Trial Outcomes & Findings for EINSTEIN Junior Phase II: Oral Rivaroxaban in Young Children With Venous Thrombosis (NCT NCT02309411)

Last Updated: 2018-08-21

Results Overview

Major bleeding is defined as overt bleeding and: * associated with a fall in hemoglobin of 2 gram/decilitre (g/dL) or more, or * leading to a transfusion of the equivalent of 2 or more units of packed red blood cells or whole blood in adults, or * occurring in a critical site, for example (e.g.) intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal, or * contributing to death. Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for major bleeding, but associated with: * medical intervention, or * unscheduled contact (visit or telephone call) with a physician, or * cessation (temporary) of study treatment, or * discomfort for the child such as pain or * impairment of activities of daily life (such as loss of school days or hospitalization).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

46 participants

Primary outcome timeframe

During or within 2 days after stop of study treatment (up to 32 days)

Results posted on

2018-08-21

Participant Flow

Study was conducted at 27 study centers in 14 countries: Australia, Austria, Brazil, Canada, Hungary, Israel, Italy, Japan, Netherlands, Russia, Spain, Switzerland, United Kingdom, and United States between 15 January 2015 (first subject first visit) and 05 April 2017 (last subject last visit).

Overall, 51 subjects were screened, of these 5 subjects were screen failures; 4 subjects withdrew from study and 1 subject failed screening. Total of 46 subjects were assigned to treatment with 6 subjects received anticoagulant comparator (standard of care) and 40 subjects received rivaroxaban.

Participant milestones

Participant milestones
Measure	Rivaroxaban, Suspension, BID, Age: 2-6 Years Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.	Rivaroxaban Suspension, BID, Age: 6 Months-2 Years Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.	Anticoagulants, Comparator, Age: 2-6 Years Subjects aged from 2 to 6 years were received comparator as per standard of care.
Overall Study STARTED	25	15	6
Overall Study COMPLETED	23	14	6
Overall Study NOT COMPLETED	2	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Rivaroxaban, Suspension, BID, Age: 2-6 Years Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.	Rivaroxaban Suspension, BID, Age: 6 Months-2 Years Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.	Anticoagulants, Comparator, Age: 2-6 Years Subjects aged from 2 to 6 years were received comparator as per standard of care.
Overall Study Physician Decision	1	0	0
Overall Study Withdrawal by Subject	1	1	0

Baseline Characteristics

EINSTEIN Junior Phase II: Oral Rivaroxaban in Young Children With Venous Thrombosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rivaroxaban, Suspension, BID, Age: 2-6 Years n=25 Participants Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.	Rivaroxaban Suspension, BID, Age: 6 Months-2 Years n=15 Participants Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.	Anticoagulants, Comparator, Age: 2-6 Years n=6 Participants Subjects aged from 2 to 6 years were received comparator as per standard of care.	Total n=46 Participants Total of all reporting groups
Age, Continuous	3.77 years STANDARD_DEVIATION 1.03 • n=5 Participants	1.26 years STANDARD_DEVIATION 0.45 • n=7 Participants	3.67 years STANDARD_DEVIATION 0.82 • n=5 Participants	2.94 years STANDARD_DEVIATION 1.45 • n=4 Participants
Sex: Female, Male Female	12 Participants n=5 Participants	9 Participants n=7 Participants	3 Participants n=5 Participants	24 Participants n=4 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	6 Participants n=7 Participants	3 Participants n=5 Participants	22 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) White	23 Participants n=5 Participants	10 Participants n=7 Participants	6 Participants n=5 Participants	39 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants

PRIMARY outcome

Timeframe: During or within 2 days after stop of study treatment (up to 32 days)

Population: SAF included all subjects who received at least one dose of the study medication.

Outcome measures

Outcome measures
Measure	Rivaroxaban, Suspension, BID, Age: 2-6 Years n=25 Participants Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.	Rivaroxaban Suspension, BID, Age: 6 Months-2 Years n=15 Participants Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.
Number of Subjects With Major Bleeding and Clinically Relevant Non-Major Bleeding Events Major bleeding events	0 Participants	0 Participants
Number of Subjects With Major Bleeding and Clinically Relevant Non-Major Bleeding Events Clinically relevant non-major bleeding events	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From start of the study treatment up to 30-days post study treatment period (approximately 60 days)

Population: FAS included all enrolled children (before Amendment 4, all children were randomized by interactive voice/web response system \[IxRS\], after Amendment 4 all children were assigned to rivaroxaban by IxRS). Screening failures were excluded.

