<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/NCT04463056</url>
  </required_header>
  <id_info>
    <org_study_id>ECU-PNH-III</org_study_id>
    <secondary_id>#546 eff date 17.10.2017</secondary_id>
    <nct_id>NCT04463056</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of Elizaria® vs. Soliris® in Patients With PNH</brief_title>
  <official_title>A Multicenter, Open Label, Randomized, Parallel-group Study of Efficacy and Safety of Eculizumab (JSC GENERIUM, Russia) vs. Soliris® (Alexion Pharma GmbH, Switzerland) in Patients With Paroxysmal Nocturnal Hemoglobinuria</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AO GENERIUM</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>AO GENERIUM</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>
      It is a multicenter, open-label, randomized, parallel-group study of the efficacy and safety&#xD;
      of Elizaria® (eculizumab, GENERIUM JSC, Russia) versus Soliris® (Alexion Pharma GmbH,&#xD;
      Switzerland) in patients with paroxysmal nocturnal hemoglobinuria.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      After screening, patients meeting all of the inclusion / non-inclusion criteria and&#xD;
      vaccinated against meningococcal infections were divided into two subgroups according to the&#xD;
      eculizumab treatment status (Soliris® naïve patients / patients who had received Soliris® at&#xD;
      a maintenance dose prior to the trial inclusion). Each subgroup included an even number of&#xD;
      patients to maintain recruitment balance. Then, patients of each subgroup were distributed&#xD;
      into one of two treatment groups by the method of stratified block randomization at a 1:1&#xD;
      ratio into groups A and B, respectively. In the first group (Group A), patients received&#xD;
      infusions of Elizaria (eculizumab, GENERIUM JSC), in the second one (Group B) - infusions of&#xD;
      Soliris®.&#xD;
&#xD;
      The duration of participation of each patient in the study, including the screening period,&#xD;
      was about 30 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 29, 2017</start_date>
  <completion_date type="Actual">October 16, 2018</completion_date>
  <primary_completion_date type="Actual">October 16, 2018</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area under the LDH concentration-time curve (LDH AUC) during the maintenance therapy with the test drug or the reference drug</measure>
    <time_frame>week 22</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Area under the LDH concentration-time curve (LDH AUC) during 26-week therapy with the test product or the reference product</measure>
    <time_frame>week 26</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hemoglobin level change during the maintenance therapy with the test drug or the reference drug</measure>
    <time_frame>week 22</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number/proportion of the patients with stable hemoglobin level during the maintenance therapy with the test drug or the reference drug</measure>
    <time_frame>week 22</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number/proportion of patients with various thrombotic complications developing during treatment with the test product or the reference product.</measure>
    <time_frame>week 26</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number/proportion of patients who needed donor red blood cell transfusions during treatment with the test product or the reference product.</measure>
    <time_frame>week 26</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of donor red blood cell transfusions during treatment with the test product or the reference product.</measure>
    <time_frame>week 26</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number/proportion of patients with breakthrough hemolysis</measure>
    <time_frame>week 26</time_frame>
    <description>Breakthrough hemolysis defined as at least one new episode or worsening of at least one previous signs of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, severe vascular complications (including thrombosis), dysphagia or erectile dysfunction) associated with increased LDH after a previous decrease during treatment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Paroxysmal Nocturnal Hemoglobinuria</condition>
  <condition>Marchiafava-Micheli Syndrome</condition>
  <condition>Paroxysmal Hemoglobinuria</condition>
  <arm_group>
    <arm_group_label>Elizaria®</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>International nonproprietary name: eculizumab</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Soliris®</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>International nonproprietary name: eculizumab</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Elizaria®</intervention_name>
