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Efficacy and Safety of Elizaria® vs. Soliris® in Patients With PNH

Primary Purpose

Paroxysmal Nocturnal Hemoglobinuria, Marchiafava-Micheli Syndrome, Paroxysmal Hemoglobinuria

Status
Completed
Phase
Phase 3
Locations
Russian Federation
Study Type
Interventional
Intervention
Elizaria®
Soliris®
Sponsored by
AO GENERIUM
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Paroxysmal Nocturnal Hemoglobinuria focused on measuring Paroxysmal Cold Hemoglobinuria, eculizumab, Complement Inactivating Agents, Hemolysis, Anemia, Hemolytic, Anemia, Hematologic Diseases, Bone Marrow Diseases, Hemoglobinuria, Proteinuria

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Written informed consent for participation in the study.
  2. Men and women aged 18 to 65 years at the time of signing the Informed Consent Form.
  3. Established diagnosis of paroxysmal nocturnal hemoglobinuria (PNH), confirmed by flow cytometry assessing the PNH red blood cell and white blood cell clone size, with intravascular hemolysis and current or previous concomitant clinical symptoms, irrespective of the need for blood transfusions and without signs of other disorders associated with bone marrow failure.
  4. For patients, who have not received Soliris® before inclusion in this study: lactate dehydrogenase (LDH) level 1.5 times the upper limit of normal or higher as assessed by the central laboratory.
  5. The patients receiving anticoagulants must take them at a stable dose for at least 4 weeks prior to screening. Patients receiving warfarin must have a stable international normalized ratio (INR) value. To confirm INR value stability, the patients have to provide a blood INR test at least 4 weeks prior to screening. The second INR assessment will be performed at the screening visit.
  6. Documented vaccination against meningococcal infections (Neisseria meningitidis serogroups A, C, Y and W-135) the protective immunity of which did not wear off, at least 14 days prior to the administration of the first dose of the test or reference drug and the patient's consent for revaccination against meningococcal infections (Neisseria meningitidis serogroups A, C, Y and W-135) during participation in the current study if the protection from previous vaccination wears off.
  7. Subjects' consent to use reliable contraceptive methods (the combination of at least 2 methods, including barrier contraception, for example, condoms with spermicide) from signing the Informed Consent Form for up to 10 weeks after stopping therapy.

Exclusion Criteria:

  1. Hypersensitivity to the test drug, reference drug and their components.
  2. Hypersensitivity to the active substance or any other component of the vaccine used to prevent meningococcal infection or a lifethreatening reaction to a previously administered vaccine containing similar ingredients.
  3. Conditions associated with bone marrow failure and PNH clone (aplastic anemia, myelodysplastic syndrome, idiopathic myelofibrosis).
  4. A history of infections caused by Neisseria meningitides.
  5. Active systemic bacterial, viral, or fungal infection within 14 days prior to the administration of the first dose of the test or reference drug.
  6. Fever of 38°С or higher within 7 days prior to the administration of the first dose of the test or reference drug.
  7. Hereditary complement deficiencies.
  8. Patients planning to undergo or with a history of bone marrow transplantation.
  9. Initial treatment cycle (induction phase) of Soliris®; completed treatment with Soliris® less than 70 days before study inclusion, not related to the current study participation.
  10. Vaccination with any live vaccine within 1 month prior to the administration of the first dose of the test or reference drug;
  11. Concomitant diseases and conditions which may, in the Investigator's opinion, compromise the patient's safety in case of participation in the study or which could affect the safety data analysis in case of an exacerbation of this disease/condition during the study, including the following:

    • Myocardial infarction or stroke within the last 3 months, severe arrhythmia, NYHA functional class III/IV heart failure;
    • Psychiatric disorders;
    • Immune and endocrine disorders which are not controlled with medications (including decompensated diabetes mellitus and thyroid disorders);
    • Hematologic disorders requiring chemotherapy;
    • Current or prior oncologic disorders, except for successfully treated basal cell carcinoma;
    • Decompensated liver diseases.
  12. Acquired immunodeficiency syndrome or human immunodeficiency virus (HIV) infection confirmed by test results.
  13. Active viral hepatitis B and/or C at screening with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels 5 times the upper limit of normal or higher.
  14. Positive syphilis test results.
  15. Body mass index (BMI) ≤17 kg/m2 or ≥30 kg/m2.
  16. Pregnancy or breastfeeding.
  17. History of tuberculosis, alcohol addiction, medication abuse, or drug addiction.
  18. Patient's participation in any clinical studies and/or using of not approved medications in the Russian federation within 30 days before screening.

