<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/NCT03822884</url>
  </required_header>
  <id_info>
    <org_study_id>HMX.1.003</org_study_id>
    <nct_id>NCT03822884</nct_id>
  </id_info>
  <brief_title>Pharmacokinetic/Pharmacodynamic Study of 3 Subcutaneous Single Dose Epoetin Alfa Formulations in Healthy Volunteers</brief_title>
  <official_title>Pharmacokinetic/Pharmacodynamic Study of 3 Subcutaneous Single Dose Epoetin Alfa Formulations in Healthy Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bio Sidus SA</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Bio Sidus SA</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Pharmacokinetic/Pharmacodynamic Study of 3 Epoetin Alfa Formulations in Single Subcutaneous&#xD;
      Doses Administered to Healthy Volunteers&#xD;
&#xD;
      SPONSOR Biosidus S.A.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      TITLE&#xD;
&#xD;
      Pharmacokinetic/ Pharmacodynamic Study of 3 Epoetin Alfa Formulations in Single Subcutaneous&#xD;
      Doses Administered to Healthy Volunteers&#xD;
&#xD;
      SPONSOR&#xD;
&#xD;
      Biosidus S.A.&#xD;
&#xD;
      PRINCIPAL INVESTIGATOR&#xD;
&#xD;
      Guillermo Di Girolamo, M.D., National License No. 56857, domiciled at Congreso 3137 (Calle&#xD;
      75), San Andrés (1651), Telephone/Fax: 4753 - 8211, e - mail: gdigirolamo@arnet.com.ar&#xD;
&#xD;
      CO-INVESTIGATORS&#xD;
&#xD;
      Guillermo Alberto Keller, M.D., National License No.106.860, domiciled at Murgiondo 376,&#xD;
      CABA. Cell Phone: 1563615376 - e-mail: drguillermokeller@yahoo.com.ar&#xD;
&#xD;
      Paola Czerniuk, M.D., National License No. 84280, domiciled at Paraguay 3559, Piso 6, Dto A,&#xD;
      CABA. Cell Phone 1550189563, e - mail: pczerniuk@intramed.net.ar SITE Centro de Medicina&#xD;
      Integral S.R.L. - Address: Avenida Belgrano 1844, CABA (C1094) - Telephone: (011) 4383 - 5145&#xD;
&#xD;
      LABORATORY&#xD;
&#xD;
      Laboratorio de Calidad de Biosidus SA - Constitución 4234 (C1254ABX) Buenos Aires, Argentina&#xD;
      - Tel. 4909 8000 - Fax 4909 8055&#xD;
&#xD;
      OBJECTIVES&#xD;
&#xD;
      Primary: To compare the pharmacokinetic and pharmacodynamic behavior of three formulations of&#xD;
      epoetin alfa after subcutaneous administration of 40,000 UI:&#xD;
&#xD;
        -  Erypo ® 40,000 UI, liquid without albumin, prefilled syringe, produced by Janssen -&#xD;
           Cilag GmbH (Reference Formulation, &quot;R&quot;)&#xD;
&#xD;
        -  Hemax® 40,000 UI, lyophilized with albumin, vial, produced by Biosidus SA (Test&#xD;
           Formulation Number 1, &quot;T1&quot;)&#xD;
&#xD;
        -  Hemax® PFS 40,000 UI, liquid without albumin, prefilled syringe, produced by Biosidus SA&#xD;
           (Test Formulation Number 2, &quot;T2&quot;)&#xD;
&#xD;
      Secondary: To assess the pharmacological action, through quantification of blood&#xD;
      reticulocytes at different time points as a surrogate pharmacodynamic marker. Assessment of&#xD;
      adverse effects and tolerance.&#xD;
&#xD;
      TRIAL DESIGN&#xD;
&#xD;
      Open, randomized, 3 - arm, cross - over, sequential, and balanced&#xD;
&#xD;
      DISCONTINUATION SCHEME&#xD;
&#xD;
      The sponsor and the investigators can independently discontinue the study at any time if&#xD;
      there is a mere possibility of or in case of occurrence of a serious adverse effect or&#xD;
      situation that might affect the volunteer's health. If the Hb exceeds 18 g/ dl confirmed by&#xD;
      repetition of the analysis at the pre - dose control in each phase, the volunteer will be&#xD;
      excluded and 1 unit of blood will be collected. If, after the procedure, it is still above 18&#xD;
      g/ dl, another 0.5 or 1 Unit of blood will be collected, based on medical judgment.&#xD;
&#xD;
      NUMBER OF VOLUNTEERS&#xD;
&#xD;
      24 (twenty - four) at first. Since it is a sequential design, if the statistical analysis of&#xD;
      the first 24 volunteers does not show biosimilarity, 12 additional volunteers will be&#xD;
      included up to a total of 36 (thirty - six) volunteers.&#xD;
&#xD;
      DURATION OF THE STUDY&#xD;
&#xD;
      3 months&#xD;
&#xD;
      Selection and recruitment period: 2 (two) months&#xD;
&#xD;
      TIME THE STUDY WILL TAKE&#xD;
&#xD;
      Visit I: Selecting volunteers, obtaining informed consents, performing baseline tests.&#xD;
&#xD;
      Visits II, III, and IV: They will consist of 3 hospitalization phases -one for subcutaneous&#xD;
      administration of Test Formulation Number 1 (T1), another for subcutaneous administration of&#xD;
      Test Formulation Number 2 (T2), and a third one for subcutaneous administration of Reference&#xD;
      Formulation (R), with a washout period of no fewer than 28 days between phases.&#xD;
&#xD;
      Sampling times for erythropoietin quantification in each phase, carried out by Biosidus SA,&#xD;
      will be: pre - dose and 1, 2, 4, 6, 7, 8, 9, 10, 11, 12, 15, 24, 48, 72, 96, and 120 hours&#xD;
      post - dose.&#xD;
&#xD;
      Telephone contact: The Principal Investigator or the healthcare staff assigned by the&#xD;
      Principal Investigator will contact the volunteer by phone after the volunteer's discharge&#xD;
      until the last (120 - hour) outpatient collection in order to ask about tolerance to the&#xD;
      medication and presence of adverse effects.&#xD;
&#xD;
      Blood samples will be collected for red blood cell, Hb, and reticulocyte counting using flow&#xD;
      cytometry performed by Biosidus SA, as an erythropoietin surrogate pharmacodynamic marker at&#xD;
      the following time points: pre - dose (0 hours), 24, 48, 72, 96, 120, and 240 hours.&#xD;
&#xD;
      Another blood sample will be collected for red blood cell and Hb count after 504 hours (21&#xD;
      days after the dose), 7 days before starting the next treatment cycle, in order to determine&#xD;
      whether the volunteer complies with one of the inclusion criteria for the next phase, i.e.&#xD;
      not exceeding 18 g/ dl of Hg.&#xD;
&#xD;
      DOSE / ROUTE / REGIME / OF THE INVESTIGATION PRODUCTS&#xD;
