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Open Label Study Comparing Efficacy and Safety of Dabigatran Etexilate to Standard of Care in Paediatric Patients With Venous Thromboembolism (VTE)

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ClinicalTrials.gov Identifier: NCT01895777
Recruitment Status : Active, not recruiting
First Posted : July 11, 2013
Last Update Posted : August 6, 2019
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Tracking Information
First Submitted Date  ICMJE July 4, 2013
First Posted Date  ICMJE July 11, 2013
Last Update Posted Date August 6, 2019
Actual Study Start Date  ICMJE September 25, 2013
Estimated Primary Completion Date October 16, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 9, 2017)
A combined efficacy endpoint of complete thrombus resolution plus freedom from recurrent VTE plus freedom from mortality related to VTE [ Time Frame: 12 weeks ]
Original Primary Outcome Measures  ICMJE
 (submitted: July 10, 2013)
  • First component of the co-primary endpoint: A combined efficacy endpoint of complete thrombus resolution plus freedom from recurrent VTE plus freedom from mortality related to VTE [ Time Frame: 12 weeks ]
  • Second component of the co-primary endpoint: Freedom from major bleeding events (a safety endpoint) [ Time Frame: 12 weeks ]
Change History Complete list of historical versions of study NCT01895777 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 4, 2018)
  • Cpre,ss (pre-dose concentration of the analyte in plasma at steady state immediately before administration of the next dose) taken at 10 to 16 hours after the last dose (trough) [ Time Frame: 3, 7, 21, 42, 63 and 84 days ]
  • Frequency of dose adjustments [ Time Frame: 12 weeks ]
  • Frequency of switch of type of anti-coagulation therapy (including dabigatran to SOC) and a switch from an intended standard of care treatment to another [ Time Frame: 12 weeks ]
  • Assessment of the acceptability of an age-appropriate formulation at end of therapy [ Time Frame: 3 weeks and 12 weeks ]
  • All bleeding events [ Time Frame: 12 weeks ]
  • All-cause mortality [ Time Frame: 12 weeks ]
  • All components of the primary efficacy endpoints [ Time Frame: 12 weeks ]
  • Pharmacodynamic assessments (aPTT, ecarin clotting time (ECT) and diluted thrombin time (dTT)(Anti-Factor IIa activity)) at visit 3 (after at least six consecutive dabigatran doses) and after 3 days following any dabigatran dose adjustment [ Time Frame: 3, 7, 21, 42, 63 and 84 days ]
  • Frequency of temporary discontinuation from therapy [ Time Frame: 12 weeks ]
  • Frequency of permanent discontinuation from therapy [ Time Frame: 12 weeks ]
  • Number of subjects with laboratory monitoring requirements for dose adjustment during the treatment phase [ Time Frame: 12 weeks ]
  • Freedom from thrombus progression at end of therapy (day 84 after randomisation or eEOT, whichever comes first) [ Time Frame: 12 weeks ]
  • Freedom from major bleeding events (a safety endpoint) [ Time Frame: 12 weeks ]
  • C2,ss (concentration of the analyte in plasma at steady state at 2 hours after administration of the last dose) taken at 1 to 3 hours after the last dose (peak) [ Time Frame: 3, 7, 21, 42, 63 and 84 days ]
Original Secondary Outcome Measures  ICMJE
 (submitted: July 10, 2013)
  • Pharmacokinetic assessments (plasma concentrations of total dabigatran) 3 days after start of treatment (after at least six consecutive dabigatran doses) and after 3 days following any dabigatran dose adjustment [ Time Frame: 3, 7, 21, 42, 63 and 84 days ]
  • Frequency of dose adjustments [ Time Frame: 12 weeks ]
  • Frequency of switch of type of anti-coagulation therapy (including dabigatran to SOC) and a switch from an intended standard of care treatment to another [ Time Frame: 12 weeks ]
  • Freedom from thrombus progression at baseline and at days 21 and 84 after randomisation [ Time Frame: 3 weeks and 12 weeks ]
  • Assessment of the acceptability of an age-appropriate formulation at end of therapy [ Time Frame: 3 weeks and 12 weeks ]
  • Freedom from recurrence of VTE at 6, 9 and 12 months [ Time Frame: 6, 9 and 12 month ]
  • Freedom from occurrence of post-thrombotic syndrome at 6, 9 and 12 months [ Time Frame: 6, 9 and 12 month ]
  • All bleeding events [ Time Frame: 12 weeks ]
  • All-cause mortality [ Time Frame: 12 weeks ]
  • All components of the primary efficacy endpoints [ Time Frame: 12 weeks ]
  • Pharmacodynamic assessments (aPTT, ecarin clotting time (ECT) and dTT) 3 days after start of treatment (after at least six consecutive dabigatran doses) and after 3 days following any dabigatran dose adjustment [ Time Frame: 3, 7, 21, 42, 63 and 84 days ]
  • Frequency of temporary discontinuation from therapy [ Time Frame: 12 weeks ]
  • Frequency of permanent discontinuation from therapy [ Time Frame: 12 weeks ]
  • Number of laboratory monitoring requirements for dose adjustment during the treatment phase [ Time Frame: 12 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Open Label Study Comparing Efficacy and Safety of Dabigatran Etexilate to Standard of Care in Paediatric Patients With Venous Thromboembolism (VTE)
Official Title  ICMJE Open-label, Randomized, Parallel-group, Active-controlled, Multi-centre Non-inferiority Study of Dabigatran Etexilate Versus Standard of Care for Venous Thromboembolism Treatment in Children From Birth to Less Than 18 Years of Age
Brief Summary The main objectives of this large phase IIb/III paediatric study are to assess the efficacy and safety of dabigatran etexilate relative to standard of care and to document the appropriateness of the proposed dabigatran etexilate dosing algorithm for use in patients from birth to less than 18 years of age.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Venous Thromboembolism
Intervention  ICMJE
  • Drug: dabigatran etexilate
    Age and weight appropriate capsule dose (combination of 50 mg, 75 mg and 110 mg capsules) or pellets or oral liquid formulation
  • Drug: standard of care
    Low molecular weight heparin, vitamin K antagonist or fondaparinux prescribed in an open label fashion for 3 months (these medications will not supplied in this study as IMP)
Study Arms  ICMJE
  • Experimental: dabigatran etexilate
    Dabigatran etexilate capsules, pellets or liquid formulation given BID in an open label fashion for 3 months
    Intervention: Drug: dabigatran etexilate
  • Active Comparator: standard of care
    Low molecular weight heparin, vitamin K antagonist or fondaparinux prescribed in an open label fashion for 3 months (these medications will not supplied in this study as IMP)
    Intervention: Drug: standard of care
Publications * Albisetti M, Biss B, Bomgaars L, Brandão LR, Brueckmann M, Chalmers E, Gropper S, Harper R, Huang F, Luciani M, Manastirski I, Mitchell LG, Tartakovsky I, Wang B, Halton JML. Design and rationale for the DIVERSITY study: An open-label, randomized study of dabigatran etexilate for pediatric venous thromboembolism. Res Pract Thromb Haemost. 2018 Mar 25;2(2):347-356. doi: 10.1002/rth2.12086. eCollection 2018 Apr.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 9, 2018)
240
Original Estimated Enrollment  ICMJE
 (submitted: July 10, 2013)
270
Estimated Study Completion Date  ICMJE November 20, 2019
Estimated Primary Completion Date October 16, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • Male or female subjects 0 to less than 18 years of age at the time of informed consent / assent
  • Documented diagnosis of clinically stable VTE (e.g. DVT, PE, central line thrombosis, sinus vein thrombosis) per investigator judgment, initially treated (minimum of 5 to 7 days, but not longer than 21 days) with parenteral anticoagulation therapy, such as unfractionated heparin (UFH) or a low molecular weight heparin (LMWH).
  • Clinical indication for at least 3 month of treatment with anticoagulants for the VTE episode defined under the above inclusion criterion.
  • Written informed consent provided by the patient's parent or legal guardian and assent provided by the patient (if applicable) at the time of informed consent form (ICF) signature according to local regulations.

