Design and rationale for the DIVERSITY study: An open‐label, randomized study of dabigatran etexilate for pediatric venous thromboembolism

Abstract

Essentials Current standard of care (SOC) for pediatric venous thromboembolism (VTE) has limitations.Dabigatran etexilate (DE) versus SOC will be studied in children with VTE in a phase IIb/III trial.A dosing algorithm for DE in children will be assessed guiding dosing.Valuable data on the safety and efficacy of DE for VTE in children will be obtained. BackgroundThe current standard of care (SOC) for pediatric venous thromboembolism (VTE) comprises unfractionated heparin (UFH), or low‐molecular‐weight heparin (LMWH) followed by LMWH or vitamin K antagonists, all of which have limitations. Dabigatran etexilate (DE) has demonstrated efficacy and safety for adult VTE and has the potential to overcome some of the limitations of the current SOC. Pediatric trials are needed to establish dosing in children and to confirm that results obtained in adults are applicable in the pediatric setting.ObjectivesTo describe the design and rationale of a planned phase IIb/III trial that will evaluate a proposed dosing algorithm for DE and assess the safety and efficacy of DE versus SOC for pediatric VTE treatment.Patients/MethodsAn open‐label, randomized, parallel‐group noninferiority study will be conducted in approximately 180 patients aged 0 to <18 years with VTE, who have received initial UFH or LMWH treatment and who are expected to require ≥3 months of anticoagulation therapy. Patients will receive DE or SOC for 3 months. DE will be administered twice daily as capsules, pellets, or an oral liquid formulation according to patient age. Initial doses will be calculated using a proposed dosing algorithm.ResultsThere will be two coprimary endpoints: a composite efficacy endpoint comprising the proportion of patients with complete thrombus resolution, freedom from recurrent VTE and VTE‐related mortality, and a safety endpoint: freedom from major bleeding events.ConclusionFindings will provide valuable information regarding the efficacy and safety of DE for the treatment of pediatric VTE. ClinicalTrials.gov registration number: NCT01895777.

Treatment of Venous Thromboembolism in Special Populations with Direct Oral Anticoagulants

“…as capsules, pellets or in liquid form according to the patient's age. 74 An interim analysis in approximately 220 patients demonstrated similar efficacy and safety of dabigatran and standard of care, and confirmed the pharmacokinetic/pharmacodynamic profile of weight-adjusted dabigatran in children. 75 In addition, an interim analysis of a single-arm, prospective cohort, phase III study demonstrated a favorable safety profile of dabigatran used for up to 12 months in approximately 200 children aged 0 to <18 years who required anticoagulation for the secondary prevention of VTE and with a persistent risk factor for VTE.…”

Current Antithrombotic Therapy Strategies in Children with a Focus on Off-Label Direct Oral Anticoagulants—A Narrative Review

“…The population enrolled in the DIVERSITY trial could be regarded as the reference to guide the clinical decision of dabigatran initiation in pediatric patients with VTE [ 21 , 29 ]. Dabigatran should be avoided in patients with pre-existing conditions associated with an increased risk of bleeding, renal dysfunction (estimated glomerular filtration rate—eGFR < 50 mL/min/1.73 m 2 or requiring dialysis), hepatic impairment (active liver disease, alanine aminotransferase, or aspartate aminotransferase > 3 × upper limit of normal—ULN), active endocarditis, heart valve prosthesis, and in children aged < 2 years with low body weight (lower than the third percentile) or whose gestational age at birth was <37 weeks.…”

“…Dabigatran should be avoided in patients with pre-existing conditions associated with an increased risk of bleeding, renal dysfunction (estimated glomerular filtration rate—eGFR < 50 mL/min/1.73 m 2 or requiring dialysis), hepatic impairment (active liver disease, alanine aminotransferase, or aspartate aminotransferase > 3 × upper limit of normal—ULN), active endocarditis, heart valve prosthesis, and in children aged < 2 years with low body weight (lower than the third percentile) or whose gestational age at birth was <37 weeks. These patients were excluded from the DIVERSITY trial; therefore, there are no available data to support dabigatran administration in the subset mentioned above of children [ 21 , 29 ].…”

Addendum to British Society for Haematology guideline on the investigation, management and prevention of venous thrombosis in children (Br. J. Haematol. 2011; 154: 196–207)

“…Children received a minimum of five days parenteral anticoagulation prior to commencing dabigatran. Dabigatran tablets, pellets or oral suspension were administered twice daily to provide exposure similar to adult populations treated therapeutically with dabigatran 10 . Participants received therapeutic anticoagulation for a minimum of three months.…”

“…Dabigatran tablets, pellets or oral suspension were administered twice daily to provide exposure similar to adult populations treated therapeutically with dabigatran. 10 Participants received therapeutic anticoagulation for a minimum of three months. Dabigatran dose adjustment was permitted once to achieve trough dabigatran levels of 50-250 ng/ml, required in 62/117 (35%) patients assigned to dabigatran with 56 requiring an increase in dose.…”