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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Paroxysmal Nocturnal Hemoglobinuria, Marchiafava-Micheli Syndrome, Paroxysmal Hemoglobinuria

Intervention / Treatment
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* Biological: Elizaria®
* Biological: Soliris®


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Elizaria®<br>International nonproprietary name: eculizumab | Biological: Elizaria®<br>* 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.<br>* Other names: eculizumab;|
| Active Comparator: Soliris®<br>International nonproprietary name: eculizumab | Biological: Soliris®<br>* 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.<br>* Other names: eculizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the LDH concentration-time curve (LDH AUC) during the maintenance therapy with the test drug or the reference drug |  | week 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the LDH concentration-time curve (LDH AUC) during 26-week therapy with the test product or the reference product |  | week 26 | 
| Hemoglobin level change during the maintenance therapy with the test drug or the reference drug |  | week 22 | 
| Number/proportion of the patients with stable hemoglobin level during the maintenance therapy with the test drug or the reference drug |  | week 22 | 
| Number/proportion of patients with various thrombotic complications developing during treatment with the test product or the reference product. |  | week 26 | 
| Number/proportion of patients who needed donor red blood cell transfusions during treatment with the test product or the reference product. |  | week 26 | 
| Number of donor red blood cell transfusions during treatment with the test product or the reference product. |  | week 26 | 
| 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. | week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paroxysmal Cold Hemoglobinuria, eculizumab, Complement Inactivating Agents, Hemolysis, Anemia, Hemolytic, Anemia, Hematologic Diseases, Bone Marrow Diseases, Hemoglobinuria, Proteinuria