<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04402762</url>
  </required_header>
  <id_info>
    <org_study_id>CRSU.P.Enox/06.01/11/19</org_study_id>
    <nct_id>NCT04402762</nct_id>
  </id_info>
  <brief_title>Pharmacodynamic Equivalence of Ovine Enoxaparin to Lovenox®</brief_title>
  <official_title>Pharmacodynamic Equivalence of Ovine Enoxaparin to Porcine Enoxaparin (Lovenox®) in Healthy Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Indonesia University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>PT Metiska Farma</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Indonesia University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is designed as a randomized, open-label, 2-way cross-over, single dose study with&#xD;
      at least 7 days wash-out period. The objective of this study is to demonstrate the&#xD;
      pharmacodynamic / pharmacokinetic equivalence of ovine enoxaparin to the reference product,&#xD;
      the originator porcine enoxaparin, Lovenox® from Sanofi, and to assess its safety and&#xD;
      tolerability in healthy volunteers.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Low molecular-weight heparins (LMWHs) are derived from unfractionated heparin (UFH) by&#xD;
      chemical or enzymatic depolymerization. Enoxaparin is one of the most widely used LMWHs and&#xD;
      is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine&#xD;
      intestinal mucosa. In contrast to UFH, enoxaparin has higher and more consistent&#xD;
      bioavailability after s.c. administration compared with UFH and has longer plasma half-life.&#xD;
&#xD;
      Because of difficulties in chemical detection of LMWH, conventional pharmacokinetic studies&#xD;
      cannot be performed. LMWH absorption and elimination are studied using pharmacodynamic&#xD;
      surrogate markers, i.e. anti-FXa activity. Measurement of this pharmacodynamic activities is&#xD;
      used to compare the biosimilar/ generic products to the reference LMWH.&#xD;
&#xD;
      This study is designed as a randomized, open-label, 2-way cross-over, single dose study with&#xD;
      at least 7 days wash-out period. The objective of this study is to demonstrate the&#xD;
      pharmacodynamic / pharmacokinetic equivalence of ovine enoxaparin to the reference product,&#xD;
      the originator porcine enoxaparin, Lovenox® from Sanofi, and to assess its safety and&#xD;
      tolerability in healthy volunteers.&#xD;
&#xD;
      The test drug is ovine enoxaparin sodium 60 mg (0.6 mL taken from 1.0 mL vial containing 100&#xD;
      mg = 10,000 IU anti-FXa), from Metiska Farma. Meanwhile, the reference drug is enoxaparin&#xD;
      sodium 60 mg (Lovenox® 0.6 mL prefilled syringe containing 60 mg = 6,000 IU anti-FXa) from&#xD;
      Sanofi, France. The drugs are not similar in appearance: ovine enoxaparin is supplied in&#xD;
      vials, whereas Lovenox® is supplied as pre-filled syringes, both are given as s.c. injection.&#xD;
      An unblinded pharmacist will prepare the study drug, and an unblinded medical doctor will&#xD;
      inject the study drug.&#xD;
&#xD;
      Study procedures&#xD;
&#xD;
        1. On day-1 of period 1, subjects will be given in fasting condition, a single s.c.&#xD;
           injection of the test or the reference drug.&#xD;
&#xD;
        2. Blood samples to assess PD parameters will be collected in both study periods at the&#xD;
           following time points: pre-dose, and 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 16, 20,&#xD;
           and 24 hours after dosing on Day-1 (16 sampling points).&#xD;
&#xD;
        3. Nine (9) mL of blood will be drawn from vena cubiti with a needle of 19 to 21 gauge with&#xD;
           a maximum of 1 minute pressure with tourniquet, the first 3 mL of blood will be&#xD;
           collected in an empty tube (to be thrown away), the second 3 mL of blood will be&#xD;
           collected in a blood collection tube containing citrate, theophylline, adenosine, and&#xD;
           dipyridamole (CTAD tube) for anti-FXa and anti-FIIa, and the third 3 mL of blood will be&#xD;
           collected in a citrate tube for TFPI. In case of failure in blood drawing, the&#xD;
           phlebotomist should change the site of blood drawing and change the needle used.&#xD;
&#xD;
        4. Subjects will return to the clinic after a wash-out period of at least 7 days, and on&#xD;
           day-1 of period 2, they will be crossed over to receive a single s.c. dose of the&#xD;
