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A Safety and Immunogenicity Study in Long-term Treatment of Eculizumab (JSC "GENERIUM", Russian Federation) (NAP)

Primary Purpose

Paroxysmal Nocturnal Hemoglobinuria

Status
Completed
Phase
Phase 3
Locations
Russian Federation
Study Type
Interventional
Intervention
Eculizumab (JSC GENERIUM, Russia)
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 eculizumab, humanized monoclonal antibodies, safety, paroxysmal nocturnal hemoglobinuria, rare disease, biosimilar, complement system, C5 component of complement, pro-inflammatory cytokines, Membrane attack complex (MAC), immunogenicity

Eligibility Criteria

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

Inclusion Criteria:

  1. Completion of participation in previous studies of Eculizumab (JSC "GENERIUM") while maintaining the clinical efficacy of the therapy with eculizumab.

    In case of significant deviations from the protocol during participation in previous studies, the decision on the possibility of patient participation in this study is made on an individual basis in agreement with the company Sponsor.

  2. Written informed consent to participate in this study.
  3. Documented vaccination against meningococcal infection (serotypes A, C, Y and W135 Neisseria meningitides) with an unexpired period of validity and consent of the patient to undergo booster vaccination against meningococcal infection (serotypes A, C, Y and W135 Neisseria meningitides) while participating in this research when the previous vaccination expires.
  4. Consent to use a reliable method of contraception (a combination of at least 2 methods, including 1 barrier method, for example, using a condom and spermicide), from the moment of signing the informed consent until 10 weeks after the last administration of the study drug.

Exclusion Criteria:

  1. Hypersensitivity to the study drug, as well as to its components.
  2. Hypersensitivity to the active ingredients or any other component of the vaccine for the prevention of meningococcal infection, or a life-threatening reaction to the previous administration of a vaccine containing similar components.
  3. Comorbidities and conditions that, in the opinion of the Investigator, endanger the safety of the patient while participating in the study.
  4. Pregnancy or breastfeeding.
  5. Alcohol, drug or drug addiction.

Sites / Locations

  • State budgetary healthcare institution "Chelyabinsk Regional Clinical Hospital"
  • Federal State Budgetary Institution of Science "Kirov Research Institute of Hematology and Blood Transfusion of the Federal Medical and Biological Agency"
  • Federal State Budgetary Educational Institution of Higher Education "First St. Petersburg State Medical University named after Academician I.P. Pavlov"
  • Federal State Budgetary Institution "National Medical Research Center of Hematology" of the Ministry of Health of the Russian Federation
  • State Budgetary Institution of Healthcare of the City of Moscow City Clinical Hospital named after S.P. Botkin of the Moscow Department of Health
  • State budgetary institution of health care of the Moscow region "Moscow Regional Research Clinical Institute named after M.F. Vladimirsky"
  • State budgetary institution of the Rostov region "Rostov Regional Clinical Hospital"
  • Federal State Budgetary Educational Institution of Higher Education "Samara State Medical University" of the Ministry of Health of the Russian Federation
  • State Budgetary Healthcare Institution of the Sverdlovsk Region "Sverdlovsk Regional Clinical Hospital No. 1"

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Eculisumab (JSC GENERIUM, Russia)

Arm Description

Eculizumab

Outcomes

Primary Outcome Measures

The frequency and severity of adverse events (AEs), serious adverse events (SAEs), including those associated with the use of the study drug.
Frequency of AE / SAE will be tabulated with an indication of the number and proportion of patients in each category. Data will be presented cumulatively for all patients, as well as by subgroup. Descriptive statistical methods will be used.
The number and proportion of patients with antidrug antibodies; titer of antidrug antibodies and their neutralizing activity.
The analysis of immunogenicity parameters will be carried out taking into account the total duration of treatment with eculizumab, including the results of previous studies. The baseline will be the results of the analysis before the first administration of the drug in clinical trials.If there is a sufficient number of data on the titer of antidrug antibodies and their neutralizing activity, they will be presented using descriptive statistics with additional indication of geometric means and coefficients of variation.
Changes in vital signs during the study.
Safety parameters, which are categorical variables (frequency of detection of abnormalities according to physical and instrumental examination data, the presence of abnormalities according to the results of ECG, Echo-CG and laboratory parameters) will be tabulated with an indication of number and proportion of patients in each category. Data will be presented cumulatively for all patients, as well as by subgroup.
Changes in physical examination during the study.
Safety parameters, which are categorical variables (frequency of detection of abnormalities according to physical and instrumental examination data, the presence of abnormalities according to the results of ECG, Echo-CG and laboratory parameters) will be tabulated with an indication of number and proportion of patients in each category. Data will be presented cumulatively for all patients, as well as by subgroup.
Changes in ECG during the study.
Safety parameters, which are categorical variables (frequency of detection of abnormalities according to physical and instrumental examination data, the presence of abnormalities according to the results of ECG, Echo-CG and laboratory parameters) will be tabulated with an indication of number and proportion of patients in each category. Data will be presented cumulatively for all patients, as well as by subgroup.
Changes in Doppler echocardiography during the study.
Safety parameters, which are categorical variables (frequency of detection of abnormalities according to physical and instrumental examination data, the presence of abnormalities according to the results of ECG, Echo-CG and laboratory parameters) will be tabulated with an indication of number and proportion of patients in each category. Data will be presented cumulatively for all patients, as well as by subgroup.

Secondary Outcome Measures

Cmin will be carried out during the transition from the original Soliris® to the investigational drug.
The collection of blood samples will be carried out in patients who received Soliris® in the course of previous studies at Visits 1, 2, 3 and 4. 5-15 minutes before the start of the study drug administration.
The activity of the components of the complement system will be carried out during the transition from the original Soliris® to the investigational drug.
The collection of blood samples will be carried out in patients who received Soliris® in the course of previous studies at Visits 1, 2, 3 and 4. 5-15 minutes before the start of the study drug administration.
Concentration of membrane attack complex (C5b-9) will be carried out during the transition from the original Soliris® to the investigational drug.
The collection of blood samples will be carried out in patients who received Soliris® in the course of previous studies at Visits 1, 2, 3 and 4. 5-15 minutes before the start of the study drug administration.
Changes in LDH when switching from the original Soliris® to the investigational drug.
Methods of descriptive statistics will be used to analyze data on changes in laboratory parameters (LDH, hemoglobin, reticulocytes and creatinine) at various visits.
Changes in creatinine when switching from the original Soliris® to the investigational drug.
Methods of descriptive statistics will be used to analyze data on changes in laboratory parameters (LDH, hemoglobin, reticulocytes and creatinine) at various visits.
Changes in hemoglobin when switching from the original Soliris® to the investigational drug.
Methods of descriptive statistics will be used to analyze data on changes in laboratory parameters (LDH, hemoglobin, reticulocytes and creatinine) at various visits.
Changes in reticulocytes when switching from the original Soliris® to the investigational drug.
Methods of descriptive statistics will be used to analyze data on changes in laboratory parameters (LDH, hemoglobin, reticulocytes and creatinine) at various visits.
Changes in the size of PNH-clone of granulocytes and erythrocytes during the study.
Methods of descriptive statistics will be used to analyze data on changes in the size of PNH-clone of granulocytes and erythrocytes at various visits.

Full Information

First Posted
November 30, 2020
Last Updated
December 24, 2020
Sponsor
AO GENERIUM
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1. Study Identification

Unique Protocol Identification Number
NCT04679103
Brief Title
A Safety and Immunogenicity Study in Long-term Treatment of Eculizumab (JSC "GENERIUM", Russian Federation)
Acronym
NAP
Official Title
A Safety and Immunogenicity Study in Long-term Treatment of Eculizumab (JSC "GENERIUM", Russian Federation) in Patients With Paroxysmal Nocturne Hemoglobinuria, Who Have Been Involved Earlier in the Clinical Trials of Eculizumab
Study Type
Interventional

2. Study Status

Record Verification Date
December 2020
Overall Recruitment Status
Completed
Study Start Date
May 3, 2018 (Actual)
Primary Completion Date
April 20, 2020 (Actual)
Study Completion Date
April 20, 2020 (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
A safety and immunogenicity study in long-term treatment of Eculizumab (JSC "GENERIUM", Russian Federation) in patients with paroxysmal nocturnal hemoglobinuria, who have been involved earlier in the clinical trials of Eculizumab (JSC "GENERIUM", Russian Federation).
Detailed Description
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®. At the present time Eculizumab (JSC GENERIUM, Russia) have already been authorized as Elizaria® in Russia. This study is a multicenter open-label study of the safety, immunogenicity and efficacy of Eculizumab (JSC GENERIUM, Russia) in patients with paroxysmal nocturnal hemoglobinuria who completed participation in previous clinical trials of Eculizumab (JSC GENERIUM, Russia). Visit 1 of this study is carried out on the day of the Visit of completion of a previously conducted study, or on another day, observing the terms of administration of the drug prescribed by the instructions for medical use of Eculizumab. At this visit, all patients who signed the informed consent form and were immunized with meningococcal vaccine will begin therapy with Eculizumab (GENERIUM JSC), which will continue until the drug is registered or, as decided by the sponsoring company, until its commercial availability. When the last patient enrolled in the study has completed 6 months of therapy, which corresponds to the completion of Visit 13, an interim analysis of the safety and immunogenicity data of the study drug will be performed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Paroxysmal Nocturnal Hemoglobinuria
Keywords
eculizumab, humanized monoclonal antibodies, safety, paroxysmal nocturnal hemoglobinuria, rare disease, biosimilar, complement system, C5 component of complement, pro-inflammatory cytokines, Membrane attack complex (MAC), immunogenicity

