Etude (Study) Phase I Enox - UnFractionated Heparin (UFH)

Thrombosis Clinical Trial

Official title:

A Phase I, Pharmacokinetic and Tolerability Study of Intravenous Unfractionated Heparin After Subcutaneous Enoxaparin 1mg/kg Bid Repeated Administration in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00622115
• Other study ID #: ENOXA_C_02537
• Secondary ID: 2007-000884-99
• Status: Completed
• Phase: Phase 1
• First received: February 13, 2008
• Last updated: March 14, 2011
• Start date: July 2007
• Est. completion date: November 2007

Study information

• Verified date: March 2011
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial Summary

Primary objective:

• to characterize the pharmacokinetic and the pharmacodynamic profile after intravenous bolus injection of unfractionated heparin (UFH) after repeated sc 100 IU anti-Xa/kg (corresponding to 1 mg/kg) twice a day during 2.5 days (every 12±2hrs) administrations of enoxaparin in Caucasian healthy subjects.

Secondary objective(s):

• to compare the pharmacokinetic and the pharmacodynamic profile between 3 different timing of administration of the UFH

• to assess the tolerability of the different anticoagulation protocols

Recruitment information / eligibility

• Status: Completed
• Enrollment: 72
• Est. completion date: November 2007
• Est. primary completion date: November 2007
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 40 Years to 60 Years

Eligibility

Inclusion Criteria:

• Caucasian

• Male and female subjects, between 40 and 60 years of age

• Body weight between 50 kg and 90 kg if male and between 40 and 80 kg if female with Body Mass Index (BMI) between 18 and 29 kg/m2

Health Status:

• Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination)

• Subject with hypertension, hypo- or hyperthyroidism or dyslipidemia will be included if their concomitant pathology is well-controlled by treatment for at least one year

• Normal vital signs after 10 minutes resting in supine position:

• 95 mmHg < systolic blood pressure (SBP) < 140 mmHg;

• 45 mmHg < diastolic blood pressure (DBP) < 90 mmHg;

• 40 bpm < heart rate < 100 bpm.

• Normal 12-lead electrocardiogram (ECG); 120 ms < PR < 220 ms, QRS < 120 ms, QTc = 430 ms for male, 450 ms for female or not considered as clinically significant by the investigator

• Laboratory parameters within the normal range unless the Investigator considers an abnormality to be clinically irrelevant for healthy subjects; hepatic enzymes (aspartate amino-transferase or AST, alanine amino-transferase or ALT) should be strictly below the upper laboratory norm.

• Platelets = 150 000 / mm3

• Mean corpuscular volume (MCV) and gamma glutamyl-transferase (GGT) should be strictly in the normal range of the laboratory

• Activated partial thromboplastin time (aPTT) ratio should be comprised between 0.95 and 1.15

• Estimated Creatinine clearance by Cockroft formula should be higher than 50 mL/min

• Non smoker or smoking the equivalent or less than 5 cigarettes a day and able not to smoke during the study hospitalization

• Normal gynecological examination no longer than 12 months before inclusion.

• For female with childbearing potential using an effective contraception method (e.g. intra-uterine device, hormonal contraception, diaphragm and condom) except if postmenopausal for more than 12 months or sterilized for more than three months

• Subject with coagulation test and blood count (including platelets) within the physiological ranges)

Regulations:

• Having given written informed consent prior to any procedure related to the study

• Covered by Health Insurance System and/or in compliance with the recommendations of National Law in force relating to biomedical research

• Not under any administrative or legal supervision

Exclusion Criteria:

Medical history and clinical status:

• Contra-indication to anticoagulant therapy

• Subject with known increased bleeding time, hemophilia, thrombocytopenia, and/or history of any vascular purpura

• Subject with detectable antibody against heparin in the blood

• Any history or presence of clinically relevant cardiovascular, gynecologic (for women), pulmonary, gastro-intestinal, hepatic, renal, metabolic, hematological, neurologic, psychiatric, systemic, ocular or infectious disease that is capable of altering the absorption, metabolism, or elimination of drugs, or of constituting a risk factor when taking the study medication; any acute infectious disease or signs of acute illness; except subject with hypertension, hypo- or hyperthyroidism or dyslipidemia if well-controlled by treatment for at least one year.

• Subject with diabetes or other cardiovascular or metabolic disease

• Subject with INR > 1.5

• Frequent headaches and/or migraine, recurrent nausea and/or vomiting (more than twice a month)

• Blood donation or blood loss within one month before administration

• Symptomatic hypotension whatever the decrease in blood pressure or asymptomatic postural hypotension defined by a decrease in SBP equal to or greater than 20 mmHg within three minutes when changing from the supine to the standing position

• Presence or history of drug allergy, or allergic disease diagnosed and treated by a physician

• History or presence of drug or alcohol abuse (alcohol consumption > 40 grams/day)

• Smoking more than 5 cigarettes or equivalent/day, or unable to stop smoking during the study

• Excessive consumption of beverages with xanthine bases (> 4 cups or glasses/day)

• Pregnancy (defined as positive beta-HCG plasma test that can not be explicated by menopauses), breast-feeding for female, any history or presence of clinically relevant gynecologic disease

Interfering substance:

• Any medication (including St John's Wort) within 14 days before administration, or within 5 times the elimination half-life of that drug, except for hormonal contraception or replacement therapy, and allowed therapy for stable pathology

• Anti-inflammatory treatments and anti-aggregant treatments are strictly forbidden during the whole study period

General conditions:

• Subject who, in the judgment of the Investigator, is likely to be non-compliant during the study, or unable to cooperate because of a language problem or poor mental development

• Subject in exclusion period of a previous study according to applicable regulations

• Subject who cannot be contacted in case of emergency

• Subject is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff thereof, directly involved in the conduct of the protocol or any other protocol of the Investigating Center

• Subject is an employee of the Investigating Center

Biological status:

• Positive reaction to any of the following tests: HBs antigen, anti-HCV antibodies, anti-HIV1 antibodies, anti-HIV2 antibodies, anti-LMWH antibodies

• Positive results on urine drug screen (amphetamines/metamphetamines, barbiturates, benzodiazepines, cannabinoids)

• Positive alcohol breath or plasma test

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Thrombosis

Intervention

Drug:
• Enoxaparin

Locations

Country	Name	City	State
France	Sanofi-Aventis Administrative Office	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Country where clinical trial is conducted

France, 

References & Publications (1)

Drouet L, Bal dit Sollier C, Martin J. Adding intravenous unfractionated heparin to standard enoxaparin causes excessive anticoagulation not detected by activated clotting time: results of the STACK-on to ENOXaparin (STACKENOX) study. Am Heart J. 2009 Aug;158(2):177-84. doi: 10.1016/j.ahj.2009.05.022. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Concentration-time profiles of anti-Xa and anti-IIa levels		At baseline (Day 2) after the morning enoxaparin injection and at day 3 from pre-dose of enoxaparin and lasting until 14 hours after the enoxaparin injection.	No
Secondary	Effect-time profiles of ACT, TGTppp and TGTprp		At baseline (Day 2) after the morning enoxaparin sc injection and at day 3 from pre-dose of enoxaparin and lasting until 14 hours after the enoxaparin injection.	No
Secondary	PFA100 levels measured		At pre-dose, 4h and 14h post dose of enoxaparin	No
Secondary	Documentation of adverse event, physical examination, clinical laboratory safety, vital signs and ECG recording at prespecified time-points.		during the entire study	Yes