Completed DOAC phase 2b/3 pediatric thrombosis trials
| Trial/phase . | Indication . | Age group . | Comparator/SOC agent . | Initial treatment . | No. of children treated . | Outcomes . | Key observations . |
|---|---|---|---|---|---|---|---|
| Rivaroxaban∗ | |||||||
| Einstein Jr phase 316 (NCT02234843) | VTE treatment and prevention of recurrent VTE | From birth to age <18 y | SOC (UFH, LMWH, fondaparinux, and VKA) | ≥5 d of SOC anticoagulant | 500 | Rivaroxaban vs SOC anticoagulant Efficacy: symptomatic recurrent VTE: 4 (1%) vs 5 (3%); HR, 0.4; 95% CI, 0.11-1.41. Safety: major bleeding/CRNMB: 10 (3%) (all nonmajor) vs 3 (2%) (1 nonmajor and 1 CRNMB); HR, 1.58; 95% CI, 0.51-6.27. | Patients received SOC anticoagulant for 5-9 d before starting rivaroxaban. CVC-provoked VTE represented 25% of study population. Infants and younger children were underrepresented (37 of 335 [11%]). Subanalysis of special populations reported: CVC, infection-related CSVT, and cancer. |
| UNIVERSE phase 317 (NCT02846532) | Thromboprophylaxis for children after Fontan procedure | 2-8 y | Part A: none Part B: aspirin | NA | 112 | Part B: rivaroxaban vs aspirin Efficacy: event rate, 2 (3%) vs 3 (9%) Safety: major bleeding, 1 (2%) in rivaroxaban CRNMB: 4 (6%) vs 3 (9%) | Shorter duration between Fontan surgery and the first study drug dose in the aspirin group (mean, 37 d) than in the rivaroxaban group (mean, 45 d). Not powered to test a formal hypothesis for efficacy. |
| Apixaban | |||||||
| PREVAPIX-ALL phase 318,19 (NCT02369653) | Thromboprophylaxis during induction chemotherapy for ALL/LL | 1-18 y | None | NA | 512 | Apixaban vs SOC anticoagulant† Efficacy: VTE occurrence, 31 (12.1%) vs 45 (17.6%); RR, 0.69 (0.45-1.05); 1-sided P = .04 Safety: major bleeding, 2 in each arm; CRNMB, 11 vs 3 events | Apixaban was not shown to be efficacious in the primary analysis but decreased VTE risk for patients with obesity The study design was powered to demonstrate the benefit of anticoagulant prophylaxis of CVL-associated thrombosis for children with ALL/LL. |
| SAXOPHONE phase 220 (NCT03395639) | Thromboprophylaxis for cardiac disease | From 29 d to <18 y of age | SOC anticoagulant (LMWH or VKA) | NA | 192 | Apixaban vs SOC anticoagulant† Efficacy: no thromboembolic (TE) events in either arm. Safety: 1 had 2 primary safety events (IR, 1.8/100 P-Y) vs 3 with 4 events (IR, 6.8/100 P-Y). | Bone density and quality of life were measured for 12 mo but not reported. |
| Edoxaban | |||||||
| ENOBLE phase 321 NCT02798471 | Thromboprophylaxis in cardiac disease | 38 wk to <18 y | SOC (UFH, LMWH, VKA) | NA | 168 | Edoxaban vs SOC anticoagulant Efficacy: none vs 2 TE events in SOC (1.7%) Safety: major, none; CRNMB, 1 in each group. Extension arm (n = 147, all on edoxaban) Efficacy: 4 TE (2.8%; 2 strokes and 2 coronary artery thrombosis or myocardial infarction) Safety: major, none; CRNMB, 1 (0.7%). | Compliance with investigational drug was measured and was 94% in the edoxaban group in the main treatment period but reduced to 55% in the extension study. |
