Prospective Observational Study of Long-term Pathogenic Treatment of Elizaria®

Study Overview
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Brief Summary
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This is prospective observational study of long-term pathogenic treatment of Elizaria® in patients with paroxysmal nocturnal hemoglobinuria.

Detailed Description
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Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, acquired, life-threatening, progressive clonal blood disease that is developed as a result of the expansion of one or more clones of hematopoietic stem cells with a somatic PIG A gene mutation. The main pathogenic mechanism of PNH development is a dysregulation of the complement system, in which there are no complement inhibitors CD55 and CD59 that are bounded by the GPI-anchor on the surface of blood cells, or there is a deficiency of them. Eculizumab is the first drug for the pathogenetic therapy of PNH, a recombinant humanized monoclonal antibody against the C5 component of complement. Binding with high affinity to C5, eculizumab prevents the cleavage of C5 into C5a and C5b, thereby inhibiting the formation of pro-inflammatory cytokines (via C5a) and Membrane attack complex (MAC) (via C5b). Using of eculizumab in patients with PNH leads to a significant decrease in hemolysis, the incidence of thrombosis and increasing of the quality of life of patients. It increases life expectancy with long-term using of eculizumab. The drug Eculizumab, developed by JSC GENERIUM, Russia, is a biological analogue (biosimilar) of the original drug Soliris®. The population of the study is the patients with an established diagnosis of PNH who have indications for pathogenic treatment and are receiving Elizaria®. The study duration for each patient will be at least 54 weeks for previously treated patients, and 58 weeks for previously untreated patients, including the Screening period and the observation period. The study will include the Screening Period and the Observation Period: Screening Period - 2 weeks (Days 1 - 14); Follow-up is 52 weeks for previously treated patients and 56 weeks for previously untreated patients. The screening period can be extended until the results of laboratory and instrumental studies are obtained, but no more than 14 days. During the observation period, for the purpose of routine examination, it is planned to conduct a number of intermediate visits, approximately every 8 weeks (an acceptable interval of 6-10 weeks) between the Screening Visit (Visit 1) and the Study End Visit (Visit 13) in accordance with the plan of the dispensary observation of the patient. Additional visits and examinations may be carried out by the decision of the research physician. If the patient is previously untreated, the patient undergoes induction therapy with Elizaria® at a dose of 600 mg weekly for 4 weeks with a further transition to maintenance therapy at a dose of 900 mg from the 5th week and then every 2 weeks.

Official Title
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Prospective Observational Study of Long-term Pathogenic Treatment of Elizaria® in Patients With Paroxysmal Nocturnal Hemoglobinuria.

Conditions
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Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
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* Biological: Elizaria®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients aged 2 years with an established diagnosis of PNH; Prescribing Elizaria® as a pathogenetic therapy; Signing by the patient of the informed consent form for participation in the study. Exclusion Criteria: 1. Intolerance to eculizumab or other components of the drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: Elizaria®|Elizaria® will be prescribed by the Physician according to the actual SMPC.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dynamics of the peripheral blood LDH level during 52 weeks of the maintenance stage of treatment with Elizaria® (between Visits 6 and 13, inclusive). | To assess the dynamics of the peripheral blood LDH level during 52 weeks the area under the LDH level - time curve (AUC) will be calculated. Descriptive statistics will be provided for the values of the LDH level at each visit, as well as for the AUC, indicating the geometric means and coefficient of variation. | 52-56 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in hemoglobin levels during maintenance therapy with Elizaria® (between Visits 6 and 13 inclusive) | A paired t-test will be used to assess the change in hemoglobin level during the period of maintenance therapy with Elizaria® (between Visits 6 and 13, inclusive). Data on hemoglobin level and its change at each visit will be presented using descriptive statistics methods. | 52-56 weeks | 
| Number / proportion of patients with a change in the level of hemoglobin in the blood ± 5 g / l and ± 10 g / l. during the period of maintenance therapy with Elizaria® (between Visits 6 and 13 inclusive) | The proportion of patients with a change in blood hemoglobin level of ± 5 g / L and ± 10 g / L will be given during the period of maintenance therapy with Elizaria® (between Visits 6 and 13 inclusive). | 52-56 weeks | 
| The number / proportion of patients with various thrombotic complications that developed during treatment with Elizaria®. | For frequency indicators (the proportion of patients with various thrombotic complications) the absolute number of patients in the n / N format and the proportion of patients will be given and also calculated 95% confidence interval (CI) for the proportion. | 52-56 weeks | 
| The number / proportion of patients requiring transfusion of erythrocyte components of donated blood during treatment with Elizaria®. | For frequency indicators (the proportion of patients requiring transfusions of erythrocyte components of donated blood) the absolute number of patients in the n / N format and the proportion of patients will be given and also calculated 95% confidence interval (CI) for the proportion. | 52-56 weeks | 
| Number/proportion of patients with breakthrough hemolysis while observing an increased LDH, after a previous decrease in the course of treatment. | For frequency indicators (the proportion of patients with breakthrough hemolysis) the absolute number of patients in the n / N format and the proportion of patients will be given. and also calculated 95% confidence interval (CI) for the proportion. | 52-56 weeks | 
| Change in the size of PNH-clone of granulocytes and erythrocytes at Visits 6 and 13 relative to the initial value at screening. | To assess the dynamics of quantitative indicators (PNH-clone of granulocytes and erythrocytes, laboratory and vital indicators) relative to the initial level, a paired t-test or Wilcoxon's test will be used in case of a significant deviation from the normal distribution. The normal distribution will be tested using the Shapiro-Wilk test. | 52-56 weeks | 
| Frequency and severity of adverse events (AEs), serious adverse events (SAEs), including those associated with the use of Elizaria®, according to complaints, physical examination, assessment of vital signs, laboratory and instrumental studies, diaries. | Adverse events (AEs) that have developed since the patient signed the informed consent form will be coded using the MedDRA medical dictionary in the latest edition at the stage of database formation, until it is closed. The data on the incidence of AE / SAE during the course of the study will be presented by organ system (SOC) and preferred terms (PT) in terms of the number and proportion of patients who developed this adverse event. A summary of the severity of AEs and their relationship to treatment will be presented for each organ system. | 52-56 weeks | 
| Changes in vital signs, physical examination results, ECG, and laboratory values at Visit 13 from baseline at screening. | The number and proportion of patients with abnormalities according to complaints, physical examination, assessment of vital signs, laboratory and instrumental studies and patient diaries will be tabulated. | 52-56 weeks | 
| Number and proportion of patients with antidrug antibodies; titer of antidrug antibodies and their neutralizing activity. | For frequency indicators (the proportion of patients with antidrug antibodies) the absolute number of patients in the n / N format and the proportion of patients will be given and also calculated 95% confidence interval (CI) for the proportion. | 52-56 weeks |