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

Healthy Volunteers Clinical Trial

Official title:

A Study to Assess the Absolute Oral Bioavailability of Milvexian Using a 14C-Microtracer and Oral Solution in Healthy Participants With Additional Food Effect Comparison of a Spray-Dried Dispersion Formulation of Milvexian in Capsules

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04965389
• Other study ID #: CV010-062
• Secondary ID: 2021-000892-35
• Status: Completed
• Phase: Phase 1
• Start date: July 16, 2021
• Est. completion date: October 1, 2021

Study information

• Verified date: September 2022
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: October 1, 2021
• Est. primary completion date: August 22, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

Drug:
• BMS-986177 Oral Solution
Specified dose on specified days
• [14C]BMS-986177 Solution for Infusion
Specified dose on specified days
• BMS-986177 Spray-dried Dispersion Capsules
Specified dose on specified days

Locations

Country	Name	City	State
United Kingdom	Local Institution	Nottingham

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Absolute Bioavailability (F)	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).	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Number of Participants Experiencing Adverse Events (AEs)	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.	Day 1 of Treatment Periods 1-5 (up to approximately 11 weeks)
Secondary	Number of Participants Experiencing Serious Adverse Events (SAE)	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.	Day 1 of Treatment Periods 1-5 (up to approximately 11 weeks)
Secondary	Number of Participants Experiencing Abnormal Vital Sign Measurements	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	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Number of Participants With Abnormal Electrocardiograms (ECGs)	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	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Number of Participants With Abnormal Physical Examinations	The number of participants with abnormal findings on physical examinations following single oral and IV administration.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Number of Participants With Clinical Laboratory Test Abnormalities	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	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Maximum Observed Plasma Concentration (Cmax)	Cmax is defined as the maximum observed plasma concentration following single administration in the fed and fasted states to healthy participants.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Time of Maximum Observed Plasma Concentration (Tmax)	Tmax is defined as the time of maximum observed plasma concentration in the fed and fasted states to healthy participants.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)]	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.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(INF)]	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	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Apparent Clearance of Drug After Extravascular Administration (CLT/F)	CLT/F is defined as the apparent clearance of drug after extravascular administration.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Renal Clearance (CLR)	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.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F)	Vz/F is defined as the apparent volume of distribution at terminal phase after extravascular administration.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Total Amount of Unchanged Drug Excreted Into the Urine (Ae)	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	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Total Percent Urinary Recovery (%UR)	%UR is defined as a percent or absolute amount of dose that is recovered in the urine as the unchanged drug.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Half-life (T-HALF)	T-HALF is defined as the time required for half the quantity of a drug to be metabolized or eliminated by normal biological processes.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Mean Residence Time (MRT) Following an IV Dose in Treatment A	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.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Volume of Distribution at Steady State (Vss) Following an IV Dose in Treatment A	Characterize the IV dose of Treatment A by Vss, which is defined as the apparent volume of distribution at steady state	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Relative Bioavailability (Frel) Based on Ratios of Cmax	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.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Relative Bioavailability (Frel) Based on Ratios of AUC(0-T) and AUC(INF)	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.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Food Effect Based on Ratios of Cmax Following an SDD Capsule Dose in Treatment B, C, D, and E	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.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Secondary	Food Effect Based on Ratios of AUC(0-T) and AUC(INF) Following an SDD Capsule Dose in Treatment B, C, D, and E	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.	Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)

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