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

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

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).

Study Overview

• Status: Completed
• Conditions: Paroxysmal Nocturnal Hemoglobinuria
• Intervention / Treatment: Biological: Eculizumab (JSC GENERIUM, Russia)

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 3

Contacts and Locations

Study Locations

• Russian Federation
  • Chelyabinsk Region
    • Chelyabinsk, Chelyabinsk Region, Russian Federation, 454076
      • State Budgetary Healthcare Institution "Chelyabinsk Regional Clinical hospital"
  • Kirov Region
    • Kirov, Kirov Region, Russian Federation, 610027
      • Federal State Budgetary Institution of Science "Kirov Research Institute of Hematology and Blood Transfusion of the Federal Medical and Biological Agency"
  • Leningrad Region
    • Saint Petersburg, Leningrad Region, Russian Federation, 197022
      • Federal State Budgetary Educational Institution of Higher Education "First St. Petersburg State Medical University named after Academician I.P. Pavlov"
  • Moscow Region
    • Moscow, Moscow Region, Russian Federation, 125167
      • Federal State Budgetary Institution "National Medical Research Center of Hematology" of the Ministry of Health of the Russian Federation
    • Moscow, Moscow Region, Russian Federation, 125284
      • State Budgetary Institution of Healthcare of the City of Moscow City Clinical Hospital named after S.P. Botkin of the Moscow Department of Health
    • Moscow, Moscow Region, Russian Federation, 129110
      • State budgetary institution of health care of the Moscow region "Moscow Regional Research Clinical Institute named after M.F. Vladimirsky"
  • Rostov Region
    • Rostov-on-Don, Rostov Region, Russian Federation, 344015
      • State budgetary institution of the Rostov region "Rostov Regional Clinical Hospital"
  • Samara Region
    • Samara, Samara Region, Russian Federation, 443099
      • Federal State Budgetary Educational Institution of Higher Education "Samara State Medical University" of the Ministry of Health of the Russian Federation
  • Sverdlovsk Region
    • Ekaterinburg, Sverdlovsk Region, Russian Federation, 620102
      • State Budgetary Healthcare Institution of the Sverdlovsk Region "Sverdlovsk Regional Clinical Hospital No. 1"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Eculisumab (JSC GENERIUM, Russia); Eculizumab	Biological: Eculizumab (JSC GENERIUM, Russia); Eculizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6 months
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.	6 months
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.	6 months
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.	6 months
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.	6 months
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.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6 months
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.	6 months
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.	6 months
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.	6 months
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.	6 months
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.	6 months
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.	6 months
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.	6 months

Collaborators and Investigators

• Sponsor: AO GENERIUM

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 3, 2018
• Primary Completion (ACTUAL): April 20, 2020
• Study Completion (ACTUAL): April 20, 2020

Study Registration Dates

• First Submitted: November 30, 2020
• First Submitted That Met QC Criteria: December 21, 2020
• First Posted (ACTUAL): December 22, 2020

Study Record Updates

• Last Update Posted (ACTUAL): December 28, 2020
• Last Update Submitted That Met QC Criteria: December 24, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: safety; immunogenicity; rare disease; biosimilar; eculizumab; paroxysmal nocturnal hemoglobinuria; pro-inflammatory cytokines; humanized monoclonal antibodies; complement system; C5 component of complement; Membrane attack complex (MAC)
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab
• Other Study ID Numbers: ECU-PNH-III-X; №205. eff.data 03 May 2018 (OTHER: Ministry of Health of the Russian Federation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No