<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/NCT03273088</url>
  </required_header>
  <id_info>
    <org_study_id>ARY.ETA.AJ.PH1.2016</org_study_id>
    <nct_id>NCT03273088</nct_id>
  </id_info>
  <brief_title>Pharmacokinetic, Safety and Tolerability Study of Altebrel in Healthy Male Subjects</brief_title>
  <official_title>A Randomised, Two-period, Two-sequence, Single-dose and Cross-over Study in Healthy Subjects to Demonstrate Pharmacokinetic Equivalence of Altebrel (Produced by Aryogen Pharmed) and Enbrel® (the Reference Drug, Produced by Amgen Company)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AryoGen Pharmed Co.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>AryoGen Pharmed Co.</source>
  <oversight_info>
    <has_dmc>No</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 aims to demonstrate pharmacokinetic (PK) similarity of biosimilar candidate&#xD;
      Altebrel relative to etanercept reference product (Enbrel®) and evaluate safety and&#xD;
      tolerability of Altebrel, in a crossover fashion in healthy male volunteers after&#xD;
      administration of a single dose (25 mg) of etanercept.&#xD;
&#xD;
      The primary objective of this study is to demonstrate that the PK of Altebrel is similar to&#xD;
      its originator, Enbrel®, as assessed by the area under the serum concentration time curve&#xD;
      (AUC) from time 0 extrapolated to infinity (AUCinf) and the Cmax.&#xD;
&#xD;
      The secondary objectives of the study are:&#xD;
&#xD;
      To further compare the PK of Altebrel and Enbrel®. To assess the safety of Altebrel.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a single-dose trial with one administration of each product (Altebrel and Enbrel®).&#xD;
      Each subject participates in two treatment period, and are randomised to receive Altebrel or&#xD;
      Enbrel® in a crossover fashion. The subjects are closely monitored during the following 24&#xD;
      hours (h), and are allowed to leave the site in the next morning post evaluation and blood&#xD;
      samples are collected prior to and at the following time points after the dose: 6, 12 and 24&#xD;
      hours post-dose (on day 2). The subjects are requested to visit the trial site 36, 48, 60,&#xD;
      72, 96, 120, 144, 168, 216, 312 and 480 h after dose administration for blood sampling and&#xD;
      evaluation of safety variable and tolerability.&#xD;
&#xD;
      Before initiation, the trial is reviewed by food and drug administration of Iran. The&#xD;
      protocol, electronic case report form (eCRF), information for subjects and informed consent&#xD;
      form are submitted to the ethics committees responsible for review and approval purposes,&#xD;
      according to national regulatory guidelines.&#xD;
&#xD;
      In this study, no subject is recruited without an informed consent. All the informed consent&#xD;
      forms which are signed by the subjects have two copies so that subjects could receive a copy&#xD;
      of it.&#xD;
&#xD;
      This is a crossover trial with a single dose of Altebrel and Enbrel®, separated by 28 days.&#xD;
      34 (group A=17, group B=17) eligible subjects have been planned to enter to the study. All of&#xD;
      whom are aged between 18 and 55 years. Subjects' randomization is done, using permuted block&#xD;
      and subjects are assigned to treatment sequences AB or BA. Both groups receive 25 mg of&#xD;
      either of the drugs as a single subcutaneous injection. The injection method and prefilled&#xD;
      syringes are totally the same in both groups. The primary objective of this study is to&#xD;
      demonstrate that the PK of Altebrel is similar to its originator, Enbrel®, as assessed by the&#xD;
      area under the serum concentration time curve (AUC) from time 0 extrapolated to infinity&#xD;
      (AUCinf) and the Cmax. Secondary objectives include assessment of the time to Cmax (tmax),&#xD;
      AUC from time 0 to the last quantifiable concentration (AUClast) of Altebrel compared with&#xD;
      Enbrel®, as well as evaluation of safety and tolerability. The safety endpoints of the trial&#xD;
      are to evaluate the incidence of reported adverse effects, detecting changes in vital signs,&#xD;
      clinical laboratory tests (hematologic, biochemistry, urine analysis and urine culture tests)&#xD;
      and ECG.&#xD;
&#xD;
      Determination of sample size:&#xD;
&#xD;
      In an equivalence test of means using two one-sided tests on data from a two-period&#xD;
      cross-over design, a total sample size of 34 achieves 81% power at a 10% significance level&#xD;
      when the true ratio of the means is 1/0000, the coefficient of variation on the original,&#xD;
      unlogged scale is 0/3600, and the equivalence limits of the mean ratio are 0/8000 and 1/2500.&#xD;
&#xD;