&#xD;
      Single 40,000 UI dose of epoetin alfa. The following formulations will be assessed after&#xD;
      administering 1 subcutaneous injection on the arm:&#xD;
&#xD;
        -  Erypo ® 40,000 UI, liquid without albumin, prefilled syringe, produced by Janssen -&#xD;
           Cilag GmbH (Reference Formulation, &quot;R&quot;)&#xD;
&#xD;
        -  Hemax® 40,000 UI, lyophilized with albumin, vial, produced by Biosidus SA (Test&#xD;
           Formulation Number 1, &quot;T1&quot;)&#xD;
&#xD;
        -  Hemax® PFS 40,000 UI, liquid without albumin, prefilled syringe, produced by Biosidus SA&#xD;
           (Test Formulation Number 2, &quot;T2&quot;)&#xD;
&#xD;
      There will be 6 randomly assigned sequences:&#xD;
&#xD;
        1. R - T1 - T2&#xD;
&#xD;
        2. R - T2 - T1&#xD;
&#xD;
        3. T1 - R - T2&#xD;
&#xD;
        4. T1 - T2 - R&#xD;
&#xD;
        5. T2 - R - T1&#xD;
&#xD;
        6. T2 - T1 - R&#xD;
&#xD;
      COMPARISON DRUG&#xD;
&#xD;
      Erypo ® 40,000 UI, liquid without albumin, prefilled syringe, produced by Janssen - Cilag&#xD;
      GmbH (Reference Formulation, &quot;R&quot;)&#xD;
&#xD;
      COMPARATIVE PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENT BETWEEN THE FORMULATIONS&#xD;
&#xD;
      Based on the erythropoietin serum concentration results, at the different sampling times, the&#xD;
      following variables will be calculated:&#xD;
&#xD;
        -  AUC0 - 120h: Area under the serum concentration - time curve 0 - 120 h.&#xD;
&#xD;
        -  AUC0 - ∞: Area under the serum concentration - time curve from time 0 extrapolated to&#xD;
           infinity (∞).&#xD;
&#xD;
        -  Cmax: Maximum serum concentration of erythropoietin.&#xD;
&#xD;
        -  Cmin: Minimum serum concentration of erythropoietin.&#xD;
&#xD;
        -  Tmax: Time to maximum serum concentration of erythropoietin.&#xD;
&#xD;
      The difference between Tmax times in each test formulations and the reference formulation&#xD;
      will be assessed, and the elimination rate constant and half - life of the drug in the body&#xD;
      will be calculated.&#xD;
&#xD;
      The average results for each formulation will be presented, as well as each volunteer's&#xD;
      individual results.&#xD;
&#xD;
      STATISTICAL ANALYSIS&#xD;
&#xD;
      CALCULATION OF THE SAMPLE SIZE:&#xD;
&#xD;
      The size of the sample (n:24) was established based on literature data and information from&#xD;
      absolute and relative bioavailability studies performed with the drug before by Biosidus SA.&#xD;
      Since it is a sequential design, if the statistical analysis of the first 24 volunteers does&#xD;
      not show biosimilarity, 12 additional volunteers will be included up to a total of 36 (thirty&#xD;
      - six) volunteers.&#xD;
&#xD;
      ANALYSIS PLAN&#xD;
&#xD;
      COMPARATIVE PHARMACOKINETIC ANALYSIS BETWEEN FORMULATIONS&#xD;
&#xD;
        -  AUCT / AUCR: Quotient between the area under the curve of the TEST formulation and the&#xD;
           area under the curve of the REFERENCE. For the log transformation, the 90% confidence&#xD;
           interval of the AUC ratio (for AUC0 - 120h and AUC0 - ∞) should be within the range of&#xD;
           0.80 - 1.25.&#xD;
&#xD;
        -  CmaxT / CmaxR: Quotient between the Cmax of the Test formulation and the Cmax of the&#xD;
           Reference. For the log transformation, the 90% confidence interval of the Cmax ratio&#xD;
           should be within the range of 0.80 - 1.25.&#xD;
&#xD;
      COMPARATIVE PHARMACODYNAMIC ANALYSIS BETWEEN THE FORMULATIONS&#xD;
&#xD;
        -  Maximum number of reticulocytesT / Maximum number of reticulocytesR: Quotient between&#xD;
           the maximum number of reticulocytes in the Test formulation and the maximum number of&#xD;
           reticulocytes in the Reference.&#xD;
&#xD;
      Using ANOVA, the possible differences between subjects, treatments, and periods will be&#xD;
      analyzed.&#xD;
&#xD;
      Outliers: In order to determine possible outliers, a selective - statistical method will be&#xD;
      applied.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2016</start_date>
  <completion_date type="Actual">December 2016</completion_date>
  <primary_completion_date type="Actual">September 2016</primary_completion_date>
  <phase>Phase 1</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>
    <primary_purpose>Other</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>AUC0-t</measure>
    <time_frame>120 h</time_frame>
    <description>AUC0-t: Area under the serum concentration curve from time 0 to time t (in this case, 120 hours).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC0-∞</measure>
    <time_frame>120hr</time_frame>
    <description>AUC0-∞: Area under the serum concentration curve resulting from extrapolation from time 0 to time ∞.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cmax</measure>
    <time_frame>120hr</time_frame>
    <description>Cmax: maximum serum concentration of epoetin alfa.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tmax</measure>
    <time_frame>120hr</time_frame>
    <description>Tmax: time to the maximum serum concentration of epoetin alfa</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Reticulocyte Response: Cmax</measure>
    <time_frame>120hr</time_frame>
    <description>Reticulocyte count by flow cytometry, as a surrogate marker of the pharmacodynamics of erythropoietin. Maximum reticulocyte concentration achieved.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reticulocyte Response: AUC 0-120h</measure>
    <time_frame>120hr</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ADAs</measure>
    <time_frame>120hr</time_frame>
    <description>Number of patients with antidrug antibodies after 3 months. Anti-erythropoietin antibodies screening was done using immunoprecipitation on the sample collected prior to the first dose of the first phase of the trial and on the 504-hour sample of the third phase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>120hr</time_frame>
    <description>Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Anemia</condition>
