treatment Period during Part 3B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 3B: Treatment Sequence OPN | EXPERIMENTAL | Participants will receive Treatment O in Treatment Period 1, followed by Treatment P in Treatment Period 2 and then Treatment N in Treatment Period 3 on Day 1 in each Treatment Period during Part 3B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 3B: Treatment Sequence PNO | EXPERIMENTAL | Participants will receive Treatment P in Treatment Period 1, followed by Treatment N in Treatment Period 2 and then Treatment O in Treatment Period 3 on Day 1 in each Treatment Period during Part 3B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 3B: Treatment Sequence NPO | EXPERIMENTAL | Participants will receive Treatment N in Treatment Period 1, followed by Treatment P in Treatment Period 2 and then Treatment O in Treatment Period 3 on Day 1 in each Treatment Period during Part 3B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 3B: Treatment Sequence ONP | EXPERIMENTAL | Participants will receive Treatment O in Treatment Period 1, followed by Treatment N in Treatment Period 2 and then Treatment P in Treatment Period 3 on Day 1 in each Treatment Period during Part 3B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 3B: Treatment Sequence PON | EXPERIMENTAL | Participants will receive Treatment P in Treatment Period 1, followed by Treatment O in Treatment Period 2 and then Treatment N in Treatment Period 3 on Day 1 in each Treatment Period during Part 3B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 4 A: Treatment Sequence QRS | EXPERIMENTAL | Participants will receive single oral Dose 1 of milvexian as Phase 3 oral tablets under fasting conditions (Treatment Q) in Treatment Period 1, followed by single oral Dose 1 of milvexian as Phase 3 oral tablets under fed conditions (Treatment R) in Treatment Period 2 and then single oral Dose 1 of milvexian as Phase 3 oral tablets under fed conditions (Treatment S) in Treatment Period 3 on Day 1 of each Treatment Period during Part 4A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 4A: Treatment Sequence RSQ | EXPERIMENTAL | Participants will receive Treatment R in Treatment Period 1, followed by Treatment S in Treatment Period 2 and then Treatment Q in Treatment Period 3 on Day 1 of each Treatment Period during Part 4A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 4A: Treatment Sequence SQR | EXPERIMENTAL | Participants will receive Treatment S in Treatment Period 1, followed by Treatment Q in Treatment Period 2 and then Treatment R in Treatment Period 3 on Day 1 of each Treatment Period during Part 4A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 4A: Treatment Sequence QSR | EXPERIMENTAL | Participants will receive Treatment Q in Treatment Period 1, followed by Treatment S in Treatment Period 2 and then Treatment R in Treatment Period 3 on Day 1 of each Treatment Period during Part 4A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 4A: Treatment Sequence RQS | EXPERIMENTAL | Participants will receive Treatment R in Treatment Period 1, followed by Treatment Q in Treatment Period 2 and then Treatment S in Treatment Period 3 on Day 1 of each Treatment Period during Part 4A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 4A: Treatment Sequence SRQ | EXPERIMENTAL | Participants will receive Treatment S in Treatment Period 1, followed by Treatment R in Treatment Period 2 and then Treatment Q in Treatment Period 3 on Day 1 of each Treatment Period during Part 4A. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 4B: Treatment Sequence TU | EXPERIMENTAL | Participants will receive single oral Dose 1 of milvexian as Phase 3 oral tablet under fed conditions (Treatment T) in Treatment Period 1, followed by single oral Dose 2 of milvexian as Phase 3 oral tablet under fed conditions (Treatment U) in Treatment Period 2 on Day 1 of each Treatment Period during Part 4B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 4B: Treatment Sequence UT | EXPERIMENTAL | Participants will receive Treatment U in Treatment Period 1, followed by Treatment T in Treatment Period 2 on Day 1 of each Treatment Period during Part 4B. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Subpart 4A: Treatment Sequence VW | EXPERIMENTAL | All participants of Subpart 4A will undertake a mandatory taste assessment on Day 5 of period 3 or Day 15 before the discharge and will receive milvexian tablet dispersed in water without a sweetener orally via syringe (Treatment V) in Treatment Period 1, followed by milvexian tablet dispersed in water with sucralose sweetener orally via syringe (Treatment W) in Treatment Period 2. Participants will cleanse their palates using 2 rinse of mineral water and one unsalted cracker and wait for a time interval of at least 1-2 hours from start of dosing before the next taste round. |
