Conditions: Primary Immune Thrombocytopenia
Keywords: IVIG ITP immunomodulatory therapy intravenous immunoglobulin chronic primary immune thrombocytopenia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
The study will involve patients with chronic immune thrombocytopenia. This disease is diagnosed in the presence of isolated thrombocytopenia (decrease in platelet count only), except for other reasons. The addition of "chronic" means that the disease lasts more than 12 months.

Patients included in the study will receive Bioven, 10% solution for infusion according to the protocol for the use of IVIG in ITP - at a dose of 0.8-1.0 g / kg 1 time per day for 2 consecutive days, the course dose of 1.6-2.0 g / kg according to the "Guideline on the clinical investigation of human normal immunoglobulin for intravenous administration (IVIG)", rev. 3, 28 June 2018. After administration of the investigational drug, patients will be under medical supervision for 28 days.

The stay of patients in the study - at least 4 weeks.

Detailed description:
The investigational drug, IVIG, is used for immunomodulatory therapy in the treatment of autoimmune diseases.

The study will involve patients with chronic immune thrombocytopenia. This autoimmune disease is diagnosed in the presence of isolated thrombocytopenia (decrease in platelet count only), except for other reasons. The addition of "chronic" means that the disease lasts more than 12 months.

Screening stage The patient or her legal representative must sign an informed consent. After the informed consent signing procedure, the patient is screened and assessed for compliance with the inclusion and non-inclusion (exclusion) criteria.

Clinical stage After the patient is included in the study, according to the protocol, he/she is hospitalized and the study drug is administered at a dose of 0.8-1.0 g/kg once a day for 2 days (the course dose is 1.6-2.0 g/kg). The next day after the administration of the drug, the patient undergoes blood sampling to determine the level of platelets, the level of immunoglobulin G (IgG) and the Coombs test. This procedure will also be carried out on days 7, 14, 21 and 28 after the first injection of the drug to monitor the patient's performance.

The final stage The blood sampling procedure to determine the above indicators will be carried out on days 7, 14, 21, and 28 after the first administration of the drug to monitor the patient's performance.

Arms:
arm 1: Patients included in the study will receive the intravenous immunoglobulin (IVIG, Bioven), 10% solution for infusion according to the protocol for the use of IVIG in ITP treatment - at a dose of 0.8-1.0 g / kg once a day for 2 consecutive days, the course dose is 1.6-2.0 g / kg.

The next day after the administration of the drug, the patient undergoes blood sampling to determine the level of platelets, the level of immunoglobulin G (IgG), and the Coombs test.

This procedure will also be carried out on days 7, 14, 21, and 28 after the first injection of the drug to monitor the patient's performance.

Interventions: intervention 1: Intravenous immunoglobulin (IVIG), 10% solution for infusion
Intervention descriptions: intervention 1: The study drug is administrated at a dose 0.8-1.0 g / kg once a day for 2 consecutive days, the course dose is 1.6-2.0 g / kg.

Protocol document:
Prot_SAP_000.pdf: 
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CONFIDENTIALITY 
 
 
 
CLINICAL STUDY PROTOCOL 
Title: Open, multicenter, international study to evaluate the efficacy, safety, and tolerability of 
Bioven, manufactured by Biopharma Plasma LLC, in adult patients with chronic primary immune 
thrombocytopenia (ITP) 
Trial Code: 2021-BV-ITP-BP 
Version: Version 1.4 from July 03, 2023   
Investigational Drug: Bioven 
International non-proprietary name: Human normal immunoglobulin for intravenous 
administration 
Pharmaceutical form: solution for infusion 
Sponsor: Biopharma Plasma, LLC 
 
 
 
 
 
 
 
 
 
 
Notice for Confidential 
This document is intended for use by the party to whom it is addressed and contains confidential 
information that cannot be disclosed and/or trade secrets that are protected from disclosure under 
applicable law. By accepting such documentation, the party acknowledges that such material is 
confidential and agrees not to disclose it to any third party without the prior written consent of 
Biopharma Plasma LLC and not to use it for any purpose other than the intended one. 
 


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CONFIDENTIALITY 
Protocol approval page (Sponsor) 
 
Title: Open, multicenter, international study to evaluate the efficacy, safety and tolerability of 
Bioven, manufactured by Biopharma Plasma LLC, in adult patients with chronic primary immune 
thrombocytopenia (ITP) 
Trial Code: 2021-BV-ITP-BP 
Version: 1.4 from July 03, 2023 
Sponsor Representative: 
 
Sofiia Matsybokh  
(employee name) 
Clinical trial lead 
Biopharma Plasma, LLC 
(position) 
 
Organization name: 
Biopharma Plasma, LLC 
Address: 
 
Ukraine, Kyiv region, Bila Tserkva, Kyivska str. 37-B 
Phone:  
+38 (067) 249-68-69 
e-mail: 
s.matsybokh@biopharma.ua   
 
 
_____________________________ 
 
«____»___________ 20__. 
Signature 
 
Date 
 
 
 
 
 


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CONFIDENTIALITY 
 
Page of consent of the Principal Investigator with the study protocol (sample) 
I, the Principal Investigator, hereby certify that I have carefully read this study protocol, the 
investigator's brochure, including potential risks and adverse reactions of the drug, and other 
information about the drug and the study provided by the Sponsor. 
I agree to conduct this study in accordance with the requirements of the protocol and to 
protect the rights, confidentiality, safety and health of patients in accordance with the ethical 
requirements of the World Medical Association (WMA) Declaration of Helsinki, ICH E6 (R2) 
Guideline for Good Clinical Practice and other regulatory requirements of Ukraine and the 
European Union. 
I agree to make changes to the protocol only after informing the Sponsor, except when 
necessary to protect the safety, rights and health of patients. I fully understand that any changes 
made by the Investigator(s) without prior approval from Sponsor representatives will constitute a 
protocol violation (other than those procedures necessary to preserve patient health). 
I agree to personally conduct or supervise the research described. 
I agree to inform patients that the drugs are used for research purposes; I will ensure 
compliance with the requirements related to obtaining informed consent, after the approval of the 
Local Ethics Committee (LEC) and in accordance with the principles of GCP. 
In accordance with GCP principles, I agree to report adverse events that develop during the 
study to the Sponsor. 
I agree to ensure that all employees, colleagues and persons involved in the conduct of the 
study are informed of their obligations to comply with the arrangements described above. I agree 
to keep adequate and accurate records and to provide those records for analysis in accordance with 
GCP principles. 
I will ensure that the LEC, acting in accordance with the requirements of the GCP, is 
responsible for carrying out the ethical review as well as for the approval of the study. I also agree 
to promptly report to the LEC all changes in research activities and all unexpected problems, 
including patient risk and other aspects. In addition, I will not make any changes to the study 
without the approval of the LEC, except for the necessary cases of eliminating a clear unexpected 
threat to the life and health of patients. 
I am ready to provide direct access to primary documents and agree to audit by auditors from 
the Sponsor's representatives and regulatory authorities. I warrant that the investigational 
product(s) supplied by Sponsor will be used only as described in this protocol. 
I agree to comply with all other requirements regarding the responsibilities of clinical 
investigators, as well as all other important requirements of Good Clinical Practice. 
Investigator: 
 
 
Signature: 
 
 
Date: 
 
Full name 
 
Position: 
 
Institution: 
 
Address: 
 
 
 


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CONTENT 
PROTOCOL APPROVAL PAGE (SPONSOR) ............................................................................................................... 2 
GENERAL INFORMATION (SYNOPSIS) ..................................................................................................................... 8 
 
GENERAL INFORMATION ........................................................................................................................ 17 
 
JUSTIFICATION OF THE STUDY ................................................................................................................ 20 
2.1 
INTRODUCTION ........................................................................................................................................... 20 
2.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL DRUG. ..................................................................................... 21 
2.3 
SUMMARY OF CLINICAL TRIAL RESULTS ....................................................................................................... 25 
2.4 
A BRIEF DESCRIPTION OF THE KNOWN AND ANTICIPATED RISKS AND BENEFITS (IF ANY) FOR THE SUBJECTS
 
29 
2.5 
DESCRIPTION AND JUSTIFICATION OF THE METHOD OF ADMINISTRATION, DOSAGE, SCHEME AND DURATION 
OF TREATMENT .......................................................................................................................................................... 35 
 
PURPOSE AND OBJECTIVES OF RESEARCH .............................................................................................. 37 
 
STUDY DESIGN ....................................................................................................................................... 38 
4.1. 
MODEL DESCRIPTION, NUMBER OF PATIENTS, GROUPS .......................................................................................... 38 
4.2 STAGES OF THE STUDY. SCREENING .............................................................................................................................. 38 
4.3 
STAGES OF THE STUDY. CLINICAL STAGE ............................................................................................................. 38 
 
SELECTION AND EXCLUSION OF RESEARCH SUBJECTS ............................................................................ 39 
5.1. 
INCLUSION CRITERIA ....................................................................................................................................... 39 
5.2 
NON-INCLUSION CRITERIA ............................................................................................................................... 39 
5.3 
CRITERIA FOR EXCLUSION OF SUBJECTS (DISCONTINUATION OF TREATMENT WITH THE STUDY DRUG): ............................. 40 
 
PATIENT EXAMINATION AND TREATMENT PLAN ................................................................................... 41 
6.1. 
SCREENING STAGE ......................................................................................................................................... 41 
6.2. 
CLINICAL STAGE ............................................................................................................................................. 42 
6.3 
STAGE OF FOLLOW-UP AND COMPLETION ........................................................................................................... 43 
6.4 
SCHEDULE OF STUDY PROCEDURES IN TABULAR FORM TABLE 1. SCHEDULE OF STUDY PROCEDURES. ............................ 44 
6.5 
STUDY PROCEDURES. ...................................................................................................................................... 45 
6.5.1 
Signing the Informed Consent Form .................................................................................................... 45 
6.5.2 
Entering information into the CRF ....................................................................................................... 45 
6.5.3 
Diagnosis verification procedure - chronic primary immune thrombocytopenia ................................ 46 
6.5.4 
Collection of anamneses, demographic data, complaints, determination of body weight ................. 46 
6.5.5 
Objective physical examination and measurement of vital signs ........................................................ 47 
6.5.6 
Bioanalytical procedures and laboratory tests .................................................................................... 48 
6.5.7 
Bioanalytical study plan ....................................................................................................................... 49 
6.5.8 
Validation of bioanalytical methods .................................................................................................... 49 
6.5.9 
Test tube labeling procedure. .............................................................................................................. 50 
6.5.10 
Blood sampling procedure ................................................................................................................... 50 
6.5.11 
Plasma production procedure .............................................................................................................. 51 
6.5.12 
Procedure for storage and transportation of biological samples ........................................................ 51 
6.5.13 
Analysis of deviations from the plan of bioanalytical study ................................................................ 52 
6.5.14 
Rules for stopping parts of a clinical trial and (or) a clinical trial in general. ...................................... 52 
6.6 
CONTENT OF VISITS ........................................................................................................................................ 53 
6.6.1 
Unscheduled visit ................................................................................................................................. 56 
6.7 
DIET AND FLUID INTAKE .................................................................................................................................. 56 
6.8 
MODE OF PHYSICAL ACTIVITY ........................................................................................................................... 56 


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7 
INFORMATION ON MEDICINAL PRODUCTS USED IN CLINICAL TRIAL ...................................................... 57 
7.1 
STUDY DRUG ................................................................................................................................................ 57 
7.2 
CIRCULATION OF THE STUDY DRUG .................................................................................................................... 57 
7.3 
LABELING OF THE STUDY DRUG ......................................................................................................................... 58 
7.4 
THE ORDER OF ADMINISTRATION OF THE STUDY DRUG........................................................................................... 58 
7.5 
CONCOMITANT THERAPY IS ALLOWED. ............................................................................................................... 59 
7.6 
CONCOMITANT THERAPY IS PROHIBITED. ............................................................................................................ 59 
8 
EVALUATION OF EFFICIENCY .................................................................................................................. 60 
8.1 
PRIMARY EFFICACY ENDPOINT: ......................................................................................................................... 60 
8.2 
SECONDARY EFFICIENCY ENDPOINTS .................................................................................................................. 60 
9 
SECURITY ASSESSMENT .......................................................................................................................... 61 
9.1 
SECURITY ENDPOINTS ..................................................................................................................................... 61 
9.2 
DEFINITIONS CONCERNING SAFETY ASSESSMENT. ................................................................................................. 61 
9.3 
DETECTION AND REGISTRATION OF AE ............................................................................................................... 62 
9.4. 
TABLE 1. TOLERANCE ASSESSMENT SCALE ........................................................................................................... 63 
9.5. 
ASSESSMENT OF THE SEVERITY OF AE ................................................................................................................ 64 
9.6. 
TABLE 2. THE SEVERITY OF NOT ACCORDING TO NCI CTCAE (VERSION 5.0) ............................................................ 64 
9.7. 
ASSESSMENT OF THE CAUSAL RELATIONSHIP OF AE WITH THE STUDY DRUG ............................................................... 64 
9.8. 
CATEGORIES OF CONSEQUENCES OF AE AND THEIR DEFINITIONS ............................................................................. 65 
9.9. 
REPORTS OF SAE .......................................................................................................................................... 66 
9.10. 
REQUIREMENTS FOR REPORTING AFTER COMPLETION OF THE STUDY DRUG ................................................................ 66 
9.11. 
CONTRACEPTION AND PREGNANCY .................................................................................................................... 66 
9.12. 
THE PERIOD OF TIME DURING WHICH THE COLLECTION OF INFORMATION ABOUT PREGNANCY IS REQUIRED. ..................... 67 
9.13. 
ACTIONS TO BE TAKEN IN CASE OF PREGNANCY. ................................................................................................... 67 
10 
STATISTICS ............................................................................................................................................. 68 
10.1 
CONTENT OF STATISTICAL ANALYSIS ................................................................................................................... 68 
10.2 
SAMPLE SIZE ASSESMENT ................................................................................................................................ 69 
10.3 
GENERAL PLAN OF STATISTICAL ANALYSIS ............................................................................................................ 70 
10.3.1. 
GENERAL PRINCIPLES OF STATISTICAL ANALYSIS .................................................................................................... 70 
10.3.2. 
ANALYSIS OF THE INITIAL STATE/BASE-LINE STATE OF THE GROUP ............................................................................ 70 
10.3.5. 
SIGNIFICANCE LEVEL ....................................................................................................................................... 73 
10.3.6. 
WORK WITH MISSING OR INCOMPLETE DATA. ...................................................................................................... 73 
10.3.7. 
CONCLUSION ON NON-INFERIORITY EFFECTIVENESS .............................................................................................. 73 
10.4. 
DATA SET FOR ANALYSIS .................................................................................................................................. 74 
10.5. 
REPRESENTATION OF SUMMARY RESULTS ........................................................................................................... 74 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................................... 75 
11.1. 
CLINICAL TRIAL MONITORING ........................................................................................................................... 75 
11.2. 
AMENDMENTS TO THE PROTOCOL, REJECTIONS, AND VIOLATIONS OF THE PROTOCOL .................................................. 75 
11.3. 
AUDITS OF QUALITY CONTROL BODIES AND REGULATORY BODIES ............................................................................. 76 
12. 
ETHICAL AND LEGAL ASPECTS OF CLINICAL TRIAL ................................................................................... 77 
12.1. 
GENERAL REQUIREMENTS ................................................................................................................................ 77 
12.2. 
ETHICAL CLINICAL TRIAL .................................................................................................................................. 77 
12.3. 
LOCAL ETHICS COMMITTEE (LEC) ..................................................................................................................... 77 
12.4. 
APPROVAL OF THE PROTOCOL BY REGULATORY AUTHORITIES .................................................................................. 77 
12.5. 
OBTAINING THE WRITTEN INFORMED CONSENT OF THE PATIENT .............................................................................. 78 


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13. 
DATA WORKING AND RECORD KEEPING ................................................................................................ 79 
13.1. 
CLINICAL TRIAL DOCUMENTS ............................................................................................................................ 79 
13.2. 
PROVISION (SUPPLY) OF STUDY MATERIALS AND DOCUMENTS. ................................................................................ 79 
13.3. 
PRIMARY DOCUMENTATION ............................................................................................................................. 79 
13.4. 
DATA COLLECTION: INDIVIDUAL REGISTRATION FORMS (IRF, ECRF) ........................................................................ 80 
13.5. 
DATA PROCESSING AND CHANGES IN THE IRF ...................................................................................................... 81 
13.6. 
CONFIDENTIALITY OF PATIENT DATA .................................................................................................................. 81 
13.7. 
INVESTIGATOR FILE ........................................................................................................................................ 81 
13.8. 
ARCHIVE DATA STORAGE. ................................................................................................................................ 82 
13.9. 
DIRECT ACCESS TO PRIMARY DOCUMENTATION .................................................................................................... 82 
14. 
FINANCING AND INSURANCE ................................................................................................................. 83 
15. 
ISSUES OF PUBLICATION AND USE OF RESEARCH RESULTS ..................................................................... 84 
16. 
FINAL REPORT ........................................................................................................................................ 85 
17. 
CONFIDENTIALITY .................................................................................................................................. 86 
18. 
AMENDMENTS TO THE PROTOCOL AND / OR UPDATED VERSION OF THE PROTOCOL ........................... 86 
19. 
TERMS OF THE STUDY ............................................................................................................................ 86 
20. 
LIST OF REFERENCES ............................................................................................................................... 87 
 
 


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CONFIDENTIALITY 
LIST OF ABBREVIATIONS 
AHA 
- Antinuclear antibodies 
CMV 
- Cytomegalovirus 
CR 
- Сomplete response 
CV 
- Coefficient of variation 
EBV 
- Epstein-Barr virus 
eCRF 
- Electronic Case Report Form (ІРФ) 
GCP 
- Good Clinical Practice (Належна клінічна практика) 
IVIG 
- Іntravenous immunoglobulin 
M.g. 
- Geometric mean phenomenon 
Max 
- Maximum value 
Mean 
- Average value 
Min 
- Minimum value 
NR 
- No response 
r  
- Correlation coefficient 
R 
- Response 
RW  
- Wasserman's reaction 
SD 
- Standard deviation 
ALT 
- Alanine transaminase 
AST 
- Aspartate transaminase 
BUN 
- Blood urea nitrogen 
BP 
- Blood pressure 
APTT 
- Activated partial thromboplastin time 
IVIG 
- Intravenous immunoglobulin 
SID 
- Secondary immunodeficiency 
HIV 
- Human immunodeficiency virus 
R 
- Response to therapy 
GCS 
- Glucocorticosteroids 
SEC MOH 
- State Enterprise "State Expert Center" of the Ministry of Health of Ukraine 
SD 
- Study drug 
ECG  
- Electrocardiography 
ORT 
- Overall response to therapy 
BMI 
- Body mass index 
IRF 
- Individual patient registration form 
ITP 
- Immune thrombocytopenia 
AE/AR  
- Adverse event/adverse reaction 
CR 
- Complete response to therapy 
PID 
- Primary immunodeficiency 
PI 
- Prothrombin index 
SAM 
- Syndrome of aseptic meningitis 
HF 
- Heart failure 
SAE 
- Serious adverse events 
TRALI 
- Transfusion-related acute lung injury 
ICF 
- Informed consent form 
RR 
- Respiratory rate 
HR 
- Heart rate 


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CONFIDENTIAL 
 
 
GENERAL INFORMATION (SYNOPSIS) 
 
Name of Sponsor/Company: 
BIOPHARMA PLASMA LLC, Ukraine 
Name of Study Drug: 
Bioven 
Study code: 
2021-BV-ITP-BP 
Name of Active Ingredient: 
Human 
normal 
immunoglobulin 
for 
intravenous 
administration 
Date 
and 
version 
of 
the 
protocol: 
 Version 1.4 from 03.07.2023 
Title of Study:  
Open, multicenter, international study to evaluate the efficacy, safety, and tolerability of Bioven, 
manufactured by Biopharma Plasma LLC, in adult patients with chronic primary immune 
thrombocytopenia (ITP). 
Indication: 
Primary immune thrombocytopenia (ITP) in patients at high risk of bleeding or prior to surgery 
to correct the platelet count. 
According to the Guideline on the clinical investigation of human normal immunoglobulin for 
intravenous administration (IVIg), EMA / CHMP / BPWP / 94033/2007 rev. 4, 16 December 
2021; Guideline on core SmPC for human normal immunoglobulin for intravenous 
administration (IVIg), EMA/CHMP/BPWP/94038/2007 Rev. 6, 16 December 2021 
Number of Study Centers: 
It is planned to involve 5-15 centers in Ukraine and 3-5 centers in the Republic of Turkey. 
Duration of Study: 
This study is expected to start in 2022 and be completed in 
2024. 
Phase of Clinical Trial:  
III 
Objectives of Study:  
To evaluate the efficacy, safety, and tolerability of Bioven in patients with chronic primary 
immune thrombocytopenia, with evidence of non-inferiority efficacy, compared with the 
literature data  
Study design: 
Open-label, multicenter, international, uncontrolled, single-group 
Number of patients: 
The number of patients to be studied in Ukraine and worldwide is 40. No more than 36 patients 
will be enrolled in Ukraine. 
Patient selection criteria: 
Inclusion criteria: 
- 
Signed Patient Informed Consent Form for participation in the study; 
- 
Men and women aged 18-65; 
- 
Confirmed primary chronic ITP (lasting > 12 months since diagnosis); 
- 
A full blood count should be normal except for the isolated thrombocytopenia. Patients 
with low hemoglobin levels (but above 90 g/L) may be included if there are symptoms 
of bleeding; 
- 
If bleeding symptoms are diagnosed, the reticulocyte count should be measured; 
- 
Platelet count <30 x 109 /L; 
- 
If the patient is taking corticosteroids, the treatment regimen/dose should be stable (at 
least 2 weeks prior to screening); 
- 
Negative pregnancy test (for women of child-bearing potential); 


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CONFIDENTIAL 
 
 
- 
Willingness to use effective and reliable methods of contraception throughout the entire 
study period; 
- 
The results of physical, instrumental and laboratory examination of patients should be 
within the normal range or deviations should be regarded by the researcher as clinically 
insignificant. 
- 
Ability, according to the researcher, to follow all the requirements of the study protocol; 
Non-inclusion criteria: 
Patients cannot participate in this study if they meet one of the following criteria: 
- 
Known intolerance to plasma and immunoglobulin preparations;  
- 
Drug allergy or hypersensitivity to immunoglobulin preparations;  
- 
Confirmed deficiency of Ig A and antibodies to IgA. 
- 
Contraindications to immunoglobulin administration according to the instructions for 
medical use; 
- 
Pregnancy and lactation; 
- 
Any clinically significant hepatic impairment (increase of serum transaminase levels by 
more than 3 times the upper limit of normal); 
- 
Serum creatinine levels are more than two times higher than the upper limit of normal 
for a given age and sex; 
- 
Severe cardiovascular insufficiency (HF III); 
- 
History of thrombosis or presence of significant risk factors for thrombosis. 
- 
Patients with preventive splenectomy;  
- 
Hemostatic disorders other than chronic thrombocytopenia; 
- 
Persons with acute or exacerbation of chronic diseases of the gastrointestinal tract 
associated with the risk of bleeding, acute infectious diseases, pathologies of the 
respiratory system; 
- 
Proven case of primary immunodeficiency; 
- 
Secondary immune thrombocytopenia; 
- 
Virus infections (Epstein-Barr, Cytomegalovirus, Parvovirus, Hepatitis B and C); 
- 
Documented HIV infection  
- 
Positive RW test result; 
- 
Systemic immunopathological diseases (rheumatic diseases, nephritis, etc.); 
- 
Oncological diseases;  
- 
Diabetes mellitus;  
- 
Thyroid diseases;  
- 
History of mental illness; 
- 
Known drug addiction; 
- 
Any other concomitant decompensated diseases or acute conditions, the presence of 
which, according to the researcher, may significantly affect the results of the study; 
- 
The need to prescribe drugs that are incompatible with the administration of the drug in 
this study: other immunoglobulin preparations in addition to the study drug, cytostatic 
drugs, monoclonal antibodies, avatrombopag); 
- 
Experimental treatment (e.g. Rituximab therapy) for 3 months prior to screening); 
- 
Blood transfusions or transfusions of blood products in the last 6 months prior to 
inclusion in the study; 
- 
Administration of IVIG 30 days prior to screening; 
- 
Participation in any other study currently or within the last 30 days; 
Criteria for exclusion of subjects (discontinuation of treatment with the study drug): 
Any patient can leave the study at any time and under any conditions. 
Patients may be excluded by the researcher from taking the study drug and from the study in the 
following circumstances: 


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- 
The desire of the patient 
- 
Occurrence of severe and/or unexpected AE/AR in patient during the study, that require 
discontinuation of the drug;  
- 
The need to prescribe drugs prohibited in this study.  
- 
Significant deterioration of the patient's condition during the study period;  
- 
Failure of the patient to adhere to the treatment regimen; 
- 
Failure of the patient to follow the procedures established under the protocol; 
Groups of patients 
One single group that will receive the study drug, will be formed from patients who have been 
screened and meet the inclusion criteria, and do not fall under the non-inclusion (exclusion) 
criteria.  
At the data analysis stage, it is possible to evaluate patients based on the detected covariates. 
Duration of treatment  
Each patient will receive the study drug at a dose of 0.8-1.0 g / kg intravenously once a day for 
2 consecutive days, the course dose is 1.6-2.0 g / kg. 
Test Product, Dose, Mode of Administration: 
Name: Bioven  
Active ingredient: Human normal immunoglobulin for intravenous administration; 
1 ml of the drug contains immunologically active protein fraction of immunoglobulin G - 0.1 g; 
Excipients: glycine (aminoacetic acid); water for injection. 
Pharmacotherapeutic group. Human normal immunoglobulin for intravenous administration 
Dosage form: solution for infusion 
Dose schedule:  
Patients included in the study will receive the drug Bioven, 10% solution for infusion 
according to the protocol for the use of IVIG in ITP treatment – at a dose of 0.8-1.0 g / kg once 
a day for 2 consecutive days, the course dose is 1.6-2.0 g / kg. Allowed repeat course at same 
dosage in period 14-28 days from first infusion, if required. 
Bioven should be administered intravenously dropwise at the initial rate of 0.5-1.0 ml/kg 
of body weight/hour for 30 minutes. If no adverse reactions occur, the rate of administration may 
be gradually increased (it is recommended to increase by 0.5-1.5 ml/kg of body weight/hour 
every 10 min). According to the data from clinical studies the maximum rate of administration 
is 8.5 ml/kg of body weight/hour.  
The study drug is administered only in hospital environment while observing the rules of 
aseptic. The solution should be of room temperature before use. Cloudy solutions and those 
containing sediment are not used. For the administration of the drug, it is necessary to use a 
separate infusion system. 
When administering the drug, it is necessary to consider the information specified in the 
relevant sections of the instructions for medical use: administration details, special safety 
measures, contraindications, interaction with other medicinal products, etc. 
Patients participating in this study may receive concomitant therapy, which is used for the 
treatment of comorbidities and life-threatening conditions. 
It is allowed to use glucocorticoids in a stable dose for at least 2 weeks before starting 
treatment with the test drug. The need to increase the dose of corticosteroids during the study is 
considered as ineffective use of the study drug. 
Duration of treatment:  
The duration of treatment with the study drug for each patient is no less 2 days. The total period 
of stay in the study is 4 weeks. 
Efficacy and safety endpoints:  
Efficacy: 
Primary efficacy endpoint: 


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Part (percent) of patients with response (R). 
R is determined according to the following criteria: 
- Patients with R: platelets count > 30x109/L and at least a two-fold increase from the 
baseline count. This must be confirmed by at least 2 blood tests at least 7 days apart, and 
the absence of bleeding; 
The primary efficacy variable is achievement of R during the study (yes/no). 
 