  <arm_group>
    <arm_group_label>Hemax® PFS 40,000 UI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hemax® 40,000 UI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Erypo ® 40,000 UI</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Epoetin Alfa 40000 UNT/ML</intervention_name>
    <description>40.000 UI subcutaneous single dose</description>
    <arm_group_label>Erypo ® 40,000 UI</arm_group_label>
    <arm_group_label>Hemax® 40,000 UI</arm_group_label>
    <arm_group_label>Hemax® PFS 40,000 UI</arm_group_label>
    <other_name>Hemax</other_name>
    <other_name>Hemax PFS</other_name>
    <other_name>Erypo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        INCLUSION CRITERIA:&#xD;
&#xD;
          1. Subjects of both sexes aged 21 - 55 years old.&#xD;
&#xD;
          2. Baseline Hb levels between 11 and 14 in women and between 12 and 15 g/ dl in men.&#xD;
&#xD;
          3. Body Mass Index (BMI) between 19 and 27 kg/ m2.&#xD;
&#xD;
          4. Volunteers whose additional tests (ECG, blood, and urine), performed before their&#xD;
             inclusion, are within the normal limits and/ or with no clinical significance based on&#xD;
             the investigator's judgment. Women of childbearing potential should have a negative&#xD;
             pregnancy test and use a safe contraceptive method during the study (UID or a&#xD;
             similarly effective method).&#xD;
&#xD;
          5. Subjects with systolic blood pressure higher than 100 mm Hg and lower than 139 mm Hg,&#xD;
             diastolic blood pressure higher than 70 mm Hg and lower than 89 mm H, heart rate&#xD;
             higher than 50 and lower than 90 heartbeats per minute after 5 minutes in sitting&#xD;
             position and then in standing position (extreme values included).&#xD;
&#xD;
          6. Volunteers who are well disposed to the study and have signed the approved informed&#xD;
             consent before the beginning of the study.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          1. History of clinically significant allergies (except untreated asymptomatic seasonal&#xD;
             allergies).&#xD;
&#xD;
          2. Decrease of more than 20 mm Hg in systolic blood pressure or more than 10 mm Hg in&#xD;
             diastolic blood pressure within the first 3 minutes after the change in body position.&#xD;
&#xD;
          3. Volunteers who are or have been taking other drugs (prescription or over - the -&#xD;
             counter) within two weeks before the study.&#xD;
&#xD;
          4. Volunteers with a history of autoimmune diseases.&#xD;
&#xD;
          5. Organic CNS, psychological, or psychiatric disorders: epilepsy, manic - depressive&#xD;
             tendencies, serious depressive episodes, insomnia, changes in personality.&#xD;
&#xD;
          6. Active infections.&#xD;
&#xD;
          7. Having received live or killed virus or bacteria vaccines within a month before&#xD;
             inclusion.&#xD;
&#xD;
          8. Allergic to epoetin alfa or related substances, to human albumin, or any of the&#xD;
             ingredients of the formulations.&#xD;
&#xD;
          9. Previous exposure to recombinant epoetin.&#xD;
&#xD;
         10. Active smoker (more than 10 cigarettes/ day).&#xD;
&#xD;
         11. Current clinical evidence of severe digestive disorders.&#xD;
&#xD;
         12. Current clinical evidence of kidney diseases.&#xD;
&#xD;
         13. Current evidence of liver disorders.&#xD;
&#xD;
         14. Current clinical evidence of respiratory or heart diseases.&#xD;
&#xD;
         15. Diabetes mellitus, thyroid dysfunction, or other endocrine disorders.&#xD;
&#xD;
         16. Evidence of active gastroduodenal disease.&#xD;
&#xD;
         17. History of peripheral thrombotic events.&#xD;
&#xD;
         18. An underlying neurological disorder.&#xD;
&#xD;
         19. Current presence of a malignant disease.&#xD;
&#xD;
         20. History of drug or alcohol abuse or addiction within the past three years.&#xD;
&#xD;
         21. History of drug or alcohol abuse within the past two years.&#xD;
&#xD;
         22. Participation in a clinical study within the past three months.&#xD;
&#xD;
         23. A subject who donated or lost blood within three months before the beginning of the&#xD;
             study, or who intends to donate blood within three months after the end of the study.&#xD;
&#xD;
         24. Heavy drinker of tea, cocoa, mate, coffee, and/ or caffeinated drinks (&gt; 5 cups/ day)&#xD;
             or alcohol (&gt; 50 ml/ day).&#xD;
&#xD;
         25. Electrocardiogram abnormalities.&#xD;
&#xD;
         26. Positive HIV, hepatitis B, or hepatitis C serological testing.&#xD;
&#xD;
         27. Abnormal clinical laboratory results (considered as clinically significant by the&#xD;
             physician).&#xD;
&#xD;
         28. Volunteers who have received oral iron supplements within the last month.&#xD;
&#xD;
         29. If Hb exceeds 18 g/ dl on the 504 - hour control before each treatment phase,&#xD;
             confirmed by repetition of the analysis.&#xD;
&#xD;
         30. Women who do not use an effective contraceptive method (IUD, condom).&#xD;
&#xD;
         31. Pregnancy and breastfeeding.&#xD;
&#xD;
         32. Uncooperative volunteer.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>November 11, 2016</study_first_submitted>
  <study_first_submitted_qc>January 29, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 30, 2019</study_first_posted>
  <results_first_submitted>January 30, 2020</results_first_submitted>
  <results_first_submitted_qc>February 11, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">February 12, 2020</results_first_posted>
  <last_update_submitted>February 11, 2020</last_update_submitted>
  <last_update_submitted_qc>February 11, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 12, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Epoetin Alfa</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Hemax PFS - Hemax - Eprex</title>