Venous thromboembolism is the formation of a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood through the circulatory system. The occurrence of recurrent venous thromboembolism was summarized by age group. Symptomatic recurrence, which is the composite of deep Vein Thrombosis (DVT), non-fatal Pulmonary Embolism (PE), and fatal PE of venous thrombosis, had to be documented using appropriate (repeat) imaging test.

Outcome measures

Outcome measures
Measure	Rivaroxaban, Suspension, BID, Age: 2-6 Years n=25 Participants Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.	Rivaroxaban Suspension, BID, Age: 6 Months-2 Years n=15 Participants Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.
Number of Subjects With Symptomatic Recurrent Venous Thromboembolism	0 Participants	0 Participants

SECONDARY outcome

Timeframe: At the end of the 30-day treatment period

The occurrence of asymptomatic deterioration in thrombotic burden was summarized by age group. At the end of the 30-day treatment period, a repeat imaging of the thrombus was performed. The images of the index event and repeat imaging were adjudicated by the central independent adjudication committee (CIAC). The thrombotic burden at the time of the index event was compared to the thrombotic burden at the time of repeat imaging. The outcome of the adjudication was classified as normalized, improved, no relevant change, deteriorated, or not evaluable. Due to missing repeated imaging, thrombotic burden assessments were not done in some subjects.

Outcome measures

Outcome measures
Measure	Rivaroxaban, Suspension, BID, Age: 2-6 Years n=25 Participants Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.	Rivaroxaban Suspension, BID, Age: 6 Months-2 Years n=15 Participants Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.
Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging Normalized	6 Participants	4 Participants
Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging Improved	15 Participants	4 Participants
Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging No relevant change	1 Participants	3 Participants
Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging Deteriorated	0 Participants	0 Participants
Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging Not evaluable	0 Participants	0 Participants
Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging Not available	0 Participants	0 Participants
Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging Missing	3 Participants	4 Participants

SECONDARY outcome

Timeframe: Day 1 (2.5-4 hours post-dose); Day 15 (2-8 hours post-dose); Day 30 (10-16 hours post-dose)

Population: PDS with evaluable subjects for this end point. PD parameters were evaluated only for subjects who received active study medication.

Prothrombin time is a global clotting test used for the assessment of the extrinsic pathway of the blood coagulation cascade. Day 30 (10-16 hours post-dose) was considered as a baseline.

Outcome measures

Outcome measures
Measure	Rivaroxaban, Suspension, BID, Age: 2-6 Years n=22 Participants Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.	Rivaroxaban Suspension, BID, Age: 6 Months-2 Years n=14 Participants Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.
Change From Baseline in Prothrombin Time at Specified Time Points Day 1: 2.5-4 hours post-dose	2.777 Seconds Standard Deviation 4.845	2.514 Seconds Standard Deviation 3.53
Change From Baseline in Prothrombin Time at Specified Time Points Day 15: 2-8 hours post-dose	2.586 Seconds Standard Deviation 2.387	4.764 Seconds Standard Deviation 4.738

SECONDARY outcome

Timeframe: Day 1 (2.5-4 hours post-dose); Day 15 (2-8 hours post-dose); Day 30 (10-16 hours post-dose)

Population: PDS with evaluable subjects for this end point. PD parameters were evaluated only for subjects who received active study medication.

The Activated partial thromboplastin time (aPTT) is a screening test for the intrinsic pathway. Day 30 (10-16 hours post-dose) was considered as a baseline.

Outcome measures

Outcome measures
Measure	Rivaroxaban, Suspension, BID, Age: 2-6 Years n=22 Participants Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.	Rivaroxaban Suspension, BID, Age: 6 Months-2 Years n=14 Participants Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.
Change From Baseline in Activated Partial Thromboplastin Time at Specified Time Points Day 1: 2.5-4 hours post-dose	6.455 Seconds Standard Deviation 17.036	-3.479 Seconds Standard Deviation 40.443
Change From Baseline in Activated Partial Thromboplastin Time at Specified Time Points Day 15: 2-8 hours post-dose	2.814 Seconds Standard Deviation 6.375	21 Seconds Standard Deviation 66.761

SECONDARY outcome

Timeframe: Day 1 (30-90 minutes, 2.5-4 hours post-dose); Day 15 (2-8 hours post-dose) and Day 30 (10-16 hours post-dose)

Population: PKS included all subjects with at least one pharmacokinetic sample in accordance with the pharmacokinetic sampling strategy.

Concentration of rivaroxaban in plasma was measured at Day 1, 15 and 30 at specified time points. In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Outcome measures
Measure	Rivaroxaban, Suspension, BID, Age: 2-6 Years n=24 Participants Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.	Rivaroxaban Suspension, BID, Age: 6 Months-2 Years n=15 Participants Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.
Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Specified Time Points Day 1: 30-90 minutes post-dose	72.8494 microgram per liter (mcg/L) Geometric Coefficient of Variation 153.76	68.0072 microgram per liter (mcg/L) Geometric Coefficient of Variation 160.77
Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Specified Time Points Day 1: 2.5-4 hours post-dose	108.6053 microgram per liter (mcg/L) Geometric Coefficient of Variation 58.18	76.5371 microgram per liter (mcg/L) Geometric Coefficient of Variation 112.91
Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Specified Time Points Day 15: 2-8 hours post-dose	112.3578 microgram per liter (mcg/L) Geometric Coefficient of Variation 46.37	61.3817 microgram per liter (mcg/L) Geometric Coefficient of Variation 451.46
Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Specified Time Points Day 30: 10-16 hours post-dose	19.8714 microgram per liter (mcg/L) Geometric Coefficient of Variation 189.49	5.9545 microgram per liter (mcg/L) Geometric Coefficient of Variation 354.51

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 1 (2.5-4 hours post-dose); Day 15 (2-8 hours post-dose) and Day 30 (10-16 hours post-dose)

Population: PDS included all subjects with at least one blood sample for clotting tests in accordance with the pharmacodynamic sampling strategy was included.

The individual anti-Factor Xa activity was determined ex-vivo using a photometric method. The anti-factor Xa assay is designed to measure plasma heparin, low molecular weight heparin and other anticoagulants. In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.

Outcome measures

Outcome measures
Measure	Rivaroxaban, Suspension, BID, Age: 2-6 Years n=22 Participants Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.	Rivaroxaban Suspension, BID, Age: 6 Months-2 Years n=14 Participants Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.
Anti-factor Xa Values at Specified Time Points Day 1: 2.5-4 hours post-dose	128.457 microgram per liter (mcg/L) Standard Deviation 69.615	87.831 microgram per liter (mcg/L) Standard Deviation 84.178
Anti-factor Xa Values at Specified Time Points Day 15: 2-8 hours post-dose	103.105 microgram per liter (mcg/L) Standard Deviation 58.343	131.369 microgram per liter (mcg/L) Standard Deviation 96.489
Anti-factor Xa Values at Specified Time Points Day 30: 10-16 hours post-dose	19.069 microgram per liter (mcg/L) Standard Deviation 17.463	16.952 microgram per liter (mcg/L) Standard Deviation 19.725

Adverse Events

Rivaroxaban BID (Suspension) (2 - 6 Years Group)

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Rivaroxaban BID (Suspension) (6 Months - 2 Years Group)

Serious events: 2 serious events

Other events: 11 other events

Deaths: 0 deaths

Anticoagulants, Comparator (2 - 6 Years Group)

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Rivaroxaban BID (Suspension) (2 - 6 Years Group) n=25 participants at risk Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.	Rivaroxaban BID (Suspension) (6 Months - 2 Years Group) n=15 participants at risk Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.	Anticoagulants, Comparator (2 - 6 Years Group) n=6 participants at risk Subjects aged from 2 to 6 years were received comparator as per standard of care.
Eye disorders Optic atrophy	0.00% 0/25 • From start of study drug administration until 30 day post study treatment (approximately 60 days)	0.00% 0/15 • From start of study drug administration until 30 day post study treatment (approximately 60 days)	16.7% 1/6 • Number of events 1 • From start of study drug administration until 30 day post study treatment (approximately 60 days)
General disorders Pyrexia	0.00% 0/25 • From start of study drug administration until 30 day post study treatment (approximately 60 days)	6.7% 1/15 • Number of events 1 • From start of study drug administration until 30 day post study treatment (approximately 60 days)	0.00% 0/6 • From start of study drug administration until 30 day post study treatment (approximately 60 days)
Nervous system disorders Headache	0.00% 0/25 • From start of study drug administration until 30 day post study treatment (approximately 60 days)	0.00% 0/15 • From start of study drug administration until 30 day post study treatment (approximately 60 days)	16.7% 1/6 • Number of events 1 • From start of study drug administration until 30 day post study treatment (approximately 60 days)
Respiratory, thoracic and mediastinal disorders Respiratory disorder	0.00% 0/25 • From start of study drug administration until 30 day post study treatment (approximately 60 days)	6.7% 1/15 • Number of events 1 • From start of study drug administration until 30 day post study treatment (approximately 60 days)	0.00% 0/6 • From start of study drug administration until 30 day post study treatment (approximately 60 days)

Other adverse events

Additional Information

Therapeutic Area Head

Bayer

Phone: (+)1-888-84 22937

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place