A Phase 1 interventional study of BMS-986177 Oral Solution and [14C]BMS-986177 Solution for Infusion in Healthy Volunteers, sponsored by Bristol-Myers Squibb. Completed at 1 site in United Kingdom. Open to participants aged 18 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-08-21.
Sponsored by Bristol-Myers Squibb · Phase 1, Interventional, and Treatment
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.
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Exclusion Criteria:
Other protocol-defined inclusion/exclusion criteria apply
Drug: BMS-986177 Oral Solution · Drug: [14C]BMS-986177 Solution for Infusion · Drug: BMS-986177 Spray-dried Dispersion Capsules
Drug: BMS-986177 Oral Solution · Drug: [14C]BMS-986177 Solution for Infusion · Drug: BMS-986177 Spray-dried Dispersion Capsules
Drug: BMS-986177 Oral Solution · Drug: [14C]BMS-986177 Solution for Infusion · Drug: BMS-986177 Spray-dried Dispersion Capsules
Drug: BMS-986177 Oral Solution · Drug: [14C]BMS-986177 Solution for Infusion · Drug: BMS-986177 Spray-dried Dispersion Capsules
Specified dose on specified days
Also known as: Milvexian, JNJ-70033093
Specified dose on specified days
Specified dose on specified days
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).
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 11 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 11 weeks)
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
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Number of Participants With Abnormal Physical Examinations
The number of participants with abnormal findings on physical examinations following single oral and IV administration.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
Apparent Clearance of Drug After Extravascular Administration (CLT/F)
CLT/F is defined as the apparent clearance of drug after extravascular administration.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
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.
Time frame: Day 1 of Treatment Periods 1-5 (up to approximately 7 weeks)
| Milestone | Treatment Sequence 1: ABCED | Treatment Sequence 2: ACDBE | Treatment Sequence 3: ADECB | Treatment Sequence 4: AEBDC |
|---|---|---|---|---|
| Started | 4 | 5 | 4 | 4 |
| Participants completed treatment period 1 | 4 | 5 | 4 | 4 |
| Participants completed treatment period 2 | 4 | 4 | 4 | 4 |
| Participants completed treatment period 3 | 3 | 4 | 4 | 4 |
| Participants completed treatment period 4 | 3 | 3 | 4 | 4 |
| Participants completed treatment period 5 | 3 | 3 | 4 | 4 |
| Completed | 3 | 3 | 4 | 4 |
| Not completed | 1 | 2 | 0 | 0 |
| Withdrew: Other reasons | 1 | 0 | 0 | 0 |
| Withdrew: Participant withdrew consent | 0 | 1 | 0 | 0 |
| Withdrew: Poor/non-compliance | 0 | 1 | 0 | 0 |
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).
| Percentage of drug | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Absolute Bioavailability (F) | 105 (103 to 109) | 54.2 (48.9 to 63.7) | 44.3 (39.6 to 53.0) | 58.2 (52.8 to 70.7) | 75.6 (71.1 to 81.8) |
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.
| Participants | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Total participants with an adverse event | 8 | 2 | 2 | 0 | 2 |
| Adverse events leading to discontinuation | 0 | 0 | 0 | 0 | 0 |
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.
| Participants | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Number of Participants Experiencing Serious Adverse Events (SAE) | 0 | 0 | 0 | 0 | 0 |
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
| Participants | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Heart Rate (bpm) Value > 100 and change from baseline > 30 | 0 | 0 | 0 | 0 | 0 |
| Heart Rate (bpm) Value < 55 and change from baseline < -15 | 0 | 0 | 0 | 0 | 0 |
| Systolic Blood Pressure (mmHg) Value > 140 and change from baseline > 20 | 0 | 0 | 1 | 0 | 0 |
| Systolic Blood Pressure (mmHg) Value < 90 and change from baseline < -20 | 0 | 0 | 0 | 0 | 1 |
| Diastolic Blood Pressure (mmHg) Value > 90 and change from baseline > 10 | 0 | 0 | 0 | 0 | 0 |
| Diastolic Blood Pressure (mmHg) Value < 55 and change from baseline < -10 | 0 | 2 | 1 | 0 | 1 |
| Respiratory Rate (breaths/min) Value > 16 or change from baseline > 10 | 13 | 10 | 10 | 9 | 7 |
| Temperature (°C)Value > 38.3°C or change from baseline > 1.6°C | 0 | 0 | 0 | 0 | 0 |
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
| Participants | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Number of Participants With Abnormal Electrocardiograms (ECGs) | 2 | 2 | 1 | 0 | 1 |
The number of participants with abnormal findings on physical examinations following single oral and IV administration.