          <description>Volunteers in this groups received&#xD;
st Period: 40,000 UI (SC) of Hemax PFS (liquid formulation, without Albumin)&#xD;
nd Period: 40,000 UI (SC) of Hemax (lyophilized)&#xD;
rd Period: 40,000 UI (SC) of Eprex/Erypo (reference rhEPO)</description>
        </group>
        <group group_id="P2">
          <title>Hemax PFS - Eprex - Hemax</title>
          <description>Volunteers in this groups received&#xD;
st Period: 40,000 UI (SC) of Hemax PFS (liquid formulation, without Albumin)&#xD;
nd Period: 40,000 UI (SC) of Eprex/Erypo (reference rhEPO)&#xD;
rd Period: 40,000 UI (SC) of Hemax (lyophilized)</description>
        </group>
        <group group_id="P3">
          <title>Hemax - Hemax PFS - Eprex</title>
          <description>Volunteers in this groups received&#xD;
st Period: 40,000 UI (SC) of Hemax (lyophilized)&#xD;
nd Period: 40,000 UI (SC) of Hemax PFS (liquid formulation, without Albumin)&#xD;
rd Period: 40,000 UI (SC) of Eprex/Erypo (reference rhEPO)</description>
        </group>
        <group group_id="P4">
          <title>Hemax - Eprex - Hemax PFS</title>
          <description>Volunteers in this groups received&#xD;
st Period: 40,000 UI (SC) of Hemax (lyophilized)&#xD;
nd Period: 40,000 UI (SC) of Eprex/Erypo (reference rhEPO)&#xD;
rd Period: 40,000 UI (SC) of Hemax PFS (liquid formulation, without Albumin)</description>
        </group>
        <group group_id="P5">
          <title>Eprex - Hemax PFS - Hemax</title>
          <description>Volunteers in this groups received&#xD;
st Period: 40,000 UI (SC) of Eprex/Erypo (reference rhEPO)&#xD;
nd Period: 40,000 UI (SC) of Hemax PFS (liquid formulation, without Albumin)&#xD;
rd Period: 40,000 UI (SC) of Hemax (lyophilized)</description>
        </group>
        <group group_id="P6">
          <title>Eprex - Hemax - Hemax PFS</title>
          <description>Volunteers in this groups received&#xD;
st Period: 40,000 UI (SC) of Eprex/Erypo (reference rhEPO)&#xD;
nd Period: 40,000 UI (SC) of Hemax (lyophilized)&#xD;
rd Period: 40,000 UI (SC) of Hemax PFS (liquid formulation, without Albumin)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="3"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="1"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="1"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Hemax PFS - Hemax - Eprex</title>
          <description>Volunteers in this groups received&#xD;
st Period: 40,000 UI (SC) of Hemax PFS (liquid formulation, without Albumin)&#xD;
nd Period: 40,000 UI (SC) of Hemax (lyophilized)&#xD;
rd Period: 40,000 UI (SC) of Eprex/Erypo (reference rhEPO)</description>
        </group>
        <group group_id="B2">
          <title>Hemax PFS - Eprex - Hemax</title>
          <description>Volunteers in this groups received&#xD;
st Period: 40,000 UI (SC) of Hemax PFS (liquid formulation, without Albumin)&#xD;
nd Period: 40,000 UI (SC) of Eprex/Erypo (reference rhEPO)&#xD;
rd Period: 40,000 UI (SC) of Hemax (lyophilized)</description>
        </group>
        <group group_id="B3">
          <title>Hemax - Hemax PFS - Eprex</title>
          <description>Volunteers in this groups received&#xD;
st Period: 40,000 UI (SC) of Hemax (lyophilized)&#xD;
nd Period: 40,000 UI (SC) of Hemax PFS (liquid formulation, without Albumin)&#xD;
rd Period: 40,000 UI (SC) of Eprex/Erypo (reference rhEPO)</description>
        </group>
        <group group_id="B4">
          <title>Hemax - Eprex - Hemax PFS</title>
          <description>Volunteers in this groups received&#xD;
st Period: 40,000 UI (SC) of Hemax (lyophilized)&#xD;
nd Period: 40,000 UI (SC) of Eprex/Erypo (reference rhEPO)&#xD;
rd Period: 40,000 UI (SC) of Hemax PFS (liquid formulation, without Albumin)</description>
        </group>
        <group group_id="B5">
          <title>Eprex - Hemax PFS - Hemax</title>
          <description>Volunteers in this groups received&#xD;
st Period: 40,000 UI (SC) of Eprex/Erypo (reference rhEPO)&#xD;
nd Period: 40,000 UI (SC) of Hemax PFS (liquid formulation, without Albumin)&#xD;
rd Period: 40,000 UI (SC) of Hemax (lyophilized)</description>
        </group>
        <group group_id="B6">
          <title>Eprex - Hemax - Hemax PFS</title>
          <description>Volunteers in this groups received&#xD;
st Period: 40,000 UI (SC) of Eprex/Erypo (reference rhEPO)&#xD;
nd Period: 40,000 UI (SC) of Hemax (lyophilized)&#xD;
rd Period: 40,000 UI (SC) of Hemax PFS (liquid formulation, without Albumin)</description>
        </group>
        <group group_id="B7">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="4"/>
            <count group_id="B2" value="4"/>
            <count group_id="B3" value="4"/>
            <count group_id="B4" value="4"/>
            <count group_id="B5" value="4"/>
            <count group_id="B6" value="4"/>
            <count group_id="B7" value="24"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="40.25" spread="12.71"/>
                    <measurement group_id="B2" value="44.25" spread="0.96"/>
                    <measurement group_id="B3" value="41.50" spread="13.77"/>
                    <measurement group_id="B4" value="37.50" spread="8.96"/>
                    <measurement group_id="B5" value="32.25" spread="12.69"/>
                    <measurement group_id="B6" value="41.50" spread="10.66"/>
                    <measurement group_id="B7" value="39.54" spread="10.37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="2"/>
                    <measurement group_id="B7" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="3"/>
                    <measurement group_id="B6" value="2"/>
                    <measurement group_id="B7" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Weight</title>
          <units>kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="76.00" spread="14.02"/>
                    <measurement group_id="B2" value="72.00" spread="8.68"/>
                    <measurement group_id="B3" value="74.00" spread="6.32"/>
                    <measurement group_id="B4" value="74.25" spread="8.73"/>
                    <measurement group_id="B5" value="69.25" spread="11.93"/>