      DATA QUALITY ASSURANCE:&#xD;
&#xD;
      AryoGen pharmed Company conducts clinical trials according to procedures that incorporate the&#xD;
      ethical principles of GCP. Accurate and reliable data collection was assured by verification&#xD;
      and cross-check of the eCRFs against the subject's records by clinical monitors (source&#xD;
      document verification was performed), and the maintenance of a drug-dispensing log by the&#xD;
      center. A comprehensive validation check program was used to verify the data, and discrepancy&#xD;
      reports were generated accordingly for resolution by the investigator.&#xD;
&#xD;
      Blinding:&#xD;
&#xD;
      This is a double-blind trial. During the clinical phase of the trial, neither the subjects&#xD;
      nor the site personnel are aware of the identity (Altebrel and Enbrel®) of the treatments&#xD;
      administered. However, there is an unblinded person who receives the randomisation list and&#xD;
      dispenses the trial drugs according to the list. The unblinded person is not otherwise&#xD;
      participate in the execution of the trial. The randomisation list determines the dispensing&#xD;
      order of the trial products for each subject and only the randomisation number appear on the&#xD;
      sample collection logs, as well as, on the sample aliquots delivered to the bioanalytical&#xD;
      laboratory. Thus, the personnel responsible for analysing the PK samples are also be blinded.&#xD;
&#xD;
      Randomisation envelopes are stored in the ISF, in a locked cabinet. In a case of emergency,&#xD;
      the code of an individual subject may be opened and the reasons for opening will be&#xD;
      documented and the subject will be discontinued from the trial&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 4, 2016</start_date>
  <completion_date type="Actual">March 15, 2017</completion_date>
  <primary_completion_date type="Actual">March 15, 2017</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>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area under the concentration-time curve from time zero to infinity (AUCinf)</measure>
    <time_frame>21 days</time_frame>
    <description>AUCinf will be calculated using the equation:AUCinf= AUClast + (Clast / Kel)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum serum concentration (Cmax)</measure>
    <time_frame>21 days</time_frame>
    <description>It is obtained directly from the observed concentration-time data</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Area under the concentration-time curve from time zero to the last quantifiable concentration (AUClast)</measure>
    <time_frame>21 days</time_frame>
    <description>It is calculated using the linear trapezoidal rule</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Cmax (Tmax)</measure>
    <time_frame>21 days</time_frame>
    <description>It is obtained directly from the observed concentration-time data</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Phase 1</condition>
  <condition>Bioequivalence</condition>
  <arm_group>
    <arm_group_label>AryoGen Pharmed etanercept</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Altebrel (etanercept prefilled syringe produced by AryoGen Pharmed Company) 25mg/0.5ml in prefilled syringe.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pfizer etanercept</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Enbrel® (etanercept prefilled syringe produced by Pfizer Company) 25mg/0.5ml in prefilled syringe.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Etanercept</intervention_name>
    <description>A single dose of etanercept (25mg/0.5ml prefilled syringe) was administered subcutaneously to healthy subjects.</description>
    <arm_group_label>AryoGen Pharmed etanercept</arm_group_label>
    <arm_group_label>Pfizer etanercept</arm_group_label>
    <other_name>Altebrel</other_name>
    <other_name>Enbrel</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Provide written IC to participate in the trial and to comply with the trial&#xD;
             procedures.&#xD;
&#xD;
             2) Take written informed consent to participate in the trial and to abide by the trial&#xD;
             restrictions.&#xD;
&#xD;
             3) Be healthy male between the ages of 18 and 55 years. Healthy is defined as no&#xD;
             clinically relevant abnormalities identified by a detailed medical history, complete&#xD;
             physical examination including blood pressure and heart rate measurement, 12 lead ECG&#xD;
             and clinical laboratory tests.&#xD;
&#xD;
             4) Have a body mass index between 20.0 and 29.9kg/m², inclusive 5) Have Chest X ray&#xD;
             with no evidence of current, active TB or previous (inactive) TB, general infections,&#xD;
