EnoxaparinPhase 1/2NCT04402762
Pharmacodynamic Equivalence of Ovine Enoxaparin to Lovenox®
A Phase 1/2 study testing Ovine Enoxaparin and Enoxaparin Prefilled Syringe [Lovenox] in people with Enoxaparin, run by Universitas Indonesia at 1 site in Indonesia.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Enoxaparin
- What is being tested?
- Ovine Enoxaparin and Enoxaparin Prefilled Syringe [Lovenox]
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteIndonesia
- Study dates
- 20 Dec 2019to 3 May 2020
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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)
Trial locations and contacts
1 site in 1 country.
Indonesia1 site
Pharma Metric Labs
Jakarta Pusat, Jakarta Special Capital Region, 10520
About this study
Official title: 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.
Read the 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).
- Conditions
- Enoxaparin
- Being tested
- Ovine Enoxaparin, Enoxaparin Prefilled Syringe [Lovenox]
- Keywords
- pharmacodynamic equivalence, anticoagulant, antithrombotic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ovine EnoxaparinDrug
Also called Ovine Enoxaparin Sodium, Ovine Enoxaparin (Metiska Farma)
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.
Enoxaparin Prefilled Syringe [Lovenox]Drug
Also called Active comparator
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.
| Study group | Role | What they receive |
|---|---|---|
| TR treatment sequence | Experimental | 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. Receives: Drug: Ovine Enoxaparin; Drug: Enoxaparin Prefilled Syringe [Lovenox] |
| RT treatment sequence | Active comparator | 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. Receives: Drug: Ovine Enoxaparin; Drug: Enoxaparin Prefilled Syringe [Lovenox] |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum activity (Amax)
Amax will be measured for anti-FXa activity, anti-FIIa activity and TFPI levels
Measured: 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
Measured: 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 outcomes (1)
Adverse events
Adverse Events - total and related (ADRs) and Serious Adverse Events - total and related (SADRs)
Measured: From informed consent signature until the study end
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 May 2020
- Study start20 Dec 2019
- Primary completion17 Apr 2020
- Study completion3 May 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for EnoxaparinStudies of the same condition, open and under way.
- More trials run by Universitas IndonesiaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Randomized, open-label, 2-way cross-over, single-dose study with at least 7 days wash-out period.
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Universitas Indonesia
- Sponsor type
- University, hospital or other
- Collaborators
- PT Metiska Farma
- Responsible party
- Principal investigator, Prof. Arini Setiawati, PhD, Universitas Indonesia
- Investigators
- Arini Setiawati, Prof, PhD, Principal investigator, Clinical Research Supporting Unit, Faculty of Medicine, University of Indonesia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04402762
- Sponsor's protocol ID
- CRSU.P.Enox/06.01/11/19
- Status last verified
- May 2020
- First submitted
- 9 Apr 2020
- Last updated
- 27 May 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 23471071Martinez 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.
PubMed 29593380
Study at a glance
From the registry record, last updated by the sponsor on 27 May 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacodynamic Equivalence of Ovine Enoxaparin to Porcine Enoxaparin (Lovenox®) in Healthy Volunteers
- ClinicalTrials.gov ID
- NCT04402762
- Acronym / sponsor ID
- CRSU.P.Enox/06.01/11/19
- Conditions
- Enoxaparin
- Keywords
- pharmacodynamic equivalence, anticoagulant, antithrombotic
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Universitas IndonesiaUniversity, hospital or other
- Collaborators
- PT Metiska Farma
- Study start
- 20 Dec 2019 (actual)
- Primary completion
- 17 Apr 2020 (actual)
- Study completion
- 3 May 2020 (actual)
- First posted
- 27 May 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Randomized, open-label, 2-way cross-over, single-dose study with at least 7 days wash-out period.
| Arm | Type | Receives |
|---|---|---|
| TR treatment sequence | Experimental | Drug: Ovine Enoxaparin, Drug: Enoxaparin Prefilled Syringe [Lovenox]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. |
| RT treatment sequence | Active comparator | Drug: Ovine Enoxaparin, Drug: Enoxaparin Prefilled Syringe [Lovenox]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. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (15 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ovine EnoxaparinAlso: Ovine Enoxaparin Sodium, Ovine Enoxaparin (Metiska Farma)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. | Drug | RT treatment sequence, TR treatment sequence |
| Enoxaparin Prefilled Syringe [Lovenox]Also: Active comparatorThe reference drug is enoxaparin sodium 60 mg (Lovenox® 0.6 mL prefilled syringe containing 60 mg = 6,000 IU anti-FXa) from Sanofi, France. | Drug | RT treatment sequence, TR treatment sequence |
Primary outcome
Maximum activity (Amax)
Time frame: 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)
Amax will be measured for anti-FXa activity, anti-FIIa activity and TFPI levels
Area under the effect curve (AUEC0-t)
Time frame: 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)
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
1 secondary outcome
Adverse events
Time frame: From informed consent signature until the study end
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 May 2020.
- Results publication: PubMed 23471071Lee 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.
- Results publication: PubMed 29593380Martinez 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.
- EMA Assessment report for Inhixa (enoxaparin sodium), 2016Link provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Arini Setiawati, Prof, PhD principal investigator
Clinical Research Supporting Unit, Faculty of Medicine, University of Indonesia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Ovine Enoxaparin and Enoxaparin Prefilled Syringe [Lovenox] in people with Enoxaparin, run by Universitas Indonesia at 1 site in Indonesia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 May 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Indonesia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum activity (Amax) (time frame: 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)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04402762, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 May 2020.