                    <measurement group_id="B6" value="72.00" spread="10.20"/>
                    <measurement group_id="B7" value="72.92" spread="9.36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Height</title>
          <units>cm</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="177.50" spread="15.20"/>
                    <measurement group_id="B2" value="127.25" spread="4.79"/>
                    <measurement group_id="B3" value="173.25" spread="3.95"/>
                    <measurement group_id="B4" value="171.00" spread="13.74"/>
                    <measurement group_id="B5" value="171.00" spread="6.83"/>
                    <measurement group_id="B6" value="170.50" spread="8.54"/>
                    <measurement group_id="B7" value="172.58" spread="9.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Mass Index</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24.01" spread="2.03"/>
                    <measurement group_id="B2" value="24.21" spread="1.63"/>
                    <measurement group_id="B3" value="24.67" spread="2.21"/>
                    <measurement group_id="B4" value="25.44" spread="1.33"/>
                    <measurement group_id="B5" value="23.39" spread="2.29"/>
                    <measurement group_id="B6" value="24.64" spread="1.33"/>
                    <measurement group_id="B7" value="24.39" spread="1.76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>AUC0-t</title>
        <description>AUC0-t: Area under the serum concentration curve from time 0 to time t (in this case, 120 hours).</description>
        <time_frame>120 h</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hemax® PFS 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O2">
            <title>Hemax® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O3">
            <title>Erypo ® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
        </group_list>
        <measure>
          <title>AUC0-t</title>
          <description>AUC0-t: Area under the serum concentration curve from time 0 to time t (in this case, 120 hours).</description>
          <units>mUI*h/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37440.71" spread="16821.67"/>
                    <measurement group_id="O2" value="34483.73" spread="13513.69"/>
                    <measurement group_id="O3" value="41150.49" spread="17095.44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>AUC0-∞</title>
        <description>AUC0-∞: Area under the serum concentration curve resulting from extrapolation from time 0 to time ∞.</description>
        <time_frame>120hr</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hemax® PFS 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O2">
            <title>Hemax® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O3">
            <title>Erypo ® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
        </group_list>
        <measure>
          <title>AUC0-∞</title>
          <description>AUC0-∞: Area under the serum concentration curve resulting from extrapolation from time 0 to time ∞.</description>
          <units>mUI*h/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="42487.04" spread="19533.78"/>
                    <measurement group_id="O2" value="36907.41" spread="14363.66"/>
                    <measurement group_id="O3" value="43978.39" spread="18786.74"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Cmax</title>
        <description>Cmax: maximum serum concentration of epoetin alfa.</description>
        <time_frame>120hr</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hemax® PFS 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O2">
            <title>Hemax® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O3">
            <title>Erypo ® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax</title>
          <description>Cmax: maximum serum concentration of epoetin alfa.</description>
          <units>mUI / ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="853.11" spread="386.49"/>
                    <measurement group_id="O2" value="808.29" spread="338.10"/>
                    <measurement group_id="O3" value="913.07" spread="429.19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Tmax</title>
        <description>Tmax: time to the maximum serum concentration of epoetin alfa</description>
        <time_frame>120hr</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hemax® PFS 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O2">
            <title>Hemax® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O3">
            <title>Erypo ® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
        </group_list>
        <measure>
          <title>Tmax</title>
          <description>Tmax: time to the maximum serum concentration of epoetin alfa</description>
          <units>h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.17" spread="5.53"/>
                    <measurement group_id="O2" value="15.04" spread="5.13"/>
                    <measurement group_id="O3" value="14.96" spread="5.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Reticulocyte Response: Cmax</title>
        <description>Reticulocyte count by flow cytometry, as a surrogate marker of the pharmacodynamics of erythropoietin. Maximum reticulocyte concentration achieved.</description>
        <time_frame>120hr</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hemax® PFS 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O2">
            <title>Hemax® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O3">
            <title>Erypo ® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
        </group_list>
        <measure>
          <title>Reticulocyte Response: Cmax</title>
          <description>Reticulocyte count by flow cytometry, as a surrogate marker of the pharmacodynamics of erythropoietin. Maximum reticulocyte concentration achieved.</description>
          <units>mUI / ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.23" spread="0.46"/>
                    <measurement group_id="O2" value="1.33" spread="0.49"/>
