Pharmacodynamic Equivalence of Ovine Enoxaparin to Lovenox®

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

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.

Study Overview

• Status: Completed
• Conditions: Enoxaparin
• Intervention / Treatment: Drug: Ovine Enoxaparin; Drug: Enoxaparin Prefilled Syringe [Lovenox]

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

1. 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.
2. 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).
3. 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.
4. 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).

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Indonesia
  • Jakarta
    • Jakarta Pusat, Jakarta, Indonesia, 10520
      • Pharma Metric Labs

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 41 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Healthy volunteers of both sexes aged 18 - 45 years with BMI 18 - 25 kg/m2 inclusive.
2. Have no clinically significant abnormalities based on medical history, clinical laboratory tests, vital sign measurements, 12-lead ECG results, and physical examination findings.
3. Willing to participate in the study by signing the informed consent.

Exclusion Criteria:

1. Female < 45 kg or male < 57 kg
2. Calculated (Cockroft & Gault formula) ClCr < 80 mL/min
3. History of or positive test result for alcohol abuse or drug addiction.
4. History of relevant drug and/or food allergies.
5. 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.
6. Administration of any investigational drug within 60 days before study drug dosing.
7. Taking anti TB rifampicin within 60 days before study drug dosing.
8. A positive test for HIV (1 or 2) Ab, HBsAg, or HepC Ab.
9. A positive fecal occult blood at screening.
10. History and/or current conditions of bleeding tendency.
11. History of thrombocytopenia, including heparin-induced (by anamnesis).
12. Known history of hypersensitivity to drugs with a chemical structure similar to enoxaparin sodium (eg. UFH, LMWH) or to pork or lamb products.

13. Females: - during menstruation period

    • Pregnancy or lactation
    • taking hormonal contraception (oral or injection)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TR treatment sequence; 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; 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.; Other Names: Ovine Enoxaparin Sodium; Ovine Enoxaparin (Metiska Farma); Drug: Enoxaparin Prefilled Syringe [Lovenox]; 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.; Other Names: Active comparator
Active Comparator: RT treatment sequence; 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; 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.; Other Names: Ovine Enoxaparin Sodium; Ovine Enoxaparin (Metiska Farma); Drug: Enoxaparin Prefilled Syringe [Lovenox]; 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.; 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

Collaborators and Investigators

• Sponsor: Indonesia University
• Collaborators: PT Metiska Farma
• Investigators: Principal Investigator: Arini Setiawati, Prof, PhD, Clinical Research Supporting Unit, Faculty of Medicine, University of Indonesia

Publications and helpful links

General Publications

• Lee S, Raw A, Yu L, Lionberger R, Ya N, Verthelyi D, Rosenberg A, Kozlowski S, Webber K, Woodcock J. Scientific considerations in the review and approval of generic enoxaparin in the United States. Nat Biotechnol. 2013 Mar;31(3):220-6. doi: 10.1038/nbt.2528.
• Martinez Gonzalez J, Monreal M, Ayani Almagia I, Llaudo Garin J, Ochoa Diaz de Monasterioguren L, Gutierro Aduriz I. Bioequivalence of a biosimilar enoxaparin sodium to Clexane(R) after single 100 mg subcutaneous dose: results of a randomized, double-blind, crossover study in healthy volunteers. Drug Des Devel Ther. 2018 Mar 19;12:575-582. doi: 10.2147/DDDT.S162817. eCollection 2018.

Helpful Links

• EMA Assessment report for Inhixa (enoxaparin sodium), 2016

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2019
• Primary Completion (Actual): April 17, 2020
• Study Completion (Actual): May 3, 2020

Study Registration Dates

• First Submitted: April 9, 2020
• First Submitted That Met QC Criteria: May 24, 2020
• First Posted (Actual): May 27, 2020

Study Record Updates

• Last Update Posted (Actual): May 27, 2020
• Last Update Submitted That Met QC Criteria: May 24, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: anticoagulant; antithrombotic; pharmacodynamic equivalence
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin; Enoxaparin sodium
• Other Study ID Numbers: CRSU.P.Enox/06.01/11/19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No