Pharmacodynamic Equivalence of Ovine Enoxaparin to Lovenox®

Study Overview
=================
Brief Summary
-----------------
This study is designed as a randomized, open-label, 2-way cross-over, single dose study with at least 7 days wash-out period. The objective of this study is to demonstrate the pharmacodynamic / pharmacokinetic equivalence of ovine enoxaparin to the reference product, the originator porcine enoxaparin, Lovenox® from Sanofi, and to assess its safety and tolerability in healthy volunteers.

Detailed Description
-----------------
Low molecular-weight heparins (LMWHs) are derived from unfractionated heparin (UFH) by chemical or enzymatic depolymerization. Enoxaparin is one of the most widely used LMWHs and is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. In contrast to UFH, enoxaparin has higher and more consistent bioavailability after s.c. administration compared with UFH and has longer plasma half-life. Because of difficulties in chemical detection of LMWH, conventional pharmacokinetic studies cannot be performed. LMWH absorption and elimination are studied using pharmacodynamic surrogate markers, i.e. anti-FXa activity. Measurement of this pharmacodynamic activities is used to compare the biosimilar/ generic products to the reference LMWH. This study is designed as a randomized, open-label, 2-way cross-over, single dose study with at least 7 days wash-out period. The objective of this study is to demonstrate the pharmacodynamic / pharmacokinetic equivalence of ovine enoxaparin to the reference product, the originator porcine enoxaparin, Lovenox® from Sanofi, and to assess its safety and tolerability in healthy volunteers. The test drug is ovine enoxaparin sodium 60 mg (0.6 mL taken from 1.0 mL vial containing 100 mg = 10,000 IU anti-FXa), from Metiska Farma. Meanwhile, the reference drug is enoxaparin sodium 60 mg (Lovenox® 0.6 mL prefilled syringe containing 60 mg = 6,000 IU anti-FXa) from Sanofi, France. The drugs are not similar in appearance: ovine enoxaparin is supplied in vials, whereas Lovenox® is supplied as pre-filled syringes, both are given as s.c. injection. An unblinded pharmacist will prepare the study drug, and an unblinded medical doctor will inject the study drug. Study procedures On day-1 of period 1, subjects will be given in fasting condition, a single s.c. injection of the test or the reference drug. Blood samples to assess PD parameters will be collected in both study periods at the following time points: pre-dose, and 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 16, 20, and 24 hours after dosing on Day-1 (16 sampling points). Nine (9) mL of blood will be drawn from vena cubiti with a needle of 19 to 21 gauge with a maximum of 1 minute pressure with tourniquet, the first 3 mL of blood will be collected in an empty tube (to be thrown away), the second 3 mL of blood will be collected in a blood collection tube containing citrate, theophylline, adenosine, and dipyridamole (CTAD tube) for anti-FXa and anti-FIIa, and the third 3 mL of blood will be collected in a citrate tube for TFPI. In case of failure in blood drawing, the phlebotomist should change the site of blood drawing and change the needle used. Subjects will return to the clinic after a wash-out period of at least 7 days, and on day-1 of period 2, they will be crossed over to receive a single s.c. dose of the alternate drug. Anti-FXa activity will be determined by a chromogenic method using a commercial kit (STA-Liquid anti-FXa, Diagnostica Stago S.A.S, France) within 4 hours after sample collection at room temperature. Meanwhile, anti-FIIa activity will be measured by a chromogenic method using a commercial kit (Biophen anti-FIIa, STA Compact Max, France) within 4 hours after sample collection at room temperature, and TFPI levels will be measured using a commercial ELISA kit (Abcam PLC, Cambridge, UK).