             heart failure, malignancy, or other clinically significant abnormalities taken at&#xD;
             Screening or within 24 weeks prior to Day 1 and read by a qualified radiologist&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Being doubtful about their availability to complete the trial.&#xD;
&#xD;
          2. history and/or current presence of clinical significant atopic allergy,&#xD;
             hypersensitivity or allergic reactions, also including known or suspected clinically&#xD;
             relevant drug hypersensitivity to any components of the test and reference IMP&#xD;
             formulation or comparable drugs.&#xD;
&#xD;
          3. Active or latent Tuberculosis or who have a history of Tuberculosis.&#xD;
&#xD;
          4. history of invasive systemic fungal infections or other opportunistic infections&#xD;
&#xD;
          5. systemic or local infection, a known risk for developing sepsis and/or known active&#xD;
             inflammatory process&#xD;
&#xD;
          6. serious infection associated with hospitalisation and/or which required intravenous&#xD;
             antibiotics&#xD;
&#xD;
          7. history of and/or current cardiac disease&#xD;
&#xD;
          8. Have received live vaccine(s) within 30 days prior to Screening or who will require&#xD;
             live vaccine(s) between Screening and the final study visit.&#xD;
&#xD;
          9. Intake medication with a half-life &gt; 24 h within 1 month or 5 half-lives of the&#xD;
             medication prior to the first administration of IMP.&#xD;
&#xD;
         10. Positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody. A&#xD;
             positive test for HIV antibody.&#xD;
&#xD;
         11. History of CNS demyelinating disorders in family (MS)&#xD;
&#xD;
         12. Have a history of smoking &gt;10 cigarettes per day&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Orchidpharmed PK/PD site</name>
      <address>
        <city>Tehrān</city>
        <state>Tehran</state>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Iran, Islamic Republic of</country>
  </location_countries>
  <reference>
    <citation>Lee YJ, Shin D, Kim Y, Kang J, Gauliard A, Fuhr R. A randomized phase l pharmacokinetic study comparing SB4 and etanercept reference product (Enbrel(R)) in healthy subjects. Br J Clin Pharmacol. 2016 Jul;82(1):64-73. doi: 10.1111/bcp.12929. Epub 2016 May 2.</citation>
    <PMID>26972584</PMID>
  </reference>
  <reference>
    <citation>Yi S, Kim SE, Park MK, Yoon SH, Cho JY, Lim KS, Shin SG, Jang IJ, Yu KS. Comparative pharmacokinetics of HD203, a biosimilar of etanercept, with marketed etanercept (Enbrel(R)): a double-blind, single-dose, crossover study in healthy volunteers. BioDrugs. 2012 Jun 1;26(3):177-84. doi: 10.2165/11631860-000000000-00000.</citation>
    <PMID>22515513</PMID>
  </reference>
  <reference>
    <citation>Davatchi F, Jamshidi AR, Banihashemi AT, Gholami J, Forouzanfar MH, Akhlaghi M, Barghamdi M, Noorolahzadeh E, Khabazi AR, Salesi M, Salari AH, Karimifar M, Essalat-Manesh K, Hajialiloo M, Soroosh M, Farzad F, Moussavi HR, Samadi F, Ghaznavi K, Asgharifard H, Zangiabadi AH, Shahram F, Nadji A, Akbarian M, Gharibdoost F. WHO-ILAR COPCORD Study (Stage 1, Urban Study) in Iran. J Rheumatol. 2008 Jul;35(7):1384. Epub 2008 May 1.</citation>
    <PMID>18464299</PMID>
  </reference>
  <reference>
    <citation>Kawai S, Sekino H, Yamashita N, Tsuchiwata S, Liu H, Korth-Bradley JM. The comparability of etanercept pharmacokinetics in healthy Japanese and American subjects. J Clin Pharmacol. 2006 Apr;46(4):418-23. doi: 10.1177/0091270006286435.</citation>
    <PMID>16554449</PMID>
  </reference>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>September 2, 2017</study_first_submitted>
  <study_first_submitted_qc>September 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 6, 2017</study_first_posted>
  <last_update_submitted>September 18, 2018</last_update_submitted>
  <last_update_submitted_qc>September 18, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">September 19, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>healthy subjects</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>etanercept</keyword>
  <keyword>single dose</keyword>
  <keyword>Anti-Inflammatory Agents, Non-Steroidal</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Etanercept</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/NCT03273088
org study id: ARY.ETA.AJ.PH1.2016
nct id: NCT03273088
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study aims to demonstrate pharmacokinetic (PK) similarity of biosimilar candidate
      Altebrel relative to etanercept reference product (Enbrel®) and evaluate safety and
      tolerability of Altebrel, in a crossover fashion in healthy male volunteers after
      administration of a single dose (25 mg) of etanercept.

