Introduction
Compliance with Ethical Guidelines
Factor Xa Inhibitors
Rivaroxaban
Completed Studies
Ongoing Studies
Apixaban
Completed Study
Ongoing Studies
Edoxaban
Ongoing Study
Direct Thrombin Inhibitor
Dabigatran
Completed Studies
Ongoing Studies
Class of anticoagulant | Medication | Authors/investigators | NCT # | Treatment | Dose |
---|---|---|---|---|---|
Factor Xa inhibitors | Rivaroxaban | Attard et al. | – | Age-specific plasma pools (i.e., 28 days to 16 years) spiked with increasing concentrations of rivaroxaban | 0–500 ng/ml |
Willmann et al. | – | Simulated PK properties of rivaroxaban in virtual populations of children | 0.143 mg/kg (10-mg adult equivalent) and 0.286 mg/kg (20-mg adult equivalent) once daily | ||
Young et al. | – | Phase I and phase II PK/PD study of a rivaroxaban dosing regimen for the treatment of VTE in patients 12 to 18 years of age | Weight-adjusted dose equivalent to 20-mg dose in adults | ||
Bayer | 01145859 | Phase I PK/PD profile of single-dose rivaroxaban in patients 6 months to 18 years of age | Weight-adjusted dose equivalent to 10- or 20-mg doses in adults | ||
Bayer | 01684423 | Phase II safety, efficacy and PK/PD properties of oral rivaroxaban compared to standard anticoagulant therapy in patients ages 6 to <18 years | Experimental: rivaroxaban 20-mg equivalent tablet once daily for children 12–18 years and 20-mg equivalent PO suspension twice daily for children aged 6 to <12 years Active comparator: continuation of anticoagulant used prior to randomization (i.e., UFH, LMWH, fondaparinux, VKA) | ||
Bayer | 02497716 | Phase I study on rivaroxaban dry powder suspension in patients 6 months to 12 years old with previous thrombosis | Single weight-adjusted dose of the reconstituted dry powder suspension | ||
Bayer | 02564718 | Phase I and II safety, efficacy and PK/PD properties of oral rivaroxaban in patients less than 6 months old | 7-day treatment of an age- and body weight-adjusted oral rivaroxaban given twice daily as an 1 mg/ml oral suspension to achieve similar exposures as those observed with 20 mg daily dosing in adults | ||
Bayer | 02309411 | Phase II safety, efficacy and PK/PD properties of oral rivaroxaban compared to standard anticoagulant therapy in patients ages 6 months to <6 years | Experimental: rivaroxaban PO suspension age and body weight adjusted twice daily to achieve similar exposure as adult 20-mg once daily Active comparator: continuation of anticoagulant used prior to randomization (i.e., UFH, LMWH, fondaparinux, VKA) | ||
Bayer | 02234843 | Efficacy and safety of rivaroxaban compared to standard of care in children ages 6 months to <18 years with acute VTE | Experimental: rivaroxaban 20-mg equivalent tablet once daily for children 12–18 years and 20-mg equivalent PO suspension twice daily for children aged 6 months to <12 years Active comparator: continuation of anticoagulant used prior to randomization (i.e., UFH, LMWH, fondaparinux, VKA) | ||
Apixaban | Bristol-Myers Squibb | 01195727 | Multiple dose apixaban PK/PD study in pediatric subjects aged 12 to <18 years with a central venous catheter | Low-dose group: 0.66 mg/m2 PO solution BID × 10 days High-dose group: 1.32 mg/m2 PO solution BID × 10 days | |
Bristol-Myers Squibb | 01707394 | Single-dose apixaban PK/PD study in subjects 37 weeks to 18 years at risk for thrombotic disorder | Neonates: dose not mentioned 28 days to <9 months: 1.08 mg/m2
9 months to <2 years: 2.43 mg/m2
2 years to <6 years: 1.17 mg/m2
6 years to <12 years: 1.8 mg/m2
12 years to <18 years: 2.19 mg/m2
| ||
Bristol-Myers Squibb | 02369653 | Safety and efficacy of apixaban to prevent clots in leukemic patients ages 1–17 years treated with PEG-asparaginase | 12–23 months: dose not yet determined ≥2 years and <35 kg: 0.05 mg/kg BID (0.4 mg/ml solution) ≥35 kg: 2.5 mg tablet BID | ||