Official Title
-----------------
Pharmacodynamic Equivalence of Ovine Enoxaparin to Porcine Enoxaparin (Lovenox®) in Healthy Volunteers

Conditions
-----------------
Enoxaparin

Intervention / Treatment
-----------------
* Drug: Ovine Enoxaparin
* Drug: Enoxaparin Prefilled Syringe [Lovenox]


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy volunteers of both sexes aged 18 - 45 years with BMI 18 - 25 kg/m2 inclusive. Have no clinically significant abnormalities based on medical history, clinical laboratory tests, vital sign measurements, 12-lead ECG results, and physical examination findings. Willing to participate in the study by signing the informed consent. Exclusion Criteria: Female < 45 kg or male < 57 kg Calculated (Cockroft & Gault formula) ClCr < 80 mL/min History of or positive test result for alcohol abuse or drug addiction. History of relevant drug and/or food allergies. Any prescription drug (especially antiplatelet or anticoagulant drug) or OTC medication including herbal, supplement, etc. that could affect coagulation within 2 weeks before study dosing. Administration of any investigational drug within 60 days before study drug dosing. Taking anti TB rifampicin within 60 days before study drug dosing. A positive test for HIV (1 or 2) Ab, HBsAg, or HepC Ab. A positive fecal occult blood at screening. History and/or current conditions of bleeding tendency. History of thrombocytopenia, including heparin-induced (by anamnesis). Known history of hypersensitivity to drugs with a chemical structure similar to enoxaparin sodium (eg. UFH, LMWH) or to pork or lamb products. Females: - during menstruation period Pregnancy or lactation taking hormonal contraception (oral or injection)

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized, open-label, 2-way cross-over, single-dose study with at least 7 days wash-out period.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TR treatment sequence<br>Period 1-Test Treatment: Ovine enoxaparin sodium 60 mg SC injection, manufactured by Metiska Farma. Period 2-Reference Treatment: Porcine enoxaparin sodium 60 mg SC injection (Lovenox), manufactured by Sanofi, France. | Drug: Ovine Enoxaparin<br>* The test drug is ovine enoxaparin sodium 60 mg (0.6 mL taken from 1.0 mL vial containing 100 mg = 10,000 IU anti-FXa), from Metiska Farma.<br>* Other names: Ovine Enoxaparin (Metiska Farma);Drug: Enoxaparin Prefilled Syringe [Lovenox]<br>* The reference drug is enoxaparin sodium 60 mg (Lovenox® 0.6 mL prefilled syringe containing 60 mg = 6,000 IU anti-FXa) from Sanofi, France.<br>* Other names: Active comparator;|
| Active Comparator: RT treatment sequence<br>Period 2-Reference Treatment: Porcine enoxaparin sodium 60 mg SC injection (Lovenox), manufactured by Sanofi, France. Period 1-Test Treatment: Ovine enoxaparin sodium 60 mg SC injection, manufactured by Metiska Farma. | Drug: Ovine Enoxaparin<br>* The test drug is ovine enoxaparin sodium 60 mg (0.6 mL taken from 1.0 mL vial containing 100 mg = 10,000 IU anti-FXa), from Metiska Farma.<br>* Other names: Ovine Enoxaparin (Metiska Farma);Drug: Enoxaparin Prefilled Syringe [Lovenox]<br>* The reference drug is enoxaparin sodium 60 mg (Lovenox® 0.6 mL prefilled syringe containing 60 mg = 6,000 IU anti-FXa) from Sanofi, France.<br>* Other names: Active comparator;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum activity (Amax) | Amax will be measured for anti-FXa activity, anti-FIIa activity and TFPI levels | Day -1 (periode 1 and 2), before dosing (pre-dose), and between 1 and 24 hours after dosing on day 1 (period 1 and 2) | 
| Area under the effect curve (AUEC0-t) | The AUEC will be measured from time 0 to the last measured activity (AUEC0-t) of anti-FXa activity, anti-FIIa activity, and TFPI levels | Day -1 (periode 1 and 2), before dosing (pre-dose), and between 1 and 24 hours after dosing on day 1 (period 1 and 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Adverse Events - total and related (ADRs) and Serious Adverse Events - total and related (SADRs) | From informed consent signature until the study end | 

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