Secondary efficacy endpoints: 
Part (percent) of patients with a complete response (CR). 
CR is determined according to the following criteria: 
- Patients with CR: platelets count > 100 x 109/L, which is confirmed by 2 blood tests 
performed at least 7 days apart and the absence of bleeding; 
 
Part (percent) of patients with no response (NR). 
NR is determined according to the following criteria: 
- Patients with NR: platelet count < 30 x 109/L or less than two-fold increase of baseline 
platelet count. This must be confirmed by at least 2 blood tests performed approximately 
1 day apart, or the presence of bleeding; 
 
Part (percent) of patients with loss of response (loss of R). 
Loss R is determined according to the following criteria: 
- Patients with loss R: a decrease platelet count < 30 x 109/L or less than two-fold increase 
of baseline platelet count, or the occurrence of bleeding. Platelet counts confirmed at least 
2 blood tests performed approximately 1 day apart. 
 
Part (percent) of patients with loss of complete response (loss of CR). 
CR loss is determined according to the following criteria: 
- Patients with loss of CR: decrease platelet count < 100 x 109/L, or the occurrence of 
bleeding. Platelet counts confirmed at least 2 blood tests performed approximately 1 day 
apart. 
 
Time (in days) from treatment start to onset of a response (R); 
Time (in days) from treatment start to onset of a complete response (CR); 
Duration (in days) of response (R); 
Duration (in days) of complete response (CR); 
 
Secondary efficacy endpoints are transformed into corresponding efficacy variables. 
 
Safety 
- Frequency (percent) of adverse events 
- Frequency (percent) of serious adverse events 
Summary data on study design, procedures, and statistical analysis plan: 
Study design:  
Screening phase 
The patient or their legal representative must sign an informed consent form. 


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After the informed consent form is signed, the screening tests are performed and the compliance 
with the inclusion / non-inclusion criteria is evaluated. The patient who passed the screening 
tests is enrolled in the study.1 
 
Clinical phase 
Patients enrolled in the study receive Bioven at a dose of: 
- 
0.8-1.0 g / kg intravenously once a day for 2 consecutive days, the course dose is 1.6-2.0 
g / kg. Allowed repeat course at same dosage in period 14-28 days from first infusion, if 
required. 
The СRF records the time of administration of the study drug, the occurrence of possible adverse 
events. 
Prescribed therapy and diagnostic results are recorded in the CRF based on the primary 
documentation. 
Data are entered into the CRF according to the patient management plan. 
 
Follow-up phase and completion of the study 
This stage lasts for 4 weeks after the last administration of the drug (possible repeat course is 
not considered). 
In all patients, the platelet count will be determined 48 hours after the start of the first 
administration of the study drug, on the 7th (± 1 day), 14th (± 2 days), 21st (± 3 days), 28th (+ 
1- 3 days) days after the start of therapy. 
The results of the study are evaluated by endpoints. 
Phase-by-phase breakdown and breakdown of visits are detailed in Section 6.4 “Tabulated 
schedule of events”. Information is entered into the CRF after each visit, according to the 
“Schedule of study events”.  
 
The decision on any examinations and diagnostic procedures in routine clinical practice is made 
and controlled by professionals.  
Blood sampling for platelet count is performed 6 times:  
­ 
at the screening phase; 
­ 
48 (± 3) hours after the start of study drug administration; 
­ 
on the 7th (± 1) day from the start of study drug administration; 
­ 
on the 14th (± 2) day from the start of study drug administration; 
­ 
on the 21st (± 3) day from the start of study drug administration; 
­ 
on the 28th (+ 1-3) day from the start of study drug administration. 
The time of each blood draw and the start time of drug administration should be recorded; during 
each administration of the drug, it is necessary to evaluate the physical data, such as heart rate, 
blood pressure, body temperature, respiratory rate, and the severity of hemorrhagic syndrome. 
Patients' serum samples should be stored frozen at the temperature of -65 - -85 ° C (second 
aliquot) to ensure the possibility of performing repeat laboratory tests if necessary, in the future.  
The study involves scheduled visits of patients to the doctor: 
1st visit (Day -14 – Day -1) – the patients are screened, checked for compliance with the criteria 
of inclusion / non-inclusion (exclusion), enrolled in the study; 
2nd visit (Day 0 - Day +1 – Day +2) – hospitalization, administration of the study drug for 2 
days, physical examination, assessment of the status of hemorrhagic syndrome, blood sampling 
to determine platelet count, manual platelet counts, Coombs test, Total IgG levels (g/l); 
 
1 Due to the variability in PLT levels in patients with chronic immune thrombocytopenia (wave-like), it is possible to re-screen or 
extend the duration of the screening stage, but only if the study subject meets all other specified inclusion criteria, does not have 
non-inclusion and exclusion criteria. 


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3rd visit (Day +7 ± 1 day) – physical examination, assessment of the status of hemorrhagic 
syndrome, blood sampling to determine platelet count, manual platelet counts, Coombs test in 
case hemolysis was detected during the previous visit (according to the laboratory data); 
4th visit (Day +14 ± 2 days) – physical examination, assessment of the status of the hemorrhagic 
syndrome, blood sampling to determine platelet count, manual platelet counts, Coombs test in 
case hemolysis was detected during the previous visit (according to the laboratory data). 
If a decrease of platelets count < 30 x 109/L was recorded, then approximately a day after the 
visit, an additional blood test is performed with a platelet count. 
This visit can be performed by telephone / video, provided that the patient's status can be 
adequately assessed and biomaterials for laboratory tests can be sampled in Local Laboratory or 
at the collection point of the or Central Laboratory designated by the Sponsor; 
5th visit (Day +21 ± 3 days) – physical examination, assessment of the status of hemorrhagic 
syndrome, blood sampling to determine platelet count, manual platelet counts, biochemical 
blood test, Coombs test in case hemolysis was detected during the previous visit (according to 
the laboratory data). 
If a decrease of platelets count < 30 x 109/L was recorded, then approximately a day after the 
visit, an additional blood test is performed with a platelet count. 
This visit can be performed by telephone / video, provided that the patient's status can be 
adequately assessed and biomaterials for laboratory tests can be sampled in Local Laboratory or 
at the collection point of the Central Laboratory designated by the Sponsor; 
6th visit (Day +28 + 1-3 days) – physical examination, assessment of the status of the 
hemorrhagic syndrome, blood sampling to determine platelet count, manual platelet counts, 
biochemical blood test, Coombs test, Total IgG levels (g/l). 
If a decrease of platelets count < 30 x 109/L was recorded, then approximately a day after the 
visit, an additional blood test is performed with a platelet count. 
This is a face-to-face visit. Completion of the study. 
Statistical analysis: 
Populations for statistical analysis: 
ITT (Intention-to-treat population) – all participants of the study who have taken the study drug 
at least once. The data obtained from this sample will be used for safety analysis. 
PP (Per Protocol) – all patients who have met the requirements of the protocol. This population 
includes all patients who received the protocol-prescribed therapy in full, who completed all the 
prescribed visits and did not have significant deviations from the protocol. The data obtained 
from this sample will be used for analysis based on efficacy criteria. 
Sample size calculation. 
Statistical analysis of endpoints will be descriptive with testing of the null hypothesis (non-
inferiority study). 
In accordance with the EU recommendations on the clinical investigation of human normal 
immunoglobulin for intravenous administration (Guideline on the clinical investigation of 
human 
normal 
immunoglobulin 
for 
intravenous 
administration 
(IVIg), 
EMA/CHMP/BPWP/94033/2007 rev. 4, 16 Dec 2021) the obtained results will be compared with 
literature data. 
Null hypothesis H0: p–p0 ≤ δ, where clinical efficacy p- is the part of patients who responded to 
therapy with BIOVEN 10%; p0 – part of patients responding to therapy according to literature 
data; δ is the limit of the difference of parts without clinical significance. Alternative hypothesis 
H1: p-p0 > δ 
The non-inferiority assessment is performed according to the EMA guideline "Points to consider 
on switching between superiority and non-inferiority" CPMP/EWP/482/99, London, July 27, 
2000, and the EMA guideline "ICH Topic E 9 Statistical Principles for Clinical Trials” 
CPMP/ICH/363/96. 


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To test the null hypothesis, a two-tailed test will be used, based on the principles of estimating a 
95% confidence interval for the difference in proportions and comparing it with the lower limit 
of equivalence (at a significance level of α 5%). For non-inferiority research, the null hypothesis 
is rejected if the following conditions are met: 
√n(p−p0 − δ) / pˆ(1 − pˆ)> zα/2 
or 
(p−p0 − δ) / ට(
𝑝𝑝(1−𝑝𝑝)
𝑛𝑛
+
𝑝𝑝0(1−𝑝𝑝0)
𝑛𝑛0
)> zα/2 
The sample size n in a group when comparing proportions for a study with no less efficiency is 
calculated by the formula (Chow, S. C., Wang, H., & Shao, J. (2007). Sample size calculations 
in clinical research. Chapman and Hall/CRC .): 
n=(Za/2+Zb/2)2×(p×(1–p))/ (p – p0 – δ)² 
According to the literature, the effectiveness of IVIG when used in patients with ITP ranges from 
60-80% [Anurag Singh, Günalp Uzun, Tamam Bakchoul / Primary Immune Thrombocytopenia: 
Novel Insights into Pathophysiology and Disease Management // J. Clin. Med. 2021, 10, 789. 
https://doi.org/10.3390/jcm10040789]. [Godeau B., Caulier M-T. Decuypere L. et al. 
Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of 
a randomized trial comparing 0´5 and 1 g/kg b.w. // British Journal of Hematology, 1999, 107, 
716-719; Ruqayyah J. Almizraq, Donald R. Branch Efficacy and mechanism of intravenous 
immunoglobulin treatment for immune thrombocytopenia in adults // Ann Blood 2021;6:2 | 
http://dx.doi.org/10.21037/aob-20-87; Drew Provan, Roberto Stasi, Adrian C. Newland et al. 
International consensus report on the investigation and management of primary immune 
thrombocytopenia // Blood, 14. - Jan 2010, Vol. 115, Number 2]). However, the most similar in 
performance evaluation standards and study design is the 2020 publication [Parodi E, Russo G, 
Farruggia P, Notarangelo LD, Giraudo MT, Nardi M, et al. Management strategies for newly 
diagnosed immune thrombocytopenia in Italian AIEOP Centers: do we overtreat? Data from a 
multicenter, prospective cohort study. Blood transfusion. 2020;18(5):396.], which indicates the 
effectiveness of IVIG in the treatment of ITP – 78% (the drug administration scheme 
recommended by the EMA and this Protocol, the total number of patients in the group is 82). 
According to our data and data from the literature, immunoglobulin belongs to drugs with a 
highly variable efficacy of 20-25%. Therefore, we consider it expedient to set the limit of the 
difference in efficacy δ between the obtained and expected results for non-inferiority research at 
-25%. 
Thus, for a significance level of 5% and a statistical power of 80%, the effectiveness of the 
comparison drug reaches 78%, the limit of the difference in fractions (difference in 
effectiveness) without clinical significance δ is -0.25. Then the calculation of the minimum 
sample size will look like this: 
n = (1,96+1,28)2×(0,78×(1–0,78) / (0,78 – 0,78+0,25)² = 29 
Taking into account the risk (20%) of dropping out of patients for various reasons, 36 patients 
will be included in the study. 
Methods of statistical analysis that will be used:  
Methods of descriptive statistics (for categorical variables – number and share in %, for 
quantitative variables – n, arithmetic mean, median, standard deviation, minimum and 
maximum), including plotting graphs and diagrams, interval estimation methods (plotting 95% 
confidence intervals for fractions and differences of fractions).  
To assess the significance of the dynamics in the case of evaluating a parameter at two visits 
(before and after) in the case of quantitative variables, the Student's t test for paired data or 
Wilcoxon signed rank test will be applied depending on the results of checking the normality of 
the distribution of differences [after - before] using the Shapiro-Wilk test. To assess the 
dynamics of categorical variables, we will use the McNimar test or the test of homogeneity of 


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marginal frequencies depending on the number of categories. To evaluate the statistical 
significance of differences in categorical variables in unrelated groups, we will use Pearson's 
chi-squared test or Fisher's exact test (depending on the frequency distribution in Table 2 * 2). 
To assess the dynamics in the case of measuring variables at more than two visits, methods 
of univariate variance analysis (Anova) will be used, followed by contrast analysis (simple 
contrasts) or a posteriori analysis using the Tukey's test. Covariance analysis (ANCOVA) will 
be used to compare the variables for which the data were inhomogeneous in the initial state. To 
check the prerequisites for applying variance and covariance analysis, the normality of the 
distribution of data and their balances will be checked using the Shapiro-Wilk test. If the 
balances are not distributed normally, or if the data does not pass the normality check, the 
corresponding rank analysis will be performed. For the Shapiro-Wilk test, the significance level 
will be 0.01, and for other criteria – 0.05. If the effect of multiple comparisons occurs, the 
significance level adjustment will be applied using the Holm method or the Benjamini–Hochberg 
procedure.  
Working with missing or incomplete data 
Missed or incomplete data will be replaced using the Last-Observation-Carried-Forward 
(LOCF) method, or the method of enlarging intervals for series where the transfer of the last 
measurement is not applicable. 
Conclusion on efficacy 
In accordance with the EMA recommendations on the clinical investigation of human normal 
immunoglobulin for intravenous administration (Guideline on the clinical investigation of 
human 
normal 
immunoglobulin 
for 
intravenous 
administration 
(IVIg), 
EMA/CHMP/BPWP/94033/2007 rev. 4, 16 Dec 2021) the obtained results will be compared with 
literature data The conclusion of non-inferiority of the drug Bioven, solution for infusions 10%, 
in the treatment of chronic immune thrombocytopenia, will be made according to the main 
efficacy variable using an approach based on confidence intervals. 
To do this, the calculated limits of the 95% confidence interval (CI) for the difference in the 
percentage of positive results according to the main variable ("the drug is effective") for the 
studied group must be compared with the limit of the non-inferiority zone - effectiveness that is 
not inferior (-25%) to the calculated based on data for comparison. If the lower limit of the CI is 
greater than the lower limit of the non-inferiority zone (non-inferiority), then it will be 
considered that the study drug is not inferior in effectiveness compared to literature data. A 
detailed description of statistical analysis is provided in the corresponding section of this 
Protocol. 
Examination methods: 
Examination methods are performed according to the schedule of events provided in the relevant 
section of the Protocol of this clinical trial. 
- 
Collection and recording of demographic data; 
- 
Collection and recording of medical history; 
- 
Verification of ITP diagnosis (according to primary documentation); 
- 
Recording information about previous ITP therapy (dose/schedule, duration, response (if 
any), and time interval since the last administration);  
- 
Recording information about symptomatic therapy and medication intake for the 
treatment of concomitant diseases;  
- 
Transfusion history;  
- 
History of allergies; 
- 
Determination of body weight; 
- 
Objective physical examination with mandatory assessment of the severity of 
hemorrhagic syndrome; 


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- 
Measurement of vital signs (blood pressure, heart rate, respiratory rate, body 
temperature); 
- 
Biomaterials sampling for laboratory tests is carried out at collection points or by mobile 
team of the Central Laboratory designated by the Sponsor: 
- 
Blood test for HIV and RW, PCR EBV, CMV; 
- 
Pregnancy test (for women of reproductive age) 
- 
Complete blood count (erythrocytes, reticulocytes, hemoglobin, hematocrit, white blood 
cells + expanded leukogram, platelets with manual counting; 
- 
Biochemical blood test (ALT, AST, creatinine, urea, glucose, total bilirubin); 
- 
Coombs test (antiglobulin test) 
- 
Determination of total IgG g / l in blood serum; 
- 
Urinalysis (specific gravity, pH, protein, glucose; sediment microscopy – white blood 
cells, red blood cells, cylinders, salts);  
- 
Coagulogram (PTI, APTT, fibrinogen) 
- 
Hepatitis B and C markers (Hbs-Ag, HCV);  
- 
Antinuclear antibodies (ANA); 
- 
12-lead ECG; 
Blinding, randomization: The study will be open, non-blinded  
 
 


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 GENERAL INFORMATION 
Protocol name, protocol identification number and date: 
Name: Open, multicenter, international study to evaluate the efficacy, safety, and tolerability of 
Bioven, manufactured by Biopharma Plasma LLC, in adult patients with chronic primary immune 
thrombocytopenia (ITP). 
Protocol identification number: 2021-BV-ITP-BP 
Version: 1.4 
Date:  from July 03, 2023 
Name and address of the sponsor and monitor (if different): 
Sponsor of the study: 
Name of organization: 
LLC “BIOPHARMA PLASMA” 
Address: 
37-V, Kyivska St, Bila Tserkva, Kyiv region 09100,Ukraine 
Phone: 
+380 (44) 277-36-10 
e-mail: 
info@biopharma.ua 
 
Contract Research Organization: 
Name of organization: 
MonitorCRO Monitor Medical Research and Consulting 
Trade LLC 
 
Address: 
Kumhuriyet Mahallesi, 2 Yeniol St., Beaumonti Plaza, 7th 
Floor, Office 58, 34380 Shishli/Istanbul 
 
Phone: 
+90 212 234 12 60 
 
e-mail: 
 info@monitorcro.com 
 
 
Name and position of persons authorized on behalf of the sponsor to sign the protocol and 
amendments to the protocol: 
Name: 
 Matsybokh Sofiia 
Position: 
 Clinical trial lead 
Name of organization: 
LLC “BIOPHARMA PLASMA” 
Address: 
Kyiv, Amurska street, 6 
Phone: 
 +38(067) 249 68 69 
e-mail: 
s.matsybokh@biopharma.ua   
 
Name, position, address, and telephone number of the sponsor-designated medical expert for 
this study: 
Expert's name: 
 Svitlana Donska 
Expert position: 
Medical advisor  
Name of organization: 
LLC “BIOPHARMA PLASMA” 
Address: 
Kyiv, Amurska street, 6 
Phone: 
+38(050) 545 98 51 
e-mail: 
s.donska@biopharma.ua 
 


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Name and position of researchers responsible for the study, as well as addresses and 
telephone numbers of clinical centers: 
Researcher's name: 
Yermolytska Iryna Pavlivna 
Researcher position: 
Head of the hematology department 
Name of organization: 
Municipal Non-Profit Enterprise "Kirovohrad Regional 
Hospital of the Kirovohrad Regional Council" 
Address: 
 
Kropyvnytskyi, University Avenue, 2/5 
Phone:  
+38 (050) 992 89 32 
e-mail: 
gematolog_kr@ukr.net 
 
Researcher's name: 
Masliak Zvenyslava Volodymyrivna 
Researcher position: 
Head of the hematology department 
Name of organization: 
State Institution "Institute of Blood Pathology and 
Transfusion Medicine of the National Academy of Medical 
Sciences of Ukraine" 
Address: 
 
Lviv, Generala Chuprinky street, 45 
Phone:  
+38 (032) 237 77 55 
e-mail: 
zvenyslava_masliak@yahoo.com 
 
 
Researcher's name: 
Khokhliuk-Alekseichuk Liudmyla Yevhenivn 
Researcher position: 
Head of the regional center of blood diseases and 
coagulopathies 
Name of organization: 
Сommunal enterprise "Rivne regional clinical hospital" of 
Rivne regional council 
Address: 
 
Rivne, Kyivska street, 78-G 
Phone:  
+38 (067) 274 37 32 
e-mail: 
khokluk67@gmail.com 
 
Researcher's name: 
Popovych Yurii Yuriiovych 
Researcher position: 
Candidate of Medical Sciences, Associate Professor, Head of 
the Hematology Department 
Name of organization: 
Municipal Non-Profit Enterprise «Zakarpattia Regional 
Clinical Hospital named after Andriy Novak» of the 
Zakarpattia Regional Council 
Address: 
 
Uzhhorod, Kapushanska street, 22 
Phone:  
+38 (066) 534 48 08 
e-mail: 
popovych.yuriy@ukr.net 
 
 
Researcher's name: 
Sivkovych Svitlana Oleksiivna 


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Researcher position: 
Director of the Kyiv City Hematology Center on the basis of 
the hematology department 
Name of organization: 
Municipal Non-Profit Enterprise «Kyiv City Clinical 
Hospital» executive body of the Kyiv City Council 
Address: 
 
Kyiv, Ryzhska, 1 
Phone:  
+38050 352 47 19 
e-mail: 
Alexey.kalyuta@gmail.com 
 
Researcher's name: 
Karnabeda Oksana Andriivna 
Researcher position: 
Resident doctor of the hematology department 
Name of organization: 
Medical Centre «ARENSIA Exploratory medicine», LLC, 
department of clinical research 
Address: 
 
Kyivs'ka oblast', selo Kapitanivka, vul. Soborna 21-B 
Phone:  
+38050 353 91 05 
e-mail: 
Oksana.karnabeda@arensia-em.com 
 
Names and addresses of clinical laboratories and other medical and / or technical services 
and / or organizations involved in the study. 
Name of organization: 
LLC "ML" DILA " 
Address: 
 
Kyiv, Podvysotskoho street, 6A 
Phone:  
+38 (044) 201-59-80 
e-mail: 
info@dila.com.ua 


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JUSTIFICATION OF THE STUDY 
 
2.1 
 Introduction 
 
Primary immune thrombocytopenia (ITP) is an acquired immune mediated disorder 
characterized by isolated thrombocytopenia, defined as a peripheral blood platelet count less than 
100 x 109 /L, and the absence of any underlying cause. Until recently, the abbreviation ITP stood 
for idiopathic thrombocytopenic purpura, but due to the current knowledge of the immune 
mediated mechanism of the disease, and the absence or minimal signs of bleeding in most cases 
have led to a revision of the terminology. 
In Europe, adult ITP has an incidence of 1.6 to 3.9 cases per 100,000 per year with increasing 
incidence with older age and equal for the sexes except in the mid-adult years (30-60 years), when 
the disease is more prevalent in women. Childhood ITP has an incidence of between 1.9 and 6.4 
per 100,000 per year with equal distribution between the sexes. [1] 
ITP is classified by duration into newly diagnosed, persistent (3-12 months’ duration) and 
chronic (≥ 12 months’ duration). Whereas ITP in adults typically has an insidious onset with no 
preceding viral or other illness and it normally follows a chronic course, ITP in children is usually 
short-lived with at least two-thirds recovering spontaneously within 6 months. [1] 
Signs and symptoms vary widely. Many patients have either no symptoms or minimal 
bruising, whereas others experience serious bleeding, which may include gastrointestinal 
hemorrhage (GI), extensive skin and mucosal hemorrhage, or intracranial hemorrhage (ICH). The 
severity of thrombocytopenia correlates to some extent but not completely with the bleeding 
risk. Additional factors (eg, age, lifestyle factors, concomitant medications, congenital or acquired 
coagulation disorders) affect the risk and should be evaluated before the appropriate management 
is determined.Although death from bleeding is a serious problem, it has been reported that the 
estimated incidence of fatal bleeding ranges from 0.02 to 0.04 cases per adult patient-year risk. 
The diagnosis of ITP is an exclusion diagnosis when the history, physical examination, 
complete blood count, and examination of the peripheral blood smear do not suggest other 
etiologies for the thrombocytopenia [2]. Physical examination should be normal aside from 
bleeding manifestations. The isolated thrombocytopenia with normal indicators of red blood cells 
and white blood cells are defined in the complete blood count. Anemia caused by significant blood 
loss may be present but it should be proportional to the amount of bleeding and may result in iron 
deficiency. The normal or big size of platelets may indicate in a peripheral blood smear, in the 
same time there should be no deviations in morphology of red blood cells and white blood cells. 
Currently, bone marrow examination is usually not performed in patients with typical 
manifestations of ITP, but it can be conducted only in some cases, such as atypical manifestations. 
The main goal of ITP treatment is to provide a platelet count that can prevent massive bleeding, 
rather than adjusting the platelet count to normal.  Treatment of ITP should be selected individually 
for each patient and it is rarely indicated in patients with platelet counts above 50 × 109/L in the absence 
of bleeding, trauma, surgery or high-risk factors (persons who receive anticoagulation therapy). The 
threshold value of the number of platelets required for the diagnosis of ITP is 100 x 109/L [2].  In some 
patients the disease may be asymptomatic, in others - manifested by hemorrhagic syndrome with 
different severity. It is known that at the level of platelets 30-50 x 109/L due to minor trauma excessive 
ecchymoses occur and at the level of platelets 10-30x109/L - spontaneous ecchymoses occur. Severe 
hemorrhagic syndrome occurs at a platelet count ≤ 10 x 109/L. [3]. 
The management of ITP varies widely and current international guidelines recommend several 
first- and second-line options, including some medicinal products that have not been approved in 
the EU for this particular condition. 