Sites / Locations

  • Federal State Budget Funded Institution National Medical Research Center of Hematology, Ministry of Health of the Russian Federation (MoH of Russia)
  • Moscow State Budget Funded Healthcare Institution S. P. Botkin City Clinical Hospital, Moscow Department of Healthcare
  • 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
  • State Budgetary Educational Institution of Higher Professional Education Samara State Medical University, Ministry of Health of the Russian Federation.

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Elizaria®

Soliris®

Arm Description

International nonproprietary name: eculizumab

International nonproprietary name: eculizumab

Outcomes

Primary Outcome Measures

Area under the LDH concentration-time curve (LDH AUC) during the maintenance therapy with the test drug or the reference drug

Secondary Outcome Measures

Area under the LDH concentration-time curve (LDH AUC) during 26-week therapy with the test product or the reference product
Hemoglobin level change during the maintenance therapy with the test drug or the reference drug
Number/proportion of the patients with stable hemoglobin level during the maintenance therapy with the test drug or the reference drug
Number/proportion of patients with various thrombotic complications developing during treatment with the test product or the reference product.
Number/proportion of patients who needed donor red blood cell transfusions during treatment with the test product or the reference product.
Number of donor red blood cell transfusions during treatment with the test product or the reference product.
Number/proportion of patients with breakthrough hemolysis
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.

Full Information

First Posted
July 3, 2020
Last Updated
August 27, 2021
Sponsor
AO GENERIUM
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1. Study Identification

Unique Protocol Identification Number
NCT04463056
Brief Title
Efficacy and Safety of Elizaria® vs. Soliris® in Patients With PNH
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
November 29, 2017 (Actual)
Primary Completion Date
October 16, 2018 (Actual)
Study Completion Date
October 16, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AO GENERIUM

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Paroxysmal Nocturnal Hemoglobinuria, Marchiafava-Micheli Syndrome, Paroxysmal Hemoglobinuria
Keywords
Paroxysmal Cold Hemoglobinuria, eculizumab, Complement Inactivating Agents, Hemolysis, Anemia, Hemolytic, Anemia, Hematologic Diseases, Bone Marrow Diseases, Hemoglobinuria, Proteinuria

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Elizaria®
Arm Type
Experimental
Arm Description
International nonproprietary name: eculizumab
Arm Title
Soliris®
Arm Type
Active Comparator
Arm Description
International nonproprietary name: eculizumab
Intervention Type
Biological
Intervention Name(s)
Elizaria®
Other Intervention Name(s)
eculizumab
Intervention 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.
Intervention Type
Biological
Intervention Name(s)
Soliris®
Other Intervention Name(s)
eculizumab
Intervention 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.
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
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
Title
Hemoglobin level change during the maintenance therapy with the test drug or the reference drug
Time Frame
week 22
Title
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
Title
Number/proportion of patients with various thrombotic complications developing during treatment with the test product or the reference product.
Time Frame
week 26
Title
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
Title
Number of donor red blood cell transfusions during treatment with the test product or the reference product.
Time Frame
week 26
Title
Number/proportion of patients with breakthrough hemolysis
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.
Time Frame
week 26

