A Study of Milvexian Using an IV Microtracer With Additional Formulation and Food Effect Comparison in Healthy Participants

Phase 1

Completed

Conditions: Healthy Volunteers

Interventions: Drug: BMS-986177 Oral Solution
Drug: [14C]BMS-986177 Solution for Infusion
Drug: BMS-986177 Spray-dried Dispersion Capsules

Registration Number: NCT04965389

Lead Sponsor: Bristol-Myers Squibb

Brief Summary: The purpose of this study is to evaluate the absolute oral bioavailability (amount of drug entering the bloodstream) of spray-dried dispersion (SDD) milvexian capsules in the fed and fasted states, and to bridge the exposures seen using only the oral solution.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 17

Inclusion Criteria

Healthy, as determined by no clinically significant deviation from normal in medical history, physical examination, electrocardiograms (ECGs), and clinical laboratory determinations
Body mass index (BMI) of 18.0 to 32.0 kg/m², inclusive. BMI = weight (kg)/ (height [m])²

Exclusion Criteria

History of gastrointestinal (GI) disease, upper or lower GI bleeding within 6 months, intracranial bleeding, tumor, aneurysms
History or evidence of abnormal bleeding or coagulation disorder and/or evidence of coagulopathy, prolonged or unexplained clinically significant bleeding, or frequent unexplained bruising or thrombus formation, or a history of spontaneous bleeding, such as epistaxis, or family history of coagulopathies
Any acute or chronic medical illness considered clinically significant by the investigator
History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory, neurological or psychiatric disorder, as judged by the investigator

Other protocol-defined inclusion/exclusion criteria apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment Sequence 1	[14C]BMS-986177 Solution for Infusion	-
Treatment Sequence 2	[14C]BMS-986177 Solution for Infusion	-
Treatment Sequence 2	BMS-986177 Spray-dried Dispersion Capsules	-
Treatment Sequence 3	BMS-986177 Oral Solution	-
Treatment Sequence 4	BMS-986177 Oral Solution	-
Treatment Sequence 1	BMS-986177 Oral Solution	-
Treatment Sequence 1	BMS-986177 Spray-dried Dispersion Capsules	-
Treatment Sequence 2	BMS-986177 Oral Solution	-
Treatment Sequence 3	[14C]BMS-986177 Solution for Infusion	-
Treatment Sequence 4	[14C]BMS-986177 Solution for Infusion	-
Treatment Sequence 4	BMS-986177 Spray-dried Dispersion Capsules	-
Treatment Sequence 3	BMS-986177 Spray-dried Dispersion Capsules	-

Primary Outcome Measures

Name	Time	Method
Absolute Bioavailability (F)	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Absolute bioavailability is defined as the amount of drug from a formulation that reaches the systemic circulation relative to an intravenous (IV) dose. Treatment A (milvexian oral solution with IV microdose) was assessed versus each treatment phase of milvexian administered as: a oral solution (fasted), high dose SDD (Spray-Dried Dispersion) capsule (fed and fasted) and low dose SDD capsule (fed and fasted).