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First line treatment options include corticosteroids, intravenous immunoglobulin (IV Ig) and 
intravenous anti-D immunoglobulin (the latter only for non-splenectomised Rhesus-D positive 
patients). Patients who fail to respond or who relapse face the options of treatment with second 
line drug therapy or splenectomy but there is no clear evidence to support the best approach. 
Splenectomy can provide long term efficacy in around 60% of cases. Second line drug therapies 
include high dose corticosteroids, high dose IV Ig or anti-D Ig, vinca alkaloids and danazol, the 
immunosuppressants cyclophosphamide, azathioprine and cyclosporine or mycophenolate 
mofetil, and the anti-CD-20 monoclonal antibody [4]. 
IVIg have been used in the treatment of ITP since 1981, after the publication of P. Imbach et 
al., Which proved the high effectiveness of IV Ig in the treatment of ITP in children. [5]. 
The therapeutic effects of IV Ig in ITP include: 
­ 
blockade of neonatal Fc receptors on the surface of endothelial cells and acceleration 
of catabolism of the whole pool of plasma immunoglobulins, including antiplatelet 
antibodies;  
­ 
inhibition of FcγRIIIa- receptors and phagocytosis mediated by them; 
­ 
suppression of the expansion of autoreactive lymphocytes by signal transduction 
through FcγRIIIa; 
­ 
idiotype-mediated inhibition of B-cell receptors and neutralization of cytokines-
survival factors: B-cell activation factor (BAFF) and proliferation-promoting ligand 
(APRIL) [6,7,8]. The binding of anti-idiotypic antibodies (BP) to membrane-bound 
Ig G or Ig M B-lymphocytes can transmit inhibitory signals and reduce the 
production of pathogenic auto-BP [9]; 
­ 
utilization of active components of complement [10]. 
In addition, IV Ig drugs cause immune tolerance by modulating subpopulations of T-
lymphocytes, namely T-reg- increasing their number and changing the quality of the composition 
[11]. 
It is likely that the effect of Ig G therapy in time exceeds the half-life of IV Ig [12]. 
Immunoglobulin drugs for intravenous administration are not generic drugs and cannot not be 
interchangeable [15,16]. 
Clinical studies on the efficacy of intravenous immunoglobulin Bioven 10% solution for 
infusion in immune thrombocytopenia have not been performed. 
 
2.2 
Name and description of the investigational drug. 
 
Composition: 
active substance: Human normal immunoglobulin for intravenous administration; 
1 ml of the drug contains 0.1 g of normal human immunoglobulin; 
excipients: glycine (aminoacetic acid), water for injections. 
Pharmaceutical form. Solution for infusion. 
General physical and chemical properties: transparent or slightly opalescent, colorless liquid or 
liquid with slightly yellowish color. 
Pharmacotherapeutic group. Human normal immunoglobulin for intravenous administration. Code 
АТС J06B A02. 
Pharmacological properties. 
Pharmacodynamics properties. 
The product is an immunologically active protein fraction (ratio of immunoglobulin G subclasses 
in the drug product: IgG1: 65.6 %, IgG2: 22.1 %, IgG3: 10.8 %, IgG4: 1.5 %) max. content of 
immunoglobulin A in the drug product is 50 µg/ml. 


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Active components of the product are antibodies that have a specific activity against different 
pathogenic agents such as viruses and bacteria including hepatitis A and B, cytomegalovirus, 
human herpes virus type 1, type 2 and type 6, Epstein-Barr virus, chicken pox, influenza, measles, 
parotitis, poliomyelitis, German measles, whooping cough, staphylococcus, Escherichia coli, 
pneumococcus, tetanus and diphtheria toxins. It also has a non-specific activity to increase 
organism resistance. 
The drug product has a low spontaneous anticomplementary activity. 
The drug product is a native immunoglobulin G and retains all biological properties: complement 
activation; effector and opsonocytophagic function. 
The product is an immunologically active protein fraction extracted from human blood serum or 
plasma and screened negative for antibodies to HIV-1, HIV-2, hepatitis C virus and surface antigen 
of hepatitis B virus, purified and concentrated by use of the fractionation method with water-
alcohol precipitating agent that passed the phase of virus inactivation by use of solvent-detergent 
method and nanofiltration method. 
Clinical studies 
In an open-label international multicenter phase III study, according to the Guideline on the clinical 
investigation of human normal immunoglobulin for intravenous administration (IVIg) 28 June 
2018 EMA/CHMP/BPWP/94033/2007 rev.3 Committee for Medicinal Products for Human Use 
(CHMP) the efficacy, safety and some parameters of the pharmacokinetics of Bioven were studied 
in patients with primary immunodeficiency (PID). Patients received Bioven for 1 year once during 
every 4 weeks at an average dose of 0.5 g / kg body weight. Patients were evaluated for 
immunoglobulin levels, the number of cases of infections, clinical and biochemical blood tests. 
The most important indicators of heart function, respiration, body temperature were determined, 
and all cases of possible adverse reactions were recorded. 
During 1 year of treatment, one case of serious infectious diseases was recorded (2.3%, or 0.023 
cases per 1 patient per year). The median minimum concentration of immunoglobulin in blood 
plasma was significantly higher than the minimum target level of 5 g/l and after 6 months of 
treatment was 8.6 g/l, and after 1 year - 8.8 g/l. 
In the group of 49 patients receiving Bioven, 20 cases of mild (2%) and moderate (0.5%) adverse 
events were reported, representing a total of 2.5% of episodes of administration. There were no 
cases of clinically significant abnormalities in laboratory tests that were associated with drug 
administration or required discontinuation of treatment. In 18 patients (adults and children), 
Bioven was administered at increasing infusion rates. At the first stage of the study, the rate of 
administration was increased to 5.0 ml/kg/h (0.08 ml/kg/min); in the second stage - up to 7.0 
ml/kg/h (0.11 ml/kg/min). The maximum rate of administration in the third stage was 8.5 ml/kg/h 
(0.14 ml/kg/min). The incidence of adverse events was low (2 cases per 35 separate injections), 
they were mild in nature and did not correlate with the infusion rate. Based on the prevalence of 
side effects and assessment of the dynamics of the main vital signs, the tolerability of Bioven at a 
maximum rate of 8.5 ml/kg/h (0.14 ml / kg / min) in 94.0% of patients was assessed as good, in 
6.0% - as satisfactory. 
The clinical efficacy of Bioven in the complex therapy of patients with severe pneumonia caused 
by coronavirus infection COVID-19 / SARS-CoV-2 is provided by its ability to have an 
immunomodulatory effect. As a result, the severity of acute respiratory distress syndrome is 
reduced and, consequently, the degree of respiratory failure is reduced. 
The clinical efficacy was confirmed in the clinical study "Open multicenter randomized study of 
the effectiveness of Bioven, manufactured by Biopharma Plasma, evaluation in the treatment of 
patients with pneumonia caused by coronavirus infection COVID-19 / SARS-CoV-2" (code 
research - 2020-BV-BP). 


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The study involved 76 patients with a confirmed diagnosis by all criteria. 66 patients who were 
screened and did not have exclusion criteria were randomized into 2 groups (study group - Bioven 
+ basic therapy and control group - only basic therapy). 
Patients were determined by the indicators of the respiratory system, general condition, duration 
of the need for intensive care, the need for artificial lung ventilation (ALV), the total duration of 
treatment. Survival during the 28-day follow-up period, laboratory blood counts (general analysis 
and biochemical), as well as cytokine levels, inflammatory factors and other indicators of the 
immune system were also assessed. 
The results of the study proved the predominant efficiency of the main variable. 
Improvement occured significantly faster: in the study group - on day 5 (interquartile range - 3.50- 
7.25 days), in the control group - on day 9 (interquartile interval - 6.00-14.75 days), p = 0, 0073. 
The probability of achieving stabilization in patients of the study group was significantly higher 
by 2.27 times (95% confidence interval (CI) - 1.26-4.11, p = 0.006) than in patients from the 
control group. 
The predominant efficiency is also confirmed by secondary variables. The mortality from COVID-
19 was significantly lower, when Bioven was used: 6.25% in the study group (2 cases out of 32 
participants), and 23.63% in the control group (8 cases out of 34 participants), p = 0.039. 
The duration of lymphopenia was also significantly reduced. The median time to achieve the level 
of lymphocytes 1000 cells/mm3 and above in the study group was 4 days (interquartile range - 
3.00-5.00 days), in the control group - 7 days (interquartile range - 3.00-7.50 days), p = 0.0097. 
Pharmacokinetics properties. 
The high level of efficacy of the Bioven product is provided by a fast and 100% entrance of 
antibodies into bloodstream as well as by normal elimination half-life. 
After intravenous administration the bioavailability of the normal human immunoglobulin in the 
circulating blood is immediate and complete. It is rapidly distributed between the plasma and 
extravascular liquid, and the balance between intra- and extravascular compartments is reached in 
approximately 3-5 days. 
For normal human immunoglobulin the half-life is approximately 40 days. This half-life period 
can differ from patient to patient, especially in case of primary immunodeficiency. IgG and IgG-
complexes degrade in reticuloendothelial system cells. 
A clinical study of individual pharmacokinetic parameters of Bioven was performed and involved 
22 patients. Сmax was 19.94 ± 4.73 g/l, Tmax – 0,63 hours, AUC(0-t) – 8309.60 ± 2631.49 g/year 
/l. The content of immunoglobulin in blood plasma was consistently kept above the minimum 
target level of 5 g/l for at least 28 days after a single administration of Bioven. 
Clinical particulars. 
Therapeutic indications. 
The product should be used for adults, children and adolescents for replacement immunotherapy 
in the treatment of primary and secondary immunodeficiency and related diseases: 
- 
primary 
immunodeficiency 
syndromes: 
congenital 
agammaglobulinemia, 
hypogammaglobulinemia, 
severe 
combined 
immunodeficiency, 
unclassified 
variable 
immunodeficiency, Wiskott — Aldrich syndrome;- secondary antibody deficiency syndrome: 
cytopenia of different genesis (acute and chronic leukemia, aplastic anemia, situation after 
cytostatic therapy), severe bacterial and toxic and viral infections (including surgical 
complications accompanying by bacteremia and septicopyemic conditions and for preparation of 
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- autoimmune diseases: idiopathic thrombocytopenic purpura with a high risk of bleeding or prior 
to surgical intervention to correct platelet level, Guillain— Barre syndrome, chronic inflammatory 
neuropathy 
(demyelinating), 
inflammatory 
myopathy, 
Wegener's 
granulomatosis, 
dermatomyositis, systemic diseases of connective tissue (rheumatoid arthritis etc.), Kawasaki 
disease; 
- bone marrow transplantation. 
Replacement therapy in adults, children, and adolescents (0 - 18 years) in: 
- syndromes of primary immunodeficiency (PID) deficiency of antibodies’ production; 
- secondary immunodeficiency (SID) in patients who suffers from severe or recurrent infections, 
ineffective antimicrobial treatments and either proven specific antibody failure (PSAF)* or serum 
IgG level of <4 g / L. 
* PSAF= failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal 
polysaccharide and polypeptide antigen vaccines. 
Use as part of the complex therapy of adult patients with severe pneumonia caused by coronavirus 
infection COVID-19 / SARS-CoV-2 
 
 
 


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2.3 
Summary of clinical trial results 
Table 1 
1 
2 
Study name 
Clinical study report «Open multicenter randomized study to evaluate the effectiveness 
of Bioven, manufactured by LLC “Biopharma Plasma”, in the complex therapy of 
patients with pneumonia caused by coronavirus infection COVID-19 / SARS-CoV-2» 
Year 
2020 
Clinical center 
Communal non-commercial enterprise “Kyiv City Clinical Hospital No.17”. Department 
of Anesthesiology and Intensive Care. 
 
Communal non-commercial enterprise of Bila Tserkva City Council “Bila Tserkva City 
Hospital No.3”, III Infectious Diseases Department.  
 
Communal non-commercial enterprise of Lviv Regional Council “Lviv Regional 
Clinical Hospital for Infectious Diseases”, Department of Resuscitation and Intensive 
Care  
 
Communal non-commercial enterprise “City Clinical Hospital for Infectious Diseases” 
of Odessa City Council, infectious boxing department No.10. 
 
Communal non-commercial enterprise “Kyiv City Clinical Hospital No.4” of the 
executive body of the Kyiv City Council (Kyiv City State Administration), Department 
of Anesthesiology and Intensive Care of Infectious Patients. 
 
Vinnytsia National Pirogov Memorial Medical University, Department of Infectious 
Diseases with a course in epidemiology, Vinnytsia National Pirogov Memorial Medical 
University on the basis of the infectious department of the communal non-commercial 
enterprise “Vinnytsia City Clinical Hospital No.1”. 
 
Communal non-commercial enterprise “Ternopil City Municipal Ambulance Hospital”, 
Infectious Diseases Department. 
 
Communal non-commercial enterprise “Central City Clinical Hospital of Ivano-
Frankivsk City Council”, therapeutic department No.1. 
 
Communal enterprise “Volyn Regional Clinical Hospital” of the Volyn Regional 
Council, Department of Pulmonology. 
Type 
Efficacy and safety 
Identifier 
2020-BV-BP 
Design and type of 
control 
Open, multicenter, randomized, controlled, in parallel groups 
Investigated drug: 
-dose; 
-regime; 
-way of administration 
 
0.8-1.0 g/kg 1 time per day; 
for 2 days  
i.v. drip, 1 ml / min 
Number of subjects 
76 
Healthy / diagnoses of 
the patients 
Severe pneumonia, according to the criteria (Appendix 10 to the “Standards of medical 
care “CORONAVIRUS DISEASE (COVID-19)”, approved by the Order of the Ministry 
of Health of Ukraine from 28.03.2020 № 722 “Organization of medical care for patients 
with coronavirus disease (COVID-19)”) 
Duration of treatment 
Shortterm (2 days) 
Study status and report 
type 
Finished. Full.  
Results 
General Conclusion: 
1) The predominant efficacy by the main variable in the inclusion of BIOVEN 
in the complex scheme of treatment of patients with pneumonia caused by coronavirus 
infection COVID-19 / SARS-CoV-2 has been proven. The median of achievement of 


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normalization in the study group – 5 days (interquartile range – 3.50-7.25 days), in the 
control group – 9 days (interquartile range – 6.00-14.75 days), (p = 0.0073). The 
probability of achieving stabilization in patients of the study group is significantly 2.27 
times higher (95% CI – 1.26-4.11), (p = 0.006) than in patients from the control group. 
2) The predominant efficacy is also confirmed by secondary variables. When 
using Bioven treatment regimen, mortality from COVID-19 is significantly lower: in 
the study group – 6.25% (2 cases out of 32 participants) in the control group – 23.63% 
(8 cases out of 34 participants), (p = 0.039). 
The duration of lymphopenia is also significantly reduced. The median of 
achievement of the level of lymphocytes 1000 cells/mm3 and above in the study group 
– 4 days (interquartile range – 3.00-5.00 days), in the control group – 7 days 
(interquartile range – 3.00-7.50 days), (p = 0.0097). 
3) For all safety variables the drug BIOVEN has shown a high safety profile 
when used in the complex therapy of patients with pneumonia caused by coronavirus 
infection COVID-19 / SARS-CoV-2. 
Bioven was well tolerated by patients, adverse effects and significant deviations 
of laboratory parameters associated with administration in the study were not recorded. 
There were no serious adverse effects associated with the drug. 
Thus, the superior efficacy and high safety of the drug BIOVEN in the complex therapy 
of patients with pneumonia caused by coronavirus infection COVID-19 / SARS-CoV-2 
was confirmed. The drug can be used for the treatment and prevention of complications 
in patients with COVID-19 / SARS-CoV-2 (course dose – 1.6-2.0 g/kg body weight). 
 
Table 2 
1 
2 
Study name 
Open, international, multicenter study to evaluate the efficacy, safety, tolerability and some 
parameters of the pharmacokinetics of the drug Bioven, solution for infusion 10% 
manufactured by LLC “Biopharma Plasma”, in patients with primary immunodeficiency. 
Year 
2017-2020 
Clinical center 
Department of Clinical Immunology, Danylo Halytsky Medical University, Regional Clinical 
Hospital, Lviv, Ukraine. 
Western Ukrainian Center for Pediatric Immunology, Lviv, Ukraine 
Department of Pediatric Infectious Diseases and Pediatric Immunology Shupyk National 
Healthcare University of Ukraine, Kyiv city children clinical hospital № 1, Kyiv, Ukraine. 
State Institution "Republican Scientific and Practical Center for Radiation Medicine and 
Human Ecology", Gomel, Republic of Belarus. 
Type 
Efficacy 
Safety 
Pharmacokinetics 
Identifier 
1601-BV-BF 
Design and type of 
control 
Open, multicenter, non-comparative, uncontrolled, prospective 
Investigated drug: 
-dose; 
-regime; 
-way 
of 
administration 
 
0.2–0.8 (average 0.5) g / kg of body weight 
1 time per 3-4 weeks for 52 weeks (14 infusions in total) 
i.v. drip, up to 8.5 ml / min 
Number of subjects 
54 
Healthy / diagnoses of 
the patients 
Humoral and combined primary immunodeficiencies 
Duration of treatment 
52 weeks (14 infusions in total) 
Study 
status 
and 
report type 
Finished. Full. 
Results 
Patients were evaluated for immunoglobulin levels, the number of cases of infections, 
clinical and biochemical blood tests. The most important indicators of heart function, 
respiration, body temperature were determined, and all cases of possible adverse reactions 
were recorded. 


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During 1 year of treatment, one case of serious infectious diseases was recorded (2.3%, or 
0.023 cases per 1 patient per year). The median minimum concentration of immunoglobulin 
in blood plasma was significantly higher than the minimum target level of 5 g/l and after 6 
months of treatment was 8.6 g/l, and after 1 year - 8.8 g/l.   
In the group of 53 patients receiving Bioven, 20 cases of mild (2%) and moderate (0.5%) 
adverse events were reported, representing a total of 2.5% of episodes of administration. 
There were no cases of clinically significant abnormalities in laboratory tests that were 
associated with drug administration or required discontinuation of treatment. 
In 18 patients (adults and children), Bioven was administered at increasing infusion rates. 
At the first stage of the study, the rate of administration increased to 5.0 ml/kg/h (0.08 
ml/kg/min); in the second stage - up to 7.0 ml/kg/h (0.11 ml/kg/min). The maximum rate of 
administration in the third stage was 8.5 ml/kg/h (0.14 ml/kg/min). The incidence of adverse 
events was low (2 cases per 35 separate injections), they were mild in nature, did not 
correlate with the infusion rate. Based on the prevalence of side effects and assessment of 
the dynamics of the main vital signs, the tolerability of Bioven at a maximum rate of 8.5 
ml/kg/h (0.14 ml/kg/min) in 94.0% of patients was assessed as good, in 6.0% - as 
satisfactory. 
The study of individual pharmacokinetic parameters of the drug Bioven was performed in a 
group of 23 patients. Cmax was 19.94 ± 4.73 g/l, Tmax was 0.63 hours, AUC (0-t) was 
8309.60 ± 2631.49 g/h/l. The content of immunoglobulin in blood plasma was consistently 
kept above the minimum target level of 5 g/l for at least 28 days after a single injection of 
Bioven. 
 
Table 3 
1 
2 
Study name 
Clinical study report "Evaluation of the effectiveness and tolerability of Bioven, 10% 
solution for infusion manufactured by PJSC" Biopharma "in comparison with Octagam®, 
solution for infusion manufactured by" Octafarma Pharmaxeuticaka Produktins "in patients 
with severe influenza complicated by pneumonia ». 
Year 
2011 
Clinical center 
Department of Infectious Diseases, Dnipropetrovsk National Medical Academy 
Type 
Effectiveness and tolerability 
Identifier 
1009 BF/BV/sol/DSMA 
Design and type of 
control 
Parallel, randomized, active control 
Investigated drug: 
-dose; 
-regime; 
-way 
of 
administration 
 
0.4 g / kg / day; 
once; 
i.v. drip, 1 ml / min 
Number of subjects 
60 
Healthy / diagnoses of 
the patients 
Influenza: severe, complicated by pneumonia (J11.0) 
Duration of treatment 
Short term (4 days) 
Study 
status 
and 
report type 
Finished. Full. 
Results 
In the process of the clinical study, the dynamics of clinical indicators of pneumonia and 
data from bacteriological examination of sputum was studied to assess the effectiveness of 
the investigated and reference drugs. In parallel, the tolerability of drugs was assessed taking 
into account the frequency of occurrence and the nature of adverse reactions. 
The following results were obtained: 
1. The Bioven, has shown high efficacy during prescribing in combination with 
antimicrobial agents in the treatment of patients with severe influenza complicated by 
pneumonia. The effectiveness of the treatment was 96.67%, which did not significantly 
differ from corresponding value in the control group.  


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2. The use of the Bioven contributed to the rapid reduction of clinical manifestations of 
pneumonia, normalization of laboratory blood parameters, normalization of basic 
immunological parameters that characterise the state of cellular immunity. There were no 
significant differences in the rate and degree of reduction of the main symptoms of the 
disease with the control group receiving the comparison drug Octagam ®, a solution for 
infusion manufactured by Octapharma Pharmazeutika Produktions. 
3. The occurrence of adverse reactions and side effects, adverse changes in laboratory 
parameters of blood and urine, objective observation data was not observed during the use 
of the investigated product. The investigated product Bioven showed good tolerability in 
100% of subjects. 
4. The data of the conducted study allow us to conclude that the studied drug Bioven, 10% 
solution for infusions manufactured by PJSC "Biopharma" is therapeutically equivalent to 
the comparison drug Octagam®, solution for infusions manufactured by Octapharma 
Pharmazeutika Produktions in terms of overall effectiveness. 
 
 
 


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2.4 A brief description of the known and anticipated risks and benefits (if any) for the 
subjects 
 
Contraindications. 
Hypersensitivity to any component of the drug. Hypersensitivity to homological 
immunoglobulins, especially in very rare cases of IgA deficiency when patient develops antibodies 
to IgA. Immunoglobulin administration is contraindicated for persons who have in their history 
any severe allergic reactions caused by human blood protein products administration. Patients with 
allergic diseases or predisposed to allergic reactions are recommended to use antihistamines during 
immunoglobulin administration and for the next 8 days. For persons with immunopathological 
systemic diseases (blood immune diseases, collagenosis, nephritis etc) the product should be 
prescribed after consultation with a specialist. During periods of allergic processes exacerbation, 
administration of the product should take place only after medical assessment by an allergist in 
accordance with life-saving indications. 
 