    <description>Induction cycle: 600 mg (2 vials of 30 mL, 10 mg/mL) intravenous infusion for 30 minutes once a week for 4 weeks. Maintenance therapy: 900 mg (3 vials of 30 mL, 10 mg/mL) intravenous infusion for 30 minutes in Week 5, followed by 900 mg every 14 days.</description>
    <arm_group_label>Elizaria®</arm_group_label>
    <other_name>eculizumab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Soliris®</intervention_name>
    <description>Induction cycle: 600 mg (2 vials of 30 mL, 10 mg/mL) intravenous infusion for 30 minutes once a week for 4 weeks. Maintenance therapy: 900 mg (3 vials of 30 mL, 10 mg/mL) intravenous infusion for 30 minutes in Week 5, followed by 900 mg every 14 days.</description>
    <arm_group_label>Soliris®</arm_group_label>
    <other_name>eculizumab</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent for participation in the study.&#xD;
&#xD;
          2. Men and women aged 18 to 65 years at the time of signing the Informed Consent Form.&#xD;
&#xD;
          3. Established diagnosis of paroxysmal nocturnal hemoglobinuria (PNH), confirmed by flow&#xD;
             cytometry assessing the PNH red blood cell and white blood cell clone size, with&#xD;
             intravascular hemolysis and current or previous concomitant clinical symptoms,&#xD;
             irrespective of the need for blood transfusions and without signs of other disorders&#xD;
             associated with bone marrow failure.&#xD;
&#xD;
          4. For patients, who have not received Soliris® before inclusion in this study: lactate&#xD;
             dehydrogenase (LDH) level 1.5 times the upper limit of normal or higher as assessed by&#xD;
             the central laboratory.&#xD;
&#xD;
          5. The patients receiving anticoagulants must take them at a stable dose for at least 4&#xD;
             weeks prior to screening. Patients receiving warfarin must have a stable international&#xD;
             normalized ratio (INR) value. To confirm INR value stability, the patients have to&#xD;
             provide a blood INR test at least 4 weeks prior to screening. The second INR&#xD;
             assessment will be performed at the screening visit.&#xD;
&#xD;
          6. Documented vaccination against meningococcal infections (Neisseria meningitidis&#xD;
             serogroups A, C, Y and W-135) the protective immunity of which did not wear off, at&#xD;
             least 14 days prior to the administration of the first dose of the test or reference&#xD;
             drug and the patient's consent for revaccination against meningococcal infections&#xD;
             (Neisseria meningitidis serogroups A, C, Y and W-135) during participation in the&#xD;
             current study if the protection from previous vaccination wears off.&#xD;
&#xD;
          7. Subjects' consent to use reliable contraceptive methods (the combination of at least 2&#xD;
             methods, including barrier contraception, for example, condoms with spermicide) from&#xD;
             signing the Informed Consent Form for up to 10 weeks after stopping therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Hypersensitivity to the test drug, reference drug and their components.&#xD;
&#xD;
          2. Hypersensitivity to the active substance or any other component of the vaccine used to&#xD;
             prevent meningococcal infection or a lifethreatening reaction to a previously&#xD;
             administered vaccine containing similar ingredients.&#xD;
&#xD;
          3. Conditions associated with bone marrow failure and PNH clone (aplastic anemia,&#xD;
             myelodysplastic syndrome, idiopathic myelofibrosis).&#xD;
&#xD;
          4. A history of infections caused by Neisseria meningitides.&#xD;
&#xD;
          5. Active systemic bacterial, viral, or fungal infection within 14 days prior to the&#xD;
             administration of the first dose of the test or reference drug.&#xD;
&#xD;
          6. Fever of 38°С or higher within 7 days prior to the administration of the first dose of&#xD;
             the test or reference drug.&#xD;
&#xD;
          7. Hereditary complement deficiencies.&#xD;
&#xD;
          8. Patients planning to undergo or with a history of bone marrow transplantation.&#xD;
&#xD;
          9. Initial treatment cycle (induction phase) of Soliris®; completed treatment with&#xD;
             Soliris® less than 70 days before study inclusion, not related to the current study&#xD;
             participation.&#xD;
&#xD;
         10. Vaccination with any live vaccine within 1 month prior to the administration of the&#xD;
             first dose of the test or reference drug;&#xD;
&#xD;
         11. Concomitant diseases and conditions which may, in the Investigator's opinion,&#xD;
             compromise the patient's safety in case of participation in the study or which could&#xD;
             affect the safety data analysis in case of an exacerbation of this disease/condition&#xD;
             during the study, including the following:&#xD;
&#xD;