Secondary Outcome Measures

Name	Time	Method
Number of Participants Experiencing Serious Adverse Events (SAE)	Day 1 of Treatment Periods 1-5 (up to approximately 11 weeks)	The number of participants experiencing SAEs following single oral and IV administration. SAEs are defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or causes prolongation of existing hospitalization.
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(INF)]	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	AUC(INF) is defined as area under the concentration-time curve from time zero extrapolated to infinity following single administration in the fed and fasted states to healthy participants
Total Amount of Unchanged Drug Excreted Into the Urine (Ae)	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Ae is defined as the total amount of unchanged drug excreted into the urine following single administration in the fed and fasted states to healthy participants
Total Percent Urinary Recovery (%UR)	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	%UR is defined as a percent or absolute amount of dose that is recovered in the urine as the unchanged drug.
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)]	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	AUC(0-T) is defined as the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration following single administration in the fed and fasted states to healthy participants.
Number of Participants With Abnormal Electrocardiograms (ECGs)	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	The number of participants with abnormal findings on ECGs following single oral and IV administration. Participants with ECG intervals outside of a pre-specified range and investigator identified ECG abnormalities will be listed. The following criteria will be used to determine ECG results that are outside of a pre-specified range: PR (msec)-Value \> 200; QRS (msec)-Value \> 120; QT (msec)-Value \> 500 or change from baseline \> 30; QTcF (msec)-Value \> 450 or change from baseline \> 30
Time of Maximum Observed Plasma Concentration (Tmax)	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Tmax is defined as the time of maximum observed plasma concentration in the fed and fasted states to healthy participants.
Renal Clearance (CLR)	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	CLR is defined as the volume of plasma completely cleared of a substance by the kidneys per unit of time, in this case by hour.
Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F)	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Vz/F is defined as the apparent volume of distribution at terminal phase after extravascular administration.
Number of Participants Experiencing Abnormal Vital Sign Measurements	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Occurrence of abnormalities in vital sign measurements exceeding pre-defined thresholds following single oral and IV administration. The pre-defined thresholds include: Heart Rate(bpm) Value \> 100 and change from baseline \> 30, or Value \< 55 and change from baseline \< -15 Systolic Blood Pressure(mmHg) Value \> 140 and change from baseline \> 20, or Value \< 90 and change from baseline \< -20 Diastolic Blood Pressure(mmHg) Value \> 90 and change from baseline \> 10, or Value \< 55 and change from baseline \< -10 Respiratory Rate(breaths/min) Value \> 16 or change from baseline \> 10 Temperature (°C) Value \> 38.3°C or change from baseline \> 1.6°C
Number of Participants With Abnormal Physical Examinations	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	The number of participants with abnormal findings on physical examinations following single oral and IV administration.
Maximum Observed Plasma Concentration (Cmax)	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Cmax is defined as the maximum observed plasma concentration following single administration in the fed and fasted states to healthy participants.
Apparent Clearance of Drug After Extravascular Administration (CLT/F)	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	CLT/F is defined as the apparent clearance of drug after extravascular administration.
Volume of Distribution at Steady State (Vss) Following an IV Dose in Treatment A	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Characterize the IV dose of Treatment A by Vss, which is defined as the apparent volume of distribution at steady state
Relative Bioavailability (Frel) Based on Ratios of Cmax	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Point estimates and 90% CI for the ratio of geometric means for Cmax will be constructed for the comparison of each milvexian capsule treatment (Treatments B, C, D, and E) separately versus the oral solution (Treatment A). No data is reported for Treatment A because it is the comparison treatment. Relative bioavailability is defined as the amount of drug from a formulation that reaches the systemic circulation relative to a different formulation (non-IV) such as an oral solution. Cmax is defined as the maximum observed plasma concentration.
Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF)	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Point estimates and 90% CI for the ratio of geometric means for AUC(0-T) and AUC(INF) will be constructed for the comparison of each milvexian capsule treatment (Treatments B, C, D, and E) separately versus the oral solution (Treatment A). No data is reported for Treatment A because it is the comparison treatment. Relative bioavailability is defined as the amount of drug from a formulation that reaches the systemic circulation relative to a different formulation (non-IV) such as an oral solution. AUC(0-T) is defined as the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration. AUC(INF) is defined as area under the concentration-time curve from time zero extrapolated to infinity.
Number of Participants Experiencing Adverse Events (AEs)	Day 1 of Treatment Periods 1-5 (up to approximately 11 weeks)	The number of participants experiencing AEs following single oral and IV administration. AEs are defined as any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Number of Participants With Clinical Laboratory Test Abnormalities	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Number of participants with abnormalities in clinical lab test measurements exceeding pre-defined thresholds following single oral and IV administration. The pre-defined thresholds include: Alanine transaminase \> 3 × upper limit of normal (ULN) Aspartate transaminase \> 3 × ULN Alkaline phosphatase \> 1.5 × ULN Total bilirubin \> 2 × ULN
Half-life (T-HALF)	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	T-HALF is defined as the time required for half the quantity of a drug to be metabolized or eliminated by normal biological processes.
Mean Residence Time (MRT) Following an IV Dose in Treatment A	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Mean residence time (MRT) represents the average time the drug stays in the body and is evaluated for the IV dose of Treatment A only.
Food Effect Based on Ratios of AUC(0-T) and AUC(INF) Following an SDD Capsule Dose in Treatment B, C, D, and E	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Food effect with low and high dose SDD capsules based on ratios of AUC(0-T) and AUC(INF). The food effect analysis will be run separately for each dose level. For the low dose level, low dose milvexian SDD fed (Treatment C) is the test treatment and low dose milvexian SDD fasted (Treatment D) is the reference treatment. For the high dose level, high dose milvexian SDD fed (Treatment E) is the test treatment and high dose milvexian SDD fasted (Treatment B) is the reference treatment. AUC(0-T) is defined as the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration. AUC(INF) is defined as area under the concentration-time curve from time zero extrapolated to infinity.
Food Effect Based on Ratios of Cmax Following an SDD Capsule Dose in Treatment B, C, D, and E	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)	Food effect analysis of the high and low dose SDD capsules based on ratios of Cmax. The food effect analysis will be run separately for each dose level. For the low dose level, low dose milvexian SDD fed (Treatment C) is the test treatment and low dose milvexian SDD fasted (Treatment D) is the reference treatment. For the high dose dose level, high dose milvexian SDD fed (Treatment E) is the test treatment and high dose milvexian SDD fasted (Treatment B) is the reference treatment. Cmax is defined as the maximum observed plasma concentration.