Special warnings and precautions for use. 
Some serious adverse reactions may be caused to the rate of product administration. Patients 
who receive immunoglobin for the first time usually experience a slight adverse reaction more 
frequently than those who receive immunoglobulin therapy regularly. The parameters of 
administration rate mentioned below should be followed and patients should be closely monitored 
both during infusion and for 1 hour after completion of the first infusion. In case of any adverse 
reactions infusion rate should be reduced or infusion itself should be stopped until undesirable 
symptoms disappear. If after administration stopping symptoms persist then symptomatic therapy 
is reasonable. In case of shock, appropriate anti-shock therapy should be initiated. The level of 
creatinine should be measured in patients with diabetes mellitus and with a risk of renal failure as 
well as in patients with systemic lupus erythematosus with kidney involvement for 3 days after 
administration of the product. During following infusions patients should be thoroughly monitored 
for 20 minutes from the moment of product administration completion. 
 
BIOVEN should only be used in a clinical setting of hospital and in compliance with aseptic 
requirements. Before administration vials should be kept at a temperature of (20±2) °С for at least 
2 hours. Solution must be transparent or slightly opalescent, colorless or of slightly yellowish 
color. Do not use if solution is cloudy or contains precipitate. A separate infusion system should 
be used for administration of the product. Special warnings and precautions for use.. 
 
Interference with serological testing 
After immunoglobulin injection a temporary increase of different antibodies blood level that 
are passively transferred can result in false positive results of serologic analyses. 
Passive transfer of antibodies to red blood cells antigens, for example, A, B or D can have an 
impact on some serologic tests for determination of alloantibodies to red blood cells (for example, 
Coombs test), reticulocyte count and haptoglobin. 
 
Particular of use. 
Precautions for product administration 
Some severe adverse reactions may relate to product infusion rate. The recommendations on 
infusion rate should be followed strictly. A patient condition should be monitored closely and 
special attention to occurrence of any symptoms during the whole period of infusion should be 
paid. 
Some adverse reactions can occur more often: 
Відформатовано: Відступ: Перший рядок:  0,5 см


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-in the case of a high infusion rate; 
-in patients who receive normal human immunoglobulin for the first time or in rare cases of 
change to normal human immunoglobulin or when a long period of time has passed from the 
moment of the previous infusion. 
 
Any potential complications can be prevented if it is ensured that: 
-a patient is not sensitive to human normal immunoglobulin during the first slow infusion of 
the product; 
-a patient is closely monitored for occurrence of any symptoms during the whole period of 
infusion. To identify signs of a potential negative impact during the first infusion and during the 
first hour after infusion it is essential to monitor condition of a patient who have not previously 
received immunoglobulin products, who received therapy using alternative products or after a long 
period of time has elapsed since the last immunoglobulin administration. Such patients require 
monitoring during the whole period of the first infusion as well as for 1 hour after administration 
is completed. All other patients should be monitored for the first 20 minutes after administration. 
 
In case of any adverse reaction in is necessary to either decrease infusion rate or stop infusion. 
Treatment required depends on the nature and severity of adverse reaction. In case of a shock 
measures should be taken in accordance with approved recommendations on anti-shock therapy. 
For all patients in case of IgG administration it is necessary to: 
-perform an adequate hydration before starting IgG infusion; 
-monitor diuresis; 
-monitor blood serum creatinine level; 
-avoid a concomitant use of loop diuretics. 
Hypersensitivity 
Some serious allergic reactions can occur. Because of this, persons who have received the 
product must be monitored for 30 minutes. In case of occurrence of such reactions administration 
of Bioven product through infusion should be immediately stopped and appropriate therapy should 
be assigned. In patients with deficiency of immunoglobulin A and antibodies to immunoglobulin 
A there is a significant risk of development of some serious allergic and anaphylactic reactions 
that can occur in connection with BIOVEN product administration. 
In rare cases human normal immunoglobulin can cause a decrease in arterial pressure with an 
anaphylactic reaction even in the patients who have previously received human normal 
immunoglobulin. 
Renal failure 
Some cases of renal failure were reported in patients who received IgG therapy. They include 
acute renal failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis. In 
most cases such risk factors were identified as preliminary existing renal failure, diabetes mellitus, 
hypovolemia, excess body weight, concomitant use of nephrotoxic drug products, age 65 years or 
older, sepsis or paraproteinemia. 
The reports about renal dysfunction and acute renal failure were associated with use of many 
licensed IgG products containing different excipients, such as sucrose, glucose and maltose 
Particularly large number of the total number of such reports were connected to medicines that 
were containing sucrose as stabilizer. In patients with increased risk IgG products that do not 
contain excipients mentioned above may be considered. 
Before start of BIOVEN product infusion it should be ensured that a patient does not have signs 
of dehydration. 
For the patients with a potential risk of acute renal failure a regular monitoring of renal function 
and diuresis should be performed. Renal function parameters including blood urea nitrogen 


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(BUN)/ blood serum creatinine should be assessed before starting the first administration of the 
BIOVEN product and with regular intervals thereafter. In case of the renal function deterioration 
administration of the product should be stopped. 
For patients with a potential risk of renal function impairment and/or thrombotic complications 
development amount of BIOVEN administered per unit time should be carefully reduced. 
Hyperproteinemia. 
Hyperproteinemia, increased blood serum viscosity and hyponatremia can occur in patients 
who receive therapy with immunoglobulin. Hyponatremia may appear to be a pseudohyponatremia 
that can manifest itself as a decreased calculated osmolarity of plasma and as an increase of 
osmolarity interval. It is clinically important to distinguish actual hyponatremia from 
pseudohyponatremia as in case of decrease of free water in blood serum target treatment of patients 
with pseudo hyponatremia can cause dehydration, and because of this blood serum viscosity may 
increase and thromboembolic complications can occur. 
Thromboembolic complications 
 
Thrombosis can occur as a result of therapy with immunoglobulin products. Risk factors: obesity, 
history of atherosclerosis, cardiac output impairment, arterial hypertension, diabetes mellitus with 
history of vessel diseases and cases of thrombosis, patients with acquired and hereditary 
thrombophilia, patients with severe hypovolemia, patients with diseases that increase blood 
viscosity, old age, long-time immobilization, hypercoagulation states, history of venous or arterial 
thrombosis, use of estrogens, central indwelling catheters, increased blood viscosity and risk of 
cardiovascular diseases. Thrombosis can occur even in cases where the known risk factors are 
absent. 
An overall assessment of blood viscosity should be performed for patients with risk of increased 
viscosity, which is connected with cryoglobulins, starvation сhylomicronemia/evidently high level 
of triglycerides or monoclonal gammopathy. For patients with risk of thrombosis minimal doses 
of immunoglobulin products are used along with a minimal rate of infusion. Before using the 
product, it should be ensured that a patient has an adequate level of hydration. Monitoring of 
thrombosis symptoms and assessment of blood viscosity should be performed for patients with a 
risk of increased viscosity. 
Aseptic meningitis syndrome 
As reported aseptic meningitis syndrome (AMS) can rarely occur in connection with 
administration of immunoglobulin products. Discontinuation of therapy with these products leads 
to remission of AMS without complications in few days. This syndrome usually occurs during the 
period from several hours to two days after using immunoglobulin products and their rapid 
administration. It is characterized by symptoms that include severe headache, rigidity of occipital 
muscles, somnolence, fever, photophobia, sensation of pain with eye movement, vomiting and 
nausea. Results of cerebrospinal fluid (CSF) analysis often reveal pleocytosis with few thousands 
of cells per mm3 predominantly of granulocytic lineage, and an increase of protein level up to few 
hundred mg/dl. Patients with such symptoms should undergo neurological examination including 
a CSF analysis to exclude other causes of meningitis. Patients who have a history of migraine are 
more disposed to it. Meningitis aseptic syndrome can occur more often in case of treatment with 
high doses IgG. 
Hemolysis 
Immunoglobulin products can contain blood group antibodies that can act as hemolysins and assist 
in vivo in covering of red blood cells with a coating of immunoglobulin leading to a direct positive 
immunoglobulin reaction and in rare cases to hemolysis. Hemolytic anemia can occur in 
connection with immunoglobulin therapy due to increase of red blood cell sequestration. Patients 
receiving immunoglobulin therapy should be monitored for clinical symptoms of hemolysis. A 


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laboratory analysis should be carried out for confirmation of hemolysis in cases of occurrence of 
such symptoms after immunoglobulin administration through infusion. 
Transfusion related acute lung injury 
Non-cardiogenic pulmonary edema was reported (transfusion related acute lung injury 
(TRALI) in patients whom immunoglobulin was administered. TRALI is characterized by severe 
respiratory impairment, pulmonary edema, hypoxemia, normal function of left ventricle and fever, 
and it usually occurs during 1-6 hours after transfusion. Oxygen therapy with adequate additional 
artificial ventilation should be used for patients with TRALI. 
Patients receiving immunoglobulin should be monitored for respiratory system adverse 
reactions. If TRALI is suspected an analysis for the presence of anti-neutrophil antibodies both in 
product and in patient's blood should be carried out. 
Laboratory testing 
Appropriate laboratory tests should be carried out in case of occurrence of symptoms of 
hemolysis after administration of immunoglobulin through infusion. 
 
If there is a suspicion of TRALI then an analysis for the presence of anti-neutrophil antibodies 
both in product and in patient's blood serum should be performed. 
In connection with a potential increased risk of thrombosis an assessment of blood viscosity 
should be performed in the patients with the risk of increased viscosity including cryoglobulins, 
starvation сhylomicronemia/evidently high level of triglycerides or monoclonal gammopathy. 
General information 
The product is manufactured from human plasma. Donor selection, screening of donor blood 
samples and plasma pools for specific markers of infection as well as inclusion of effective 
manufacture stages for inactivation/elimination of viruses are standard measures for infection 
prevention occurring as a result of use of drug product manufactured from human blood or plasma. 
Nevertheless, risk of infection transmission in case of administration of drug product manufactured 
from human blood and plasma cannot be completely eliminated. The same applied to unknown 
and new viruses and other pathogens. 
The taken measures are considered effective for enveloped viruses such as HIV, hepatitis B 
virus and hepatitis C virus. In respect of viruses without envelop such as hepatitis A virus and 
parvovirus B19, these measures can have a limited effectiveness. Clinical experience evidently 
demonstrates the absence of cases of hepatitis A and parvovirus B19 transmission in case of 
administration of human immunoglobulin products. In addition, it is assumed that antibody content 
is important for increase of viral safety. 
The product does not contain preservative or antibiotics. 
Elderly patients 
Patients over the age of 65 may be at risk for some adverse reactions, such as thromboembolic 
complications and acute renal failure. 
Pregnancy and lactation. 
Safety of the product for pregnant women has not been established by controlled clinical 
studies, and therefore, it should be prescribed with caution to pregnant and breastfeeding women. 
The study of IgG product use in pregnant women has shown it crosses placenta, especially during 
a III trimester. The clinical experience of immunoglobulin use demonstrates that the product has 
no adverse effect on pregnancy course, fetus or baby. 
Immunoglobulins penetrate into breast milk and can facilitate transmission of protective 
antibodies to a newborn. 
The clinical experience of immunoglobulin use has shown the product does not have any effect 
on fertility. 
Effects on ability to drive and use machines. 


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No effect on the ability to drive a vehicle or operate other mechanisms has been reported. 
Special safety measures. 
Some serious adverse reactions may be caused to the rate of product administration. Patients 
who receive immunoglobin for the first time usually experience a slight adverse reaction more 
frequently than those who receive immunoglobulin therapy regularly. The parameters of 
administration rate mentioned below should be followed and patients should be closely monitored 
both during infusion and for 1 hour after completion of the first infusion. In case of any adverse 
reactions infusion rate should be reduced or infusion itself should be stopped until undesirable 
symptoms disappear. If after administration stopping symptoms persist then symptomatic therapy 
is reasonable. In case of shock, should be followed appropriate anti-shock therapy. The level of 
creatinine should be measured in patients with diabetes mellitus and a risk of renal failure as well 
as in patients with systemic lupus erythematosus with kidney involvement for 3 days after 
administration of the product. During following infusions patients should be thoroughly monitored 
for 20 minutes from the moment of product administration completion. 
BIOVEN should only be used in a clinical setting of hospital and in compliance with aseptic 
requirements. Before administration vials should be kept at a temperature of (20±2) °С for at least 
2 hours.  
Solution must be transparent or slightly opalescent, colorless or of slightly yellowish color. 
Do not use if solution is cloudy or contains precipitate.  
A separate infusion system should be used for administration of the product. 
Drug-drug interactions and other kinds of interactions.  
Administration of this product can be combined with administration of other drug products. 
Live attenuated viral vaccines 
Immunoglobulin administration can decrease effectiveness of live attenuated viral vaccines 
against measles, rubella, epidemic parotitis and chicken pox during a period of 6 weeks to 3 
months. A period of 3 months is required after administration of this product before vaccination 
with live attenuated viral vaccines. In case of vaccination against measles this attenuation of 
vaccine effectiveness can last up to 1 year. Therefore, in patients administering vaccine against 
measles antibody status should be checked. 
After vaccination against these infections the product should be administered not earlier than 
after two weeks; if it is needed to use Bioven earlier, vaccination against measles or epidemic 
parotitis should be repeated. Vaccination against any other infection can be performed at any time 
before or after administration of this product. 
Impact on results of serologic tests 
After immunoglobulin injection a temporary increase of different antibodies blood level that 
are passively transferred can result in false positive results of serologic analyses. 
Passive transfer of antibodies to red blood cells antigens, for example, A, B or D can have an 
impact on some serologic tests for determination of alloantibodies to red blood cells (for example, 
Coombs test), reticulocyte count and haptoglobin. 
Administration details. 
Warnings on product administration 
Some severe adverse reactions may be connected with product infusion rate. The 
recommendations on infusion rate should be followed strictly. A patient condition should be 
monitored closely and special attention for occurrence of any symptoms during the whole period 
of infusion should be paid. 
Some adverse reactions can occur more often: 
− in the case of a high infusion rate; 


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− in patients who receive normal human immunoglobulin for the first time or in rare cases 
of change to normal human immunoglobulin or when a long period of time has passed 
from the moment of the previous infusion. 
Any potential complications can be prevented if it is ensured that: 
− a patient is not sensitive to human normal immunoglobulin during the first slow infusion 
of the product; 
− a patient is closely monitored for occurrence of any symptoms during the whole period 
of infusion. In particular, to identify signs of a potential negative impact during the first 
infusion and during the first hour after infusion it is essential to monitor condition of a 
patient who have not previously received immunoglobulin products, who received 
therapy using alternative products or after a long period of time has elapsed since the 
last immunoglobulin administration. Such patients require monitoring during the whole 
period of the first infusion as well as for 1 hour after administration is completed. All 
other patients should be monitored for the first 20 minutes after administration. 
In case of any adverse reaction in is necessary to either decrease infusion rate or stop infusion. 
Treatment required depends on the nature and severity of adverse reaction. In case of a shock 
measures should be taken in accordance with approved recommendations on anti-shock therapy. 
For all patients in case of IgG administration it is necessary to: 
− perform an adequate hydration before starting IgG infusion; 
− monitor diuresis; 
− monitor blood serum creatinine level; 
− avoid a concomitant use of loop diuretics. 
Overdose. 
Overdose can cause hypervolemia and increase of blood viscosity especially in patients with 
such risks including older patients or patients with renal impairment. 
Adverse reactions.  
Blood and lymphatic system disorders: anemia, lymphadenopathy, hemolysis, leukopenia, 
hemolytic anemia. 
Immune system disorders: hypersensibility, anaphylactic shock, anaphylactic reactions, 
anaphylactoid reactions, angioneurotic edema, facial edema. 
Endocrine system disorders: abnormality of thyroid function. 
Nervous system disorders: headache, disorder of cerebral circulation, aseptic meningitis, 
migraine, dizziness, paresthesia, hyposthesia, amnesia, burning sensation, dysarthria, dysgeusia, 
balance disorders, transient ischemic attack, tremor. 
Psychiatric disorders: excitation, anxiety, insomnia. 
Cardiac disorders: myocardial infarction, tachycardia, palpilation, cyanosis. 
Vascular disorders: peripheral vascular failure, arterial hypotension, arterial hypertension, 
peripheral coldness, phlebitis, deep venous thrombosis. 
Respiratory, thoracic and mediastinal disorders: respiratory failure, pulmonary embolism, 
pulmonary edema, bronchial spasm, dyspnea, cough, increased respiratory rate, rhinorrhea, 
asthma, nasal blockage, oropharyngeal edema, pharyngolaryngeal pain. 
Gastrointestinal disorders: nausea, vomiting, diarrhea, abdominal pain. 
Skin and subcutaneous tissue disorders: eczema, urticaria, rash, erythematous rash, dermatitis, 
pruritus, alopecia, cold sweat, photosensitivity reactions, night sweating. 
Musculoskeletal and connective tissue disorders: back pain, pain in extremities, arthralgia, 
muscle spasm, clonus, myalgia. 
Renal and urinary disorders: acute renal failure, proteinuria. 
Eye disorders: conjunctivitis, eye pain, eye edema. 
Ear and labyrinth disorders: vertigo, liquid in internal ear. 


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General disorders and administration site conditions: fever, influenza-like symptoms, 
weakness, chest discomfort, pain, chest congestion, asthenia, malaise, peripheral edemas, fever 
sensation, fatigue, rigor, hot flushes, hyperemia, hyperhidrosis; administration site reactions, 
including pain, increased sensibility, hyperemia, edema, phlebitis, pruritus. 
Laboratory tests: increase of hepatic enzymes, false positive level of blood glucose, increase 
of blood creatinine, increased level of blood cholesterol, increased level of urea, decreased level 
of hematocrit, decreased level of red blood cells, positive direct Coombs test, decreased level of 
saturation with oxygen. 
Infections and infestations: bronchitis, nasopharyngitis, chronic sinusitis, mycosis, infection, 
renal infection, sinusitis, infections of upper airways, urinary tract infections, bacterial infections 
of urinary tract. 
Injuries, poisoning and general procedural complications: contusion, transfusion related acute 
lung injury. 
Children: During clinical trials of BIOVEN, most adverse reactions in children were assessed 
as mild, resolved rapidly on their own or in response to simple measures (decreasing of the speed 
of infusion, or stop of the infusion). 
 
2.5 
Description and justification of the method of administration, dosage, scheme and 
duration of treatment 
 
As part of this clinical study, patients will receive the drug Bioven, a 10% solution for infusion 
produced by "Biopharma Plasma" LLC in a dose 0.8-1.0 g/kg 1 time per day for 2 consecutive 
days (course dose 1.6-2.0 g/kg). 
Bioven should be administered intravenously, at an initial rate of 0.5 - 1.0 ml/kg of body weight 
/h for 30 minutes. If no unwanted adverse reactions are occurred, the rate of administration can be 
gradually increased (recommended increase by 0.5 - 1.5 ml/kg of body weight/h every 10 minutes). 
According to clinical studies, the maximum rate of administration is 8.5 ml/kg of body weight/h. 
The investigational drug is administered only in a hospital setting in accordance with the rules 
of asepsis. The solution should be at room temperature before use. Turbid solutions and solutions 
with precipitate are not used. A separate infusion system should be used for drug administration. 
The information specified in the instructions for medical use in the relevant sections: 
Administration details, Special safety measures, Contraindications, Drug-drug interactions and 
other kinds of interactions, etc. should be taken into account during the drug administration. 
Including, but not limited to, measures to control the state of the coagulation system, hydration 
levels, kidney function and others. 
According to the section "Administration details" of the Package leaflet for medical use of the 
drug, and as described in section 2.4. of this protocol, the administration of immunoglobulins in 
minimal doses and with a minimum infusion rate is practiced for patients with risk of thrombosis. 
It is necessary to make sure the patient's hydration level is adequate before using the drug. Patients 
with a risk of high blood viscosity should be monitored for thrombosis symptoms and blood 
viscosity assessed. 
Patients who are participating in this study may receive concomitant therapy, which is used to 
treat comorbidities and for vital signs. 
The route of administration and dosage does not exceed the maximum single and course doses 
that can be used in the treatment of patients, according to the approved Package leaflet for medical 
use of the drug Bioven. They fully meet the requirements for the medicinal product, which are 
strictly regulated by the European Pharmacopoeia (monograph Eur. Ph.0918), the State 
Pharmacopoeia of Ukraine, and are laying within the limits set out in the Guideline on Core SmPC 
for human normal immunoglobulin for intravenous administration (IVIg) EMA / CHMP / BPWP 


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/ 94038/2007 Rev. 5 June 28, 2018. 
 
Route of administration and dosage in accordance with the approved Package leaflet for 
medical use of the drug Bioven. 
Bioven should be administered intravenously, at an initial rate of 0.5 - 1.0 ml/kg of body weight 
/h for 30 minutes. If no unwanted adverse reactions are occurred, the rate of administration can be 
gradually increased (recommended increase by 0.5 - 1.5 ml/kg of body weight/h every 10 minutes). 
According to clinical studies, the maximum rate of administration is 8.5 ml/kg of body weight/h. 
In cases of congenital agammaglobulinemia or hypogammaglobulimenia, severe combined 
immunodeficiency, unclassified variable immunodeficiency, Wiscott-Aldrich syndrome: 4-5 ml 
(0.4-0.5g)/kg (minimal dose is 2 ml (0.2 g)/kg, maximal dose is 8 ml (0,8 g)/kg every 3-4 weeks, 
and adjustment of the dose should be decided individually depending on intensity of infective 
syndrome (achievement of a serum level of IgG 5 g/l but not less than 3-4 g/l is considered to be 
optimal). 
In case of replacement therapy and secondary immunodeficiency (in general): 2-4 ml (0.2-0.4 
g)/kg every 3-4 weeks. 
In case of cytopenia of different genesis (acute and chronic leukemia, aplastic anemia, status 
post cytostatic therapy): 2-4 ml (0.2-0.4 g)/kg/day for 4-5 days or 10 ml (1 g)/kg/day for 2 days. 
In case of severe bacterial and toxic and viral infections (including surgical complications 
accompanied by bacteremia and septicopyemic conditions and for preparation of surgical patients 
for operation): 4 ml (0.4 g)/kg/day for 1-4 days. 
In case of idiopathic thrombocytopenic purpura: 2-4 ml (0.2-0.4 g)/kg/day for 2-5 days or 8-10 
ml (0.8-1 g)/kg/day on the first day and if required on the third day. 
In case of Guillain-Barre syndrome, chronic inflammatory neuropathy (demyelinating), 
inflammatory myopathy, Wegener's granulomatosis: 2-4 ml (0.2-0.4 g)/kg/day for 3-7 days, and if 
required a 5-day course of treatment should be repeated at intervals of 4 weeks.  
In case of dermatomyositis: 10 ml (1 g)/kg/day for 3-5 days. 
In case of systemic diseases of connective tissues (rheumatoid arthritis etc.): 2-5 ml (0.2-0.5 
g)/kg/day for 5 days. 
In case of Kawasaki disease: 10-20 ml (1-2 g)/kg in equal doses for 2-5 days or 20 ml (2 g)/kg 
as single dose (addition to treatment with acetylsalicylic acid). 
In case of bone marrow transplantation: 5 ml (0.5 g)/kg as a single dose 7 days prior to 
transplantation, thereafter once weekly for 3 months after transplantation. 
For use in the complex therapy of adult patients with severe pneumonia caused by coronavirus 
infection COVID-19 / SARS-CoV-2 (see section "Indications"), the recommended dose of 0.8-1.0 
g/kg body weight per day for 2 days (course dose 1.6-2.0 g/kg body weight). 
The physician depending on the patient’s condition determines the frequency of infusions and 
the rate of administration. The daily dose may be adjusted for reasons of not exceeding the 
maximum allowable daily volume of infusion therapy. Monitoring of the coagulation system and 
diuresis is mandatory, especially for overweight patients. 
Pediatric patients. For children (aged 0 to 18 years) might be use same dosage as per body 
weight as for adults, however the dosage should be corrected for body weight and adjusted 
accordingly to the clinical tests.  
Children. The product might be use in pediatric practice. (see section "Indications"). 
 
 


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PURPOSE AND OBJECTIVES OF RESEARCH 
 
Objective: To evaluate the efficacy, safety and tolerability of Bioven in patients with chronic 
primary immune thrombocytopenia, with evidence of non-inferiority compared to the literature 
data regarding the level of effectiveness of existing IVIG products.. 
 