                    <measurement group_id="O3" value="1.31" spread="0.48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Reticulocyte Response: AUC 0-120h</title>
        <time_frame>120hr</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hemax® PFS 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O2">
            <title>Hemax® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O3">
            <title>Erypo ® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
        </group_list>
        <measure>
          <title>Reticulocyte Response: AUC 0-120h</title>
          <units>mUI*h/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="341.65" spread="162.98"/>
                    <measurement group_id="O2" value="344.49" spread="132.89"/>
                    <measurement group_id="O3" value="345.58" spread="150.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>ADAs</title>
        <description>Number of patients with antidrug antibodies after 3 months. Anti-erythropoietin antibodies screening was done using immunoprecipitation on the sample collected prior to the first dose of the first phase of the trial and on the 504-hour sample of the third phase</description>
        <time_frame>120hr</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hemax® PFS 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O2">
            <title>Hemax® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O3">
            <title>Erypo ® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
        </group_list>
        <measure>
          <title>ADAs</title>
          <description>Number of patients with antidrug antibodies after 3 months. Anti-erythropoietin antibodies screening was done using immunoprecipitation on the sample collected prior to the first dose of the first phase of the trial and on the 504-hour sample of the third phase</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
                <count group_id="O3" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Anti-erythropoietin antibodies</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No anti-erythropoietin antibodies detected</title>
                  <measurement_list>
                    <measurement group_id="O1" value="24"/>
                    <measurement group_id="O2" value="24"/>
                    <measurement group_id="O3" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Adverse Events</title>
        <description>Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0</description>
        <time_frame>120hr</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hemax® PFS 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O2">
            <title>Hemax® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
          <group group_id="O3">
            <title>Erypo ® 40,000 UI</title>
            <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
          </group>
        </group_list>
        <measure>
          <title>Adverse Events</title>
          <description>Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
                <count group_id="O3" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Asthenia</title>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Myalgia</title>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Pruritus of trunk</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Generalized myalgia</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Arthralgia</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Dorsal myalgia</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Fracture</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Headache</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Pyrosis</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Vomiting</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Diarrhea</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Nausea</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No adverse events registered</title>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="17"/>
                    <measurement group_id="O3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>The security profile was determined in all 3 periods of drug administration. All the volunteers were planned to received 3 doses of rhEPO. The duration of all clinical phase was 75 days. so, safety information was collected during 75 days.</time_frame>
      <desc>Adverse Event Reporting was conducted according to the regulation 6677/2010 (Section B.7) of the National Regulatory Agency</desc>
      <group_list>
        <group group_id="E1">
          <title>Hemax® PFS 40,000 UI</title>
          <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
        </group>
        <group group_id="E2">
          <title>Hemax® 40,000 UI</title>
          <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
        </group>
        <group group_id="E3">
          <title>Erypo ® 40,000 UI</title>
          <description>Epoetin Alfa 40000 UNT/ML subcutaneous single dose&#xD;
Epoetin Alfa 40000 UNT/ML: 40.000 UI subcutaneous single dose</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>WHO</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Severe low back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>WHO</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Generalized myalgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Dorsal myalgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritus of trunk</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The PI is not allowed to disclose any confidential information of the clinical trial.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Clinical Trial Manager - Dr. Roberto A. Diez</name_or_title>
      <organization>Biosidus S.A.</organization>
      <phone>+5411 4909 8000</phone>
      <email>r.diez@biosidus.com.ar</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03822884
org study id: HMX.1.003
nct id: NCT03822884
lead sponsor: 
has dmc: No
Pharmacokinetic/Pharmacodynamic Study of 3 Epoetin Alfa Formulations in Single Subcutaneous
      Doses Administered to Healthy Volunteers

