Investigation Into the Therapeutic Dosage of Fondaparinux Sodium, a Medication Used to Prevent Blood Clots in Morbidly Obese Volunteers

Pulmonary Embolism Clinical Trial

Official title:

Pharmacokinetic Properties of Fondaparinux Sodium in Morbidly Obese Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00436787
• Other study ID #: ART108029
• Status: Completed
• Phase: Phase 2
• First received: February 16, 2007
• Last updated: May 15, 2008
• Start date: February 2007
• Est. completion date: December 2007

Study information

• Verified date: May 2008
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Morbidly obese individuals are at high risk for potentially life threatening blood clots around the time of abdominal surgical procedures. Fondaparinux sodium (Arixtra) is an FDA- approved medication used in the prevention of deep venous thrombosis (DVT) at the time of orthopedic or abdominal surgery, as well as for the treatment of DVT and pulmonary embolism (PE). As with many medications, therapeutic dosages have not been fully investigated for the morbidly obese population. Our goal is to study the therapeutic blood levels, after 2 different dosages of the medication are given to morbidly obese volunteers. We will recruit 21 morbidly obese (Body Mass Index (BMI) > 35) individuals who are in the evaluation process for bariatric surgery. They will be divided into 7 groups: 3 participants with BMI 35 - 39.9, 3 with a BMI of 40 - 49.9, 3 with a BMI of 50 - 59.9, 3 with a BMI > 60, 3 with a weight of 100 - 149 KG, 3 with a weight of 150 - 199 KG and 3 with a weight of 200 - 249 KG. Participants will be administered two different doses of the medication with a 2-week interval in between, then blood will be drawn in various intervals throughout the next 48 hours to see which dose provides the best therapeutic levels. Participants will be monitored closely for any side effects or complications.

Description:

Bariatric surgery carries a mortality rate of 0.5-1%, with PE found to be the most frequent postoperative complications and causes of death. Currently employed prophylactic methods include unfractionated or low molecular weight heparins in combination with mechanical calf compression. However, despite the implementation of these standard measures, the reported incidence of fatal PE has ranged from 0.2 to 0.64% accounting for between 30 to 50% of deaths after bariatric surgery.

With a reported 40,000 bariatric surgical procedures in 2001, and the numbers growing rapidly every year, there is clearly a need for a more effective prophylaxis from DVT and PE. The pentasaccharide fondaparinux is an anti-thrombotic agent used in the prophylaxis of venous thromboembolism after orthopedic or abdominal surgery. Its clinical value has been established in multiple randomized double blind studies in high-risk major orthopedic surgery where it showed a 55% greater reduction in DVT episodes compared to enoxaparin (Lovenox®) Although fondaparinux has been administered in obese patients in clinical studies for prevention of venous thromboembolism after orthopedic surgery and preliminary results show no influence of ABW on the clinical outcome, the pharmacokinetic properties of the drug in the morbidly obese have not been investigated. Previously published fondaparinux pharmacokinetic studies excluded patients whose body weight was more than 30% of ideal, with the heaviest group being 77.2+/-10.1 Kg and with a BMI of 25.7+/2.6 Kg/m2. Similar studies on low molecular weight heparins, such as enoxaparin and dalteparin, showed predictable anti-Xa activity with weight-based dosing in the morbidly obese.

There has been no study on the pharmacokinetics of this drug in the morbidly obese (BMI>35 Kg/m2). It is clinically imperative to have a predictable anti-Xa level and a predictable DVT prophylactic effect in the morbidly obese whose body weight may vary by as much as 3 to 4 fold higher compared to the average 70 Kg adult. This has become a critical issue in view of the large number of bariatric surgical operations being undertaken, which has increased 150% in the last two years.

The purpose of this study is to assess the pharmacokinetic properties of fondaparinux in morbidly obese volunteers. This is a prospective crossover, randomized study with a 2-week washout period comparing two dosing regimens of fondaparinux in morbidly obese volunteers.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: December 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

INCLUSION

1. Age 19-65 years

2. BMI 35-65 Kg/m2

3. Pregnancy test Negative on day of study

4. Past DVT/PE/MI These patients will not be excluded providing they are not on current therapy with anticoagulants, aspirin, or anti-platelet agents.

EXCLUSION

1. BP = 160/90

2. Temperature > 37.5 0C (99.5 0F)

3. Nursing mothers Exclude if nursing

4. Pregnancy test Positive on day of study

5. Medications Anticoagulants, anti-platelet agents, aspirin, NSAIDs within a month of the study

Past medical history

1. cerebrovascular accident (including TIA within 6 months of the study)

2. Diabetic retinopathy proven by fundoscopy

3. History of inherited thrombotic/hypercoagulable defect

4. Active peptic ulcer disease diagnosed by upper endoscopy

5. Known bleeding disorder, thrombophilia

6. History of heparin induced thrombocytopenia

7. History of bacterial endocarditis

8. Known hypersensitivity to fondaparinux

9. Ulcerative colitis

10. History of GI bleeding

11. History of hematuria

12. Recent surgery (last 3 months)

13. Recent trauma (last 3 months)

Laboratory values

1. Platelet count = 100,000 mm3

2. Hemoglobin < 12 g/dL (women), or < 14 g/dL (men)

3. Prothrombin time > 13 sec

4. PTT > 35 sec

5. ALT 3xULN and bilirubin 1.5xULN (>35% direct); or ALT 5xULN; or ALT 3xULN if associated with the appearance or worsening of hepatitis symptoms or rash

6. Estimated urinary creatinine clearance = 50 ml/min

7. Hematuria on urine dipstick

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Embolism
• Pulmonary Embolism
• Thrombosis
• Venous Thrombosis

Intervention

Drug:
• Fondaparinux Sodium

Locations

Country	Name	City	State
United States	Magee Women's Hospital	Pittsburgh	Pennsylvania
United States	Shadyside Medical Building	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pittsburgh	GlaxoSmithKline

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The pharmacokinetic properties of fondaparinux sodium in morbidly obese individuals.
Secondary	Comparisons of the pharmacokinetic parameters of morbidly obese participants receiving 2.5 mg or 5 mg dose of fondaparinux sodium with those of healthy normal-weight volunteers established from previous studies.
Secondary	Comparison of the pharmacokinetic parameters of the 2.5 mg and 5 mg dosage of fondaparinux sodium.
Secondary	Evaluate the effect of BMI and ABW on the pharmacokinetic parameters of the 2.5 mg and 5 mg dosages of fondaparinux sodium.
Secondary	Assess the safety of fondaparinux sodium, as measured by defined safety endpoints, and compare the 2 dose groups for differences in the incidence of adverse events (AE).