Rationale and Design of a Phase IIb/III Open-Label, Multicenter Study of Dabigatran Etexilate for Venous Thromboembolism in Children: The Diversity Study

Background

Venous thromboembolism (VTE) is increasing in children. The current standard of care comprises unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for at least 5 days followed by UFH, LMWH or Vitamin K antagonists (VKA) for approximately 3 months in general. All of the current options have limitations: UFH and LMWH require parenteral administration; VKA requires frequent international normalized ratio (INR) monitoring and is associated with multiple food and drug interactions. The direct thrombin inhibitor, dabigatran, which is orally administered as the prodrug, dabigatran etexilate (DE) is effective for the treatment of VTE in adults and may overcome some of the limitations associated with standard of care.

Objective

To describe the design of a study evaluating the appropriateness of a proposed DE dosing algorithm and assessing the safety and efficacy of DE versus standard of care in pediatric patients with VTE.

Methods

This open-label, randomized, parallel-group, active-controlled, multi-center, non-inferiority study (NCT01895777) will be conducted in approximately 100 sites in approximately 30 countries. Patients aged 0 to < 18 years with an imaging-confirmed diagnosis of VTE initially receiving parenteral treatment with UFH or LMWH for 5-7 days (but no more than 21 days) who are expected to require anticoagulation therapy for at least 3 months will be eligible for inclusion. Main exclusion criteria include conditions associated with an increased risk of bleeding, renal dysfunction, active infective endocarditis, mechanical or biological heart valve prosthesis, hepatic disease and anemia or thrombocytopenia.

Patients will be stratified into three age groups: stratum 1 (12 to < 18 years), stratum 2 (2 to < 12 years) and stratum 3 (birth to < 2 years). Recruitment will begin in stratum 1, being subsequently escalated to strata 2 and 3, respectively based on recommendations from the Data Monitoring Committee.

Patients will be randomized (2:1) to receive DE versus standard of care (LMWH or VKA). DE will be administered twice daily as capsules, pellets or an oral liquid formulation depending on patient age and the patient's ability to swallow pellets or capsules. Upon completion of a 3-month treatment period (including the initial parenteral treatment phase) patients will be followed off-study drug for any adverse events.

DE will be dosed to achieve steady-state measured trough circulating plasma concentrations (≥50 and < 250 ng/mL); the initial dose required will be calculated using a nomogram, which adjusts dosing according to the age and weight of the child. Dabigatran plasma concentrations will be evaluated at all study visits (7 scheduled during treatment period); DE will be up- or down-titrated as required.

Results

In terms of efficacy, the study will evaluate the proportion of patients with complete thrombus resolution, freedom from recurrent VTE (including symptomatic and asymptomatic, contiguous progression or non-contiguous new thrombus, deep vein thrombosis, pulmonary and paradoxical embolism, and thrombus progression) and freedom from VTE-related mortality. With regards to safety, the key endpoint will be freedom from major bleeding events, as per International Society on thrombosis and Haemostasis (ISTH) pediatric-specific criteria. All components of the primary efficacy and key safety endpoints will be adjudicated by an independent blinded committee.

Conclusion

This study, one of the largest controlled pediatric studies for VTE, will provide data on the safety and efficacy of DE compared with standard of care for the treatment of VTE in children aged 0 to < 18 years.