Tasks of study: 
­ To evaluate the proportion (%) of patients who achieved the response (R) during the study, 
platelet count> 30x109 / l and at least double their initial number, as confirmed by at least 2 
blood tests performed every 7 days; absence of bleeding) during therapy with the studied 
drug Bioven. 
­ To evaluate the effeciency of the studied drug Bioven in comparison with the literature data  
­ To evaluate the presence and severity of hemorrhagic syndrome as a result, which is 
included within 4 weeks after starting therapy; 
­ To evaluate the proportion (%) of patients who achieved a complete response (CR) during 
the study (platelet count> 100 x 109 / l, confirmed by at least 2 blood tests performed every 7 
days; no bleeding) during treatment with the study drug Bioven. 
­  To evaluate the proportion (%) of patients who did not respond (NR) during the study with 
a platelet count <30 x 109 / L or less than a 2-fold increase in platelet count from baseline. 
This must be confirmed by at least 2 blood tests with a difference of one day, or the presence 
of bleeding during therapy with the study drug Bioven. 
­  To evaluate the proportion (%) of patients who lost the response (R) during the study (a 
decrease in platelet count (<30 x 109 / L, or less than twice the initial or bleeding. Platelet 
counts should be confirmed at least twice with an interval of 1 day). 
­ To evaluate the proportion (%) of patients who lost a complete response (CR) during the 
study, a decrease in platelet count, <100 x 109 / l, or the occurrence of bleeding. Platelet 
counts should be confirmed at least twice with an interval of 1 day). 
­ To determine the time from the start of treatment with the study drug Bioven to the onset of 
the response (R); 
­ To determine the time from the start of treatment with the studied drug Bioven to the onset 
of a complete response (CR); 
­ To set the duration of the response (R); 
­ To set the duration of the complete response (CR); 
­ To evaluate the frequency and severity of possible adverse events/adverse reactions 
(AE/AR).  
­ To evaluate the frequency of clinically significant changes in laboratory parameters after 
infusion of the study drug using the study drug Bioven. 
­ To evaluate the frequency of clinically significant changes in vital signs after infusion of the 
study drug using the study drug Bioven. 
 
 


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STUDY DESIGN 
 
4.1. 
Model description, number of patients, groups 
 
Study design: open-label, multicenter, international, non-randomized, non-controlled, single-
group study evaluating the efficacy, safety and tolerability of Bioven, 10% solution for infusion. 
 
Number of patients: The number of subjects in Ukraine and worldwide is 40 patients: men and 
women aged 18-65 years with a confirmed diagnosis of chronic primary immune 
thrombocytopenia (at least 12 months from the date of diagnosis). In Ukraine, no more than 36 
patients will be enrolled. 
Groups: This study does not provide for the division of patients into groups. Patients who have 
been screened and meet the inclusion criteria, who do not have non-inclusion (exclusion) criteria 
and those who have signed the Informed Consent Form (ICF), are included in the study, and 
receive the study drug (SD). 
 
4.2 Stages of the study. Screening 
The patient or his or her legal representative must sign an informed consent form. 
After signing the informed consent form, the screening surveys are performed and the compliance 
with the inclusion / non-inclusion criteria is assessed. 
At the screening stage, verification of the diagnosis of chronic primary ITP is required (based on 
primary documentation data) (Section 6.5.3 of the Protocol). 
 
4.3 
Stages of the study. Clinical stage 
The stage starts after the screening is completed. 
Patients receive the study drug Bioven, solution for infusion of 10%, at a dose of 0.8-1.0 g / kg 1 
time per day for 2 consecutive days (course dose 1.6 - 2.0 g / kg). 
The time of administration of the studied drug, the occurrence of adverse events is recorded in the 
CRF. 
Prescribed therapy and examination results are recorded in the CRF based on primary 
documentation. 
The CRF data are entered according to the patient's management plan (Section 6 of the Protocol). 
Patients participating in this study may receive corticosteroid therapy if the patient is taking long-
term and stable doses (at least 2 weeks before screening). Increasing the dose of corticosteroids 
less than 2 weeks before, during, and after SD administration is considered an ineffectiveness of 
SD. 
If the patient has been treated with cyclophosphamide, azathioprine or attenuated androgens, the 
treatment regimen and dose should be stable for at least 2 months before day 0 
(immunosuppressant dose should remain unchanged until day 30). 
 
4.4 
Stages of the study. Follow-up and completion of the study 
 
The stage starts after the last administration of the drug and lasts for 4 weeks. At this stage a set of 
laboratory tests, measurement of vital signs is carried out. AE/AR registration is also performed. 
The results of the study are entered into the CRF according to the "Schedule of research 
procedures" (Section 6.4 Table 1 of the Protocol). 
 


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SELECTION AND EXCLUSION OF RESEARCH SUBJECTS 
 
5.1. 
Inclusion criteria 
 
- Signed Informed consent form to participate in the study; 
- Men and women aged 18-65 years; 
- Significantly confirmed chronic primary ITP (at last 12 months after diagnosis); 
- The general analysis of blood should be normal except for the isolated thrombocytopenia. 
Patients with low hemoglobin (but above 90 g / l) may be included if there are symptoms 
of bleeding; 
- In case of diagnosis of bleeding symptoms, reticulocyte counts should be monitored; 
- Platelet count < 30 х 109/L; 
- If the patient is taking corticosteroids, the treatment regimen / dose should be stable (at least 
2 weeks before screening); 
- Negative pregnancy test (in women of reproductive age), willingness to use reliable methods 
of contraception throughout the study; 
- The results of physical, instrumental and laboratory examination of patients - within the 
norm and deviations are considered by the investigator as clinically insignificant; 
- The ability, according to the investigator, to follow all the requirements of the study 
protocol. 
 
5.2 
Non-inclusion criteria 
 
A patient cannot participate in this study if he or she meets one of the following criteria: 
- 
Known intolerance to plasma and immunoglobulin drugs; 
- 
Drug allergy or hypersensitivity to immunoglobulin drugs; 
- 
Confirmed deficiency of IgA and antibodies to IgA; 
- 
Contraindications to immunoglobulin according to the instructions for medical use; 
- 
Pregnancy and lactation; 
- 
Any clinically significant hepatic impairment (increase serum transaminases levels by 
more than 3 times the upper limit of normal); 
- 
Serum creatinine level is more than 2 times higher than the upper limit of normal for a 
given age and sex; 
- 
Severe heart failure (NYHA III); 
- 
History of thrombosis or presence of significant risk factors for thrombosis; 
- 
Patients with preventive splenectomy; 
- 
Hemostasis disorders other than chronic thrombocytopenia; 
- 
Persons with acute or exacerbation of chronic diseases of the gastrointestinal tract 
associated with the risk of bleeding, acute infectious diseases, pathologies of the 
respiratory system; 
- 
Proven case of primary immunodeficiency; 
- 
Secondary immune thrombocytopenia; 
- 
Refractory thrombocytopenia; 
- 
Viral infections (Epstein-Barr (EBV), cytomegalovirus (CMV), hepatitis B and C); 
- 
Presence of documented HIV infection; 
- 
Positive RW test result; 
- 
Systemic immunopathological diseases (rheumatic diseases, nephritis, etc.); 
- 
Oncological diseases; 


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- 
Diabetes mellitus; 
- 
Thyroid diseases; 
- 
History of mental illness; 
- 
Known drug addiction; 
- 
Any other concomitant decompensated diseases or acute conditions, the presence of 
which, according to the investigator, may significantly affect the results of the study; 
- 
The need to prescribe drugs that are incompatible with the administration of the drug in 
this study: other immunoglobulin drugs in addition to the study drug, cytostatics, 
monoclonal antibodies, Avatrombopag); 
- 
Experimental treatment (e.g. Rituximab therapy) for 3 months before screening); 
- 
Blood transfusions or transfusions of blood products in the last 6 months before inclusion 
in the study; 
- 
Administration of IVIG 30 days before screening; 
- 
Participate in any other study now or in the previous 30 days. 
 
5.3 
Criteria for exclusion of subjects (discontinuation of treatment with the study drug):  
 
Any patient can leave the study at any time and under any conditions. 
Patients may be excluded by the investigator from taking the study drug and from the study in 
the following circumstances: 
 
- Patient's wish  
- Occurrence of severe and/or unexpected AE/AR in patient during the study, that require 
discontinuation of the drug;  
- The need to prescribe drugs prohibited in this study.  
- Significant deterioration of the patient's condition during the study period;  
- Failure of the patient to adhere to the treatment regimen; 
- Failure of the patient to follow the procedures established under the protocol; 
Due to the variability of PLT levels in patients with chronic immune thrombocytopenia (wave), 
it is possible to re-screen or extend the duration of the screening phase, but only if the subject 
meets all other specified inclusion criteria and has no inclusion or exclusion criteria. 
Patients who drop out at the screening stage are not included in the efficacy and safety analysis, 
as they do not receive any doses of the investigational drug (ID). 
Patients who do not receive a full course of study drug are included in the safety analysis but 
not in the efficacy analysis. 
Patients who dropped out of the study after completion of SD administration during the follow-
up period are considered in the efficacy and safety analysis. The data of such patients are evaluated 
by parameters that can be analyzed at a certain point in time. The dropped data are not analyzed. 
For all patients who complete the study due to AE, requiring discontinuation of treatment with 
the studied drugs, it is necessary to conduct the procedures of the final visit in the near future after 
the development of AE. After stopping treatment, the patient should be monitored until the reaction 
disappears or its clinically significant signs. Patients who received at least 1 dose of SD but 
prematurely dropped out of the study are included by the investigator in the analysis of tolerability 
of the study drug. 
The reasons for premature withdrawal from the study are indicated in the Individual registration 
form.  
 


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PATIENT EXAMINATION AND TREATMENT PLAN 
 
A breakdown into visits is provided for this Clinical Study. 
The study is conducted in stages. 
A detailed plan and content of the Stages and visits of the study are given in section 6 "Plan of 
examination and treatment" (subclauses 6.1, 6.2, 6.3), a step-by-step breakdown is also set out in 
section 6.4 "Schedule of procedures in tabular form". 
The information is entered into the CRF in accordance with the "Schedule of study procedures". 
 
 
6.1. 
Screening stage 
 
After signing the Informed Consent, at the screening stage, the procedures provided for by the 
Protocol are performed to assess the eligibility criteria (inclusion/exclusion) of the patient for 
participation in the study.    
Due to the variability of PLT levels in patients with chronic immune thrombocytopenia (wave-
like), it is possible to re-screen or extend the duration of the screening stage, but only if the subject 
meets all other specified inclusion criteria and has no inclusion and exclusion criteria. 
Procedures are performed according to the schedule of procedures (Section 6.4, Table 1). 
­ Signing the Informed Consent Form; 
­ Collection and registration of demographic data; 
­ Collection and registration of medical history; 
­ Verification of the diagnosis of ITP; 
­ Registration of information on the reception of previous ITP therapy (dose / 
schedule, duration, response (if any) and time interval since the last administration); 
­ Registration of information on symptomatic therapy and administration of drugs for 
the treatment of comorbidities; 
­ Transfusion history;  
­ Allergic history; 
­ Determination of body weight; 
­ Objective physical examination with obligatory assessment of the severity of the 
hemorrhagic syndrome; 
­ Measurement of vital signs (blood pressure, heart rate, frequency of respiratory 
movements, body temperature); 
­ Collection of biomaterials for laboratory research (performed at the collection point 
or by the visiting team of the Central Laboratory designated by the Sponsor): 
­ Blood test for HIV and RW, PCR EBV, CMV; 
­ Blood test for blood group and Rh factor; 
­ General blood test (erythrocytes, reticulocytes) (with low hemoglobin, but not less 
than 90 g / l), hemoglobin, hematocrit, leukocytes and expanded leukocyte formula, platelet 
counting by the Fonio method; 
­ Biochemical blood test (ALT, AST, creatinine, urea, glucose, total bilirubin); 
­ Coombs' test (antiglobulin test); 
­ Determination of total serum IgG in grams per liter; 
­ General analysis of urine (specific gravity, pH, protein, glucose; sediment 
microscopy - leukocytes, erythrocytes, cylinders, salts); pregnancy test (for women of 
reproductive age); 
­ Coagulogram (PTI, APTT, fibrinogen); 


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­ Hepatitis B and C markers (Hbs-Ag, anti-HCV); 
­ Antinuclear antibodies (АНА); 
­ Electrocardiogram in 12 leads. 
 
6.2. 
Clinical stage 
 
Visiting plan 
The study involves scheduled visits of patients to the doctor: 
1st visit (Day -14 – Day -1) - Screening, verification of compliance with the 
inclusion/exclusion criteria, enrollment in the study; due to the variability of PLT levels in patients 
with chronic immune thrombocytopenia (wave), it is possible to re-screen or extend the duration 
of the screening phase, but only if the subject meets all other specified inclusion criteria and has 
no inclusion or exclusion criteria; 
2nd visit (Day 0 - Day +1 – Day +2) - hospitalization, administration of the study drug for 2 
days, physical examination, assessment of the status of hemorrhagic syndrome, blood sampling to 
determine the platelet count by Fonio, Coombs test, determination of Ig G level (g/l); 
3rd visit (Day +7 ± 1 day) - physical examination, assessment of the status of hemorrhagic 
syndrome, blood sampling to determine platelet counting by the Fonio method, Coombs test in 
case hemolysis was detected during the previous visit (according to the laboratory data); 
4th visit (Day +14 ±2 day) -physical examination, assessment of the status of hemorrhagic 
syndrome, blood sampling to determine the level of platelets by Fonio; Coombs tests, in case of 
detection of hemolysis according to the laboratory examination at the previous visit, determination 
of the level of Ig G (g/l). If a decrease in platelet count < 30 x 109/L is detected, an additional 
blood test with Fonio platelet count is performed one day after the visit. 
This visit can be performed by telephone/video, if it is possible to adequately assess the 
patient's status and take biomaterials for laboratory tests at the collection point of the Central 
Laboratory designated by the Sponsor; 
 5th visit (Day +21 ±3 day) – physical examination, assessment of the status of hemorrhagic 
syndrome, blood sampling to determine platelet counting by the Fonio method, biochemical blood 
test, Coombs test in case hemolysis was detected during the previous visit (according to the 
laboratory data). 
This visit can be performed by telephone / video, provided that the patient's status can be 
adequately assessed and biomaterials for laboratory tests can be sampled at the collection point of 
the Central Laboratory designated by the Sponsor; 
6th visit (Day +30 ± 3 days) - physical examination, assessment of the status of the 
hemorrhagic syndrome, blood sampling to determine platelet counting by the Fonio method, 
biochemical blood test, Coombs test, determination of Ig G levels (g / l). This is a face-to-face 
visit. Completion of the study. 
 
Patients' serum samples should be stored frozen at the temperature of -65 - -85 ° C (second 
aliquot) to ensure the possibility of performing repeat laboratory tests, if necessary, in the future.  
 
Patients receive Biven 10% solution for infusion, produced by LLC "Biopharma Plasma" at a dose 
of 0.8-1.0 g / kg 1 time per day for 2 consecutive days, the course dose of 1.6-2.0 g / kg. Allowed 
repeat course at same dosage in period 14-28 days from first infusion, if required. 
 
Bioven should be administered intravenously dropwise at the initial rate of 0.5-1.0 ml/kg of 
body weight/hour for 30 minutes. If no adverse reactions occur, the rate of administration may be 
gradually increased (it is recommended to increase by 0.5-1.5 ml/kg of body weight/hour every 10 


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min). According to the data from clinical studies the maximum rate of administration is 8.5 ml/kg 
of body weight/hour.  
The study drug is administered only in hospital environment while observing the rules of 
aseptics. The solution should be of room temperature before use. Cloudy solutions and those 
containing sediment are not used. For the administration of the drug, it is necessary to use a 
separate infusion system. 
When administering the drug, it is necessary to consider the information specified in the 
relevant sections of the instructions for medical use: administration details, special safety 
measures, contraindications, interaction with other medicinal products, etc. Including, but not 
limited to, measures to control the condition of the coagulation system, hydration levels, renal 
function, etc.  
According to the section of the instructions for the drug " Administration details ", and as 
described in section 3.4. and 3.5 of this protocol for patients at risk of thrombosis practice the 
introduction of immunoglobulin drugs in minimal doses and with a minimum infusion rate. Before 
using the drug, make sure the patient's level of hydration is adequate. Patients at risk of high 
viscosity should be monitored for thrombosis symptoms and blood viscosity assessed. 
The CRF records the time of administration of the study drug, the occurrence of possible 
side effects. 
Prescribed therapy and examination results are recorded in the CRF based on primary 
documentation. 
CRF data are entered according to the patient's management plan. 
 
6.3 
Stage of follow-up and completion 
 
The stage lasts from the last administration of the study drug and for 4 weeks. 
The procedures are performed according to the schedule of procedures (Section 6.4, Table 1). 
If a decrease in platelet count < 30 x 109/L is detected, an additional blood test with platelet 
count by Fonio is performed one day after the visit. 
Face-to-face or telephone/video visits are made to assess the patient's condition. The patient visits 
the blood collection point for laboratory testing. The investigator fills in all information about the 
patient's condition and examination results in the IRF. 


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6.4 Schedule of study procedures in tabular form Table 1. Schedule of study procedures. 
 
 
2 The stage may be extended or re-screened by the decision of the PI and/or agreement with the Sponsor. 
3 Body weight before the introduction of the IMP 
4  ITP disease, data on previous ITP therapy (dose/schedule, duration, response (if applicable) and time interval since the last administration), data on therapy of comorbidities; transfusion anamnesis, allergic anamnesis; 
5  Визначення вираженості геморагічного синдрому (огляд шкіри і слизових оболонок, наявність кровотечі); аускультація і перкусія серця і легень; пальпація та перкусія органів черевної порожнини; 
6  Blood pressure, heart rate, respiratory rate, body temperature; 
7  Hemoglobin, hematocrit, erythrocytes, reticulocytes (in case of diagnosis of bleeding symptoms), leukocytes and leukocyte formula, Fonio platelet count; 
8  ALT, AST, total bilirubin, creatinine, urea, glucose; 
9  Color, transparency, specific gravity; pH, glucose, protein, ketone bodies, sediment microscopy (erythrocytes, leukocytes, cylinders, crystals, bacteria/fungi); pregnancy test for women of reproductive age; 
10  PCR EBV, CMV, or data from primary documentation; 
*   The Coombs test at the 3rd, 4th, and 5th visits is carried out in case of detection of hemolysis according to laboratory examination at the previous visit. 
* If a decrease in the level of platelets < 30 x 109/l was recorded, then a day after the visit, an additional blood test is performed with a platelet count, according to Fonio. 
Visits 
Visits 1 
Visits 2 (госпіталізація) 
Visits 3 
PLT 
control 
Visits 4 
PLT 
control 
Visits 5 
PLT 
control 
Visits 6 
PLT 
control 
Study stage 
Screening2 
IMP admin. IMP admin 
Follow-up 
Follow-up 
every 
other 
day* 
 
Follow-up 
every 
other 
day* 
Follow-up 
every 
other 
day* 
Follow-up 
every 
other 
day* 
Day relative to the first administration of the drug/Injection 
Day (-14 -1) 
Day 0 
Day +1 
         Day +2 
       Day +7 
Day +14 
Day +21 
Day +28 
Signing the Informed Consent Form 
● 
 
 
 
 
 
 
 
 
 
 
 
Collection of demographics data 
● 
 
 
 
 
 
 
 
 
 
 
 
Collection of anthropometric data, body weight3 
● 
● 
● 
 
 
 
 
 
 
 
 
 
Collection of medical history 4 
● 
 
 
 
 
 
 
 
 
 
 
 
Objective physical examination 5 
● 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 
Measurement of vital signs 6 
● 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 
ECG in 12 leads; 
● 
 
 
 
 
 
 
 
 
 
 
 
Coombs Direct Test (Antiglobulin Test) * 
● 
 
 
● 
* 
 
* 
 
* 
 
● 
 
Determination of the level of total Ig G in the blood (g/l) 
● 
 
 
● 
   ● 
 
● 
 
● 
 
● 
 
General blood test 7 
● 
 
 
● 
● 
* 
● 
* 
● 
* 
● 
* 
Biochemical blood test 8 
● 
 
 
 
 
 
 
 
 
 
● 
 
Blood test for blood group and Rh factor 
● 
 
 
 
 
 
 
 
 
 
 
 
Coagulogram (PTI, APTT, fibrinogen) 
● 
 
 
 
 
 
 
 
 
 
 
 
General urine analysis 9 
● 
 
 
 
 
 
 
 
 
 
 
 
Antinuclear antibodies (AHA) 
● 
 
 
 
 
 
 
 
 
 
 
 
Blood test for HIV, RW, HBs-Ag, anti-HCV, EBV, CMV10 
● 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (for women of reproductive age) 
● 
 
 
 
 
 
 
 
 
 
 
 
Assessment of patients' compliance with the inclusion/non-
inclusion criteria based on the results of screening 
● 
 
 
               
               
 
               
 
                
 
 
             
Evaluation of exclusion criteria 
● 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 
Setting a date for your next visit 
● 
 
 
● 
● 
 
● 
 
● 
 
 
 
Administration of the study drug 
 
● 
● 
 
 
 
 
 
 
 
 
 
Registration AE/AR 
 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 


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6.5 
Study procedures. 
 
6.5.1 
Signing the Informed Consent Form 
 
All patients enrolled in the study, or the patient's legal representative, must obtain written 
informed consent to participate in the study. 
Before enrolling in a study, the patient must be explained his or her rights and responsibilities 
associated with participating in the study. The patient, or legal representative, should be aware that 
he may at any time refuse to participate in the study without prejudice to his further treatment, that 
his participation in the study is strictly confidential, that only his initials will be used in clinical 
trial documents and ID number. 
The patient should be explained that his personal data obtained during the study will be used 
for statistical processing of study results and reporting and can be discussed with the persons 
conducting the study and may be provided to government officials during the clinical audit. 
The patient, or legal representative, should have sufficient time to consider the possibility of 
participating in the study and to ask the investigator questions of interest. The investigator is 
required to explain in detail the sections of the Informed Consent that the patient has questions 
about. The investigator should not put pressure on the patient to influence his decision. 
If the patient, or legal representative, has decided to participate in the study, he must personally 
fill in 2 copies and sign the Informed Consent Form. One copy of the Informed Consent is handed 
over to the patient, the other remains in the investigator's file. 
The fact of discussing the informed consent should be recorded in the medical history and CRF 
with the date of signing. 
The screening and inclusion of the patient in the clinical trial provided for in this protocol is 
carried out only after signing the Informed Consent Form. 
 
 
6.5.2 
Entering information into the CRF  
 
­ 
The study provides for the use of electronic CRF (eCRF, electronic Case report Form). 
Investigators receive separate training on eCRF. 
­ 
Entering the CRF / eCRF begins after signing the Informed Consent 
­ 
The date of signing the Informed Consent must be indicated; 
­ 
The two-digit center number (for example 01) is indicated; 
­ 
The information identifying the patient in the study is filled in; 
­ 
A four-digit screening number is assigned immediately (for example 0101 - consists of a 
two-digit number of the Center + a two-digit serial number according to the sequence of 
patient recruitment at the Center); 
­ 
Demographic data of the patient, date of diagnosis are entered; 
­ 
The breakdown of this Clinical Study into Visits is provided. 
The detailed plan and content of each of the Study Visits is specified in Section 6 “Examination 
and Treatment Plan” (sub-items 6.1, 6.2, 6.3), the step-by-step breakdown is also set out in the 
section “Schedule of procedures in tabular form”. 
Upon completion of the patient's participation in the study, the completion date and the patient's 
condition at the time of completion are recorded. 
The data entered must be carefully verified. 
 
 
 


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6.5.3 
Diagnosis 
verification 
procedure 
- 
chronic 
primary 
immune 
thrombocytopenia 
 
Patients should have a confirmed chronic primary ITP (lasting at least 12 months from 
diagnosis). 
Examination data from primary medical records are considered. The volume of the conducted 
research and their sufficiency for differential diagnosis with other variants of thrombocytopenia is 
estimated. 
In case of doubt about the reliability of the diagnosis of chronic primary immune 
thrombocytopenia, additional studies are scheduled according to a list previously agreed with the 
Sponsor. 
You should also pay attention to the fact that: 
­ 
general blood test should be normal, except for isolated thrombocytopenia. If patients 
with symptoms of bleeding are included in the Clinical Study, low hemoglobin levels 
are acceptable. But the hemoglobin level should be at least 90 g/l; 
­ 
bone marrow examination (aspirate and biopsy) is performed as part of routine clinical 
practice and is not provided for in this protocol. 
 
6.5.4 Collection of anamneses, demographic data, complaints, determination of body 
weight 
 
When collecting a medical history, the investigator should pay special attention to the 
presence of direct and indirect data in the patient, which may indicate the impossibility of including 
the patient in the study. Available medical records of comorbidities of the patient, medical and 
non-medical treatment received by the patient should be reviewed. The patient's life history and 
illness should be reflected in the primary documentation and CRF. When collecting anamnesis, 
attention is paid to previously transferred diseases, concomitant chronic diseases, heredity, 
habitual intoxications (smoking status, alcohol, drug use), allergy history, operations and injuries, 
professional anamnesis, permanent or periodic drug therapy. 
The primary documentation records the patient's gender and age, as well as race and ethnicity. 
Medical scales are used to measure body weight. 
Anthropometric studies will be conducted in accordance with the recommendations Health 
Risk Monitoring (EHRM) Recommendation for indicators, international collaboration, protocol 
and manual of operations for chronic disease risk factor surveys, 2002 (European Health Risk 
Monitoring (EHRM), 2002). 
Patients should be weighed in the morning on an empty stomach, after urination and stool, in 
underwear (followed by a discharge of medium weight clothing). The scales must stand on a rigid 
base, horizontally. The measurement error according to the standards should not exceed 0.2 kg. It 
is not possible to record weight from the patient's words, even in cases where weight measurement 
is not possible. 
 