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Model Description
Interventional
Masking
None (Open Label)
Masking Description
NAP
Allocation
N/A
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Eculisumab (JSC GENERIUM, Russia)
Arm Type
Experimental
Arm Description
Eculizumab
Intervention Type
Biological
Intervention Name(s)
Eculizumab (JSC GENERIUM, Russia)
Intervention Description
Eculizumab
Primary Outcome Measure Information:
Title
The frequency and severity of adverse events (AEs), serious adverse events (SAEs), including those associated with the use of the study drug.
Description
Frequency of AE / SAE will be tabulated with an indication of the number and proportion of patients in each category. Data will be presented cumulatively for all patients, as well as by subgroup. Descriptive statistical methods will be used.
Time Frame
6 months
Title
The number and proportion of patients with antidrug antibodies; titer of antidrug antibodies and their neutralizing activity.
Description
The analysis of immunogenicity parameters will be carried out taking into account the total duration of treatment with eculizumab, including the results of previous studies. The baseline will be the results of the analysis before the first administration of the drug in clinical trials.If there is a sufficient number of data on the titer of antidrug antibodies and their neutralizing activity, they will be presented using descriptive statistics with additional indication of geometric means and coefficients of variation.
Time Frame
6 months
Title
Changes in vital signs during the study.
Description
Safety parameters, which are categorical variables (frequency of detection of abnormalities according to physical and instrumental examination data, the presence of abnormalities according to the results of ECG, Echo-CG and laboratory parameters) will be tabulated with an indication of number and proportion of patients in each category. Data will be presented cumulatively for all patients, as well as by subgroup.
Time Frame
6 months
Title
Changes in physical examination during the study.
Description
Safety parameters, which are categorical variables (frequency of detection of abnormalities according to physical and instrumental examination data, the presence of abnormalities according to the results of ECG, Echo-CG and laboratory parameters) will be tabulated with an indication of number and proportion of patients in each category. Data will be presented cumulatively for all patients, as well as by subgroup.
Time Frame
6 months
Title
Changes in ECG during the study.
Description
Safety parameters, which are categorical variables (frequency of detection of abnormalities according to physical and instrumental examination data, the presence of abnormalities according to the results of ECG, Echo-CG and laboratory parameters) will be tabulated with an indication of number and proportion of patients in each category. Data will be presented cumulatively for all patients, as well as by subgroup.
Time Frame
6 months
Title
Changes in Doppler echocardiography during the study.
Description
Safety parameters, which are categorical variables (frequency of detection of abnormalities according to physical and instrumental examination data, the presence of abnormalities according to the results of ECG, Echo-CG and laboratory parameters) will be tabulated with an indication of number and proportion of patients in each category. Data will be presented cumulatively for all patients, as well as by subgroup.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Cmin will be carried out during the transition from the original Soliris® to the investigational drug.
Description
The collection of blood samples will be carried out in patients who received Soliris® in the course of previous studies at Visits 1, 2, 3 and 4. 5-15 minutes before the start of the study drug administration.
Time Frame
6 months
Title
The activity of the components of the complement system will be carried out during the transition from the original Soliris® to the investigational drug.
Description
The collection of blood samples will be carried out in patients who received Soliris® in the course of previous studies at Visits 1, 2, 3 and 4. 5-15 minutes before the start of the study drug administration.
Time Frame
6 months
Title
Concentration of membrane attack complex (C5b-9) will be carried out during the transition from the original Soliris® to the investigational drug.
Description
The collection of blood samples will be carried out in patients who received Soliris® in the course of previous studies at Visits 1, 2, 3 and 4. 5-15 minutes before the start of the study drug administration.
Time Frame
6 months
Title
Changes in LDH when switching from the original Soliris® to the investigational drug.
Description
Methods of descriptive statistics will be used to analyze data on changes in laboratory parameters (LDH, hemoglobin, reticulocytes and creatinine) at various visits.
Time Frame
6 months
Title
Changes in creatinine when switching from the original Soliris® to the investigational drug.
Description
Methods of descriptive statistics will be used to analyze data on changes in laboratory parameters (LDH, hemoglobin, reticulocytes and creatinine) at various visits.
Time Frame
6 months
Title
Changes in hemoglobin when switching from the original Soliris® to the investigational drug.
Description
Methods of descriptive statistics will be used to analyze data on changes in laboratory parameters (LDH, hemoglobin, reticulocytes and creatinine) at various visits.
Time Frame
6 months
Title
Changes in reticulocytes when switching from the original Soliris® to the investigational drug.
Description
Methods of descriptive statistics will be used to analyze data on changes in laboratory parameters (LDH, hemoglobin, reticulocytes and creatinine) at various visits.
Time Frame
6 months
Title
Changes in the size of PNH-clone of granulocytes and erythrocytes during the study.
Description
Methods of descriptive statistics will be used to analyze data on changes in the size of PNH-clone of granulocytes and erythrocytes at various visits.
Time Frame
6 months