      The primary objective of this study is to demonstrate that the PK of Altebrel is similar to
      its originator, Enbrel®, as assessed by the area under the serum concentration time curve
      (AUC) from time 0 extrapolated to infinity (AUCinf) and the Cmax.

      The secondary objectives of the study are:

      To further compare the PK of Altebrel and Enbrel®. To assess the safety of Altebrel.
This is a single-dose trial with one administration of each product (Altebrel and Enbrel®).
      Each subject participates in two treatment period, and are randomised to receive Altebrel or
      Enbrel® in a crossover fashion. The subjects are closely monitored during the following 24
      hours (h), and are allowed to leave the site in the next morning post evaluation and blood
      samples are collected prior to and at the following time points after the dose: 6, 12 and 24
      hours post-dose (on day 2). The subjects are requested to visit the trial site 36, 48, 60,
      72, 96, 120, 144, 168, 216, 312 and 480 h after dose administration for blood sampling and
      evaluation of safety variable and tolerability.

      Before initiation, the trial is reviewed by food and drug administration of Iran. The
      protocol, electronic case report form (eCRF), information for subjects and informed consent
      form are submitted to the ethics committees responsible for review and approval purposes,
      according to national regulatory guidelines.

      In this study, no subject is recruited without an informed consent. All the informed consent
      forms which are signed by the subjects have two copies so that subjects could receive a copy
      of it.

      This is a crossover trial with a single dose of Altebrel and Enbrel®, separated by 28 days.
      34 (group A=17, group B=17) eligible subjects have been planned to enter to the study. All of
      whom are aged between 18 and 55 years. Subjects' randomization is done, using permuted block
      and subjects are assigned to treatment sequences AB or BA. Both groups receive 25 mg of
      either of the drugs as a single subcutaneous injection. The injection method and prefilled
      syringes are totally the same in both groups. The primary objective of this study is to
      demonstrate that the PK of Altebrel is similar to its originator, Enbrel®, as assessed by the
      area under the serum concentration time curve (AUC) from time 0 extrapolated to infinity
      (AUCinf) and the Cmax. Secondary objectives include assessment of the time to Cmax (tmax),
      AUC from time 0 to the last quantifiable concentration (AUClast) of Altebrel compared with
      Enbrel®, as well as evaluation of safety and tolerability. The safety endpoints of the trial
      are to evaluate the incidence of reported adverse effects, detecting changes in vital signs,
      clinical laboratory tests (hematologic, biochemistry, urine analysis and urine culture tests)
      and ECG.

      Determination of sample size:

      In an equivalence test of means using two one-sided tests on data from a two-period
      cross-over design, a total sample size of 34 achieves 81% power at a 10% significance level
      when the true ratio of the means is 1/0000, the coefficient of variation on the original,
      unlogged scale is 0/3600, and the equivalence limits of the mean ratio are 0/8000 and 1/2500.

      DATA QUALITY ASSURANCE:

      AryoGen pharmed Company conducts clinical trials according to procedures that incorporate the
      ethical principles of GCP. Accurate and reliable data collection was assured by verification
      and cross-check of the eCRFs against the subject's records by clinical monitors (source
      document verification was performed), and the maintenance of a drug-dispensing log by the
      center. A comprehensive validation check program was used to verify the data, and discrepancy
      reports were generated accordingly for resolution by the investigator.