Exclusion criteria:

  • Conditions associated with an increased risk of bleeding
  • Renal dysfunction (eGFR < 50 mL/min/1.73m^2 using the Schwartz formula) or requirement for dialysis. eGFR retesting during the screening period is allowed (once).
  • Active infective endocarditis
  • Subjects with a heart valve prosthesis requiring anticoagulation.
  • Hepatic disease:

Active liver disease, including known active hepatitis A, B or C or, Persistent alanine aminotransferase (ALT) or aspartate transaminase (AST) or alkaline phosphatase (AP) > 3 × upper limit of normal (ULN) within 3 months of screening

  • Pregnant or breast feeding females. Females who have reached menarche and are not using a medically accepted contraceptive method per local guidelines. Acceptable methods of birth control must be used in a correct and consistent manner
  • Patients in stratum 3 (0 to < 2 years) with gestational age at birth < 37 weeks or with body weight lower than the 3rd percentile
  • Anemia (hemoglobin < 80g/L) or thrombocytopenia (platelet count < 80 x 109/L) at screening. Transfusions during the screening period are allowed, provided that a satisfactory hemoglobin or platelet level is attained prior to visit 2
  • Patients who have taken prohibited or restricted medication within one week of the first dose of study medication other than medication for prior VTE treatment and P-glycoprotein inhibitors..
  • Patients who have received an investigational drug in the past 30 days prior to screening
  • Patients who are allergic/sensitive to any component of the study medication including solvent
  • Patients or parents/legal guardians considered unreliable to participate in the trial per investigator judgment or any condition which would present a safety hazard to the patient based on investigator judgment
  • Patients or parents/legal guardians who are unwilling or unable to undergo or permit repeat of the baseline imaging tests required to confirm thrombus resolution at study day 84 (or eEOT, whichever comes first) or in whom repeating such imaging tests at these pre-specified time points may not be medically in the patient's best interest. Examples may include unwarranted radiation exposure as a result of a repeat CT scan at day 84 for a patient with an isolated case of pulmonary embolism evaluated at baseline solely by a CT scan. In such cases, the baseline radiological assessment (e.g. CT) may be supplemented with an acceptable non-radiological assessment at baseline (e.g. MRI) which could then be repeated at day 84 hence alleviating any potential unwarranted radiation exposure.
  • Further exclusion criteria apply
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Austria,   Belgium,   Brazil,   Canada,   Czechia,   Denmark,   Finland,   France,   Germany,   Greece,   Hungary,   Israel,   Italy,   Lithuania,   Mexico,   Norway,   Russian Federation,   Spain,   Sweden,   Switzerland,   Taiwan,   Thailand,   Turkey,   Ukraine,   United States
Removed Location Countries Bulgaria,   Colombia,   Czech Republic,   Slovakia,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT01895777
Other Study ID Numbers  ICMJE 1160.106
2013-002114-12 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Boehringer Ingelheim
Study Sponsor  ICMJE Boehringer Ingelheim
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
PRS Account Boehringer Ingelheim
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP