Study of Pharmacodynamic Equivalence of Enoxaparin Rovi to Clexane®, in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
To demonstrate the pharmacodynamic (PD) equivalence of enoxaparin Rovi (100 mg/mL) 100-mg SC injection to Clexane® (100 mg/mL) 100-mg SC injection in healthy volunteers. As secondary objective, to evaluate the safety and tolerability of enoxaparin Rovi (100 mg/mL) in healthy volunteers.

Detailed Description
-----------------
This is a single-dose, randomized, double-blind, 2-period, 2 sequence crossover study. Subjects will be screened up to 30 days before the study begins and admitted to the clinic on Day -1 of Period 1 for baseline assessments. Before dosing on Day 1 of Period 1, subjects will be randomly assigned to a treatment sequence. Subjects will receive a single dose of study drug on Day 1 of each treatment period. On Day 1 of Period 1, subjects will receive a single dose by subcutaneous route of the assigned study drug: enoxaparin (100 mg/mL) 100-mg SC injection manufactured by Rovi Spain, or Clexane (100 mg/mL) 100-mg SC injection manufactured by Sanofi EU; after an overnight fasting period of at least 10 hours. Subjects will continue fasting for at least 4 hours after study drug administration. The washout period between administrations of study drug in each period will be at least 7 days. On Day 1 of Period 2, subjects will cross over to receive the dose of the other drug, after an overnight fasting period of at least 10 hours. The total duration of the study will be approximately 6 weeks.

Official Title
-----------------
Demonstration of Pharmacodynamic Equivalence of Enoxaparin Rovi (100-mg Subcutaneous Injection) to Clexane® (100-mg Subcutaneous Injection) in Healthy Volunteers

Conditions
-----------------
Healthy

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject provides informed consent (approved by an Independent Ethical Committee (IEC)) before any study specific evaluation is performed. Subject is between the ages of 18 and 45 years, inclusive. All female subjects must have a negative pregnancy test at Screening and upon check-in to the clinic. Women of childbearing potential must use or have used one of the following acceptable birth control methods: Surgical sterilization (bilateral tubal ligation, hysterectomy, bilateral oophorectomy) for at least 6 months before the first dose of study drug;Intrauterine device in place for at least 3 months before the first dose of study drug; or barrier method (condom, diaphragm) for at least 21 days before the first dose of study drug and throughout the study. Subject has a body mass index between 18 and 30 kg/m2, inclusive. Subject is able and willing to abstain from alcohol from 48 hours before the first dose of study drug through the end of the study. Subject has no clinically significant abnormalities in medical history, vital sign measurements, or physical examination findings. Subject has computerized 12-lead electrocardiogram (ECG) results showing no signs of clinically relevant pathology or deviations, as judged by the investigator. Subject has hematology, serum chemistry, coagulation, and urinalysis test results within the reference ranges (Hb ≥7.5 mmol/L and ≥8.5 mmol/L for female and male, respectively) or showing no clinically relevant deviations, as judged by the investigator. Thrombocytes at screening have to be within the normal range. Subject is a nonsmoker or has quit smoking at least 6 months before the first dose of study drug. Exclusion Criteria: Subjects are excluded from the study if any of the following criteria are met: Subject has active or recurring clinically significant skin, head, ears, eyes, nose, throat, respiratory, cardiovascular, gastrointestinal, endocrine/metabolic, genitourinary, neurologic, hematologic, musculoskeletal, immunologic, allergic, psychological/psychiatric, or other disease requiring medical treatment. Female subject with weight < 45 kg or male subject with weight < 57 kg. Subject is a woman who is pregnant or breastfeeding. Subject has systolic blood pressure greater than 150 mm Hg or diastolic blood pressure greater than 90 mm Hg at Screening (confirmed upon repeat measurement). Subject has a calculated (Cockroft & Gault formula) creatinine clearance less than 80 mL/minute and the value does not return to within reference range upon retest. Subject has Hb <7.5 mmol/L and <8.5 mmol/L for female and male, respectively. Subject has an active malignancy of any type other than nonmelanomatous skin malignancies. Subject has any history of alcohol abuse or drug addiction. Subject has any history of relevant drug and/or food allergies. Subject has used an investigational drug within 60 days before the first dose of study drug. Subject has used any prescription drugs (with special attention to antiplatelet or anticoagulant medication, eg, acetyl salicylic acid, NSADs, clopidogrel, warfarin, acenocumarol, heparin, low molecular weight heparin, dabigatran, rivaroxaban, apixaban) or over-the-counter medication that may affect coagulation (including aspirin or NSAIDs) within 4 weeks before dosing, or any other over-the-counter medication (including vitamins, herbal supplements, or dietary supplements) within 2 weeks before dosing. Subject has donated or lost 550 mL or more of blood (including plasmapheresis) within 60 days before the first dose of study drug. Subject has a positive test result for drugs of abuse (opiates, methadone, cocaine, amphetamines, cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, oxycodone), cotinine, or alcohol. Subject has a positive test result for human immunodeficiency virus (1 or 2) antibody, hepatitis B surface antigen, or hepatitis C virus antibody. Subject has any illness within 5 days before the first dose of study drug. Subject has a positive test for fecal occult blood at Screening. Subject has any history and/or current conditions of bleeding tendency such as: active bleeding, known bleeding diathesis or hemostatic defects due to severe hepatic or renal disease; recent gastrointestinal or genitourinary bleeding (10 days before study entry) women of child-bearing potential with normal cyclic bleeding which is not considered as heavy menstruation by the investigator, are allowed for inclusion; diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions. Subject has a known history or family history of any relevant congenital or acquired coagulation disorder (eg, hemophilia, von Willebrand-Jürgens syndrome, or activated protein C resistance based upon Factor V Leiden mutation). Subject has a history of thrombocytopenia, including heparin induced thrombocytopenia. Subject has a known history of hypersensitivity to drugs with a similar chemical structure to enoxaparin sodium (eg, unfractionated heparin, low molecular weight heparin) or to pork products. Subject is a member of the professional or ancillary personnel involved in the study. Subject is deemed not suitable for entry into the study in the opinion of the investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 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: Crossover Assignment
Interventional Model Description: single-dose, randomized, double-blind, 2-period, 2-sequence crossover study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AB treatment sequence<br>Period 1-Test Treatment A: enoxaparin (100 mg/mL) 100-mg SC injection, manufactured by Rovi (Spain) Period 2-Reference Treatment B: Clexane (100 mg/mL) 100-mg SC injection, manufactured by Sanofi (EU) | Drug: Enoxaparin<br> <br> * Other names: enoxaparin sodium;Drug: Clexane<br> <br> * Other names: enoxaparin sodium;|
| Active Comparator: BA treatment sequence<br>Period 1-Reference Treatment B: Clexane (100 mg/mL) 100-mg SC injection, manufactured by Sanofi (EU) Period 2-Test Treatment A: enoxaparin (100 mg/mL) 100-mg SC injection, manufactured by Rovi (Spain) | Drug: Enoxaparin<br> <br> * Other names: enoxaparin sodium;Drug: Clexane<br> <br> * Other names: enoxaparin sodium;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUEC0-inf for anti-FXa | area under the effect curve (AUEC) from time 0 to infinity, for anti-FXa | Day -1 (Periods 1 and 2), before dosing (Pre-dose), and between 0.5 and 36 hours after dosing on Day 1 (Periods 1 and 2) | 
| AUEC0-T for anti-FXa and anti-FIIa | area under the effect curve (AUEC) from time 0 to the last measured activity (T), for anti-FXa and anti-FIIa | Day -1 (Periods 1 and 2), before dosing (Pre-dose), and between 0.5 and 36 hours after dosing on Day 1 (Periods 1 and 2) | 
| Amax for anti-FXa and anti-FIIa | peak effect for anti-FXa activity (anti-FXamax), and anti-FIIa activity (anti-FIIamax) | Day -1 (Periods 1 and 2), before dosing (Pre-dose), and between 0.5 and 36 hours after dosing on Day 1 (Periods 1 and 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RAUEC | ratio of AUEC0-T of anti-FXa to anti-FIIa | Day -1 (Periods 1 and 2), before dosing (Pre-dose), and between 0.5 and 36 hours after dosing on Day 1 (Periods 1 and 2) | 
| Amax for TFPI levels | peak effect activity (Amax) forTissue factor pathway inhibitor (TFPI) | Day -1 (Periods 1 and 2), before dosing (Pre-dose), and between 0.5 and 36 hours after dosing on Day 1 (Periods 1 and 2) | 
| AUEC0-T for TFPI levels | Area under the effect curve (AUEC) from time 0 to the last measured activity (T) forTissue factor pathway inhibitor (TFPI) | Day -1 (Periods 1 and 2), before dosing (Pre-dose), and between 0.5 and 36 hours after dosing on Day 1 (Periods 1 and 2) | 
| AUEC0-inf for TFPI levels | Area under the effect curve (AUEC) from time 0 to infinity forTissue factor pathway inhibitor (TFPI) | Day -1 (Periods 1 and 2), before dosing (Pre-dose), and between 0.5 and 36 hours after dosing on Day 1 (Periods 1 and 2) | 
| Tmax for anti-FXa and anti-FIIa | time of observed maximum measured plasma activity for anti-FXa and anti-FIIa | Day -1 (Periods 1 and 2), before dosing (Pre-dose), and between 0.5 and 36 hours after dosing on Day 1 (Periods 1 and 2) | 
| t1/2 for anti-FXa and anti-FIIa | apparent first order terminal elimination half-life for anti-FXa and anti-FIIa | Day -1 (Periods 1 and 2), before dosing (Pre-dose), and between 0.5 and 36 hours after dosing on Day 1 (Periods 1 and 2) | 
| CL/F for anti-FXa and anti-FIIa | apparent plasma clearance after extravascular administration for anti-FXa and anti-FIIa | Day -1 (Periods 1 and 2), before dosing (Pre-dose), and between 0.5 and 36 hours after dosing on Day 1 (Periods 1 and 2) | 
| MRT for anti-FXa and anti-FIIa | mean residence time for anti-FXa and anti-FIIa | Day -1 (Periods 1 and 2), before dosing (Pre-dose), and between 0.5 and 36 hours after dosing on Day 1 (Periods 1 and 2) | 
| Adverse Events (AEs) | All treatment emergent AEs (TEAEs), relationship of TEAEs to study drug, severity of TEAEs, treatment emergent serious AEs, relationship of treatment emergent serious AEs to study drug, and TEAEs leading to study drug discontinuation. The frequency of TEAEs will be summarized by system organ class and preferred term | from Informed Consent signature until 14 days after the last study drug administration (independently of the period) | 
| hematology | clinical laboratory results | at Screening, Day -1 (Period 1 only), and Day 3 (Period 2 only) and at the follow up visit (Day 7 of Period 2 only) | 
| Serum chemistry | measurements of a variety of compounds in the serum layer of blood | at Screening, Day -1 (Period 1 only), and Day 3 (Period 2 only) and at the follow up visit (Day 7 of Period 2 only) | 
| Coagulation | Prothrombin time (reported in seconds) and activated partial thromboplastin time (aPTT) | at Screening, Day -1 (Period 1 only), and Day 3 (Period 2 only) and at the follow up visit (Day 7 of Period 2 only) | 
| Urianalysis | measurements of a variety of compounds in urine | at Screening, Day -1 (Period 1 only), and Day 3 (Period 2 only) and at the follow up visit (Day 7 of Period 2 only) | 
| Blood presure | systolic and diastolic blood presure recorded after the subject had been resting for at least 5 minutes | at Screening, Day -1 (Period 1 only), and before dosing (Pre-dose) and 0.5 hours after dosing on Day 1 (Periods 1 and 2) | 
| Pulse rate | recorded after the subject had been resting | at Screening, Day -1 (Period 1 only), and before dosing (Pre-dose) and 0.5 hours after dosing on Day 1 (Periods 1 and 2) | 
| Respiratory rate | measured subsequently to pulse rate | at Screening, Day -1 (Period 1 only), and before dosing (Pre-dose) and 0.5 hours after dosing on Day 1 (Periods 1 and 2) | 
| Tympanic temperature | measured subsequently to pulse rate | at Screening, Day -1 (Period 1 only), and before dosing (Pre-dose) and 0.5 hours after dosing on Day 1 (Periods 1 and 2) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
antithrombotic, heparin, anticoagulant, low molecular weight heparin, pharmacodynamic equivalence