           alternate drug.&#xD;
&#xD;
      Anti-FXa activity will be determined by a chromogenic method using a commercial kit&#xD;
      (STA-Liquid anti-FXa, Diagnostica Stago S.A.S, France) within 4 hours after sample collection&#xD;
      at room temperature. Meanwhile, anti-FIIa activity will be measured by a chromogenic method&#xD;
      using a commercial kit (Biophen anti-FIIa, STA Compact Max, France) within 4 hours after&#xD;
      sample collection at room temperature, and TFPI levels will be measured using a commercial&#xD;
      ELISA kit (Abcam PLC, Cambridge, UK).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 20, 2019</start_date>
  <completion_date type="Actual">May 3, 2020</completion_date>
  <primary_completion_date type="Actual">April 17, 2020</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Randomized, open-label, 2-way cross-over, single-dose study with at least 7 days wash-out period.</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum activity (Amax)</measure>
    <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)</time_frame>
    <description>Amax will be measured for anti-FXa activity, anti-FIIa activity and TFPI levels</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the effect curve (AUEC0-t)</measure>
    <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)</time_frame>
    <description>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</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>From informed consent signature until the study end</time_frame>
    <description>Adverse Events - total and related (ADRs) and Serious Adverse Events - total and related (SADRs)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Enoxaparin</condition>
  <arm_group>
    <arm_group_label>TR treatment sequence</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RT treatment sequence</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ovine Enoxaparin</intervention_name>
    <description>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.</description>
    <arm_group_label>RT treatment sequence</arm_group_label>
    <arm_group_label>TR treatment sequence</arm_group_label>
    <other_name>Ovine Enoxaparin Sodium</other_name>
    <other_name>Ovine Enoxaparin (Metiska Farma)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enoxaparin Prefilled Syringe [Lovenox]</intervention_name>
    <description>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.</description>
    <arm_group_label>RT treatment sequence</arm_group_label>
    <arm_group_label>TR treatment sequence</arm_group_label>
    <other_name>Active comparator</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Healthy volunteers of both sexes aged 18 - 45 years with BMI 18 - 25 kg/m2 inclusive.&#xD;
&#xD;
          2. Have no clinically significant abnormalities based on medical history, clinical&#xD;
             laboratory tests, vital sign measurements, 12-lead ECG results, and physical&#xD;
             examination findings.&#xD;
&#xD;
          3. Willing to participate in the study by signing the informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Female &lt; 45 kg or male &lt; 57 kg&#xD;
&#xD;
          2. Calculated (Cockroft &amp; Gault formula) ClCr &lt; 80 mL/min&#xD;
&#xD;
          3. History of or positive test result for alcohol abuse or drug addiction.&#xD;
&#xD;
          4. History of relevant drug and/or food allergies.&#xD;
&#xD;
          5. Any prescription drug (especially antiplatelet or anticoagulant drug) or OTC&#xD;
             medication including herbal, supplement, etc. that could affect coagulation within 2&#xD;
             weeks before study dosing.&#xD;
&#xD;
          6. Administration of any investigational drug within 60 days before study drug dosing.&#xD;
&#xD;
          7. Taking anti TB rifampicin within 60 days before study drug dosing.&#xD;
&#xD;
          8. A positive test for HIV (1 or 2) Ab, HBsAg, or HepC Ab.&#xD;
&#xD;
          9. A positive fecal occult blood at screening.&#xD;
&#xD;
         10. History and/or current conditions of bleeding tendency.&#xD;
&#xD;
         11. History of thrombocytopenia, including heparin-induced (by anamnesis).&#xD;
&#xD;
         12. Known history of hypersensitivity to drugs with a chemical structure similar to&#xD;
             enoxaparin sodium (eg. UFH, LMWH) or to pork or lamb products.&#xD;
&#xD;
         13. Females: - during menstruation period&#xD;
&#xD;
