Clinical trial NCT00622115: Etude (Study) Phase I Enox - UnFractionated Heparin (UFH)
Official title: A Phase I, Pharmacokinetic and Tolerability Study of Intravenous Unfractionated Heparin After Subcutaneous Enoxaparin 1mg/kg Bid Repeated Administration in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Thrombosis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2008-02-22
Enrollment: 72
Sex: ALL
Minimum age (years): 40
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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


Eligibility criteria: 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

Primary outcomes:
measure: Concentration-time profiles of anti-Xa and anti-IIa levels
timeFrame: 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.
Secondary outcomes:
measure: Effect-time profiles of ACT, TGTppp and TGTprp
timeFrame: 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.
measure: PFA100 levels measured
timeFrame: At pre-dose, 4h and 14h post dose of enoxaparin
measure: Documentation of adverse event, physical examination, clinical laboratory safety, vital signs and ECG recording at prespecified time-points.
timeFrame: during the entire study
Other outcomes:
Locations:
city: Paris
country: France
facility: Sanofi-Aventis Administrative Office
Study officials:
affiliation: Sanofi
name: Kazuki Otani
role: STUDY_DIRECTOR
References:
citation: 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.