Pilot Dose Finding and Pharmacokinetic Study of Fondaparinux in Children With Thrombosis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
FDA Office of Orphan Products Development
ClinicalTrials.gov Identifier:
NCT00412464
First received: December 15, 2006
Last updated: February 2, 2012
Last verified: October 2011
  Purpose

This study will evaluate the use of a blood thinner, fondaparinux, which is approved for use in adults (not in children) in a children aged 1-18 years. Subject with a blood clot (thrombosis) or heparin-induced thrombocytopenia who need to be on a blood thinner will be eligible to participate. Subjects will receive a once daily dose of fondaparinux followed by blood tests at 2, 4, 12, and 24 hours after the first dose in order to determine the proper dose for this age group. The hypothesis is that children receiving fondaparinux will be able to receive a once daily dose. The currently available alternative agent, enoxaparin, needs to be given twice daily. In addition, an evaluation of the safety of this medication will be made by assessing for side effects, especially bleeding.


Condition Intervention Phase
Thrombosis
Heparin-induced Thrombocytopenia
Drug: Fondaparinux
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Dose-finding and Pharmacokinetic Study of Fondaparinux in Children With Deep Vein Thrombosis or Heparin-induced Thrombocytopenia

Resource links provided by NLM:


Further study details as provided by FDA Office of Orphan Products Development:

Primary Outcome Measures:
  • Number of Abnormal Lab Results Resulting in Adverse Events. [ Time Frame: Study period which was up to 21 days of fondaparinux ] [ Designated as safety issue: Yes ]
    The primary outcome measure was assessment of safety by reporting the number of abnormal lab results resulting in adverse events. Safety laboratory assessments are as follows: Liver and kidney toxicity will be determined by serial measurements of AST, ALT, total bilirubin, BUN and creatinine. Hematologic toxicity will be assessed by serial CBCs.

  • Therapeutic Plasma Concentration of Fondaparinux at 21 Days [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    Subjects all had detailed pharmacokinetic measurements done which were subsequently analyzed in a population pharmacokinetic model. This model then informed the dosing recommendations that were published as a result of the study.

  • Bleeding Events [ Time Frame: Study period which was up to 21 days of fondaparinux ] [ Designated as safety issue: Yes ]
    Bleeding assessment Patients will be monitored for bleeding symptoms by physician and nursing assessment. Major bleeding will be defined as bleeding which is in a critical space (intracranial, retroperitoneal, or visceral) or leads to the need for blood transfusion. Minor bleeding will be all other bleeding and will be classified as clinically significant (i.e. If the physician has to take action to treat the minor bleed) or clinically insignificant (i.e. if the physician does not need to intervene to treat the minor bleed).

  • Adverse Events [ Time Frame: Study period which was up to 21 days of fondaparinux ] [ Designated as safety issue: Yes ]
    Adverse events will be defined as any untoward or unexpected event which can be a symptom, physical exam sign or laboratory abnormality. Adverse events will be classified as serious if they lead to prolonged hospitalization, re-hospitalization, transfer to an intensive care unit, or death. Adverse events will be categorized in terms of their likely association with fondaparinux as probably related, possibly related, unrelated, or unknown, and will be recorded according to standard adverse reporting guidelines for clinical trials.

  • Thrombocytopenic Events [ Time Frame: Study period which was up to 21 days of fondaparinux ] [ Designated as safety issue: Yes ]
    Patient's platelet counts should be kept above 50 x 10^9/L while on study with platelet transfusions as needed with the exception of patients enrolled under the HIT/ suspicion of HIT inclusion (platelet transfusions are contraindicated in HIT). With regards to study patients who experience progressive decreases in platelet count to below 50 x 10^9/L while receiving fondaparinux (excluding patients being treated for HIT or suspicion of HIT), fondaparinux will be discontinued.


Enrollment: 24
Study Start Date: September 2006
Study Completion Date: December 2009
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Fondaparinux
    Fondaparinux 0.1 mg/kg (up to 7.5 mg max initial dose) once daily for up to 21 days.
    Other Name: Arixtra
Detailed Description:

This clinical trial will assess the pharmacokinetics and safety of the novel anticoagulant, fondaparinux sodium (Arixtra) in pediatric patients with thromboembolism. Currently available anticoagulants have significant limitations especially as it applies to the pediatric population. Thus novel agents with improved pharmacologic properties are needed to improve the care of this increasingly recognized complication in children. Furthermore, the only available agent for long-term anticoagulation in children with heparin-induced thrombocytopenia is warfarin. Anticoagulation with warfarin in the pediatric population is problematic due to its narrow therapeutic index and the numerous drug and food interactions necessitating frequent laboratory monitoring. In addition, oral administration of warfarin (which cannot be compounded to a liquid) is difficult in young children. Thus a novel agent for this condition is needed and fondaparinux does not cross-react with heparin antibodies. The aims of the study are to determine the proper dosing regimen (dose and interval) and safety in patients less than 18 years of age with thrombosis or heparin-induced thrombocytopenia. Another aim is to assess the utility of thromboelastography as a monitoring tool for patients on fondaparinux. This will be a pilot study which will have a total of 24 patients in 3 age cohorts with 8 patients per cohort as follows: 1-5 years, 6 -12 years, and 12-18 years as the pharmacokinetics of medications differ by age. Patients will receive an initial dose of 0.1mg/kg subcutaneously daily. After the first dose, fondaparinux levels will be drawn at 2,4,12, and 24 hours after administration. Dose adjustments will be made based on the 4 hour (peak) level and trough levels at 12 and 24 hours will determine if daily dosing is feasible. Thromboelastography will be performed at 2 or 4 hours and 24 hours with the results correlated with the plasma activity level. Safety will be assessed by physical examination, laboratory testing, and if necessary diagnostic imaging to determine the incidence of minor and major bleeding. Pharmacokinetic analyses as well as safety and efficacy determinations will be made which will provide valuable information on this promising new anticoagulant for pediatric patients.

  Eligibility

Ages Eligible for Study:   1 Year to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Children between 1 year and 18 years of age.
  • The presence of documented venous or arterial thrombosis confirmed by diagnostic imaging.
  • Weight greater than 8.3 kg.
  • Signed informed consent/assent.

Exclusion Criteria:

  • Patients with active bleeding.
  • Patients with planned invasive procedures less than 2 weeks from the time of enrollment.
  • Patients with a contraindication to anticoagulation.
  • Patients receiving thrombolytic agents.
  • Patients with an INR>1.5 or an activated partial thromboplastin time (PTT)>40 seconds.
  • Patients with a creatinine level above 1.2 times the upper limit of normal expected for age.
  • Children <1 year of age.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00412464

Locations
United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
Children's Hospital of Orange County
Orange, California, United States, 92868
United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Investigators
Principal Investigator: Guy Young, MD Children’s Hospital of Orange County
  More Information

Publications:
Responsible Party: FDA Office of Orphan Products Development
ClinicalTrials.gov Identifier: NCT00412464     History of Changes
Other Study ID Numbers: 3091
Study First Received: December 15, 2006
Results First Received: July 28, 2011
Last Updated: February 2, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by FDA Office of Orphan Products Development:
fondaparinux
thrombosis
heparin-induced thrombocytopenia
pediatrics

Additional relevant MeSH terms:
Thrombosis
Venous Thrombosis
Embolism and Thrombosis
Thrombocytopenia
Blood Platelet Disorders
Hematologic Diseases
Vascular Diseases
Cardiovascular Diseases
Fondaparinux
PENTA
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents

ClinicalTrials.gov processed this record on August 26, 2014