      SPONSOR Biosidus S.A.
TITLE

      Pharmacokinetic/ Pharmacodynamic Study of 3 Epoetin Alfa Formulations in Single Subcutaneous
      Doses Administered to Healthy Volunteers

      SPONSOR

      Biosidus S.A.

      PRINCIPAL INVESTIGATOR

      Guillermo Di Girolamo, M.D., National License No. 56857, domiciled at Congreso 3137 (Calle
      75), San Andrés (1651), Telephone/Fax: 4753 - 8211, e - mail: gdigirolamo@arnet.com.ar

      CO-INVESTIGATORS

      Guillermo Alberto Keller, M.D., National License No.106.860, domiciled at Murgiondo 376,
      CABA. Cell Phone: 1563615376 - e-mail: drguillermokeller@yahoo.com.ar

      Paola Czerniuk, M.D., National License No. 84280, domiciled at Paraguay 3559, Piso 6, Dto A,
      CABA. Cell Phone 1550189563, e - mail: pczerniuk@intramed.net.ar SITE Centro de Medicina
      Integral S.R.L. - Address: Avenida Belgrano 1844, CABA (C1094) - Telephone: (011) 4383 - 5145

      LABORATORY

      Laboratorio de Calidad de Biosidus SA - Constitución 4234 (C1254ABX) Buenos Aires, Argentina
      - Tel. 4909 8000 - Fax 4909 8055

      OBJECTIVES

      Primary: To compare the pharmacokinetic and pharmacodynamic behavior of three formulations of
      epoetin alfa after subcutaneous administration of 40,000 UI:

        -  Erypo ® 40,000 UI, liquid without albumin, prefilled syringe, produced by Janssen -
           Cilag GmbH (Reference Formulation, "R")

        -  Hemax® 40,000 UI, lyophilized with albumin, vial, produced by Biosidus SA (Test
           Formulation Number 1, "T1")

        -  Hemax® PFS 40,000 UI, liquid without albumin, prefilled syringe, produced by Biosidus SA
           (Test Formulation Number 2, "T2")

      Secondary: To assess the pharmacological action, through quantification of blood
      reticulocytes at different time points as a surrogate pharmacodynamic marker. Assessment of
      adverse effects and tolerance.

      TRIAL DESIGN

      Open, randomized, 3 - arm, cross - over, sequential, and balanced

      DISCONTINUATION SCHEME

      The sponsor and the investigators can independently discontinue the study at any time if
      there is a mere possibility of or in case of occurrence of a serious adverse effect or
      situation that might affect the volunteer's health. If the Hb exceeds 18 g/ dl confirmed by
      repetition of the analysis at the pre - dose control in each phase, the volunteer will be
      excluded and 1 unit of blood will be collected. If, after the procedure, it is still above 18
      g/ dl, another 0.5 or 1 Unit of blood will be collected, based on medical judgment.

      NUMBER OF VOLUNTEERS

      24 (twenty - four) at first. Since it is a sequential design, if the statistical analysis of
      the first 24 volunteers does not show biosimilarity, 12 additional volunteers will be
      included up to a total of 36 (thirty - six) volunteers.

      DURATION OF THE STUDY

      3 months

      Selection and recruitment period: 2 (two) months

      TIME THE STUDY WILL TAKE

      Visit I: Selecting volunteers, obtaining informed consents, performing baseline tests.

      Visits II, III, and IV: They will consist of 3 hospitalization phases -one for subcutaneous
      administration of Test Formulation Number 1 (T1), another for subcutaneous administration of
      Test Formulation Number 2 (T2), and a third one for subcutaneous administration of Reference
      Formulation (R), with a washout period of no fewer than 28 days between phases.

      Sampling times for erythropoietin quantification in each phase, carried out by Biosidus SA,
      will be: pre - dose and 1, 2, 4, 6, 7, 8, 9, 10, 11, 12, 15, 24, 48, 72, 96, and 120 hours
      post - dose.

      Telephone contact: The Principal Investigator or the healthcare staff assigned by the
      Principal Investigator will contact the volunteer by phone after the volunteer's discharge
      until the last (120 - hour) outpatient collection in order to ask about tolerance to the
      medication and presence of adverse effects.

      Blood samples will be collected for red blood cell, Hb, and reticulocyte counting using flow
      cytometry performed by Biosidus SA, as an erythropoietin surrogate pharmacodynamic marker at
      the following time points: pre - dose (0 hours), 24, 48, 72, 96, 120, and 240 hours.

      Another blood sample will be collected for red blood cell and Hb count after 504 hours (21
      days after the dose), 7 days before starting the next treatment cycle, in order to determine
      whether the volunteer complies with one of the inclusion criteria for the next phase, i.e.
      not exceeding 18 g/ dl of Hg.

