VTE Prophylaxis
Conditions
Brief summary
This trial was a Phase 1, open-label, multicenter study of the pharmacokinetics (PK), pharmacodynamics (PD), and safety of a single dose of betrixaban in pediatric participants at risk of venous thromboembolism (VTE).
Detailed description
This study was to be conducted in 2 parts: Part 1 and Part 2. Part 1 (the initial opening of the study) was conducted in 21 adolescent participants (12 to \< 18 years of age) who were assessed to be at risk for VTE. Participants in Part 1 received either 40 or 80 milligrams (mg) of study drug. The PK and PD data from Part 1 was to be used for dose determination for the next youngest age group using population PK and physiological-based PK modeling and simulation. Following analysis of Part 1 data, Part 2 of the study was to commence and enroll 12 participants 2 to \< 12 years of age. However, after completion of Part 1 and prior to initiating Part 2, the Sponsor decided to cease developing betrixaban, prompting early study closure.
Interventions
DRUGBetrixaban
Factor Xa inhibitor.
Sponsors
Portola Pharmaceuticals, LLC (a wholly owned subsidiary of Alexion Pharmaceuticals)
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Pediatric participants in the following age categories: 12 to \< 18 years of age and 2 to \< 12 years of age. Part 1 of the study enrolled only adolescent participants 12 to \< 18 years of age. 2. Pediatric participant who was assessed to be at risk for VTE but did not require immediate anticoagulant therapy, for example: 1. Had previous thrombosis and completed a course of anti-coagulant therapy, and is considered to have a risk for recurrence of VTE, or 2. Had any stable disease with a risk for arterial or venous thromboembolism, or 3. Had any functional central venous access device in the upper or lower venous system. 3. Participant had normalized coagulation parameters (international normalized ratio or partial thromboplastin time, as appropriate) within 7 days of study drug administration.
Exclusion criteria
Participants who meet any one of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under The Plasma Concentration-Time Curve From 0 To Infinity (AUC(0-inf)) Of Betrixaban | Up to 6 days post dose | Following the Sponsor's decision to cease developing betrixaban, data for AUC(0-inf) were not collected. |
| Maximum Observed Plasma Concentration (Cmax) Of Betrixaban | Up to 6 days post dose | Data reported as 0.200 indicates that the data are below the lower limit of quantification. Note that the Measure of Central Tendency could not be determined for Cohort 1 or Cohort 2 due to the values that are below the lower limit of quantification. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time To Maximum Observed Plasma Concentration (Tmax) Of Betrixaban | Up to 6 days post dose | The Tmax that the highest (maximum) Cmax of betrixaban was observed per group up to Day 6 (120 hours) post dosing is reported. |
| Apparent Total Body Clearance Of Betrixaban From Plasma (CL) | Up to 6 days post dose | Following the Sponsor's decision to cease developing betrixaban, data for CL were not collected. |
| AUC To The Last Measurable Concentration Above The Quantitation Limit (AUC(0-last)) Of Betrixaban | Up to 6 days post dose | Following the Sponsor's decision to cease developing betrixaban, data for AUC(0-last) were not collected. |
| Percent Change From Baseline In Thrombin Level At Day 6 | Baseline, Day 6 | Following the Sponsor's decision to cease developing betrixaban, data for thrombin levels were not collected. |
| Count Of Participants With Treatment-related Adverse Events | Up to 7 days post dose | A treatment-related adverse event was any undesirable event or any untoward medical occurrence that occurs to a participant during the course of a study, or the protocol-defined time after study termination. An Investigator qualified in medicine made the determination of relationship to the investigational product for each adverse event (Unrelated, Unlikely Related, Possibly Related, or Probably Related). If the relationship between the adverse event and the investigational product was determined to be possible or probable, the event was considered to be related to the investigational product for the purposes of expedited regulatory reporting. One participant experienced a mild study-drug-related headache that resolved in less than 2 hours. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module. |
| Apparent Volume Of Distribution (Vd) Of Betrixaban | Up to 6 days post dose | Following the Sponsor's decision to cease developing betrixaban, data for Vd were not collected. |
| Terminal Plasma Half-life (t½) Of Betrixaban | Up to 6 days post dose | Following the Sponsor's decision to cease developing betrixaban, data for t½ were not collected. |
Countries
Russia, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
After a screening period of up to 30 days, eligible participants who had provided assent and for whom a parent or legal guardian had provided signed informed consent entered the hospital, clinical research unit, or Phase 1 unit on Day -1. Those who were already inpatients remained hospitalized.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Betrixaban 40 mg Participants received a single, oral dose of betrixaban at 40 mg in a fed state, and had 10 PK blood sampling time points. | 3 |
| Cohort 2: Betrixaban 80 mg Participants received a single, oral dose of betrixaban at 80 mg in a fed state, and had 5 PK sampling time points. | 18 |
| Total | 21 |
Baseline characteristics
| Characteristic | Total | Cohort 2: Betrixaban 80 mg | Cohort 1: Betrixaban 40 mg |
|---|---|---|---|
| Age, Customized Age Categorical 85 years and over | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Age Categorical Adolescents (12-17 years) | 21 Participants | 18 Participants | 3 Participants |
| Age, Customized Age Categorical Adults (18-64 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Age Categorical Children (2-11 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Age Categorical From 65 to 84 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Age Categorical In utero | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Age Categorical Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Age Categorical Preterm newborn - gestational age < 37 wk | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 17 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 15 Participants | 3 Participants |
| Region of Enrollment Russia | 14 participants | 11 participants | 3 participants |
| Region of Enrollment Ukraine | 2 participants | 2 participants | 0 participants |
| Region of Enrollment United Kingdom | 1 participants | 1 participants | 0 participants |
| Region of Enrollment United States | 4 participants | 4 participants | 0 participants |
| Sex: Female, Male Female | 11 Participants | 9 Participants | 2 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 18 |
| other Total, other adverse events | 0 / 3 | 5 / 18 |
| serious Total, serious adverse events | 0 / 3 | 0 / 18 |
Outcome results
Primary
Area Under The Plasma Concentration-Time Curve From 0 To Infinity (AUC(0-inf)) Of Betrixaban
Following the Sponsor's decision to cease developing betrixaban, data for AUC(0-inf) were not collected.
