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

• Sponsor: Children's Hospital Los Angeles (Other)
• Overall Status: Completed
• CT.gov ID: NCT00412464
• Collaborator: (none)
• Enrollment: 24
• Locations: 4
• Duration (Months): 39
• Patients Per Site: 6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Thrombosis; Heparin-induced Thrombocytopenia	Drug: Fondaparinux	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Outcome Measures

Primary Outcome Measures

1. Number of Abnormal Lab Results Resulting in Adverse Events. [Study period which was up to 21 days of fondaparinux]

   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.

2. Therapeutic Plasma Concentration of Fondaparinux at 21 Days [21 days]

   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.

3. Bleeding Events [Study period which was up to 21 days of fondaparinux]

   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).

4. Adverse Events [Study period which was up to 21 days of fondaparinux]

   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.

5. Thrombocytopenic Events [Study period which was up to 21 days of fondaparinux]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
2	Children's Hospital of Orange County	Orange	California	United States	92868
3	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
4	Texas Children's Hospital	Houston	Texas	United States	77030

Sponsors and Collaborators

• Children's Hospital Los Angeles

Investigators

• Principal Investigator: Guy Young, MD, Children's Hospital of Orange County

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00412464
• Other Study ID Numbers: 3091
• First Posted: Dec 18, 2006
• Last Update Posted: Apr 15, 2015
• Last Verified: Oct 1, 2011

• Keywords provided by , ,: fondaparinux; thrombosis; heparin-induced thrombocytopenia; pediatrics
• Additional relevant MeSH terms: Thrombosis; Thrombocytopenia; PENTA; Fondaparinux

Study Results

Participant Flow

Recruitment Details	Subjects were recruited between September, 2006 and June, 2009 at 4 sites (Children's Hospital Los Angeles, Children's Hospital of Orange County, Texas Children's Hospital and Nationwide Children's Hospital). All subjects were in the inpatient units of these hospitals for the duration of their study participation.
Pre-assignment Detail	All recruited subjects entered and completed the study.

Arm/Group Title	Fondaparinux Group
Arm/Group Description	Single arm group receiving fondaparinux 0.1 mg/kg.
Period Title: Overall Study
STARTED	24
COMPLETED	24
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Fondaparinux Group
Arm/Group Description	Single arm group receiving fondaparinux 0.1 mg/kg.
Overall Participants	24
Age (Count of Participants)
<=18 years	24 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12 (4)
Sex: Female, Male (Count of Participants)
Female	14 58.3%
Male	10 41.7%
Region of Enrollment (participants) [Number]
United States	24 100%

Outcome Measures

1. Primary Outcome

Title	Number of Abnormal Lab Results Resulting in Adverse Events.
Description	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.
Time Frame	Study period which was up to 21 days of fondaparinux

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fondaparinux Group
Arm/Group Description	Single arm group receiving fondaparinux 0.1 mg/kg.
Measure Participants	24
Number [Adverse Events]	0

2. Primary Outcome

Title	Therapeutic Plasma Concentration of Fondaparinux at 21 Days
Description	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.
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fondaparinux Group
Arm/Group Description	Single arm group receiving fondaparinux 0.1 mg/kg.
Measure Participants	24
Mean (Standard Deviation) [mg/dL]	24 (0.001)

3. Primary Outcome

Title	Bleeding Events
Description	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).
Time Frame	Study period which was up to 21 days of fondaparinux

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fondaparinux Group
Arm/Group Description	Single arm group receiving fondaparinux 0.1 mg/kg.
Measure Participants	24
Number [Adverse Events]	2

4. Primary Outcome

Title	Adverse Events
Description	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.
Time Frame	Study period which was up to 21 days of fondaparinux

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fondaparinux Group
Arm/Group Description	Single arm group receiving fondaparinux 0.1 mg/kg.
Measure Participants	24
Number [Adverse Events]	0

5. Primary Outcome

Title	Thrombocytopenic Events
Description	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.
Time Frame	Study period which was up to 21 days of fondaparinux

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fondaparinux Group
Arm/Group Description	Single arm group receiving fondaparinux 0.1 mg/kg.
Measure Participants	24
Number [Adverse Events]	0

Adverse Events

Arm/Group Title	Fondaparinux Group
Arm/Group Description	Single arm group receiving fondaparinux 0.1 mg/kg.
All Cause Mortality
	Fondaparinux Group
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Fondaparinux Group
	Affected / at Risk (%)	# Events
Total	0/24 (0%)
Other (Not Including Serious) Adverse Events
	Fondaparinux Group
	Affected / at Risk (%)	# Events
Total	0/24 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.