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: Completion of participation in previous studies of Eculizumab (JSC "GENERIUM") while maintaining the clinical efficacy of the therapy with eculizumab. In case of significant deviations from the protocol during participation in previous studies, the decision on the possibility of patient participation in this study is made on an individual basis in agreement with the company Sponsor. Written informed consent to participate in this study. Documented vaccination against meningococcal infection (serotypes A, C, Y and W135 Neisseria meningitides) with an unexpired period of validity and consent of the patient to undergo booster vaccination against meningococcal infection (serotypes A, C, Y and W135 Neisseria meningitides) while participating in this research when the previous vaccination expires. Consent to use a reliable method of contraception (a combination of at least 2 methods, including 1 barrier method, for example, using a condom and spermicide), from the moment of signing the informed consent until 10 weeks after the last administration of the study drug. Exclusion Criteria: Hypersensitivity to the study drug, as well as to its components. Hypersensitivity to the active ingredients or any other component of the vaccine for the prevention of meningococcal infection, or a life-threatening reaction to the previous administration of a vaccine containing similar components. Comorbidities and conditions that, in the opinion of the Investigator, endanger the safety of the patient while participating in the study. Pregnancy or breastfeeding. Alcohol, drug or drug addiction.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Oksana Markova, MD
Organizational Affiliation
AO GENERIUM
Official's Role
Study Chair
Facility Information:
Facility Name
State budgetary healthcare institution "Chelyabinsk Regional Clinical Hospital"
City
Chelyabinsk
State/Province
Chelyabinsk Region
ZIP/Postal Code
454076
Country
Russian Federation
Facility Name
Federal State Budgetary Institution of Science "Kirov Research Institute of Hematology and Blood Transfusion of the Federal Medical and Biological Agency"
City
Kirov
State/Province
Kirov Region
ZIP/Postal Code
610027
Country
Russian Federation
Facility Name
Federal State Budgetary Educational Institution of Higher Education "First St. Petersburg State Medical University named after Academician I.P. Pavlov"
City
Saint Petersburg
State/Province
Leningrad Region
ZIP/Postal Code
197022
Country
Russian Federation
Facility Name
Federal State Budgetary Institution "National Medical Research Center of Hematology" of the Ministry of Health of the Russian Federation
City
Moscow
State/Province
Moscow Region
ZIP/Postal Code
125167
Country
Russian Federation
Facility Name
State Budgetary Institution of Healthcare of the City of Moscow City Clinical Hospital named after S.P. Botkin of the Moscow Department of Health
City
Moscow
State/Province
Moscow Region
ZIP/Postal Code
125284
Country
Russian Federation
Facility Name
State budgetary institution of health care of the Moscow region "Moscow Regional Research Clinical Institute named after M.F. Vladimirsky"
City
Moscow
State/Province
Moscow Region
ZIP/Postal Code
129110
Country
Russian Federation
Facility Name
State budgetary institution of the Rostov region "Rostov Regional Clinical Hospital"
City
Rostov-on-Don
State/Province
Rostov Region
ZIP/Postal Code
344015
Country
Russian Federation
Facility Name
Federal State Budgetary Educational Institution of Higher Education "Samara State Medical University" of the Ministry of Health of the Russian Federation
City
Samara
State/Province
Samara Region
ZIP/Postal Code
443099
Country
Russian Federation
Facility Name
State Budgetary Healthcare Institution of the Sverdlovsk Region "Sverdlovsk Regional Clinical Hospital No. 1"
City
Ekaterinburg
State/Province
Sverdlovsk Region
ZIP/Postal Code
620102
Country
Russian Federation

12. IPD Sharing Statement

Plan to Share IPD
No

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A Safety and Immunogenicity Study in Long-term Treatment of Eculizumab (JSC "GENERIUM", Russian Federation)

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