               -  Myocardial infarction or stroke within the last 3 months, severe arrhythmia, NYHA&#xD;
                  functional class III/IV heart failure;&#xD;
&#xD;
               -  Psychiatric disorders;&#xD;
&#xD;
               -  Immune and endocrine disorders which are not controlled with medications&#xD;
                  (including decompensated diabetes mellitus and thyroid disorders);&#xD;
&#xD;
               -  Hematologic disorders requiring chemotherapy;&#xD;
&#xD;
               -  Current or prior oncologic disorders, except for successfully treated basal cell&#xD;
                  carcinoma;&#xD;
&#xD;
               -  Decompensated liver diseases.&#xD;
&#xD;
         12. Acquired immunodeficiency syndrome or human immunodeficiency virus (HIV) infection&#xD;
             confirmed by test results.&#xD;
&#xD;
         13. Active viral hepatitis B and/or C at screening with alanine aminotransferase (ALT)&#xD;
             and/or aspartate aminotransferase (AST) levels 5 times the upper limit of normal or&#xD;
             higher.&#xD;
&#xD;
         14. Positive syphilis test results.&#xD;
&#xD;
         15. Body mass index (BMI) ≤17 kg/m2 or ≥30 kg/m2.&#xD;
&#xD;
         16. Pregnancy or breastfeeding.&#xD;
&#xD;
         17. History of tuberculosis, alcohol addiction, medication abuse, or drug addiction.&#xD;
&#xD;
         18. Patient's participation in any clinical studies and/or using of not approved&#xD;
             medications in the Russian federation within 30 days before screening.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Oksana A. Markova, MD</last_name>
    <role>Study Chair</role>
    <affiliation>AO GENERIUM</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Federal State Budget Funded Institution National Medical Research Center of Hematology, Ministry of Health of the Russian Federation (MoH of Russia)</name>
      <address>
        <city>Moscow</city>
        <zip>125167</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moscow State Budget Funded Healthcare Institution S. P. Botkin City Clinical Hospital, Moscow Department of Healthcare</name>
      <address>
        <city>Moscow</city>
        <zip>125284</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>State Budget Funded Institution of Higher Education Academician I. P. Pavlov Saint-Petersburg State Medical University of the Ministry of Health of the Russian Federation</name>
      <address>
        <city>Saint Petersburg</city>
        <zip>197022</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>State Budgetary Educational Institution of Higher Professional Education Samara State Medical University, Ministry of Health of the Russian Federation.</name>
      <address>
        <city>Samara</city>
        <zip>443079</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Russian Federation</country>
  </location_countries>
  <link>
    <url>https://doi.org/10.1182/blood-2019-125693</url>
    <description>Phase III Clinical Trial of Elizaria® and Soliris® in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria: Results of Comparative Analysis of Efficacy, Safety, and Pharmacological Data</description>
  </link>
  <link>
    <url>https://link.springer.com/article/10.1007/s00277-021-04624-7#citeas</url>
    <description>Kulagin, A.D., Ptushkin, V.V., Lukina, E.A. et al. Randomized multicenter noninferiority phase III clinical trial of the first biosimilar of eculizumab. Ann Hematol (2021). https://doi.org/10.1007/s00277-021-04624-7</description>
  </link>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>July 3, 2020</study_first_submitted>
  <study_first_submitted_qc>July 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 9, 2020</study_first_posted>
  <last_update_submitted>August 27, 2021</last_update_submitted>
  <last_update_submitted_qc>August 27, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 1, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Paroxysmal Cold Hemoglobinuria</keyword>
  <keyword>eculizumab</keyword>
  <keyword>Complement Inactivating Agents</keyword>
  <keyword>Hemolysis</keyword>
  <keyword>Anemia, Hemolytic</keyword>
  <keyword>Anemia</keyword>
  <keyword>Hematologic Diseases</keyword>
  <keyword>Bone Marrow Diseases</keyword>
  <keyword>Hemoglobinuria</keyword>
  <keyword>Proteinuria</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemoglobinuria</mesh_term>
    <mesh_term>Hemoglobinuria, Paroxysmal</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Eculizumab</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/NCT04463056
org study id: ECU-PNH-III
secondary id: #546 eff date 17.10.2017
nct id: NCT04463056
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
It is a multicenter, open-label, randomized, parallel-group study of the efficacy and safety
      of Elizaria® (eculizumab, GENERIUM JSC, Russia) versus Soliris® (Alexion Pharma GmbH,
      Switzerland) in patients with paroxysmal nocturnal hemoglobinuria.