| Participants | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Number of Participants With Abnormal Physical Examinations | 0 | 2 | 0 | 1 | 0 |
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
| Participants | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Alanine transaminase > 3 × upper limit of normal (ULN) | 0 | 0 | 0 | 0 | 0 |
| Aspartate transaminase > 3 × ULN | 0 | 0 | 0 | 0 | 0 |
| Alkaline phosphatase > 1.5 × ULN | 0 | 0 | 0 | 0 | 0 |
| Total bilirubin > 2 × ULN | 0 | 0 | 0 | 0 | 0 |
Cmax is defined as the maximum observed plasma concentration following single administration in the fed and fasted states to healthy participants.
| ng/mL | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) | 2929 ± NA | 1200 ± NA | 130 ± NA | 185 ± NA | 1696 ± NA |
Tmax is defined as the time of maximum observed plasma concentration in the fed and fasted states to healthy participants.
| Hours | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Time of Maximum Observed Plasma Concentration (Tmax) | 1.27 (0.500 to 4.00) | 4.00 (1.50 to 5.00) | 4.00 (1.00 to 6.00) | 4.00 (1.25 to 6.00) | 5.00 (4.00 to 10.0) |
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.
| ng.h/mL | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)] | 30844 ± NA | 15855 ± NA | 1603 ± NA | 2183 ± NA | 21972 ± NA |
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
| ng.h/mL | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(INF)] | 31435 ± NA | 16464 ± NA | 1569 ± NA | 2061 ± NA | 22496 ± NA |
CLT/F is defined as the apparent clearance of drug after extravascular administration.
| Liters/hour | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Apparent Clearance of Drug After Extravascular Administration (CLT/F) | 6.36 ± NA | 12.1 ± NA | 15.9 ± NA | 12.1 ± NA | 8.89 ± NA |
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.
| Liters/hour | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Renal Clearance (CLR) | 1.63 ± NA | 1.68 ± NA | 1.91 ± NA | 1.84 ± NA | 1.70 ± NA |
Vz/F is defined as the apparent volume of distribution at terminal phase after extravascular administration.
| Liters | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) | 121 ± NA | 243 ± NA | 344 ± NA | 245 ± NA | 159 ± NA |
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
| mg | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Total Amount of Unchanged Drug Excreted Into the Urine (Ae) | 50.2 ± NA | 26.7 ± NA | 3.06 ± NA | 4.01 ± NA | 37.3 ± NA |
%UR is defined as a percent or absolute amount of dose that is recovered in the urine as the unchanged drug.
| Percentage of milvexian recovered | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Total Percent Urinary Recovery (%UR) | 25.1 ± NA | 13.3 ± NA | 12.2 ± NA | 16.0 ± NA | 18.6 ± NA |
T-HALF is defined as the time required for half the quantity of a drug to be metabolized or eliminated by normal biological processes.
| Hours | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Half-life (T-HALF) | 13.3 ± 2.02 | 14.3 ± 4.08 | 15.8 ± 6.13 | 14.5 ± 4.10 | 12.8 ± 3.65 |
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.
| Hours | Treatment A: Oral Solution With IV |
|---|---|
| Mean Residence Time (MRT) Following an IV Dose in Treatment A | 14.8 ± NA |
Characterize the IV dose of Treatment A by Vss, which is defined as the apparent volume of distribution at steady state
| Liters | Treatment A: Oral Solution With IV |
|---|---|
| Volume of Distribution at Steady State (Vss) Following an IV Dose in Treatment A | 99.1 ± NA |
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.
| ng/mL | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Relative Bioavailability (Frel) Based on Ratios of Cmax | NA (NA to NA) | 0.403 (0.354 to 0.459) | 0.358 (0.307 to 0.418) | 0.510 (0.427 to 0.610) | 0.574 (0.524 to 0.629) |
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.
| ng.h/mL | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| AUC(0-T) | NA (NA to NA) | 0.513 (0.446 to 0.591) | 0.425 (0.367 to 0.492) | 0.570 (0.466 to 0.697) | 0.716 (0.661 to 0.775) |
| AUC(INF) | NA (NA to NA) | 0.522 (0.455 to 0.600) | 0.436 (0.375 to 0.507) | 0.543 (0.453 to 0.651) | 0.720 (0.664 to 0.780) |
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.