      DOSE / ROUTE / REGIME / OF THE INVESTIGATION PRODUCTS

      Single 40,000 UI dose of epoetin alfa. The following formulations will be assessed after
      administering 1 subcutaneous injection on the arm:

        -  Erypo ® 40,000 UI, liquid without albumin, prefilled syringe, produced by Janssen -
           Cilag GmbH (Reference Formulation, "R")

        -  Hemax® 40,000 UI, lyophilized with albumin, vial, produced by Biosidus SA (Test
           Formulation Number 1, "T1")

        -  Hemax® PFS 40,000 UI, liquid without albumin, prefilled syringe, produced by Biosidus SA
           (Test Formulation Number 2, "T2")

      There will be 6 randomly assigned sequences:

        1. R - T1 - T2

        2. R - T2 - T1

        3. T1 - R - T2

        4. T1 - T2 - R

        5. T2 - R - T1

        6. T2 - T1 - R

      COMPARISON DRUG

      Erypo ® 40,000 UI, liquid without albumin, prefilled syringe, produced by Janssen - Cilag
      GmbH (Reference Formulation, "R")

      COMPARATIVE PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENT BETWEEN THE FORMULATIONS

      Based on the erythropoietin serum concentration results, at the different sampling times, the
      following variables will be calculated:

        -  AUC0 - 120h: Area under the serum concentration - time curve 0 - 120 h.

        -  AUC0 - ∞: Area under the serum concentration - time curve from time 0 extrapolated to
           infinity (∞).

        -  Cmax: Maximum serum concentration of erythropoietin.

        -  Cmin: Minimum serum concentration of erythropoietin.

        -  Tmax: Time to maximum serum concentration of erythropoietin.

      The difference between Tmax times in each test formulations and the reference formulation
      will be assessed, and the elimination rate constant and half - life of the drug in the body
      will be calculated.

      The average results for each formulation will be presented, as well as each volunteer's
      individual results.

      STATISTICAL ANALYSIS

      CALCULATION OF THE SAMPLE SIZE:

      The size of the sample (n:24) was established based on literature data and information from
      absolute and relative bioavailability studies performed with the drug before by Biosidus SA.
      Since it is a sequential design, if the statistical analysis of the first 24 volunteers does
      not show biosimilarity, 12 additional volunteers will be included up to a total of 36 (thirty
      - six) volunteers.

      ANALYSIS PLAN

      COMPARATIVE PHARMACOKINETIC ANALYSIS BETWEEN FORMULATIONS

        -  AUCT / AUCR: Quotient between the area under the curve of the TEST formulation and the
           area under the curve of the REFERENCE. For the log transformation, the 90% confidence
           interval of the AUC ratio (for AUC0 - 120h and AUC0 - ∞) should be within the range of
           0.80 - 1.25.

        -  CmaxT / CmaxR: Quotient between the Cmax of the Test formulation and the Cmax of the
           Reference. For the log transformation, the 90% confidence interval of the Cmax ratio
           should be within the range of 0.80 - 1.25.

      COMPARATIVE PHARMACODYNAMIC ANALYSIS BETWEEN THE FORMULATIONS

        -  Maximum number of reticulocytesT / Maximum number of reticulocytesR: Quotient between
           the maximum number of reticulocytes in the Test formulation and the maximum number of
           reticulocytes in the Reference.

      Using ANOVA, the possible differences between subjects, treatments, and periods will be
      analyzed.

      Outliers: In order to determine possible outliers, a selective - statistical method will be
      applied.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Other
masking: Single (Outcomes Assessor)
measure: AUC0-t
time frame: 120 h
description: AUC0-t: Area under the serum concentration curve from time 0 to time t (in this case, 120 hours).
measure: AUC0-∞
time frame: 120hr
description: AUC0-∞: Area under the serum concentration curve resulting from extrapolation from time 0 to time ∞.
measure: Cmax
time frame: 120hr
description: Cmax: maximum serum concentration of epoetin alfa.
measure: Tmax
time frame: 120hr
description: Tmax: time to the maximum serum concentration of epoetin alfa
measure: Reticulocyte Response: Cmax
time frame: 120hr
description: Reticulocyte count by flow cytometry, as a surrogate marker of the pharmacodynamics of erythropoietin. Maximum reticulocyte concentration achieved.
measure: Reticulocyte Response: AUC 0-120h
time frame: 120hr
measure: ADAs
time frame: 120hr
description: Number of patients with antidrug antibodies after 3 months. Anti-erythropoietin antibodies screening was done using immunoprecipitation on the sample collected prior to the first dose of the first phase of the trial and on the 504-hour sample of the third phase
measure: Adverse Events
time frame: 120hr
description: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0
arm group label: Hemax® PFS 40,000 UI
arm group type: Experimental
description: Epoetin Alfa 40000 UNT/ML subcutaneous single dose
arm group label: Hemax® 40,000 UI
arm group type: Experimental
description: Epoetin Alfa 40000 UNT/ML subcutaneous single dose
arm group label: Erypo ® 40,000 UI
arm group type: Active Comparator
description: Epoetin Alfa 40000 UNT/ML subcutaneous single dose
intervention type: Drug
intervention name: Epoetin Alfa 40000 UNT/ML
description: 40.000 UI subcutaneous single dose
arm group label: Erypo ® 40,000 UI
arm group label: Hemax® 40,000 UI
arm group label: Hemax® PFS 40,000 UI
other name: Hemax
other name: Hemax PFS
other name: Erypo
criteria: 
gender: All
minimum age: 21 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
responsible party type: Sponsor
mesh term: Epoetin Alfa
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 