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

Study Overview
=================
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

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

Conditions
-----------------
Thrombosis

Intervention / Treatment
-----------------
* Drug: Enoxaparin


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>70 U/kg of UnFractionated Heparin (UFH) administered intravenously at 4 hours following the last injection of enoxaparin | Drug: Enoxaparin<br> <br> |
| Experimental: B<br>70 U/kg of UnFractionated Heparin (UFH) administered intravenously at 6 hours following the last injection of enoxaparin | Drug: Enoxaparin<br> <br> |
| Experimental: C<br>70 U/kg of UnFractionated Heparin (UFH) administered intravenously at 10 hours following the last injection of enoxaparin | Drug: Enoxaparin<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| PFA100 levels measured |  | At pre-dose, 4h and 14h post dose of enoxaparin | 
| Documentation of adverse event, physical examination, clinical laboratory safety, vital signs and ECG recording at prespecified time-points. |  | during the entire study |