      Blinding:

      This is a double-blind trial. During the clinical phase of the trial, neither the subjects
      nor the site personnel are aware of the identity (Altebrel and Enbrel®) of the treatments
      administered. However, there is an unblinded person who receives the randomisation list and
      dispenses the trial drugs according to the list. The unblinded person is not otherwise
      participate in the execution of the trial. The randomisation list determines the dispensing
      order of the trial products for each subject and only the randomisation number appear on the
      sample collection logs, as well as, on the sample aliquots delivered to the bioanalytical
      laboratory. Thus, the personnel responsible for analysing the PK samples are also be blinded.

      Randomisation envelopes are stored in the ISF, in a locked cabinet. In a case of emergency,
      the code of an individual subject may be opened and the reasons for opening will be
      documented and the subject will be discontinued from the trial
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Area under the concentration-time curve from time zero to infinity (AUCinf)
time frame: 21 days
description: AUCinf will be calculated using the equation:AUCinf= AUClast + (Clast / Kel)
measure: Maximum serum concentration (Cmax)
time frame: 21 days
description: It is obtained directly from the observed concentration-time data
measure: Area under the concentration-time curve from time zero to the last quantifiable concentration (AUClast)
time frame: 21 days
description: It is calculated using the linear trapezoidal rule
measure: Time to Cmax (Tmax)
time frame: 21 days
description: It is obtained directly from the observed concentration-time data
arm group label: AryoGen Pharmed etanercept
arm group type: Experimental
description: Altebrel (etanercept prefilled syringe produced by AryoGen Pharmed Company) 25mg/0.5ml in prefilled syringe.
arm group label: Pfizer etanercept
arm group type: Active Comparator
description: Enbrel® (etanercept prefilled syringe produced by Pfizer Company) 25mg/0.5ml in prefilled syringe.
intervention type: Drug
intervention name: Etanercept
description: A single dose of etanercept (25mg/0.5ml prefilled syringe) was administered subcutaneously to healthy subjects.
arm group label: AryoGen Pharmed etanercept
arm group label: Pfizer etanercept
other name: Altebrel
other name: Enbrel
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Iran, Islamic Republic of
citation: Lee YJ, Shin D, Kim Y, Kang J, Gauliard A, Fuhr R. A randomized phase l pharmacokinetic study comparing SB4 and etanercept reference product (Enbrel(R)) in healthy subjects. Br J Clin Pharmacol. 2016 Jul;82(1):64-73. doi: 10.1111/bcp.12929. Epub 2016 May 2.
PMID: 26972584
citation: Yi S, Kim SE, Park MK, Yoon SH, Cho JY, Lim KS, Shin SG, Jang IJ, Yu KS. Comparative pharmacokinetics of HD203, a biosimilar of etanercept, with marketed etanercept (Enbrel(R)): a double-blind, single-dose, crossover study in healthy volunteers. BioDrugs. 2012 Jun 1;26(3):177-84. doi: 10.2165/11631860-000000000-00000.
PMID: 22515513
citation: Davatchi F, Jamshidi AR, Banihashemi AT, Gholami J, Forouzanfar MH, Akhlaghi M, Barghamdi M, Noorolahzadeh E, Khabazi AR, Salesi M, Salari AH, Karimifar M, Essalat-Manesh K, Hajialiloo M, Soroosh M, Farzad F, Moussavi HR, Samadi F, Ghaznavi K, Asgharifard H, Zangiabadi AH, Shahram F, Nadji A, Akbarian M, Gharibdoost F. WHO-ILAR COPCORD Study (Stage 1, Urban Study) in Iran. J Rheumatol. 2008 Jul;35(7):1384. Epub 2008 May 1.
PMID: 18464299
citation: Kawai S, Sekino H, Yamashita N, Tsuchiwata S, Liu H, Korth-Bradley JM. The comparability of etanercept pharmacokinetics in healthy Japanese and American subjects. J Clin Pharmacol. 2006 Apr;46(4):418-23. doi: 10.1177/0091270006286435.
PMID: 16554449
responsible party type: Sponsor
mesh term: Etanercept
sharing ipd: No