| Subpart 4A: Treatment Sequence WV | EXPERIMENTAL | All participants of Subpart 4A will undertake a mandatory taste assessment on Day 5 of period 3 or Day 15 before the discharge and will receive Treatment W in Treatment Period 1, followed by Treatment V in Treatment Period 2. Participants will cleanse their palates using 2 rinse of mineral water and one unsalted cracker and wait for a time interval of at least 1-2 hours from start of dosing before the next taste round. |
| Part 5: Treatment Sequence XYZ | EXPERIMENTAL | Participants will receive a single oral Dose 1 of milvexian as DC whole tablets under fasting conditions (Treatment X) in Treatment Period 1 followed by a single oral Dose 1 of milvexian as DC tablets dispersed in water and then mixed with apple sauce under fasting conditions (Treatment Y) in Treatment Period 2 and then a single oral Dose 1 of milvexian as DC tablets dispersed in water administered through a nasogastric (NG) tube under fasting conditions (Treatment Z) in Treatment Period 3 on Day 1 of each Treatment Period during Part 5. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 5: Treatment Sequence YZX | EXPERIMENTAL | Participants will receive Treatment Y in Treatment Period 1 followed by Treatment Z in Treatment Period 2 and then Treatment X in Treatment Period 3 on Day 1 of each Treatment Period during Part 5. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 5: Treatment Sequence ZXY | EXPERIMENTAL | Participants will receive Treatment Z in Treatment Period 1 followed by Treatment X in Treatment Period 2 and then Treatment Y in Treatment Period 3 on Day 1 of each Treatment Period during Part 5. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 5: Treatment Sequence XZY | EXPERIMENTAL | Participants will receive Treatment X in Treatment Period 1 followed by Treatment Z in Treatment Period 2 and then Treatment Y in Treatment Period 3 on Day 1 of each Treatment Period during Part 5. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 5: Treatment Sequence YXZ | EXPERIMENTAL | Participants will receive Treatment Y in Treatment Period 1 followed by Treatment X in Treatment Period 2 and then Treatment Z in Treatment Period 3 on Day 1 of each Treatment Period during Part 5. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| Part 5: Treatment Sequence ZYX | EXPERIMENTAL | Participants will receive Treatment Z in Treatment Period 1 followed by Treatment Y in Treatment Period 2 and then Treatment X in Treatment Period 3 on Day 1 of each Treatment Period during Part 5. There will be a wash-out period of 5 days between Day 1 of adjacent treatment periods. |
| 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. |
| 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. |
| 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 |
|---|---|---|
| Milvexian | DRUG | Milvexian will be administered orally. |
| Apixaban | DRUG | Apixaban will be administered orally. |
| Placebo | DRUG | Milvexian matching milvexian placebo will be administered orally. |
| Apixaban Placebo | DRUG | Apixaban matching apixaban placebo will be administered orally. |
| Midazolam | DRUG | Midazolam will be administered orally. |
| Ethinylestradiol | DRUG | Ethinylestradiol will be administered orally. |
| Drospirenone | DRUG | Drospirenone will be administered orally. |
| Atorvastatin | DRUG | Participants will receive atorvastatin tablets orally qd for 5 days as per the assigned treatment sequence. |
| 4-Factor Prothrombin Complex Concentrate (4F-PCC) | BIOLOGICAL | 4F-PCC will be administered intravenously. |
| Recombinant Human Factor VIIa (rFVIIa) | BIOLOGICAL | rFVIIa will be administered intravenously. |
| Placebo matching to 4F-PCC | BIOLOGICAL | Placebo matching to 4F-PCC will be administered intravenously. |
| Placebo matching to rFVIIa | BIOLOGICAL | Placebo matching to rFVIIa will be administered intravenously. |
Inclusion Criteria: * Minimum age of 18 years * Medically stable and appropriate for chronic antithrombotic treatment * Atrial fibrillation eligible to receive anticoagulation * Participant must satisfy one or both of the following categories of risk factors (a or b): a) one or more of the followin...