| HOKUSAI-Jr phase 314 (NCT02798471) | VTE treatment | From 38 wk to <18 y of age | SOC (UFH, LMWH, fondaparinux, and VKA) | ≥5 d of parenteral treatment | 290 | Not available | Study completed; study results not published. |
| Dabigatran∗ | |||||||
| DIVERSITY phase 2b/322 (NCT01895777) | VTE treatment and prevention of recurrent VTE | From birth to age 17 y | SOC anticoagulant (LMWH, VKA, or fondaparinux) | ≥5 d of parenteral treatment | 260 | Dabigatran vs SOC anticoagulant Efficacy: Composite outcome: 81 (46%) vs 38 (42%); P = .001 Safety: on treatment bleeding, 38/176 (22%) vs 22/90 (24%); HR, 1·15; 95% CI, 0·68-1·94; P = ·61 Major bleeding: 4/176 (2%) vs 2/90 (2%); HR, 0·94; 95% CI, 0·17-5·16; P = ·95 | Patients received 5-21 d of SOC anticoagulant before starting dabigatran. Dabigatran drug levels were monitored to determine appropriate dose. 17 of 176 (∼10%) of the population prematurely discontinued dabigatran because of failure to achieve target dabigatran plasma concentration after 1 dose adjustment allowed per protocol. Infants and younger children were underrepresented (22/176 [12.5%]). Subanalysis of special populations: CVC, CSVT, and thrombophilia from birth to <2 y of age. |
| DIVERSITY phase 38 NCT 02197416 | VTE secondary prevention (single arm) | From birth to <18 y of age | NA | NA | 203 | Efficacy: 1% (2/203) recurrence Safety: major bleeding, 1.5% (3/203). CRNMB, 1% (2/203). | Study reported development of postthrombotic syndrome in 2 of 162 participants (1.2%) with DVT- or CVC-related thrombosis. |
| Trial/phase . | Indication . | Age group . | Comparator/SOC agent . | Initial treatment . | No. of children treated . | Outcomes . | Key observations . |
|---|---|---|---|---|---|---|---|
| Rivaroxaban∗ | |||||||
| Einstein Jr phase 316 (NCT02234843) | VTE treatment and prevention of recurrent VTE | From birth to age <18 y | SOC (UFH, LMWH, fondaparinux, and VKA) | ≥5 d of SOC anticoagulant | 500 | Rivaroxaban vs SOC anticoagulant Efficacy: symptomatic recurrent VTE: 4 (1%) vs 5 (3%); HR, 0.4; 95% CI, 0.11-1.41. Safety: major bleeding/CRNMB: 10 (3%) (all nonmajor) vs 3 (2%) (1 nonmajor and 1 CRNMB); HR, 1.58; 95% CI, 0.51-6.27. | Patients received SOC anticoagulant for 5-9 d before starting rivaroxaban. CVC-provoked VTE represented 25% of study population. Infants and younger children were underrepresented (37 of 335 [11%]). Subanalysis of special populations reported: CVC, infection-related CSVT, and cancer. |
| UNIVERSE phase 317 (NCT02846532) | Thromboprophylaxis for children after Fontan procedure | 2-8 y | Part A: none Part B: aspirin | NA | 112 | Part B: rivaroxaban vs aspirin Efficacy: event rate, 2 (3%) vs 3 (9%) Safety: major bleeding, 1 (2%) in rivaroxaban CRNMB: 4 (6%) vs 3 (9%) | Shorter duration between Fontan surgery and the first study drug dose in the aspirin group (mean, 37 d) than in the rivaroxaban group (mean, 45 d). Not powered to test a formal hypothesis for efficacy. |
| Apixaban | |||||||
| PREVAPIX-ALL phase 318,19 (NCT02369653) | Thromboprophylaxis during induction chemotherapy for ALL/LL | 1-18 y | None | NA | 512 | Apixaban vs SOC anticoagulant† Efficacy: VTE occurrence, 31 (12.1%) vs 45 (17.6%); RR, 0.69 (0.45-1.05); 1-sided P = .04 Safety: major bleeding, 2 in each arm; CRNMB, 11 vs 3 events | Apixaban was not shown to be efficacious in the primary analysis but decreased VTE risk for patients with obesity The study design was powered to demonstrate the benefit of anticoagulant prophylaxis of CVL-associated thrombosis for children with ALL/LL. |