Pfizer | 02464969 | Efficacy of apixaban for the treatment of VTE in pediatric patients less than 18 years old | <12 years: dose not yet determined 12 to <18 years and ≤40 kg: 0.2 mg/kg BID × 7 days, then 0.1 mg/kg BID 12 to <18 years and >40 kg: 10 mg BID × 7 days, then 5 mg BID | ||
Edoxaban | Daiichi Sanyoko Inc. | 02303431 | Phase I PK/PD study in subjects 0 to <18 years after single dose of edoxaban | Low-dose group: matched to 30-mg exposure in adults High-dose group: matched to 60-mg exposure in adults | |
Direct thrombin inhibitor | Dabigatran | Boehringer Ingelheim | 00844415 | Phase II study evaluate the safety and tolerability of dabigatran for 3 days in patients 12–18 years old who had finished standard anticoagulation for primary VTE | 1.71 mg/kg ×1, then adjusted to a target dose of 2.14 mg/kg BID based on TT and clinical assessment |
Dietrich et al. | – | Optimal coagulation assay for dabigatran and anticoagulant effect of dabigatran in vitro in pediatric patients 0 to <18 years old | 0, 50, 250, 450 ng/ml | ||
Boehringer Ingelheim | 01083732 | Phase II study evaluating the safety & tolerability of a dabigatran oral solution in 1 to 12 years old | Age- and weight-adjusted equivalent of adult dose | ||
Boehringer Ingelheim | 01773174 | Phase II study evaluating the PK, safety, and tolerability of a dabigatran oral solution in 1–2 years old | Age- and weight-adjusted equivalent of adult dose | ||
Boehringer Ingelheim | 02223260 | Phase II study evaluating the PK/PD, safety and tolerability of a dabigatran oral solution in <1 year old | Age- and weight-adjusted equivalent of adult dose | ||
Boehringer Ingelheim | 01895777 | Phase III study evaluating dabigatran vs. SOC for VTE treatment in children 0 to <18 years old | Dabigatran group: age- and weight-appropriate dose BID × 3 months (capsules, pellets, or liquid formulation) SOC: LMWH or VKA × 3 months | ||
Boehringer Ingelheim | 02197416 | Phase III study evaluating dabigatran for secondary prevention of VTE in patients 0 to <18 years old | Dabigatran group: age- and weight-appropriate capsule |
Class of anticoagulant | Medication | Authors/investigators | NCT # | 1° Outcome(s) | 2° Outcome(s) | Anticipated end date/published date |
---|---|---|---|---|---|---|
Factor Xa inhibitors | Rivaroxaban | Attard et al. | – | No significant in vitro differences in rivaroxaban effect across the age groups | – | Published July 2012 |
Willmann et al. | – | AUC, C
max and C
24h throughout the investigated age ranges largely overlapped with adult reference ranges | Infants and children <40 kg: AUC, C
max and C
24h were <90% CI threshold of adult Adolescents >70 kg: AUC and C
24h were higher than the 90% CI of adult | Published January 2014 | ||
Young et al. | – | Observed plasma concentrations and AUC were similar to predicted model | 30–50 kg: probably will require 15 mg daily >50 kg: probably will require 20 mg daily | Published June 2015 | ||
Bayer | 01145859 | PK: AUC, C
max (day 1–2) PD: PT, aPTT, anti-factor Xa (day 1–2) | Safety and tolerability (day 1, 2, and 7) | Completed July 2015 | ||
Bayer | 01684423 | Composite major and clinically relevant non-major bleeding events after 31 days Composite major and clinically relevant non-major bleeding events after 60 days | Recurrent VTE and asymptomatic deterioration after 31 days Recurrent VTE after 60 days PT, aPTT, anti-factor Xa | January 2016 | ||
Bayer | 02497716 | AUC and C
max between 20 and 24 h after administering medication | PT, aPTT, and anti-factor Xa activity of rivaroxaban compared between 5 h prior to drug administration and 20–24 h post exposure | April 2016 | ||
Bayer | 02564718 | Plasma concentration of rivaroxaban from day 1 to day 8 | Incidence of major bleeding, clinical relevant non-major bleeding and symptomatic recurrent thromboembolism on days 1 to 7 Incidence of asymptomatic worsening of thrombotic burden on day 8 post dose | October 2016 | ||