Growth should be measured for all patients (reasons that make it impossible to measure height 
include features of the hair (eg mohawk), refusal of the patient to remove the headdress for any 
reason (eg turban), inability of the patient to stand, exceeding the height scale). To determine the 
height is a height meter - a vertically placed board with divisions in centimeters and a sliding ruler. 
The standard scale error should not exceed 2 millimeters. The patient is asked to remove shoes, 
tight clothing, hairpins, and hair accessories. The patient should touch the vertical board with the 
back of the head, back, buttocks, calves and heels, socks together. The upper limit of the opening 
of the external auditory canal should be at the same horizontal level with the lower border of the 


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edge of the orbit (chin bone).  The patient is asked to look directly. If the patient's height is higher 
than the investigator's height, the latter gets on the platform. The ruler of the height meter is 
lowered on the head and the divisions are counted. The growth is observed until the patient came 
out from under the measuring visor. The error should not exceed half a centimeter. 
The CRF registers information on the onset of the disease, the date of diagnosis, studies 
the primary documentation for objective studies based on which the diagnosis was 
confirmed. 
Information about comorbidities is recorded. Any medication that the patient has taken for 3 
months prior to the start of the study should be registered with the CRF as prior / concomitant 
therapy, indicating the appropriate indications for use, start and end dates. 
 
6.5.5 
Objective physical examination and measurement of vital signs 
 
Objective examination includes auscultation of the heart and lungs, examination of the skin 
and mucous membranes, palpation of the abdomen, measurement of heart rate, blood pressure and 
body temperature, as well as other methods of physical examination according to the current 
clinical situation. Data on changes recorded during the survey are entered in the primary 
documentation and CRF.  
Measurements of heart rate, respiratory rate, blood pressure, body temperature are made at 
rest (after 15 minutes of rest, not earlier than one hour after smoking cigarettes and 2 hours after 
eating). Heart rate (HR) is measured by auscultation of the heart in parallel with the determination 
of pulse rate in the radial artery (or carotid artery with weak pulsation in the radial artery) for one 
minute in a sitting position, in case of pulse deficit both parameters are recorded: heart rate and 
pulse rate. Respiratory rate (RR) is measured for a minute at rest in a supine position, noting the 
respiratory movements of the chest or abdominal wall, without attracting the attention of the 
patient. 
Blood pressure will be measured on the brachial artery in the supine position according to the 
Korotkov method using a certified sphygmomanometer or tonometer using a cuff length and width 
selected by the length and circumference of the patient's shoulder. The size of the cuff should 
correspond to the size of the hand: the rubber part of the cuff should cover at least 80% of the 
circumference of the shoulder; for adults a cuff 12-13 cm wide and 30-35 cm long (medium size) 
is used; but it is necessary to have a large and a small cuff for full and thin arms, respectively. The 
mercury column or tonometer needle must be at the zero mark before the start of the measurement. 
To assess the level of blood pressure on each arm should perform at least two measurements with 
an interval of at least 1 min; with a blood pressure difference ≥ 5 mmHg perform one additional 
measurement; the minimum of three dimensions is taken as the final (registered) value. 
Measurement technique: 
• Quickly pump air into the cuff to a pressure level 20 mmHg higher than systolic pressure 
(after the pulse disappears); 
• Blood pressure is measured with an accuracy of 2 mmHg; 
• Reduce the cuff pressure at a rate of approximately 2 mm Hg in 1 second; 
• The level of pressure at which the 1st tone appears corresponds to systolic pressure (1 
phase of Korotkov tones); 
• The level of pressure at which the disappearance of tones (phase 5 Korotkov tones) 
corresponds to diastolic pressure; in children, adolescents and young people 
immediately after exercise, in some pathological conditions in adults, when it is 
impossible to determine the 5th phase, you should try to determine the 4th phase of 
Korotkov tones, which is characterized by a significant weakening of tones; 


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• If the tones are very weak, you should raise your hand and perform a few compressive 
movements with a brush, then repeat the measurement, without squeezing the artery 
with the membrane of the phonendoscope; 
• At the initial examination of the patient, the pressure on both arms should be measured; 
further measurements are performed on the hand on which the blood pressure is higher. 
Temperature measurements are performed in the axilla using a medical thermometer 
(thermometer), and the end of the thermometer after shaking should be tightly pressed to her 
shoulder; the skin of the axilla should be dry, because with wet skin the thermometer shows a 
lower temperature. The thermometer is kept for 10-15 minutes (the lower the temperature, the 
longer the column of mercury reaches a peak). The patient should remain completely calm. 
Auscultation of the lungs and heart, palpation of the abdomen and examination of the skin and 
mucous membranes are carried out according to standard procedures adopted in clinical practice 
at the screening stage, considering the general serious condition of patients. The task of these 
procedures is to detect pathological changes, including clinically significant. During the 
observation period, a physically less burdensome set of procedures is performed according to the 
standard procedure adopted in clinical practice, which allows to assess the patient's condition. 
An examination for hemorrhagic syndrome is required. The scale of assessment of severity 
according to Table 1. 
 
Table.1 Assessment of the severity of hemorrhagic syndrome 
 
No signs of bleeding 
No 
Several petechiae (<100 in total) and / or <5 small ecchymoses (<3 cm in diameter, 
without mucosal bleeding) 
Mild 
Multiple petechiae (100 and more) and / or 5 large ecchymoses, 3 cm in diameter, 
no bleeding of mucous membranes 
Moderate 
Multiple bleeding of mucous membranes, bleeding gums, menorrhagia, 
gastrointestinal bleeding 
Severe 
 
6.5.6 
Bioanalytical procedures and laboratory tests 
 
Blood and urine are taken as biomaterial. 
The procedure for taking biomaterial for laboratory analysis is carried out at the study site or 
at the collection point (if the investigator thinks the patient is mobile), or by the visiting team of 
the Central Laboratory designated by the Sponsor. 
Blood samples for analysis will be taken on an empty stomach (8-10 hours after the last meal) 
from a vein with a disposable sterile syringe, catheter, or vacutainer under aseptic / antiseptic 
conditions. 
The amount of blood taken is determined by the list of laboratory tests that need to be 
performed.  
For the general analysis of urine, the morning average portion after adequate hygiene of a 
perineum is collected, urine must be delivered to laboratory within two hours after collecting. 
Blood tests for HIV, blood samples for clinical blood tests, biochemical blood tests, urine 
samples for general analysis, inflammatory markers are selected according to standard procedures 
according to laboratory guidelines, according to the "Schedule of study procedures" (Table 1, 
Section 6.4).  
List of laboratory tests: 


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- blood test for HIV, RW, HBs-Ag, anti-HCV (virological screening), PCR CMV, EBV 
or primary documentation data; 
- general blood test (erythrocytes, hemoglobin, platelet counting by the Fonio method, 
leukocytes and leukocyte formula, reticulocytes with low hemoglobin, but not less 
than 90 g / l); 
- biochemical blood test (ALT, AST, creatinine, urea, glucose, total bilirubin); 
- Coombs' test (antiglobulin test); 
- determination of the level of total IgG g / l in serum; 
- antinuclear antibodies (АНА); 
- general analysis of urine (color, transparency, specific gravity, pH, glucose, protein, 
ketone bodies, sediment microscopy (erythrocytes, leukocytes, cylinders, crystals, 
bacteria / fungi);  
- pregnancy test for women of reproductive age. 
 
6.5.7 
Bioanalytical study plan 
 
Bioanalytical research procedures will be conducted in a certified laboratory designated by 
the Sponsor of the study, whose activities are organized in accordance with the requirements of 
Good Clinical Practice - GSP. 
All plasma and serum samples, as well as the blood itself, including samples obtained from 
patients who did not pass the study in full (prematurely dropped out of the study) are subject to 
bioanalytical tests. 
Examination of samples that have not been subjected to freezing is carried out according to 
standard methods by routine methods of biochemical and hematological analysis. 
Defrosting of plasma samples should be performed at room temperature. 
 
 
6.5.8 
Validation of bioanalytical methods 
 
The bioanalytical method used must be properly validated and documented in accordance with 
GSP standards and regulatory requirements during the study period. 
The main purpose of validation is to prove the reliability of this method for quantifying the 
concentration of the analyte in serum. 
Validation is carried out considering the main criteria for the acceptability of the bioanalytical 
method set out in the guidelines. 
The following characteristics of the bioanalytical method should be evaluated during the 
validation process: 
1) selectivity; 
2) transfer of the sample; 
3) lower limit of quantification; 
4) the range of concentrations to be determined and the shape of the calibration curve; 
5) correctness; 
6) precision; 
7) extraction degree; 
8) stability of the basic and working solutions of the analyte, stability of the analyte in the 
biomaterial (blood serum) under processing conditions and throughout the storage 
period (post-preparation stability; short-term temperature stability, stability after 
freezing / thawing; long-term stability). 
Validation of each bioanalytical method should consist of two separate phases: 


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1) phase preceding the study, during which the compliance of the method of quantification 
of the above characteristics is checked; 
2) phase of the study itself, during which the validated bioanalytical method is checked for 
compliance with the obtained results to the criteria of acceptability - to decide on the 
acceptance of the results of analytical runs in the routine analysis of biosamples. 
The results and progress of the validation should be presented in the validation report (for the 
first phase of validation) and in the Analytical report (for the second phase of validation), prepared 
by the laboratory involved in the study. 
 
6.5.9 
Test tube labeling procedure. 
 
The procedure for taking biomaterial for laboratory analysis is carried out at the collection 
point (if the investigator thinks the patient is mobile) or by the visiting team of the Central 
Laboratory designated by the Sponsor. 
In case of taking biomaterial not at the point of collection, blood sampling tubes, plasma 
vacutainers are pre-labeled. Markings are applied by the printer on labels and protected with an 
adhesive tape. 
The label should contain the following information: 
• 
study code; 
• 
site code (01, 02, 03 …); 
• 
patient number (01001, 01002 …); 
• 
date and time (or time point) of biomaterial capture. 
 
 
6.5.10 
Blood sampling procedure  
 
Blood samples for analysis will be taken on an empty stomach (8-10 hours after the last meal) 
from a vein with a disposable sterile syringe, catheter or vacutainer with asepsis/antiseptics. The 
blood is mixed with the anticoagulant (if required by the procedure for preparing the sample to 
obtain plasma) and in vitro on the day of blood collection is sent at room temperature to the central 
laboratory. 
Blood volume: 
- general blood test (erythrocytes, reticulocytes, hemoglobin, leukocytes and expanded 
leukocyte formula, platelet counting by the Fonio method- 4 ml; 
- biochemical analysis of blood (ALT, AST, creatinine, urea, glucose, total bilirubin 
and its fractions) and determination of IgG levels in serum - 10 ml; 
- virological screening and antinuclear antibodies - 5 ml; 
- blood type and Rh factor - up to 5 ml; 
- Coombs test - 4 ml; 
- coagulogram - 4 ml. 
 
Blood volume by visits: 
­ at the screening stage - 32 ml, 
­ on the 2nd visit - 13 ml, 
­ on the 3rd visit - 9 ml, 
­ on the 4th visit - 9 ml, 
­ on the 5th visit - 9 ml, 
­ on the 6th visit - 23 ml. 
1 additional blood sample (20 ml in total) is allowed. 


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On other days of visits, blood sampling is provided to perform a general blood test. Each test 
requires 4 ml of blood. Additional blood sampling for a general blood test is performed one day 
after the visit, which showed a decrease in platelet count below 30 x 109 /l. 
Patients may also have periodic general blood tests and / or biochemical blood tests. The 
amount of blood required for these tests is determined by the patient's condition and duration of 
treatment, and will be determined in fact, taking into account the non-harm to the patient. 
If the sample was not taken according to the time scheduled by the protocol (missed), the 
labeled tube remains empty. Information explaining this event is entered into the CRF and 
primary documentation, and sampling continues at the scheduled time. 
 
6.5.11 
Plasma production procedure 
 
In detail, the process is regulated by the Manual of Laboratory Procedures provided by the 
Central Laboratory selected by the Sponsor. 
After sampling, the closed tubes are inverted several times to ensure mixing with the 
anticoagulant recommended for the study (citrate / EDTA). The presence of visible clots indicates 
that the study is impossible. In this case, the Sponsor is informed immediately. 
The tubes are centrifuged at a temperature of 21 ° C at 2000g for 20 minutes The presence of 
visible hemolysis indicates the unsuitability of the material. In this case, the Sponsor is informed 
immediately. 
Plasma over the precipitate of blood cells is collected in a plastic tube (0.4-0.5 ml of plasma 
over the precipitate is not taken!) And re-centrifuged for 20 min at 2000 g (the last 0.2 ml of plasma 
after re-centrifugation is not taken). The total plasma yield should be at least 3.8 - 4 ml. 
The obtained plasma sample is sent to the central laboratory determined by the Sponsor 
(temperature regime - in accordance with the manual of laboratory procedures provided by the 
contracting laboratory). 
 
6.5.12 
Procedure for storage and transportation of biological samples 
 
In detail, the process is regulated by the Manual of Laboratory Procedures provided by the 
Central Laboratory selected by the Sponsor. 
Storage of aliquots of blood plasma samples from the moment of their receipt to the beginning 
of bioanalytical procedures is carried out at a temperature regulated by the manual of laboratory 
procedures provided by the contracting laboratory. The main samples that do not require freezing 
after receipt until the moment of transfer to the courier should be stored in a packaged, ready for 
transfer form at a temperature of 2-8 ° C. Sending such samples to the Bioanalytical Laboratory is 
carried out in accordance with laboratory guidelines. 
Re-thawing / freezing of aliquots of plasma samples is not allowed for samples requiring 
freezing. 
All plasma samples (basic and archival aliquots) are subject to transfer to the Bioanalytical 
Laboratory). 
The main samples must be stored in packaged form after receipt and until transfer to the 
Bioanalytical Laboratory. 
Time of storage of archival aliquots of plasma on a clinical basis before transfer to the 
Bioanalytical laboratory - no more than the term provided by the laboratory manual. 
The transfer of serum samples from the clinical base to the Bioanalytical Laboratory is 
accompanied by the Direction and the Act of acceptance and transfer of samples of the courier 
company, determined by the Sponsor. The forms of the above documents are provided by the 
Sponsor. 


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The referral is signed by the Responsible Investigator of the clinical base, or a person 
authorized by him. The original is transferred to the Bioanalytical Laboratory, a copy remains at 
the clinical base. The act of acceptance and transfer of samples (in 2 copies) is signed by the 
Responsible investigator of the clinical base (or his authorized person) and a representative of the 
courier company, and upon delivery to the Bioanalytical Laboratory - a representative of the 
courier company and responsible executor of the bioanalytical laboratory. 
If necessary, if provided by the laboratory manual, the transport of biosamples to the 
laboratory is carried out by a specialized courier service. Period of transportation - no more than 8 
hours or the term provided by the laboratory manual, in the frozen kind in the cryocontainers filled 
with "dry ice" (solid carbon dioxide). 
Upon full completion of the study and after the period of storage of archival samples agreed 
with the Sponsor and obtaining the written permission of the Sponsor for their disposal, the 
remaining unclaimed archival samples of blood plasma are subject to destruction in the 
Bioanalytical Laboratory. An appropriate act on the destruction of archival samples of blood 
plasma, which is stored in the archives of the bioanalytical laboratory for at least 15 years. 
Serum samples for serological and biochemical tests, as well as whole blood for hematological 
tests are delivered to the Bioanalytical Laboratory on the day of their receipt by a special courier 
service at room temperature. The design of the accompanying documentation is similar to that for 
plasma samples. 
Invoices are stored together with the directions and acts of acceptance of the transfer for 15 
years in the archives of the research center. 
 
6.5.13 
Analysis of deviations from the plan of bioanalytical study  
 
All deviations from the initial statistical processing plan will be described and justified in the 
relevant sections of the Final Clinical Trials Report. The method of analysis of deviations from the 
research plan is based on the principles set out in the current instructions. 
The withdrawal of subjects from the study will be analyzed against the criteria under this 
Protocol. Quantitative determination will be performed for all biosamples received for analysis, 
including biosamples of subjects that dropped out of the study. The results obtained will be 
included in the Analytical Report. 
Re-analysis using archival biosamples, if necessary, should be carried out in all cases of 
confirmed inability to obtain a reliable result: 
• in case of confirming the fact of mixing biosamples; 
• in case of confirming the error of the operator/performer during the sample preparation, 
analytical procedure, and post-analytical period; 
• in the absence of sufficient amount of biomateur; 
• in case of technical problems with equipment or reagents, conditions of transportation 
and/or storage of biosamples. 
The statistical analysis will not include the results of those subjects for whom the data obtained 
will not be suitable for analysis. Such data should be excluded from the calculations. 
 
 
6.5.14 
Rules for stopping parts of a clinical trial and (or) a clinical trial in general. 
 
The study may be stopped for the following reasons: 
1. Initiated by the Sponsor: 


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a. obtaining new toxicological or pharmacological data, or data on SAE related to the 
study drug, forcing a review of a previous evaluation of the benefits / risks of 
participating in the study; 
b. the frequency of AEs associated with the study drug and / or their severity do not 
allow to continue the study; 
c.  other reasons, including administrative. 
2. At the initiative of the investigator: the frequency of AEs associated with the drug and 
/ or their severity unacceptably increases the risk of participation of patients in the 
study; 
3. According to the decision of regulatory authorities. 
In case of premature termination of the study, the sponsor should inform the staff of the 
research centers, as well as regulatory authorities, indicating the reason for the premature 
termination of the study. 
 
 
6.6 
Content of visits 
 
Visit 1 (days -14 … -1) Screening. Assessment of compliance with inclusion / exclusion 
(exclusion) criteria based on screening results. 
The procedure for taking biomaterial for laboratory analysis is carried out at the collection 
point (if the researcher thinks the patient is mobile) or the visiting team of the Central Laboratory 
designated by the Sponsor. 
The following procedures will be performed: 
• Signing an Informed Consent Form to participate in the study; forms for processing the 
results of routine examination in a clinical trial; 
• Collection and registration of demographic data (sex, age, race); 
• Collection of anthropometric data (height, body weight, BMI calculation); 
• Collection of medical anamneses (anamnesis of ITP, data on the reception of previous 
therapy ITP, allergy anamnesis, transfusion anamnesis, comorbidity analysis, data on the 
treatment of comorbidities, bad habits) 
 • Physical exploring (necessarily be sure to assess the severity of the hemorrhagic syndrome 
(exploring of the skin and mucous membranes, the presence of bleeding); palpation and 
percussion of the abdominal organs; auscultation and percussion of the heart and lungs. 
• Measurement of vital signs (body temperature, heart rate, blood pressure, respiratory rate); 
• Electrocardiography in 12 deviations; 
• General blood test: hemoglobin, hematocrit, erythrocytes, reticulocytes (at the lowered level 
of hemoglobin, but not below 90 g/L), leukocytes + expanded leukocyte formula, platelet 
count according to Fonio; 
• Biochemical blood test: ALT, AST, bilirubin, creatinine, urea, glucose; 
• Analysis for HIV, RW, HBsAg, anti-HCV, CMV, EBV or data from primary documentation; 
• Determination of the level of total IgG in blood serum in grams per liter; 
• Blood test for blood type and rhesus factor; 
• Coagulogram (PTI, fibrinogen, APTT); 
• Blood test for antinuclear antibodies (ANA); 
• Straight Coombs' test (antiglobulin test); 
• General urine analysis: color, transparency, question. weight; pH, glucose, protein, ketone 
bodies; sediment microscopy (erythrocytes, leukocytes, cylinders, crystals, bacteria / fungi); 
• Pregnancy test for women of reproductive age; 


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• Assessment of the patient's compliance with the inclusion / non-inclusion criteria based on 
the screening results; 
• Rating according to the exclusion criteria; 
• Appointment of the date of hospitalization. 
 
All screening data are entered into the primary documentation and IRF of patients. The researcher 
checks the patient's compliance with the inclusion/exclusion (exclusion) criteria and decides on 
possible participation in the clinical trial. Due to the variability in PLT levels in patients with chronic 
immune thrombocytopenia (wave-like), it is possible to re-screen or extend the duration of the 
screening stage, but only if the study subject meets all other specified inclusion criteria, does not have 
non-inclusion and exclusion criteria. 
 
 
Visit 2. (Day 0, Day +1, Day +2): Study Drug administration within 2 days. Observation. 
 
Content of the visit: 
The patient is hospitalized for 3 days for the introduction of the Study Drug (SD).  
• 15 minutes before the start of each SD administration and after drug administration, a 
physical exploring is performed: determination of the dynamics of the hemorrhagic 
syndrome (exploring of the skin and mucous membranes, the presence / absence of 
bleeding); palpation and percussion of the abdominal organs; auscultation and percussion of 
the heart and lungs; Measurement of vital signs (body temperature, heart rate, blood pressure, 
respiratory rate); 
• Administration of SD for 2 consecutive days at a dose of 0.8-1.0 g/kg per day (course dose 
1.6-2.0 g/kg); 
• After 48 hours (+/- 2 hours) from the beginning of the first SD administration, a blood sample 
is taken for general blood test, biochemical blood test, Coombs' test and Ig G level according 
to the "Schedule of Procedures"; 
• AE/AR registration; 
• Discharge of the patient and appointment of the date of the next visit. 
 
Visit 3 (Day +7 ± 1 day): Observations. 
The patient is: 
• Physical exploring is performed: determination of the dynamics of the hemorrhagic 
syndrome (exploring of the skin and mucous membranes, the presence / absence of 
bleeding); palpation and percussion of the abdominal organs; auscultation and percussion of 
the heart and lungs;  
• Measurement of vital signs (body temperature, heart rate, blood pressure, respiratory rate); 
• General blood test: hemoglobin, hematocrit, erythrocytes, leukocytes, platelet count 
according to Fonio; 
• Coombs' test is performed in case of hemolysis according to the laboratory test at the 
previous visit; 
• Determination of total IgG in serum (g/l); 
• Rating according to the exclusion criteria; 
• AE/AR registration; 
• Discharge of the patient and appointment of the date of the next visit. 
 
Visit 4 (Day 14 ± 2 days): Observations. 


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The visit may be conducted by telephone / video, provided that an adequate assessment of the 
patient's condition is possible and that a laboratory examination is mandatory at the collection 
point of the Central Laboratory designated by the Sponsor. 
At visit 4, the following procedures are performed: 
• Physical exploring is performed: determination of the dynamics of the hemorrhagic 
syndrome (exploring of the skin and mucous membranes, the presence / absence of 
bleeding); palpation and percussion of the abdominal organs; auscultation and percussion of 
the heart and lungs;  
• Measurement of vital signs (body temperature, heart rate, blood pressure, respiratory rate); 
• General blood test: hemoglobin, hematocrit, erythrocytes, leukocytes, platelet count 
according to Fonio; 
• Coombs' test is performed in case of hemolysis according to the laboratory test at the 
previous visit; 
• Determination of total IgG in serum (g/l); 
• Rating according to the exclusion criteria; 
• AE/AR registration; 
• Discharge of the patient and appointment of the date of the next visit. 
 
Visit 5 (Day 21 ± 3 days): Observations. 
The visit may be conducted by telephone / video, provided that an adequate assessment of the 
patient's condition is possible and that a laboratory examination is mandatory at the collection 
point of the Central Laboratory designated by the Sponsor. 
At visit 4, the following procedures are performed: 
• Physical exploring is performed: determination of the dynamics of the hemorrhagic 
syndrome (exploring of the skin and mucous membranes, the presence / absence of 
bleeding); palpation and percussion of the abdominal organs; auscultation and percussion of 
the heart and lungs;  
• Measurement of vital signs (body temperature, heart rate, blood pressure, respiratory rate); 
• General blood test: hemoglobin, hematocrit, erythrocytes, leukocytes, platelet count 
according to Fonio; 
• Coombs' test is performed in case of hemolysis according to the laboratory test at the 
previous visit; 
• Determination of total IgG in serum (g/l); 
• Rating according to the exclusion criteria; 
• AE/AR registration; 
• Discharge of the patient and appointment of the date of the next visit. 
 
Visit 6 (Day 28 ± 1- 3 days): Observations. 
Face-to-face visit. 
At visit 6, the following procedures are performed: 
• Physical exploring is performed: determination of the dynamics of the hemorrhagic 
syndrome (exploring of the skin and mucous membranes, the presence / absence of 
bleeding); palpation and percussion of the abdominal organs; auscultation and percussion of 
the heart and lungs;  
• Measurement of vital signs (body temperature, heart rate, blood pressure, respiratory rate); 
• General blood test: hemoglobin, hematocrit, erythrocytes, leukocytes, platelet count 
according to Fonio; 
• Biochemical blood test: ALT, AST, bilirubin, creatinine, urea, glucose, Coombs' test; 
• Determination of total IgG in serum (g/l); 


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• Rating according to the exclusion criteria; 
• AE/AR registration; 
• Final visit. 
 