| SAXOPHONE phase 220 (NCT03395639) | Thromboprophylaxis for cardiac disease | From 29 d to <18 y of age | SOC anticoagulant (LMWH or VKA) | NA | 192 | Apixaban vs SOC anticoagulant† Efficacy: no thromboembolic (TE) events in either arm. Safety: 1 had 2 primary safety events (IR, 1.8/100 P-Y) vs 3 with 4 events (IR, 6.8/100 P-Y). | Bone density and quality of life were measured for 12 mo but not reported. |
| Edoxaban | |||||||
| ENOBLE phase 321 NCT02798471 | Thromboprophylaxis in cardiac disease | 38 wk to <18 y | SOC (UFH, LMWH, VKA) | NA | 168 | Edoxaban vs SOC anticoagulant Efficacy: none vs 2 TE events in SOC (1.7%) Safety: major, none; CRNMB, 1 in each group. Extension arm (n = 147, all on edoxaban) Efficacy: 4 TE (2.8%; 2 strokes and 2 coronary artery thrombosis or myocardial infarction) Safety: major, none; CRNMB, 1 (0.7%). | Compliance with investigational drug was measured and was 94% in the edoxaban group in the main treatment period but reduced to 55% in the extension study. |
| HOKUSAI-Jr phase 314 (NCT02798471) | VTE treatment | From 38 wk to <18 y of age | SOC (UFH, LMWH, fondaparinux, and VKA) | ≥5 d of parenteral treatment | 290 | Not available | Study completed; study results not published. |
| Dabigatran∗ | |||||||
| DIVERSITY phase 2b/322 (NCT01895777) | VTE treatment and prevention of recurrent VTE | From birth to age 17 y | SOC anticoagulant (LMWH, VKA, or fondaparinux) | ≥5 d of parenteral treatment | 260 | Dabigatran vs SOC anticoagulant Efficacy: Composite outcome: 81 (46%) vs 38 (42%); P = .001 Safety: on treatment bleeding, 38/176 (22%) vs 22/90 (24%); HR, 1·15; 95% CI, 0·68-1·94; P = ·61 Major bleeding: 4/176 (2%) vs 2/90 (2%); HR, 0·94; 95% CI, 0·17-5·16; P = ·95 | Patients received 5-21 d of SOC anticoagulant before starting dabigatran. Dabigatran drug levels were monitored to determine appropriate dose. 17 of 176 (∼10%) of the population prematurely discontinued dabigatran because of failure to achieve target dabigatran plasma concentration after 1 dose adjustment allowed per protocol. Infants and younger children were underrepresented (22/176 [12.5%]). Subanalysis of special populations: CVC, CSVT, and thrombophilia from birth to <2 y of age. |
| DIVERSITY phase 38 NCT 02197416 | VTE secondary prevention (single arm) | From birth to <18 y of age | NA | NA | 203 | Efficacy: 1% (2/203) recurrence Safety: major bleeding, 1.5% (3/203). CRNMB, 1% (2/203). | Study reported development of postthrombotic syndrome in 2 of 162 participants (1.2%) with DVT- or CVC-related thrombosis. |
CRNMB, clinically relevant nonmajor bleeding; CVC, central venous catheter; HR, hazard ratio; NA, not applicable; LL, lymphoblastic lymphoma; VKA, vitamin K antagonists.
Approved in North America and the United Kingdom and by the European Medicines Agency.
Abstracts at International Society of Thrombosis and Hemostasis Congress annual meeting, 2022.