| ng/mL | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|
| Food Effect Based on Ratios of Cmax Following an SDD Capsule Dose in Treatment B, C, D, and E | 1197 (1039 to 1378) | 128 (105 to 156) | 185 (153 to 223) | 1709 (1521 to 1920) |
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.
| ng.h/mL | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|
| AUC(0-T) | 15871 (13678 to 18415) | 1592 (1287 to 1969) | 2170 (1763 to 2670) | 22171 (19578 to 25108) |
| AUC(INF) | 16480 (14067 to 19307) | 1545 (1291 to 1848) | 2069 (1749 to 2447) | 22774 (19892 to 26073) |
Collected over Participants were assessed for all-cause mortality from their first dose to study completion (up to approximately 11 weeks). Serious Adverse events and other adverse events were assessed from date of first dose to 30 days following date of last dose (up to approximately 11 weeks).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Treatment A: Oral Solution With IV | 0/17 (0%) | 0/17 (0%) | 8/17 (47.1%) |
| Treatment B: High Dose SDD Fasted | 0/15 (0%) | 0/15 (0%) | 2/15 (13.3%) |
| Treatment C: Low Dose SDD Fed | 0/15 (0%) | 0/15 (0%) | 2/15 (13.3%) |
| Treatment D: Low Dose SDD Fasted | 0/15 (0%) | 0/15 (0%) | 0/15 (0%) |
| Treatment E: High Dose SDD Fed | 0/14 (0%) | 0/14 (0%) | 2/14 (14.3%) |
| Event | Treatment A: Oral Solution With IV | Treatment B: High Dose SDD Fasted | Treatment C: Low Dose SDD Fed | Treatment D: Low Dose SDD Fasted | Treatment E: High Dose SDD Fed |
|---|---|---|---|---|---|
| Abdominal discomfortGastrointestinal disorders | 2/17 | 0/15 | 1/15 | 0/15 | 0/14 |
| ConstipationGastrointestinal disorders | 2/17 | 0/15 | 0/15 | 0/15 | 0/14 |
| DiarrhoeaGastrointestinal disorders | 2/17 | 1/15 | 0/15 | 0/15 | 0/14 |
| Back painMusculoskeletal and connective tissue disorders | 2/17 | 0/15 | 0/15 | 0/15 | 0/14 |
| HeadacheNervous system disorders | 2/17 | 1/15 | 0/15 | 0/15 | 0/14 |
| ContusionInjury, poisoning and procedural complications | 1/17 | 0/15 | 0/15 | 0/15 | 1/14 |
| Skin lacerationInjury, poisoning and procedural complications | 0/17 | 0/15 | 0/15 | 0/15 | 1/14 |
| ErythemaSkin and subcutaneous tissue disorders | 0/17 | 0/15 | 0/15 | 0/15 | 1/14 |
| Joint injuryInjury, poisoning and procedural complications | 0/17 | 1/15 | 0/15 | 0/15 | 0/14 |
| Vascular access site haemorrhageInjury, poisoning and procedural complications | 0/17 | 0/15 | 1/15 | 0/15 | 0/14 |
| Age, Continuous(Years) | Treatment Sequence 1: ABCED | Treatment Sequence 2: ACDBE | Treatment Sequence 3: ADECB | Treatment Sequence 4: AEBDC | Total |
|---|---|---|---|---|---|
| Mean | 40.0 ± 14.5 | 45.4 ± 10.1 | 45.8 ± 15.0 | 37.3 ± 16.2 | 42.3 ± 13.0 |
| Sex: Female, Male(Participants) | Treatment Sequence 1: ABCED | Treatment Sequence 2: ACDBE | Treatment Sequence 3: ADECB | Treatment Sequence 4: AEBDC | Total |
|---|---|---|---|---|---|
| Female | 1 | 1 | 2 | 0 | 4 |
| Male | 3 | 4 | 2 | 4 | 13 |
| Ethnicity (NIH/OMB)(Participants) | Treatment Sequence 1: ABCED | Treatment Sequence 2: ACDBE | Treatment Sequence 3: ADECB | Treatment Sequence 4: AEBDC | Total |
|---|---|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 | 0 | 0 |
| Not Hispanic or Latino | 4 | 5 | 4 | 4 | 17 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Treatment Sequence 1: ABCED | Treatment Sequence 2: ACDBE | Treatment Sequence 3: ADECB | Treatment Sequence 4: AEBDC | Total |
|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 2 | 0 | 0 | 0 | 2 |
| White | 2 | 4 | 4 | 4 | 14 |
| More than one race | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 1 | 0 | 0 | 1 |
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Bristol-Myers Squibb