Clinical Trial of BCD-148 and Soliris® for the Treatment of Patients With Paroxysmal Nocturnal Hemoglobinuria

Study Overview
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Brief Summary
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This clinical study is a randomized, open-label, international, multi-center, comparative study of efficacy and safety of BCD-148 and Soliris® in PNH patients. It is planned to investigate the efficacy, safety, and immunogenicity of one-year eculizumab course in this study. PNH - Paroxysmal nocturnal hemoglobinuria

Official Title
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Randomized, Open-Label, International, Multi-center, Comparative Study of Efficacy and Safety of BCD-148 (JSC BIOCAD, Russia) and Soliris® in Patients With Paroxysmal Nocturnal Hemoglobinuria

Conditions
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Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
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* Biological: BCD-148
* Biological: Soliris


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: He/she gave written informed consent. Male or female ≥18 and ≤65 years of age. PNH diagnosis documented by flow cytometry data at screening . PNH granulocyte clone size ≥10% (according to flow cytometry performed at screening). Lactate dehydrogenase (LDH) level ≥1.5 times the upper limit of normal (ULN) at screening and at least one of the following symptoms/syndromes: hemoglobinuria, thrombotic complications, transfusion-dependent chronic hemolysis, anemic syndrome, acute kidney injury episodes or chronic kidney disease, pulmonary hypertension, and signs of smooth muscle dystonia (e.g., abdominal pain, dysphagia, erectile dysfunction, and etc.) within three months before informed consent. Platelet count ≥30х109/L at screening. Absolute count of neutrophil granulocytes ≥0.75х109/L at screening. Willingness to undergo vaccination against Neisseria meningitidis during the screening period and at least 14 days before the first administration of an investigational product . If immunosuppressive drug products are used, the duration of this therapy should be at least three months by informed consent date. The willingness of patients and their sexual partners of childbearing potential to use reliable contraception methods starting from the informed consent, throughout the study, and for four weeks after the last dose of an investigational product. This requirement does not apply to patients who underwent surgical sterilization and women with menopause established more than two years ago. Reliable contraception methods include one barrier method in combination with one of the following: spermicides or an intrauterine device. The patient is able, in the Investigator's opinion, to follow study procedures. Exclusion Criteria: History of meningococcal infection (either well-documented or according to oral information provided by a patient). Other well-documented complement deficiencies (except for those concerning complement component 5). History of bone marrow transplantation (either well-documented or according to oral information provided by a patient). HIV, hepatitis B, active hepatitis C, and syphilis . A patient with newly diagnosed or relapsing aplastic anemia and/or progressive bone marrow failure with indications for allogeneic bone marrow transplantation or combined immunosuppressive therapy within 6 months after informed consent. Acute infection (either well-documented and/or according to oral information provided by a patient) within 4 weeks before informed consent and/or during the screening period and/or relapse of chronic disease at the moment of informed consent and/or during the screening period . Any other chronic diseases present at the time of the informed consent which can negatively affect the patient's safety during the study, in the Investigator' opinion. Use of eculizumab and/other anti-C5 monoclonal antibodies within three months before informed consent . Hypersensitivity to any of BCD-148/Soliris® ingredients, murine proteins and other ingredients of these drug products, and to any of meningococcal vaccine ingredients. Documented malignancy, except for cured basal cell carcinoma or cervical carcinoma in situ . A known alcoholic or drug abuse or signs of present alcoholic/drug abuse that, in the Investigator's opinion, can be a contraindication to treatment with an investigational product or limit treatment compliance. Participation in other clinical studies within 30 days before informed consent and during this study. Pregnancy or lactation or planning for pregnancy/paternity during the clinical study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Interventional Model Description: During the main period (first 27 weeks), test product BCD-148 and reference product Soliris®. After Week 27, patients of both study arms will be switched to BCD-148 900 mg biweekly as maintenance therapy. Duration of this maintenance therapy will be 25 weeks.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BCD-148<br>14 participants in BCD-148 group. During the main period (first 27 weeks), test product BCD-148 will be administered as 25- to 45-minute intravenous infusions. After Week 27 BCD-148 900 mg will be administered biweekly as maintenance therapy. | Biological: BCD-148<br>* Active substance of BCD-148 is eculizumab - a monoclonal antibody that targets complement protein C5. Cycle 1 (induction therapy): 600 mg of eculizumab QW for the first four weeks; Cycle 2 (maintenance therapy): 900 mg of eculizumab at Week 5 and 900 mg of eculizumab every 14±2 days until Week 27 (inclusive) afterwards (dosing regimen for the main study period). QW - once weekly<br>|
| Active Comparator: Soliris<br>14 participants in Soliris group. During the main period (first 27 weeks), Soliris® will be administered as 25- to 45-minute intravenous infusions. After Week 27, patients be switched to BCD-148 900 mg biweekly as maintenance therapy. | Biological: BCD-148<br>* Active substance of BCD-148 is eculizumab - a monoclonal antibody that targets complement protein C5. Cycle 1 (induction therapy): 600 mg of eculizumab QW for the first four weeks; Cycle 2 (maintenance therapy): 900 mg of eculizumab at Week 5 and 900 mg of eculizumab every 14±2 days until Week 27 (inclusive) afterwards (dosing regimen for the main study period). QW - once weekly<br>Biological: Soliris<br>* Active substance of Soliris is eculizumab - a monoclonal antibody that targets complement protein C5. Cycle 1 (induction therapy): 600 mg of eculizumab QW for the first four weeks; Cycle 2 (maintenance therapy): 900 mg of eculizumab at Week 5 and 900 mg of eculizumab every 14±2 days until Week 27 (inclusive) afterwards (dosing regimen for the main study period).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC LDH | AUC - Area Under Curve of Lactate dehydrogenase | Weeks 5-27 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with thrombotic complications |  | week 27, week 52 | 
| The proportion of patients who required red blood cell transfusion |  | week 27, week 52 | 
| The proportion of patients with stable Hb level during the maintenance therapy period |  | Weeks 5-27 | 
| Mean Hb level over the maintenance therapy period |  | Weeks 5-27 | 
| Frequency of breakthrough hemolysis episodes |  | week 27, week 52 | 
| Changes in LDH level over time |  | week 27, week 52 | 
| Change in the count of circulating red blood cells with the PNH phenotype RBC | Red blood cells (RBC ) | week 27, week 52 | 
| Change in mean FACIT-Fatigue score | FACIT Fatigue Scale is a short, 13-item, easy to administer tool that measures an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue is measured on a four point Likert scale (4 = not at all fatigued to 0 = very much fatigued) | week 27, week 52 | 
| Change in mean EORTC QLQ-C30 score | EORTC QLQ-C30 is questionnaire developed to assess the quality of life. All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient). QLQ - Quality of Life Questionnaire | week 27, week 52 | 
| The proportion of patients with AE/SAE related to an investigational product, in the Investigator's opinion | AE - adverse event, SAE - serious adverse event | week 27, week 52 | 
| The proportion of patients with СТСАЕ v.5.0 Grade 3-4 AE related to an investigational product, in the Investigator's opinion, by arm |  | week 27, week 52 | 
| The proportion of patients who discontinued early due to AE/SAE related to an investigational product, in the Investigator's opinion, by arm |  | week 27, week 52 | 
| The proportion of BAb- and NAb-positive patients. | BAb - Binding antibodies, NAb - neutralizing antibodies | week 27, week 52 |