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OpenTrials
Completed

NCT Number: NCT01895777

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

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.

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Key information

Conditions

Venous Thromboembolism Cardiovascular Diseases Embolism and Thrombosis Thromboembolism Vascular Diseases

Age range

Up to 17 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Hospital General de Niños Pedro de Elizalde, CABA, Argentina

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Dabigatran Etexilate

Drug

Age and weight appropriate capsule dose (combination of 50 mg, 75 mg and 110 mg capsules) or pellets or oral liquid formulation

Standard of care

Drug

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)

Primary outcomes

  1. Composite Primary Endpoint

    Time frame: From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.

    The primary endpoint was the combined endpoint of the proportions of patients with:

    • Complete thrombus resolution
    • Freedom from recurrent VTE
    • Freedom from mortality related to VTE. The events outlined in the above combined primary endpoint were assessed by radiologists or other such qualified clinicians using an appropriate method such as ultrasound, echocardiography, venography, or CT scan, based on the location of the thrombus and the test used to perform the baseline assessment.

    The primary efficacy endpoint contained 3 components. Each component was evaluated separately, and only if the criteria for all 3 components were satisfied, the primary endpoint was considered achieved.

Secondary outcomes

  1. Freedom From Major Bleeding Events (MBEs)

    Time frame: From first administration of trial medication until last administration of trial medication +6 days (residual effect period). Up to 97 days.

    Freedom from major bleeding events (MBEs), defined as either fatal bleeding, clinically overt bleeding associated with a decrease in haemoglobin of at least 20 g/L in a 24-hour period, bleeding that is retroperitoneal, pulmonary, intracranial or otherwise involves the central nervous system, or bleeding that requires intervention in an operating suite.

  2. Steady State Plasma Concentrations of Total Dabigatran at Visit 3

    Time frame: From the time of randomisation until visit 3

    Descriptive statistics for steady state plasma concentrations of total dabigatran etexilate at visit 3

  3. Steady State Plasma Concentrations After at Least 3 Days Following Any Dabigatran Etexilate Dose Adjustment

    Time frame: From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.

    Descriptive statistics for steady state plasma concentrations of total dabigatran etexilate after at least 3 days following any dabigatran etexilate dose adjustment

  4. Frequency of Dose Adjustment During the Treatment Phase

    Time frame: From first administration of trial medication until last administration of trial medication +6 days (residual effect period).

    Frequency of dose adjustments (i.e. number of patients with dose adjustment), temporary and permanent discontinuation from therapy, and number of patients with laboratory monitoring requirements for dose

  5. Frequency of Patients Switching the Type of Anti-coagulation Therapy Including Dabigatran Etexilate to Standard of Care Treatment and Switching From One Standard of Care Treatment to Another

    Time frame: From first administration of trial medication until last administration of trial medication +6 days (residual effect period).

    Frequency of patients switching the type of anti-coagulation therapy including Dabigatran etexilate (DE) to standard of care (SoC) treatment and switching from one standard of care treatment to another.

    For DE arm, only the switch from DE to SoC was counted, while for the SoC arm, all switches among SoC treatments were counted.

  6. Freedom From Thrombus Progression at End of Therapy Compared With Baseline

    Time frame: From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.

    Freedom from thrombus progression at end of therapy compared with baseline, based on adjudication-confirmed data.

  7. All Bleeding Events

    Time frame: From first administration of trial medication until last adminstration of trial medication +6 days (residual effect period). Up to 97 days.

    The number of participants with bleeding events includes major bleeding events (MBEs), clinically relevant non-major (CRNM) bleeding, minor bleeding events, any bleeding events, and the numbers of the combined endpoint of major and CRNM bleeding events was presented, based on adjudication-confirmed data.

  8. All-cause Mortality

    Time frame: From first administration of trial medication until last administration of trial medication +6 days (residual effect period). Up to 97 days.

    Patients being alive at the end of observational period will be censored for all-cause mortality at the date of patients' last date known to be alive, or the date of data cut-off whichever comes first.

  9. All Components of the Primary Efficacy Endpoint

    Time frame: From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.

    Patients with VTE-related death occurring between randomisation to Day 84 + 7 days were considered as not meeting the endpoint. The presence of recurrent VTE(s) was examined throughout the trial, and only the date of first occurrence was used for analysis. Assessment of index VTE status (best overall response) was scheduled on Day 84 ± 7 days (Visit 8) for patients who were alive without an early consent withdraw. In the case a Patient discontinued trial medication prematurely due to any reason the index VTE assessment took place at the early end of treatment visit.

  10. Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Capsules)

    Time frame: Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination.

    Acceptability was defined as the overall ability and willingness of the patient to use the medicinal product. Questions regarding acceptability were to be answered by the patient and/or parent/caregiver (as applicable) and by the investigator/site staff.

    Investigator questionnaire capsules: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad).

    Parents questionnaire capsules: How acceptable was the DE treatment for the child? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad).

    Patients questionnaire capsules: Was taking the study capsules easy or difficult? The score is 1 (Very easy), 2 (easy), 3 (neither easy nor difficult), 4 (difficult) and 5 (very difficult).

    Scores refers to the end of treatment.

  11. Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Pellets)

    Time frame: Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination.

    Acceptability was defined as the overall ability and willingness of the patient to use the medicinal product. Questions regarding acceptability were to be answered by the patient and/or parent/caregiver (as applicable) and by the investigator/site staff.

    Investigator questionnaire pellets: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad).

    Parents questionnaire pellets: Do you think that spitting occurs? The score is 1 (Never), 2 (sometimes) and 3 (often).

    Scores refers to the end of treatment.

  12. Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Oral Liquid Formulation - OLF)

    Time frame: Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination.

    Acceptability was defined as the overall ability and willingness of the patient to use the medicinal product. Questions regarding acceptability were to be answered by the patient and/or parent/caregiver (as applicable) and by the investigator/site staff.

    Investigator questionnaire flavoured OLF: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad).

    Investigator questionnaire unflavoured OLF: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad).

    Parents questionnaire flavoured OLF.: Do you think spitting occurs? The score ranges form 1 (never), 2 ( sometimes) to 3 (often).

    Parents questionnaire unflavoured OLF:Do you think spitting occurs? The score ranges form 1 (never), 2 ( sometimes) to 3 (often).

    Scores refers to the end of treatment.

Sponsors and collaborators

Lead sponsor

Boehringer Ingelheim

Industry

Registry information

Official study title

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

Important dates

Study start
2013
Primary completion
2019
Study completion
2019
First posted
Jul 11, 2013
Registry last updated
Jul 7, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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