Bayer | 02309411 | Major bleeding and clinically relevant non-major bleeding | Recurrent symptomatic VTE PT, aPTT, anti-factor Xa, concentration of rivaroxaban in blood Incidence of asymptomatic deterioration in thrombotic burden on repeat imaging | March 2017 | ||
Bayer | 02234843 | Composite symptomatic recurrent VTE up to 3 months Composite overt major and clinically relevant non-major bleeding up to 3 months | Composite symptomatic recurrent VTE and asymptomatic deterioration on repeat imaging up to 3 months | November 2018 | ||
Apixaban | Bristol-Myers Squibb | 01195727 |
C
max, AUC, C
min, T
max
Plasma concentration vs. time | Anti-Xa PD analysis | Terminated July 2012 | |
Bristol-Myers Squibb | 01707394 |
C
max, AUC, T
max up to 26 h post dose | Safety Anti-Xa PD analysis | August 2016 | ||
Bristol-Myers Squibb | 02369653 | Composite of non-fatal DVT/PE, CVST and VTE-related death (up to 1 month post treatment) Major bleeding | Non-fatal asymptomatic DVT Non-fatal symptomatic DVT Non-fatal PE Non-fatal CSVT VTE-related death Non-major bleeding | May 2019 | ||
Pfizer | 02464969 | Composite of major and non-major bleeding Composite of confirmed symptomatic and asymptomatic recurrent VTE and death due to VTE (up to 3 months post treatment) | Apixaban concentration and anti-Xa levels on day 14 | October 2020 | ||
Edoxaban | Daiichi Sanyoko Inc. | 02303431 | Clearance (days 1–3) | PT, aPTT, anti-Xa levels, safety/tolerability (AE, VS, heme), metabolite exposure, palatability of liquid oral suspension | December 2016 | |
Direct thrombin inhibitor | Dabigatran | Boehringer Ingelheim | 00844415 | No major and minor bleeding events 2 patients with DRAE on-treatment and 1 patient with SAE 72 h post treatment Free dabigatran levels: 100 mg (~28 ng/ml) 125 mg (~41.6 ng/ml) Total dabigatran levels: 100 mg (~34.2 ng/ml) 125 mg (~58.2 ng/ml) Centrally measured TT: 100 mg (36.9 ± 3.61 s) 125 mg (37.4 ± 3.97 s) | Centrally measured aPTT: 100 mg (38.6 ± 2.94 s) 125 mg (47.4 ± 4.42 s) Ecarin clotting time: 100 mg (43.3 ± 1.31 s) 125 mg (49.6 ± 11.6 s) No patient with clinical significant changes in vital signs, ECG, and other labs 1 patient had a recurrent VTE within 3 days of dabigatran | Completed February 2012 |
Dietrich et al. | – | No difference in response to dabigatran in different pediatric age groups; dTT best assay to measure dabigatran concentrations in pediatric patients | – | Published April 2015 | ||
Boehringer Ingelheim | 01083732 | Ecarin clotting time, factor IIa inhibition and aPTT Plasma levels of total and free dabigatran and of BIBR 1048 BS, BIBR 951 BS, and BIBR 1087 SE Incidence of bleeding and adverse events | Tolerability, taste assessment, and change in clinical parameters and labs | November 2015 | ||
Boehringer Ingelheim | 01773174 | Ecarin clotting time, factor IIa inhibition and aPTT Plasma levels of total and free dabigatran and of BIBR 1048 BS, BIBR 951 BS, and BIBR 1087 SE Incidence of bleeding and adverse events | Tolerability, taste assessment, and change in clinical parameters and labs | December 2015 | ||
Boehringer Ingelheim | 02223260 | Ecarin clotting time, anti-factor IIa activity, aPTT and total dabigatran level 2 and 12 h post dose | Tolerability and PK/PD relationship Incidence of bleeding and adverse events | April 2016 | ||
Boehringer Ingelheim | 01895777 | Combined efficacy of complete thrombus resolution and freedom from recurrent VTE and VTE mortality for 3 months Freedom from major bleeding events for 3 months | Plasma concentration of dabigatran, frequency of dose adjustments, freedom from recurrence of VTE, all bleeding events, all-cause mortality, frequency of switching anticoagulation therapy | March 2018 | ||
Boehringer Ingelheim | 02197416 | Recurrence of VTE (6–12 months), major and minor bleeding events, overall mortality and related to thromboembolic events | Number of dose adjustments needed in treatment period, occurrence of post thrombotic syndrome, aPTT, ECT | June 2018 |