 
6.6.1 Unscheduled visit 
 
An unscheduled visit may be made at any time throughout the clinical trial at the request of 
the patient or at the discretion of the principal investigator and/or the investigating physician. 
The date and reason for the unscheduled visit will be recorded in the primary medical record 
and individual registration form. The data of the unscheduled visit will be registered in the primary 
medical documentation and the individual registration form of the patient. 
The reasons for an unscheduled visit may be: 
• Occurrence of AE/AR or observation of the course of AE/AR; 
• Assessment of the dynamics of the patient's condition; 
• Assessment of the dynamics of instrumental survey indicators; 
• Changes in concomitant therapy; 
• Another significant reason (must be specified). 
The following clinical trial procedures will be performed during the unscheduled visit: 
• Physical exploring; 
• Measurement of vital signs (body temperature, heart rate, blood pressure, respiratory rate); 
• Assessment of the presence and severity of AE/AR. 
Additional clinical trial procedures during an unscheduled visit may include any of the clinical 
trial procedures that will be decided on a case-by-case basis by the investigating physician in 
consultation with the Sponsor. 
 
6.7 
Diet and fluid intake 
 
Patients should follow a regular diet, fluid intake and physical activity throughout the study 
period. 
Patients are advised to refrain from food and drink that may impair kidney and liver function 
(eg., alcoholic beverages, high-fat foods, fried foods in large quantities). When receiving blood 
samples - the last meal the day before at least 12 hours. Blood sampling is also performed on an 
empty stomach. 
 
6.8 
Mode of physical activity 
 
Throughout the study period, patients should adhere to physiologically normal sleep and activity, 
without increased physical activity and exercise. 
 


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7 
INFORMATION ON MEDICINAL PRODUCTS USED IN CLINICAL 
TRIAL 
 
7.1 
Study drug  
 
Name of the medicinal product: BIOVEN 
Composition: 
active substance: Human normal immunoglobulin for intravenous administration; 
1 ml of the drug contains normal human immunoglobulin 0.1 g (including immunoglobulin G (IgG) 
at least 95%); 
Excipients: glycine (amino acetic acid); water for injections. 
Pharmacotherapeutic group: Human normal immunoglobulin for intravenous administration. 
ATC code J06B A02 
Dosage form: solution for infusion. 
The product is an immunologically active protein fraction (ratio of immunoglobulin G 
subclasses in the drug product: IgG1: 65.6 %, IgG2: 22.1 %, IgG3: 10.8 %, IgG4: 1.5 %) max. 
content of immunoglobulin A in the drug product is 50 µg/ml. 
Active components of the product are antibodies that have a specific activity against different 
pathogenic agents such as viruses and bacteria including hepatitis A and B, herpes, chicken pox, 
influenza, measles, parotitis, poliomyelitis, German measles, whooping cough, staphylococcus, 
Escherichia coli and pneumococcus. It also has a non-specific activity to increase organism 
resistance. 
The drug product is a native immunoglobulin G and retains all biological properties: 
complement activation; effector and opsonocytophagic function. 
The product is an immunologically active protein fraction extracted from human blood serum 
or plasma and screened negative for antibodies to HIV-1, HIV-2, hepatitis C virus and surface 
antigen of hepatitis B virus, purified and concentrated by use of the fractionation method with 
water-alcohol precipitating agent that passed the phase of virus inactivation by use of solvent-
detergent method and nanofiltration method. 
 
7.2 
Circulation of the study drug 
Manufacturing, packaging and labeling of the investigated drug is carried out by the Sponsor 
- the manufacturer of the drug LLC "BIOPHARMA PLASMA".  
The study drug is provided to the clinical base by the Sponsor in the amount required for this 
study. Transfer of the drug is confirmed by the act of transfer, which indicates: the number of 
drugs, batch numbers, expiration date, date of transfer. The act is signed by the Sponsor and the 
Responsible Researcher of the clinical base. 
On a clinical basis, the study drug should be placed in an individual clearly marked package 
for each patient. The drug should be stored in a dry, protected from light at a temperature of 2- 8 
degrees Celsius. The drug should be stored indoors, accessible only to the investigating physician 
or members of the research team to whom the responsible researcher has delegated the appropriate 
authority. 
The person authorized by the Responsible Researcher keeps a journal of the study drug. 
The journal, at each delivery of the drug to the patient, indicates: the name of the drug, date of 
issue, quantity, as well as the patient's number in this clinical trial and the patient's initials, the 
researcher's signature. 


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The packaging of the used drug is stored for a period determined by the Sponsor. Unused drugs 
are returned to the Sponsor, which is confirmed by the act of transfer. 
To allow for re-testing if required by the Authority, the Study Sponsor must maintain a 
sufficient number of specimens of investigational medicinal products for one year after the 
expiration date or for two years after completion of the study (whichever is longer). 
 
7.3 
 Labeling of the study drug 
 
The study drug should be marked with the following symbols and fields: 
• mark "Only for clinical trials"; 
• drug name; 
• composition, including the content of active substances in the vial; 
• method of administration; 
• manufacturer's name, location, telephone number; 
• serial number; 
• expiration date; 
• storage conditions; 
• clinical trial code; 
• center code; 
• patient code. 
The serial number indicated on the label must correspond to the batch number indicated in the 
quality certificate of BIOPHARMA PLASMA LLC. 
 
7.4 
The order of administration of the study drug  
 
The introduction of SD will be carried out in a hospital or day hospital under the supervision 
of a investigator. The primary documentation and IRF record the time of drug administration, the 
occurrence of possible side effects. 
As part of this clinical study, patients will receive the drug Bioven, 10% infusion solution, 
manufactured by "Biopharma Plasma" LLC at a dose of 0.8-1.0 g / kg 1 time per day for 2 consecutive 
days (course dose 1.6-2.0 g / kg). Allowed repeat course at same dosage in period 14-28 days from 
first infusion, if required. 
 
Bioven should be administered intravenously at an initial rate of 0.5 - 1.0 ml / kg body weight 
/ h for 30 minutes. In the absence of any undesirable side effects, the rate of administration can be 
gradually increased (recommended increase by 0.5 - 1.5 ml / kg body weight / h every 10 minutes). 
According to clinical studies, the maximum rate of administration is 8.5 ml / kg body weight/ hour. 
The study drug is administered only in a hospital setting in accordance with the rules of 
asepsis. 
The solution should be at room temperature before use. Turbid and sedimentary solutions are 
not used. A separate infusion system should be used for drug administration. When administering 
the drug should take into account the information provided in the instructions for medical use in 
the relevant sections: Features of application, Special safety measures, Contraindications, 
Interaction with other drugs, etc. Including but not limited to, measures to control the state of the 
coagulation system, hydration levels, kidney function and more. 
According to the section "Special features of use", and as described in section 2.5 "Specifics 
of use" of this protocol for patients at risk of thrombosis, the introduction of immunoglobulin drugs 
in minimal doses and with a minimum infusion rate. 


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Before using the drug, make sure the patient's level of hydration is adequate. Patients at risk 
of high viscosity should be monitored for thrombosis symptoms and blood viscosity assessed. 
Patients in this study may receive concomitant therapy, which is used to treat comorbidities and 
vital signs.  
The route of administration and dosage doesn’t exceed the maximum single and course doses 
that can be used in the treatment of patients, according to the approved Instructions for medical 
use of the drug Bioven. They fully meet the requirements for the finished medicinal product, which 
are strictly regulated by the European Pharmacopoeia (monograph Eur. Ph.0918), the State 
Pharmacopoeia of Ukraine, and are within the limits set out in the Guideline on core SmPC for 
human normal immunoglobulin for intravenous administration (IVIg) EMA / CHMP / BPWP / 
94038/2007 Rev. 5 June 28, 2018. 
 
7.5 
Concomitant therapy is allowed. 
 
The use of any drugs other than those listed in section 7.4 is permitted. Patients should refrain 
from unprotected sexual intercourse throughout the study. Within 30 days of completion, study 
participants with preserved reproductive potential should use effective barrier contraception. The 
purpose of barrier contraception is to prevent sexually transmitted diseases, including HIV, HBV, 
HCV. 
Effective methods of contraception include: 
• Full maintenance; 
• Condom or double barrier method. 
 
7.6 
Concomitant therapy is prohibited. 
 
The following drugs are prohibited during the participation of patients in a clinical trial: 
1. Corticosteroids are allowed only if the patient is taking long-term stable doses at least 2 
weeks before screening; 
2. The dose of corticosteroids or other immunosuppressant should remain unchanged for 
up to 31 days; 
3. If patients have been treated with cyclophosphamide, azathioprine or attenuated 
androgens, the treatment regimen should be stable for at least 2 months before Day 0; 
4. Monoclonal antibodies; 
5. Avatrombopag; 
6. Antiplatelet agents; 
7. Anticoagulants. 
 
 


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8 
EVALUATION OF EFFICIENCY 
 
8.1 
Primary efficacy endpoint: 
 
Part (percent) of patients with response (R). 
 
R is determined according to the following criteria: 
- Patients with R: platelets count > 30x109/L and at least a two-fold increase from the baseline 
count. This must be confirmed by at least 2 blood tests at least 7 days apart, and the absence of 
bleeding; 
The primary efficacy variable is achievement of R during the study (yes/no). 
 
 
8.2 
Secondary efficiency endpoints 
 
Part (percent) of patients with a complete response (CR). 
CR is determined according to the following criteria: 
- Patients with CR: platelets count > 100 x 109/L, which is confirmed by 2 blood tests performed 
at least 7 days apart and the absence of bleeding; 
 
Part (percent) of patients with no response (NR). 
NR is determined according to the following criteria: 
- Patients with NR: platelet count < 30 x 109/L or less than two-fold increase of baseline platelet 
count. This must be confirmed by at least 2 blood tests performed approximately 1 day apart, 
or the presence of bleeding; 
 
Part (percent) of patients with loss of response (loss of R). 
Loss R is determined according to the following criteria: 
- Patients with loss R: a decrease platelet count < 30 x 109/L or less than two-fold increase of 
baseline platelet count, or the occurrence of bleeding. Platelet counts confirmed at least 2 blood 
tests performed approximately 1 day apart. 
 
Part (percent) of patients with loss of complete response (loss of CR). 
CR loss is determined according to the following criteria: 
- Patients with loss of CR: decrease platelet count < 100 x 109/L, or the occurrence of bleeding. 
Platelet counts confirmed at least 2 blood tests performed approximately 1 day apart. 
 
Time (in days) from treatment start to onset of a response (R); 
Time (in days) from treatment start to onset of a complete response (CR); 
Duration (in days) of response (R); 
Duration (in days) of complete response (CR); 
 
Secondary efficacy endpoints are transformed into corresponding efficacy variables 
 
Safety 
- Frequency (percent) of adverse events 
- Frequency (percent) of serious adverse events 
 
 


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9 
SECURITY ASSESSMENT  
 
9.1 
Security endpoints  
 
- Frequency of side effects; 
- Frequency of serious side effects; 
- Frequency of clinically significant changes in laboratory parameters and vital signs after 
infusion of the study drug; 
- Dynamics of laboratory parameters. 
 
9.2 
Definitions concerning safety assessment.  
 
Adverse event 
Adverse event (AE) is any adverse change in the health of a patient or subject who has been 
administered a drug, regardless of the causal relationship with its use. 
AE can be any adverse and unintentional change, symptom or disease, the time of occurrence 
of which does not exclude a causal relationship with the use of the drug, regardless of the presence 
or absence of a relationship with the use of the drug. 
AEs may be abnormal laboratory parameters, first-time symptoms, or diseases that are related 
to the use of the drug, or if they existed before treatment of a condition whose severity or frequency 
increased after administration of the study drug. 
Any medical condition present at the time of the patient's screening, but not deteriorating 
during the study, should not be recorded as an AE. However, if this medical condition worsens at 
any time during the study, it should be recorded as an AE. 
Medical interventions, such as surgeries, diagnostic and treatment procedures, are not AEs, 
but they are interventions to treat the relevant medical condition and should be registered as a 
treatment for ANs. 
Deviations from the norm of laboratory parameters 
Any deviation from the norm of the laboratory indicator, which appeared for the first time, or 
the degree of severity, the frequency of which has increased compared to baseline, and meets at 
least one of the following criteria, must be recorded as AE: 
- Requires medical intervention or diagnostic procedure; 
- Leads to the cancellation of the study drug; 
- Accompanied by complaints or symptoms, or causes them; 
- Considered by the researcher as "clinically significant". 
If there is any doubt as to whether a clinical event is an АE, it should be recorded as an АЕ. 
 
Adverse reaction 
Adverse reaction (AR) is an adverse reaction of the body associated with the use of a 
medicinal product (study drug), which implies the presence of at least a possible relationship with 
the use of a suspected drug (study drug). 
During the study period, the investigator or study staff should conduct surveys and record 
information on adverse events / reactions as defined in this section of the protocol. 
  
Unforeseen adverse reaction 
Unforeseen АR - adverse reaction, nature, severity or outcome of which does not correspond 
to the information contained in the general characteristics of the medicinal product (instructions 
for medical use) or in the researcher's brochure (for unregistered medicinal product). 


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Serious adverse event 
Serious adverse event (SAE)- Adverse medical event that leads to death, threatens life, requires 
hospitalization or continuation of hospitalization, leads to permanent or severe disability or 
incapacity, congenital anomalies or malformations, requires medical intervention to prevent the 
development of these conditions. 
Death- is usually the result of the underlying clinical phenomenon that causes it. Therefore, 
the cause of death should not be considered serious. The only exception is "sudden death", when 
its causes have been established. In this case, "sudden death" should be considered AE, the reason 
for its "seriousness" - its "lethality". 
Threat to life- the term "threat to life" is defined as an AE during which there was a threat to 
the patient's life. This does not mean any AE that can hypothetically lead to death in the case of its 
increased complexity. 
Hospitalization- any adverse event leading to hospitalization or continuation of hospitalization 
will automatically be considered serious if it does not meet any of the non-inclusion criteria listed 
below: 
hospitalization lasts less than 12 hours or hospitalization is planned in advance (it is an 
optional or planned operation, which was agreed upon before the start of this study). 
Disability is defined as a significant impairment of a person's ability to perform daily 
functions, such as a congenital anomaly / malformation. 
 
9.3 
 Detection and registration of AE 
 
Detection and registration of SAE begins from the moment of signing the informed consent 
and lasts until the end of the patient's participation in the study. 
Detection and registration of AE begins with the introduction of the drug and lasts until the 
end of the patient's participation in the study. 
AE that occur between screening and administration of a drug, but does not considered as a 
SAE should be recorded as a medical history. 
All AEs arising from the administration of the drug reported by the patient or detected during 
observation, physical examination and other diagnostic procedures must be registered in the AE 
Reporting Form attached to the Individual Registration Card. 
Laboratory parameters will be evaluated during screening and throughout the study. 
 
Information on any AE observed during the study period, from the first use of the study drug 
to the end of its use, is recorded in the patient's medical history / outpatient card and in the IRF 
registration section. All AEs are subject to registration, regardless of the severity or the presence 
of a causal relationship with the investigational medicinal product. 
 
As AE should be classified: 
• exacerbation of previous diseases; 
• increase in the frequency or intensity of diseases or episodic phenomena observed 
earlier; 
• diseases detected or diagnosed after the start of the study drug, even if it is possible 
before the patient's participation in the study; 
• long-term, persistent disease or symptoms that were in the initial stage, the severity 
of which increased after the start of the patient's participation in the study; 


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• the appearance of new signs or an increase in the severity of the signs and symptoms 
of diabetes mellitus, which require urgent therapy, hospitalization, surgery and / or 
other intervention; 
• clinically significant abnormalities detected by laboratory diagnostics or other 
examinations after the start of the study drug or available at baseline, the severity of 
which increased on the background of the study drug. 
 
AS a AE should not be classified: 
1. diseases or pathologies detected or diagnosed before the use of the investigational 
medicinal product, the severity of which does not increase; 
2. situations in which there is no medically unfavorable event (for example, 
hospitalization for the planned surgery); 
3. overdose of any of the studied drugs or concomitant drugs without unwanted signs 
or symptoms; 
4. any clinically significant deviation of the laboratory indicator from the norm, 
detected before the first use of the study drug; 
5. signs and symptoms observed during the study, which are associated with insufficient 
effectiveness of treatment. 
 
The study will monitor the occurrence of any adverse events (AE). Table 1 presents the 
tolerance assessment scale. 
 
9.4. 
Table 1. Tolerance assessment scale 
 
Category 
Category description 
Good 
At objective inspection in dynamics any pathological changes or 
clinically significant deviations does not find, data of laboratory 
inspection do not change reliably and do not go out of norm, the patient 
does not feel the side reactions. 
Satisfactory 
At objective inspection in dynamics insignificant changes which have 
temporary character and do not demand change of the scheme of 
treatment and carrying out additional medical actions come to light. 
and / or 
laboratory test data deviate slightly from normal. 
and / or 
there are minor side effects that do not cause serious problems to the 
patient and do not require discontinuation of the drug 
Unsatisfactory 
At objective inspection in dynamics the pathological changes demanding 
drug cancellation and carrying out additional medical actions come to 
light. 
and / or 
laboratory test data undergo clinically significant negative changes, 
which entails the need for additional examination and interpretation of 
data 
and / or 
there is an undesirable side effect that has a significant negative impact 
on the patient's condition, requiring discontinuation of the drug and the 
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Signs and symptoms, which are based on general pathology, if possible, should be noted as 
one complex phenomenon. If the diagnosis is known, it should be registered as the name of the 
AE. If the diagnosis is unknown, each complaint and symptom should be recorded as a separate 
AE. 
The information to be recorded includes the type of phenomenon, the date of development of 
the AE, the researcher's assessment of the severity and relationship of the AE with the study drug, 
the date of termination (decision) of the AE, the severity of the AE, the measures taken and the 
outcome of the AE. 
All the AEs should be monitored until they are adequately addressed. 
During and after the subject's participation in the study, the researcher (medical institution) 
must ensure that the subject is provided with the necessary medical care in the event of any study-
related adverse events, including clinically significant changes in laboratory parameters. The 
researcher (medical institution) is obliged to inform the research subject about intercurrent diseases 
that require medical care, which became known to the researcher. 
 
9.5. 
Assessment of the severity of AE 
The severity (expressiveness) of AEs indicates the extent to which AEs affect the patient's 
daily activities. The severity of the AE will be determined according to the NCI CTCAE criteria 
developed by the US National Cancer Institute (version 5.0) (in each paragraph a semicolon means 
"or") Table 2. 
 
9.6. 
Table 2. The severity of NOT according to NCI CTCAE (version 5.0) 
 
Severity 1 
Easy; no symptoms or minor symptoms; only clinical or diagnostic 
observations; no intervention is required 
Severity 2 
Moderate; requires minimal, local or non-invasive intervention (eg, 
tamponade, cauterization); the restriction corresponds to the Social Daily 
Activities (SDA), Instrumental Activities of Daily Living (ADL *) 
Severity 3 
Severe or clinically significant but not life-threatening; hospitalization 
or continuation of hospitalization is required; restriction of vital activity; 
Self Care Activities of Daily Living (ADL **) 
Severity 4 
Life-threatening condition; immediate intervention is required 
Severity 5 
Death associated with AE 
 
Daily activity (ADL): 
* Social daily activities (SDA) include cooking, buying food or clothing, using the phone, handling money, etc. 
** Self-care (SC) includes taking a bath, dressing and undressing, eating alone, using the toilet, taking medication and 
not being bedridden. 
 
The terms "serious" and "severe" are not synonymous. Severe AE (Grade 3 or 4) should not 
always be considered serious. For example, leukocyte counts between 1000 and 2000 / mm3 should 
be considered grade 3 (severe), but such may not be considered severe. The benchmark for submitting 
information to regulators is the severity (not the expressiveness) of the AE. 
 
9.7. 
Assessment of the causal relationship of AE with the study drug 
 
In assessing the cause-and-effect relationship, the investigator should consider the possible 
etiology of the observed AE / AR phenomenon, which may be due to the study drug, concomitant 


Bi o ve n  
Pa ge  6 5   
Trial C o de:  2 0 2 1 -B V -I T P-B P  
Versi o n  1. 4  fr o m J ul y 0 3 , 2 0 2 3    
 
 
C O N FI D E N TI A L  
 
 
me dicati o ns, u n derl yi n g disease, c o m or bi dities, st u d y pr oce d ures, a n d ot her reas o ns. F or all p ossi ble 
reas o ns, t he researc her m ust deter mi ne t he o ne t hat has t he m ost li kel y ca usal relati o ns hi p wit h t he 
p he n o me n o n. W h e n assessi n g t he ca usal relati o ns hi p i n  t he case of a s eri o us A R, t he re p ort m ust 
pr o vi de a j ustificati o n f or t his assess me nt. T h e j ustificati o n s h o ul d i ncl u de all a v aila ble e vi de nce 
c o nfir mi n g t he assess me nt, i ncl u di n g t he res ults of la b orat or y tests a n d ot h er dia g n ostic pr oce d ures. 
•  T he c a us al rel ati o ns hi p is deter mi ne d. T he cli nical p he n o me n o n a n d / or c ha n g es i n 
la b orat or y  para meters  are  ti me-relate d  t o  t he  dr u g  a n d  ca n n ot  be  e x plai ne d  b y  
c o m or bi dities, ot her dr u gs or c h e micals. T h e res p o nse t o dr u g wit h dra wal s h o ul d be 
cli nicall y  acc urate.  T he  p he n o me n o n  was  c o nfir me d  b y  c o n d ucti n g,  if  necessar y,  a  
pr o v ocati ve test pr o ce d ure. 
•  Pr o b a ble c a us ati o n .Cli nical e ve nts a n d / or c ha n ges i n la b orat or y p ara meters relate d t o 
t he ti me of a d mi nistrati o n of t he dr u g, w hic h ca n har dl y be e x plai ne d b y c o nc o mita nt 
disease or t he us e of ot h er dr u gs or c he mical c o m p o u n ds, i n t he pres e nce of a cli nicall y 
pr o n o u nce d res p o nse t o dr u g wit h dra wal.  
•  A c a us al rel ati o ns hi p is p ossi ble.  Cli nical p he n o me n o n a n d / or c h a n ges i n la b orat or y 
para meters relate d t o t he ti me ass ociate d wit h t he dr u g, b ut w hic h ca n be e x plai ne d b y 
t he prese nce of c o m or bi dities or ot her dr u gs a n d c he micals. I nf or mati o n o n dr u g res p o nse 
ma y be missi n g or u nclear.  
•  U nli kel y c a us ati o n .Cli nical e ve nts a n d / or c h a n ges i n la b orat or y p ara meters ma y be 
relate d  i n  ti me  t o  t he  a d mi nistrati o n  of  t he  dr u g,  b ut  ot her  dr u gs,  c he micals  or  
c o m or bi dities pr o vi de a m ore pla usi ble e x pla n ati o n f or t he p he n o me n o n.  
•  N o c o n necti o n .T he cli ni cal p he n o me n o n a n d / or c ha n ges i n la b orat or y p ara meters are 
certai nl y n ot relate d t o t he use of t he dr u g d ue t o t he u nreas o na bl e te m p oral relati o ns hi p 
bet wee n t he dr u g a n d A R a n d / or t he i m pr o ba bilit y of s uc h a relati o ns hi p.  
 
9. 8.  
 C ate g ories of c o nse q ue nces of A E a n d t heir defi niti o ns  
 
Me as ures t ake n: 
 Wit h o ut tre at me nt;  
 C a ncell ati o n of t he s us pecte d dr u g; 
 Re d uci n g t he d ose of t he s us pecte d dr u g; 
 C a ncell ati o n of c o nc o mit a nt tre at me nt; 
 Use of dr u g t her a py; 
 N o n- dr u g t her a py (i ncl u di n g s ur gery). 
 
T he p he n o me n o n p asse d wit h o ut c o nse q ue nces -t here are n o s y m pt o ms, a n d t he patie nt is n ot 
treate d t o eli mi nate t his A R. 
St a biliz ati o n of t he st ate -t he res ult of A R is classifie d as sta bilizati o n of t he state acc or di n g t o 
t he researc h er. 
T he  p he n o me n o n  p asse d  wit h  c o nse q ue nces  -t he  p he n o m e n o n  was  c urtaile d,  b ut  its  
c o nse q ue nces re mai ne d; as a res ult of A R t he patie nt has a te m p orar y or per m a ne nt disa bilit y / 
i nca pacit y; a n y A R t hat h a ve passe d wit h c o nse q u e nces are classifie d as seri o us A R. 
T he p he n o me n o n h as n ot yet p asse d -s y m pt o ms persist. 
De at h of t he p atie nt.  
T he res ult is u n k n o w n.  
 
 
 


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9.9. 
Reports of SAE 
 
In the case of any SAE, the Study Sponsor must be notified within 24 hours of the researcher 
first learning about the SAE. During the development of SAE, the researcher fills in the SAE 
registration form and determines whether it is associated with the study drug and sends by fax or e-
mail the completed form to the Sponsor of the study. The original SAE form and the fax confirmation 
letter must be kept. The fact of SAE should be recorded in the IRF. The sponsor has the right to 
urgently request from the researcher additional information about SAE for reporting to health 
authorities. 
After the initial urgent notification, a detailed written notification must be submitted as soon as 
possible. Primary and subsequent reports should identify the subjects of the study by the unique code 
assigned to them, and not by the names of the subjects, personal identification numbers and (or) 
addresses. 
In case of hospitalization of the patient in connection with the development of SAE, it is 
necessary to send as soon as possibleby fax or e-mail to the Sponsor of the study a copy of the hospital 
discharge. 
 