               -  Pregnancy or lactation&#xD;
&#xD;
               -  taking hormonal contraception (oral or injection)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Arini Setiawati, Prof, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Clinical Research Supporting Unit, Faculty of Medicine, University of Indonesia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Pharma Metric Labs</name>
      <address>
        <city>Jakarta Pusat</city>
        <state>Jakarta</state>
        <zip>10520</zip>
        <country>Indonesia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Indonesia</country>
  </location_countries>
  <link>
    <url>https://www.ema.europa.eu/en/documents/assessment-report/inhixa-epar-public-assessment-report_en.pdf</url>
    <description>EMA Assessment report for Inhixa (enoxaparin sodium), 2016</description>
  </link>
  <results_reference>
    <citation>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.</citation>
    <PMID>23471071</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>29593380</PMID>
  </results_reference>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>April 9, 2020</study_first_submitted>
  <study_first_submitted_qc>May 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 27, 2020</study_first_posted>
  <last_update_submitted>May 24, 2020</last_update_submitted>
  <last_update_submitted_qc>May 24, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 27, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Indonesia University</investigator_affiliation>
    <investigator_full_name>Prof. Arini Setiawati, PhD</investigator_full_name>
    <investigator_title>Prof, PhD</investigator_title>
  </responsible_party>
  <keyword>pharmacodynamic equivalence</keyword>
  <keyword>anticoagulant</keyword>
  <keyword>antithrombotic</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Enoxaparin</mesh_term>
    <mesh_term>Enoxaparin sodium</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04402762
org study id: CRSU.P.Enox/06.01/11/19
nct id: NCT04402762
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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).
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Randomized, open-label, 2-way cross-over, single-dose study with at least 7 days wash-out period.
primary purpose: Other
masking: None (Open Label)
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)
description: Amax will be measured for anti-FXa activity, anti-FIIa activity and TFPI levels
measure: 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)
description: 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
measure: Adverse events
time frame: From informed consent signature until the study end
description: Adverse Events - total and related (ADRs) and Serious Adverse Events - total and related (SADRs)
arm group label: TR treatment sequence
arm group type: Experimental
description: 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.
arm group label: RT treatment sequence
arm group type: Active Comparator
description: 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.
intervention type: Drug
intervention name: Ovine Enoxaparin
description: 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.
arm group label: RT treatment sequence
arm group label: TR treatment sequence
other name: Ovine Enoxaparin Sodium
other name: Ovine Enoxaparin (Metiska Farma)
intervention type: Drug
intervention name: Enoxaparin Prefilled Syringe [Lovenox]
description: 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.
arm group label: RT treatment sequence
arm group label: TR treatment sequence
other name: Active comparator
criteria: 
gender: All
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Arini Setiawati, Prof, PhD
role: Principal Investigator
affiliation: Clinical Research Supporting Unit, Faculty of Medicine, University of Indonesia
facility: 
country: Indonesia
url: https://www.ema.europa.eu/en/documents/assessment-report/inhixa-epar-public-assessment-report_en.pdf
description: EMA Assessment report for Inhixa (enoxaparin sodium), 2016
citation: 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.
PMID: 23471071
citation: 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.
PMID: 29593380
responsible party type: Principal Investigator
investigator affiliation: Indonesia University
investigator full name: Prof. Arini Setiawati, PhD
investigator title: Prof, PhD
mesh term: Enoxaparin
mesh term: Enoxaparin sodium
sharing ipd: No