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Written informed consent for participation in the study. Men and women aged 18 to 65 years at the time of signing the Informed Consent Form. Established diagnosis of paroxysmal nocturnal hemoglobinuria (PNH), confirmed by flow cytometry assessing the PNH red blood cell and white blood cell clone size, with intravascular hemolysis and current or previous concomitant clinical symptoms, irrespective of the need for blood transfusions and without signs of other disorders associated with bone marrow failure. For patients, who have not received Soliris® before inclusion in this study: lactate dehydrogenase (LDH) level 1.5 times the upper limit of normal or higher as assessed by the central laboratory. The patients receiving anticoagulants must take them at a stable dose for at least 4 weeks prior to screening. Patients receiving warfarin must have a stable international normalized ratio (INR) value. To confirm INR value stability, the patients have to provide a blood INR test at least 4 weeks prior to screening. The second INR assessment will be performed at the screening visit. Documented vaccination against meningococcal infections (Neisseria meningitidis serogroups A, C, Y and W-135) the protective immunity of which did not wear off, at least 14 days prior to the administration of the first dose of the test or reference drug and the patient's consent for revaccination against meningococcal infections (Neisseria meningitidis serogroups A, C, Y and W-135) during participation in the current study if the protection from previous vaccination wears off. Subjects' consent to use reliable contraceptive methods (the combination of at least 2 methods, including barrier contraception, for example, condoms with spermicide) from signing the Informed Consent Form for up to 10 weeks after stopping therapy. Exclusion Criteria: Hypersensitivity to the test drug, reference drug and their components. Hypersensitivity to the active substance or any other component of the vaccine used to prevent meningococcal infection or a lifethreatening reaction to a previously administered vaccine containing similar ingredients. Conditions associated with bone marrow failure and PNH clone (aplastic anemia, myelodysplastic syndrome, idiopathic myelofibrosis). A history of infections caused by Neisseria meningitides. Active systemic bacterial, viral, or fungal infection within 14 days prior to the administration of the first dose of the test or reference drug. Fever of 38°С or higher within 7 days prior to the administration of the first dose of the test or reference drug. Hereditary complement deficiencies. Patients planning to undergo or with a history of bone marrow transplantation. Initial treatment cycle (induction phase) of Soliris®; completed treatment with Soliris® less than 70 days before study inclusion, not related to the current study participation. Vaccination with any live vaccine within 1 month prior to the administration of the first dose of the test or reference drug; Concomitant diseases and conditions which may, in the Investigator's opinion, compromise the patient's safety in case of participation in the study or which could affect the safety data analysis in case of an exacerbation of this disease/condition during the study, including the following: Myocardial infarction or stroke within the last 3 months, severe arrhythmia, NYHA functional class III/IV heart failure; Psychiatric disorders; Immune and endocrine disorders which are not controlled with medications (including decompensated diabetes mellitus and thyroid disorders); Hematologic disorders requiring chemotherapy; Current or prior oncologic disorders, except for successfully treated basal cell carcinoma; Decompensated liver diseases. Acquired immunodeficiency syndrome or human immunodeficiency virus (HIV) infection confirmed by test results. Active viral hepatitis B and/or C at screening with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels 5 times the upper limit of normal or higher. Positive syphilis test results. Body mass index (BMI) ≤17 kg/m2 or ≥30 kg/m2. Pregnancy or breastfeeding. History of tuberculosis, alcohol addiction, medication abuse, or drug addiction. Patient's participation in any clinical studies and/or using of not approved medications in the Russian federation within 30 days before screening.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Oksana A. Markova, MD
Organizational Affiliation
AO GENERIUM
Official's Role
Study Chair
Facility Information:
Facility Name
Federal State Budget Funded Institution National Medical Research Center of Hematology, Ministry of Health of the Russian Federation (MoH of Russia)
City
Moscow
ZIP/Postal Code
125167
Country
Russian Federation
Facility Name
Moscow State Budget Funded Healthcare Institution S. P. Botkin City Clinical Hospital, Moscow Department of Healthcare
City
Moscow
ZIP/Postal Code
125284
Country
Russian Federation
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
City
Saint Petersburg
ZIP/Postal Code
197022
Country
Russian Federation
Facility Name
State Budgetary Educational Institution of Higher Professional Education Samara State Medical University, Ministry of Health of the Russian Federation.
City
Samara
ZIP/Postal Code
443079
Country
Russian Federation

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34398258
Citation
Kulagin AD, Ptushkin VV, Lukina EA, Davydkin IL, Korobkin AV, Shamrai VS, Konstantinova TS, Kaporskaya TS, Mitina TA, Ksenzova TI, Zuev EV, Markova OA, Gapchenko EV, Kudlay DA. Randomized multicenter noninferiority phase III clinical trial of the first biosimilar of eculizumab. Ann Hematol. 2021 Nov;100(11):2689-2698. doi: 10.1007/s00277-021-04624-7. Epub 2021 Aug 16.
Results Reference
derived
Links:
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

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Efficacy and Safety of Elizaria® vs. Soliris® in Patients With PNH

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