Time frame: Up to 6 days post dose
Population: After completion of Part 1 of the study and prior to initiating Part 2, the Sponsor decided to stop developing betrixaban and closed the study early. Therefore, data for this Outcome Measure were not collected.
Primary
Maximum Observed Plasma Concentration (Cmax) Of Betrixaban
Data reported as 0.200 indicates that the data are below the lower limit of quantification. Note that the Measure of Central Tendency could not be determined for Cohort 1 or Cohort 2 due to the values that are below the lower limit of quantification.
Time frame: Up to 6 days post dose
Population: The evaluable PK population included all participants who received the study drug and had sufficient blood samples through Day 3 to compute either Cmax or total AUC assessments with the extrapolated portion of the AUC(0-inf) less than 30%.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort 1: Betrixaban 40 mg | Maximum Observed Plasma Concentration (Cmax) Of Betrixaban | NA nanograms (ng)/milliliters (mL) |
| Cohort 2: Betrixaban 80 mg | Maximum Observed Plasma Concentration (Cmax) Of Betrixaban | NA nanograms (ng)/milliliters (mL) |
Secondary
Apparent Total Body Clearance Of Betrixaban From Plasma (CL)
Following the Sponsor's decision to cease developing betrixaban, data for CL were not collected.
Time frame: Up to 6 days post dose
Population: After completion of Part 1 of the study and prior to initiating Part 2, the Sponsor decided to stop developing betrixaban and closed the study early. Therefore, data for this Outcome Measure were not collected.
Secondary
Apparent Volume Of Distribution (Vd) Of Betrixaban
Following the Sponsor's decision to cease developing betrixaban, data for Vd were not collected.
Time frame: Up to 6 days post dose
Population: After completion of Part 1 of the study and prior to initiating Part 2, the Sponsor decided to stop developing betrixaban and closed the study early. Therefore, data for this Outcome Measure were not collected.
Secondary
AUC To The Last Measurable Concentration Above The Quantitation Limit (AUC(0-last)) Of Betrixaban
Following the Sponsor's decision to cease developing betrixaban, data for AUC(0-last) were not collected.
Time frame: Up to 6 days post dose
Population: After completion of Part 1 of the study and prior to initiating Part 2, the Sponsor decided to stop developing betrixaban and closed the study early. Therefore, data for this Outcome Measure were not collected.
Secondary
Count Of Participants With Treatment-related Adverse Events
A treatment-related adverse event was any undesirable event or any untoward medical occurrence that occurs to a participant during the course of a study, or the protocol-defined time after study termination. An Investigator qualified in medicine made the determination of relationship to the investigational product for each adverse event (Unrelated, Unlikely Related, Possibly Related, or Probably Related). If the relationship between the adverse event and the investigational product was determined to be possible or probable, the event was considered to be related to the investigational product for the purposes of expedited regulatory reporting. One participant experienced a mild study-drug-related headache that resolved in less than 2 hours. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Time frame: Up to 7 days post dose
Population: Safety population: all participants enrolled in Part 1 of the study who received study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Betrixaban 40 mg | Count Of Participants With Treatment-related Adverse Events | 0 Participants |
| Cohort 2: Betrixaban 80 mg | Count Of Participants With Treatment-related Adverse Events | 1 Participants |
Secondary
Percent Change From Baseline In Thrombin Level At Day 6
Following the Sponsor's decision to cease developing betrixaban, data for thrombin levels were not collected.
Time frame: Baseline, Day 6
Population: After completion of Part 1 of the study and prior to initiating Part 2, the Sponsor decided to stop developing betrixaban and closed the study early. Therefore, data for this Outcome Measure were not collected.
Secondary
Terminal Plasma Half-life (t½) Of Betrixaban
Following the Sponsor's decision to cease developing betrixaban, data for t½ were not collected.
Time frame: Up to 6 days post dose
Population: After completion of Part 1 of the study and prior to initiating Part 2, the Sponsor decided to stop developing betrixaban and closed the study early. Therefore, data for this Outcome Measure were not collected.
Secondary
Time To Maximum Observed Plasma Concentration (Tmax) Of Betrixaban
The Tmax that the highest (maximum) Cmax of betrixaban was observed per group up to Day 6 (120 hours) post dosing is reported.
Time frame: Up to 6 days post dose
Population: The evaluable PK population included all participants who received the study drug and had sufficient blood samples through Day 3 to compute either Cmax or total AUC assessments with the extrapolated portion of the AUC(0-inf) less than 30%.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Betrixaban 40 mg | Time To Maximum Observed Plasma Concentration (Tmax) Of Betrixaban | 2 hours |
| Cohort 2: Betrixaban 80 mg | Time To Maximum Observed Plasma Concentration (Tmax) Of Betrixaban | 2 hours |