After screening, patients meeting all of the inclusion / non-inclusion criteria and
      vaccinated against meningococcal infections were divided into two subgroups according to the
      eculizumab treatment status (Soliris® naïve patients / patients who had received Soliris® at
      a maintenance dose prior to the trial inclusion). Each subgroup included an even number of
      patients to maintain recruitment balance. Then, patients of each subgroup were distributed
      into one of two treatment groups by the method of stratified block randomization at a 1:1
      ratio into groups A and B, respectively. In the first group (Group A), patients received
      infusions of Elizaria (eculizumab, GENERIUM JSC), in the second one (Group B) - infusions of
      Soliris®.

      The duration of participation of each patient in the study, including the screening period,
      was about 30 weeks.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Area under the LDH concentration-time curve (LDH AUC) during the maintenance therapy with the test drug or the reference drug
time frame: week 22
measure: Area under the LDH concentration-time curve (LDH AUC) during 26-week therapy with the test product or the reference product
time frame: week 26
measure: Hemoglobin level change during the maintenance therapy with the test drug or the reference drug
time frame: week 22
measure: Number/proportion of the patients with stable hemoglobin level during the maintenance therapy with the test drug or the reference drug
time frame: week 22
measure: Number/proportion of patients with various thrombotic complications developing during treatment with the test product or the reference product.
time frame: week 26
measure: Number/proportion of patients who needed donor red blood cell transfusions during treatment with the test product or the reference product.
time frame: week 26
measure: Number of donor red blood cell transfusions during treatment with the test product or the reference product.
time frame: week 26
measure: Number/proportion of patients with breakthrough hemolysis
time frame: week 26
description: Breakthrough hemolysis defined as at least one new episode or worsening of at least one previous signs of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, severe vascular complications (including thrombosis), dysphagia or erectile dysfunction) associated with increased LDH after a previous decrease during treatment.
arm group label: Elizaria®
arm group type: Experimental
description: International nonproprietary name: eculizumab
arm group label: Soliris®
arm group type: Active Comparator
description: International nonproprietary name: eculizumab
intervention type: Biological
intervention name: Elizaria®
description: Induction cycle: 600 mg (2 vials of 30 mL, 10 mg/mL) intravenous infusion for 30 minutes once a week for 4 weeks. Maintenance therapy: 900 mg (3 vials of 30 mL, 10 mg/mL) intravenous infusion for 30 minutes in Week 5, followed by 900 mg every 14 days.
arm group label: Elizaria®
other name: eculizumab
intervention type: Biological
intervention name: Soliris®
description: Induction cycle: 600 mg (2 vials of 30 mL, 10 mg/mL) intravenous infusion for 30 minutes once a week for 4 weeks. Maintenance therapy: 900 mg (3 vials of 30 mL, 10 mg/mL) intravenous infusion for 30 minutes in Week 5, followed by 900 mg every 14 days.
arm group label: Soliris®
other name: eculizumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Oksana A. Markova, MD
role: Study Chair
affiliation: AO GENERIUM
facility: 
facility: 
facility: 
facility: 
country: Russian Federation
url: https://doi.org/10.1182/blood-2019-125693
description: Phase III Clinical Trial of Elizaria® and Soliris® in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria: Results of Comparative Analysis of Efficacy, Safety, and Pharmacological Data
url: https://link.springer.com/article/10.1007/s00277-021-04624-7#citeas
description: Kulagin, A.D., Ptushkin, V.V., Lukina, E.A. et al. Randomized multicenter noninferiority phase III clinical trial of the first biosimilar of eculizumab. Ann Hematol (2021). https://doi.org/10.1007/s00277-021-04624-7
responsible party type: Sponsor
mesh term: Hemoglobinuria
mesh term: Hemoglobinuria, Paroxysmal
mesh term: Eculizumab
sharing ipd: No