The sponsor of the study or his authorized representative is responsible for notifying by telephone 
or fax of unforeseen or life-threatening SAEs related to the use of the study drug (in the form of urgent 
reports) to the relevant authorities and competent authorities within 7 calendar days obtaining 
information about SAE. The sponsor of the study or his authorized representative will report other 
significant SAEs related to the use of the study drug to the appropriate authorities, researchers and 
the local ethics committee by providing a written safety report within 15 calendar days of receiving 
the information about SAE. 
In Ukraine, the sponsor shall immediately register and within 7 calendar days from the moment 
he became aware of it, inform the SEC of the Ministry of Health of Ukraine and the Ethics 
Commission of all suspected unforeseen serious adverse reactions to the investigational medicinal 
product that resulted in death or threat for the life of the subject. Additional information on this subject 
is provided by the SEC of the Ministry of Health of Ukraine and the Ethics Commission within the 
next 8 calendar days. The notification of a suspected unforeseen serious adverse reaction must be 
made in accordance with the order of the Ministry of Health of Ukraine № 690 of 23.09.2009, as 
amended. 
In addition to the death notification, the researcher shall provide any additional information at 
the request of the regulatory authority (autopsy report and final medical reports after their proper 
preparation in accordance with the legislation of the country where the study is conducted - Ukraine). 
 
 
9.10. Requirements for reporting after completion of the study drug  
 
If the Researcher receives information about any AR that has occurred at any time after the 
patient has taken the study drug, and there are sufficient grounds to suggest a connection between this 
phenomenon and the study drug, the Researcher must notify Sponsor. 
 
9.11. Contraception and pregnancy 
 
Prior to the start of the study, men and women of childbearing potential will be informed of the 
importance of contraception during the study and within 3 weeks of completion. Reliable methods of 
contraception include: surgical sterilization, double barrier method of contraception, local 
contraception. The study will also be open to women who do not use acceptable methods of 


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contraception if they are declared unfit for childbirth: women who have undergone a hysterectomy 
(removal of the uterus) or tubal ligation, women with a clinical diagnosis of infertility, and women 
who are in the menopausal period more than 1 year (absence of menstruation for at least 12 months). 
 
9.12. The period of time during which the collection of information about pregnancy is 
required. 
 
It is necessary to collect information on the course of any pregnancy throughout the clinical trial, 
starting with the first dose of the study drug. 
 
 
9.13. Actions to be taken in case of pregnancy. 
 
The researcher will collect information about the pregnancy of any patient who became pregnant 
during the study. The researcher will record information about the onset of pregnancy and pass the 
information to the Sponsor of the study. The procedure for reporting a pregnancy is similar to the 
procedure for reporting a serious adverse event. 
Pregnancy is not considered as a AE, but any complication of pregnancy or planned termination 
of pregnancy on medical grounds will be registered as AE, and such a patient will be monitored. 
Spontaneous abortion is always considered a AE and should also be reported to the Sponsor. In 
addition, the Sponsor must be notified of any AE that has occurred as a result of a post-study 
pregnancy that is considered by the investigator to be reasonably related to the study drug being 
studied. Although the researcher is not required to actively seek this information from former study 
participants, he / she may learn about AE spontaneously from the participants' own reports. Patients 
who become pregnant will be excluded from the study. 
 
 


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10 
 STATISTICS 
 
10.1 
Content of statistical analysis 
 
The null hypothesis for the primary efficacy endpoint Н0: p−p0  ≤  δ, where clinical effectiveness p 
is the proportion of patients who responded to therapy with the study drug BIOVEN; p0- proportion 
of patients responding to therapy according to literature data: δ- the limit of the difference of 
proportions without clinical significance. An alternative hypothesis Н1: p-p0 > δ («non-inferiority 
study» according to the guideline ЕМА «Points to consider on switching between superiority and 
non-inferiority» CPMP/EWP/482/99, London, 27 July 2000 та ЕМА “ICH Topic E 9 Statistical 
Principles for Clinical Trials” CPMP/ICH/363/96). 
According to the EU recommendations on clinical studies of immunoglobulin normal for 
intravenous administration (Guideline on the clinical investigation of human normal immunoglobulin 
for intravenous administration (IVIg), EMA/CHMP/BPWP/94033/2007 rev. 3, 28 June 2018) the 
obtained results will be compared with literature data. 
To test the null hypothesis, a two-tailed test will be used, based on the principles of estimating 
a 95% confidence interval for the difference in proportions and comparing it with the lower limit of 
equivalence (at a significance level of α 5%). For non-inferiority research, the null hypothesis is 
rejected if the conditions are met: 
 
√n(p−p0−δ) / pˆ(1 − pˆ)> zα/2 
 
or 
 
(p−p0−δ) / ට(
𝑝𝑝(1−𝑝𝑝)
𝑛𝑛
+
𝑝𝑝0(1−𝑝𝑝0)
𝑛𝑛0
)> zα/2 
 
Confidence intervals of the difference will be calculated according to the generally accepted Wald 
method: 
(p1-p2)± zα/2* √(
p1(1−p1)
n1
+
p2(1−p2)
n2
) 
 
The number of patients for the portion taken from literature sources is taken from the 2020 publication 
and will be 82 [Parodi E, Russo G, Farruggia P, Notarangelo LD, Giraudo MT, Nardi M, et al. 
Management strategies for newly diagnosed immune thrombocytopenia in Italian AIEOP Centres: do 
we overtreat? Data from a multicentre, prospective cohort study. Blood Transfus. 2020;18(5):396.] 
 
Methods of descriptive statistics (for categorical variables - number and part in %, for quantitative 
variables - n, arithmetic mean, median, standard deviation, minimum and maximum), including 
construction of graphs and charts, methods of interval estimation (calculate of 95% confidence 
intervals for proportions and differences of fractions). 
For variables that are "time to event" survival curves will be constructed in each group using the 
Kaplan-Meier method, median survival will be estimated, and group comparisons will be made using 
the log-rank test. If the survival curves intersect, then Cox regression will be used to compare the 
groups according to these variables. 
 


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To evaluate the significance in the dynamics in the case of evaluating the parameter on two visits 
(before and after): 
- To assess the dynamics of quantitative variables, the Student's test for paired data or the Wilcoxon 
signed rank test will be applied, depending on the results of testing the normality of the distribution 
of differences [after - before] using the Shapiro-Wilk test. 
- To assess the dynamics of categorical variables in groups, the McNemar criterion or the criterion of 
homogeneity of marginal frequencies will be applied, depending on the number of categories. 
- To assess the statistical significance of differences in categorical variables in unrelated groups, 
Pearson's chi-square or Fisher's exact test will be applied (depending on the frequency distribution in 
table 2*2). 
To evaluate the dynamics in the case of measuring variables on more than two visits, methods of 
univariate analysis of variance (ANOVA) will be used followed by contrast analysis (simple 
contrasts) or a posteriori analysis using Tukey's test. Analysis of covariance (ANCOVA) will be used 
to compare those variables for which the data were heterogeneous at baseline. 
To verify the prerequisites for the application of variance and covariance analyses, a check of the 
normality of the data distribution and their residuals will be performed using the Shapiro-Wilk test. 
If the residuals are not normally distributed, or if the data fail the normality test, an appropriate rank 
analysis will be performed. 
For the Shapiro-Wilk test, the significance level will be 0.01, and for other criteria - 0.05. In the event 
of the effect of multiple comparisons, an adjustment of the level of significance will be applied using 
the Holm method or the Benjamini-Hochberg method. 
 
10.2 
Sample size assesment 
 
The sample size is determined in accordance with S.C.  Chow, J. Shao, H.Wang. Sample Size 
Calculations in Clinical Research. London: Taylor&Francis, 2003. – 358 p. 
Since the main variable will be expressed as the proportion of patients who responded to therapy with 
BIOVEN 10%, the sample size was determined based on the possibility of using non-inferior efficacy 
assessment criteria with a two-sided test at a significance level of α 5%. 
Null hypothesis Н0: p−p0  ≤  δ, where the clinical effectiveness p-  the proportion of patients who 
responded to therapy with the drug BIOVEN 10%; p0- proportion of patients responding to therapy 
according to literature data. δ- the limit of the difference of proportions without clinical significance. 
An alternative hypothesis Н1: p-p0 > δ. 
The sample size in a group when comparing proportions for a study with non-inferiority efficiency is 
calculated by the formula  (Chow, S. C., Wang, H., & Shao, J. (2007). Sample size calculations in 
clinical research. Chapman and Hall/CRC.): 
n=(Za/2+Zb/2)2×(p×(1–p))/ (p – p0 – δ)² 
According to the literature, the effectiveness of IVIG when used in patients with ITP varies between 
60-80% [Anurag Singh, Günalp Uzun, Tamam Bakchoul / Primary Immune Thrombocytopenia: 
Novel Insights into Pathophysiology and Disease Management // J. Clin. Med. 2021, 10, 789. 
https://doi.org/10.3390/jcm10040789], [Godeau B., Caulier M-T. Decuypere L. et al. Intravenous 
immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial 
comparing 0´5 and 1 g/kg b.w. // British Journal of Haematology, 1999, 107, 716-719; Ruqayyah J. 
Almizraq, Donald R. Branch Efficacy and mechanism of intravenous immunoglobulin treatment for 
immune thrombocytopenia in adults // Ann Blood 2021;6:2 | http://dx.doi.org/10.21037/aob-20-87; 
Drew Provan, Roberto Stasi, Adrian C. Newland et al. International consensus report on the 
investigation and management of primary immune thrombocytopenia // Blood, 14. - Jan 2010, Vol. 
115, Number 2]). However, the most similar to this study (in terms of performance evaluation 
standards and study design) is the 2020 publication. In this publication, the drug administration 


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scheme is recommended by the EMA and this Protocol, the total number of patients in the group is 
82, the effectiveness of the use of IVIG in the treatment of ITP is indicated - 78% [Parodi E, Russo 
G, Farruggia P, Notarangelo LD, Giraudo MT, Nardi M, et al. Management strategies for newly 
diagnosed immune thrombocytopenia in Italian AIEOP Centres: do we overtreat? Data from a 
multicentre, prospective cohort study. Blood Transfus. 2020;18(5):396.]. According to our data and 
data from the literature, immunoglobulin belongs to drugs with a highly variable efficiency of 20-
25%. Therefore, for a non-inferiority study, we consider it appropriate to set δ (the limit of the 
difference in efficiency between the obtained and expected results) at the level of -25%. 
 
Thus, for a significance level of 5% and a statistical power of 80%, the effectiveness of the drug in 
the comparison model reaches 78%, the limit of the difference in specific weights (difference in 
effectiveness) without clinical significance δ is - 0.25. Then the calculation of the minimum sample 
size will look like this: 
n = (1,96+1,28)2× (0,78×(1–0,78) / (0,78 – 0,78+0,25)² = 29 
 
Considering the risk of dropping out of patients for various reasons (20%), 36 patients will be 
included in the study. 
 
10.3 
General plan of statistical analysis 
 
10.3.1. General principles of statistical analysis 
 
Statistical analysis is performed by a qualified biostatistician. It includes: 
— description of patients included in the study; 
— the number of patients dropped out of the study; 
— the number of AE/AR, SAE; 
— analysis of initial homogeneity; 
— efficiency analysis; 
— tolerability and safety analysis; 
— statistical conclusions. 
 
10.3.2. Analysis of the initial state/base-line state of the group 
 
Analyze the group according to clinical and demographic parameters at the time of inclusion in the 
study. Use methods of descriptive statistics to describe the initial state/base-line state in groups (for 
quantitative parameters - n, arithmetic mean, median, standard deviation, minimum and maximum 
value; for categorical parameters - number and share in %). 
 
10.3.3. Analysis of effectiveness 
 
Additional information about the statistical model for evaluating the effectiveness of the drug by the 
main variable is given in Section 10.1. “The content of statistical analysis”. 
 
A) The primary outcome of efficiency – Proportion (%) of patients with response (R). 
 
Primary efficiency variable – achievement of R during the study. 
R is defined according to criteria *: 


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- 
 Patients with R: the number of platelets > 30x109/l and at least a two-fold increase from the 
baseline count. This must be confirmed by at least 2 blood tests performed once every 7 days 
and the absence of bleeding; 
The categories of the variable will be defined as "Yes" or "No" respectively. 
 
* The criteria are defined according to the Guideline on the clinical investigation of human normal 
immunoglobulin for intravenous administration (IVIg), EMA/CHMP/BPWP/94033/2007 rev. 4, 16 
December 2021 as well as according to the criteria of the international working group on ITP in 
2009. (Rodeghiero, F., Stasi, R., Gernsheimer, T., Michel, M., Provan, D., Arnold, D. M., ... & 
George, J. N. (2009). Standardization of terminology, definitions, and outcome criteria in immune 
thrombocytopenic purpura of adults and children: report from an international working group. 
Blood, The Journal of the American Society of Hematology, 113(11), 2386-2393.);  
 
B) Secondary effectiveness variables. 
For variables assessed once at the final visit, descriptive statistics methods will be used to describe 
these variables (for quantitative parameters - n, arithmetic mean, median, standard deviation, 
minimum and maximum value; for categorical parameters - number and share in %) . 95% confidence 
intervals will be calculated. In the case of measuring variables at more than two visits, one-way 
analysis of variance (ANOVA) methods will be used. 
Censored data will be analyzed using the Kaplan-Meier method or the log-rank test. 
Secondary efficacy endpoints are transformed into corresponding efficacy variables: 
 
Achieving a complete response (CR) during the study. 
CR is determined according to the criteria *: 
- 
Patients with CR: platelets count > 100 x 109/L, which is confirmed by 2 blood tests performed 
at least 7 days apart and the absence of bleeding; 
The categories of the variable will be defined as "Yes" or "No" respectively. 
The variable is analyzed for patients who achieved a response (R) during the study. 
 
Non-response (NR) during the study. 
NR is determined according to the criteria *: 
- 
Patients with NR: platelet count < 30 x 109/L or less than two-fold increase of baseline platelet 
count. This must be confirmed by at least 2 blood tests performed approximately 1 day apart, 
or the presence of bleeding; 
The categories of the variable will be defined as "Yes" or "No" respectively. 
The variable is analyzed relative to the total number of patients included in the analysis. 
 
Loss of response (loss of R). 
R loss is determined according to the criteria *: 
- 
Patients with loss R: a decrease platelet count < 30 x 109/L or less than two-fold increase of 
baseline platelet count, or the occurrence of bleeding. Platelet counts confirmed at least 2 
blood tests performed approximately 1 day apart. 
The categories of the variable will be defined as "Yes" or "No" respectively. 
The variable is analyzed for patients who achieved a response (R) during the study. 
 
Loss of complete response (loss of CR). 
CR loss is determined according to the criteria *: 
- 
Patients with loss of CR: decrease platelet count < 100 x 109/L, or the occurrence of bleeding. 
Platelet counts confirmed at least 2 blood tests performed approximately 1 day apart. 


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The categories of the variable will be defined as "Yes" or "No" respectively. 
The variable is analyzed for patients who achieved a complete response (CR) during the study. 
 
Time (in days) from treatment start to onset of a response (R); 
A Kaplan Meier curve will be constructed and the median time to event will be estimated. The 
variable is analyzed for patients who achieved a response (R) during the study. 
 
Time (in days) from treatment start to onset of a complete response (CR);  
A Kaplan Meier curve will be constructed and the median time to event will be estimated. The 
variable is analyzed for patients who achieved a complete response (CR) during the study. 
 
Duration (in days) of response (R); 
A Kaplan Meier curve will be constructed and the median time to event will be estimated. The 
variable is analyzed for patients who achieved a response (R) during the study. 
 
Duration (in days) of complete response (CR); 
A Kaplan Meier curve will be constructed and the median time to event will be estimated. The 
variable is analyzed for patients who achieved a complete response (CR) during the study. 
 
C) Quantitative variables of efficiency, which are measured at study entry (T start) and at the 
final visit (T endpoint). 
Provide indicators of descriptive statistics (n, arithmetic mean, median, standard deviation, minimum 
and maximum value) for time points T start and T endpoint, and also for differences [Т endpoint – T start]. 
Represent this dynamic graphically. 
Calculate for these parameters their relative change in comparison with the initial state/base-line 
according to the formula: 
 
X (%) = 
Т 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒−T start
T start
*100, 
Evaluate the dynamics using the Student's paired test or the Wilcoxon signed rank test, depending on 
the results of testing the normality of the distribution of differences [Т endpoint – T start] using the 
Shapiro-Wilk test. 
 
D) Evaluation of quantitative variables measured at more than two measurement points. 
Specify the indicators of descriptive statistics (n, arithmetic mean, median, standard deviation, 
minimum and maximum value) for each measurement point, as well as for the differences [T i – 
T start], where i are subsequent visits. Build a dynamics graph. 
Calculate for these parameters their relative change at each subsequent visit in comparison with the 
initial state according to the formula: 
X (%) = 
Т 𝑖𝑖−Т 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
Т 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠*100, 
where i is subsequent visits according to the patient examination scheme. 
Evaluate the dynamics of changes in quantitative variables using univariate analysis of variance 
(ANOVA) or rank analysis depending on the normality of the distribution, which is tested using the 
Shapiro-Wilk test. At the same time, the dependent variable is the analyzed parameter, the "visit" 
factor is a fixed parameter. To assess the magnitude and significance of the difference between visits 
using contrast analysis (simple contrasts) or post hoc analysis using Tukey's test (for ANOVA) or 
Wilcoxon signed rank test with Holm's correction (for rank test). To verify the prerequisites for the 
application of variance analysis, a check of the normality of the distribution of residuals will be 


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performed using the Shapiro-Wilk test. In the event that the balances are not normally distributed, an 
appropriate rank analysis will be performed. 
Make statistical conclusions. 
 
10.3.4. Analysis of safety and tolerability parameters 
 
A) Data on AE/AR, Indicators of descriptive statistics (frequency and part in percent) and a list of 
adverse reactions according to the MeDRA classification 
B) Data on SAE. Indicators of descriptive statistics (frequency and part in percent) and a list of adverse 
reactions according to the MeDRA classification. 
Clinically significant deviations in indicators characterizing the safety and tolerability of the drug: 
Laboratory results of general blood analysis, biochemical blood analysis and general urinalysis; the 
result of determining the Coombs test and signs of hemolysis. 
Provide descriptive statistics for these indicators (n, arithmetic mean, median, standard deviation, 
minimum and maximum value) for all visits. 
To evaluate the dynamics of laboratory indicators, we used the Student's test for paired data or the 
Wilcoxon signed rank test, depending on the normality of the distribution of paired differences 
["after" - "before"]. Create dichotomous variables with the categories "normal" and "abnormal", 
calculate the indicators of descriptive statistics (frequency and part in %) for these variables. 
Measurement results of heart rate, blood pressure, respiratory rate, body temperature. Indicators of 
descriptive statistics (n, arithmetic mean, median, standard deviation, minimum and maximum value) 
for each visit in accordance with the patient examination scheme. Evaluate the trend of changing 
these parameters. 
 
10.3.5. Significance level 
 
The level of significance for the Shapiro-Wilk test is set at 0.01, and for other statistical tests at 0.05. 
In the case of the effect of multiple comparisons, the adjustment of the level of significance will be 
applied using the Holm method or the Benjamini-Hochberg method. 
 
10.3.6. Work with missing or incomplete data. 
 
Missing or incomplete data will be replaced using the Last-Observation-Carried-Forward (LOCF) 
method. Or by the method of enlarging the intervals for series where the transfer of the last 
measurement is not applicable. 
 
10.3.7. Conclusion on non-inferiority effectiveness 
 
In accordance with EMA recommendations for clinical studies of immunoglobulin normal for 
intravenous administration (Guideline on the clinical investigation of human normal immunoglobulin 
for intravenous administration (IVIg), EMA/CHMP/BPWP/94033/2007 rev. 4, 16 December 2021) 
the obtained results will be compared with literature data The conclusion of non-inferiority of the 
drug Bioven, solution for infusions 10%, in the treatment of chronic immune thrombocytopenia, will 
be made according to the main efficacy variable using an approach based on confidence intervals. 
To do this, the calculated limits of the 95% confidence interval (CI) for the difference in the 
percentage of positive results according to the main variable ("the drug is effective") for the studied 
group must be compared with the limit of the non-inferiority zone - effectiveness that is not inferior 
(-25%) to the calculated based on data for comparison. If the lower limit of the CI is greater than the 


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lower limit of the non-inferiority zone (non-inferiority), then it will be considered that the study drug 
is not inferior in effectiveness compared to literature data.  
 
10.4. Data set for analysis 
 
ITT (Intention-to-treat population) - all study participants who took the study drug at least once. Data 
from this sample will be used for safety analysis. 
PP (Per Protocol) - all patients who met the requirements of the protocol. This population includes 
all patients who received protocol therapy in full, completed all scheduled visits, and had no 
significant protocol deviations. The data obtained on this sample will be used for analysis according 
to the criteria of drug effectiveness. 
 
10.5. Representation of summary results 
 
The results of the statistical analysis of the obtained results should be presented in the form of tables, 
which, if necessary, are illustrated with graphs and diagrams. Presentation of data should be 
structured, in accordance with the purpose and tasks of Study. It is necessary to clearly indicate the 
methods used, to characterize the array of data. 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE  
 
11.1.  Clinical trial monitoring 
 
Regular visits of the study monitor on behalf of the sponsor and in accordance with standard 
operating procedures (SOPs), before, during and after the study contribute to the success of the study, 
and guarantee accurate data collection, timely detection of possible errors, documentation of clinical 
trials and ensuring the protection of the rights of clinical trial participants, compliance of the trial with 
the requirements of the legislation of Ukraine and Republic of Turkey. 
Routine monitoring of the study includes: 
• confirmation of the proper conduct and documentation of the process of obtaining informed 
consent, as well as screening and inclusion of participants in the study; 
• verification of data in the IRF (eCRF) and primary medical records of study participants; 
• confirmation of compliance with the requirements of the clinical center staff to perform 
diagnostic and therapeutic procedures of the study protocol; 
• confirmation of documented deliveries, storage, distribution and disposal of the investigational 
medicinal product and clinical trial materials; 
• confirmation of the competence of the staff of the clinical center, external laboratory, necessary 
for the study; 
• confirmation of compliance of diagnostic and laboratory equipment with the requirements of 
safe and adequate use during the study; 
• confirmation of the investigator's interaction with the local ethics committee on clinical trial 
safety and making amendments to the clinical trial protocol agreed with the sponsor. 
Quality control of trial results is carried out by the Sponsor's staff / Sponsor's authorized 
representative (eg., CRO) who maintains an electronic survey database that identifies inconsistencies, 
erroneously entered data and omitted data. 
If you have any questions or need clarification, the investigator is sent a special form by e-mail / 
fax, the request for which must be satisfied in writing within 7 days after delivery. In accordance with 
the requirements of the legislation, the sponsor or authorized state bodies have the right to inspect 
(audit) the logistics of the study and clinical trial documentation. The investigator must provide access 
to the documentation and all necessary information to the persons authorized to conduct the audit or 
inspection. 
 
11.2. Amendments to the protocol, rejections, and violations of the protocol 
 
The signatures of the investigators on the page of the protocol mean a written confirmation of 
consent to conduct study in accordance with this protocol. During the clinical study, changes and 
additions may be made to the study materials. Such changes and additions should be considered as 
amendments. 
Amendments to clinical trial materials are considered significant if they may affect the 
objectives, forms of organization, methodology, statistical methods of processing the results of 
clinical trials. Amendments to the protocol should be kept together with the original version of the 
protocol. The number of the amendment and the date of its entry into force must be written on the 
title page of the protocol. 
All deviations from the protocol during the study should be recorded during the monitoring of 
the clinical trial and reported to the Sponsor. 
The investigator should not deviate from the protocol, except where it is necessary to exclude a 
serious risk to the health of patients in the study. If there are other unexpected circumstances that 


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require deviations from the protocol procedures, the investigator should consult the developer of the 
medicinal product or its representative (and the Ethics Committee, if necessary) to determine the 
appropriate procedure. 
The study center must document all deviations from the protocol in the patient's original 
documentation. In the event of a significant deviation, the center should notify the developer of the 
medicinal product or its representative (and the Ethics Committee, if required). To do this, the 
investigator must fill out the form "Violation / deviation from the protocol" which is sent by fax to 
the clinical trial department of the company developing the drug. During the monitoring of the study 
center, the monitor of the clinical trial department may detect violations / deviations from the clinical 
trial protocol. In this case, he is responsible for notifying the investigators of the identified violations 
and for compiling the form "Violation / deviation from the protocol." 
Violations/deviations from the protocol can be divided into gross (significant) and non-gross 
(minor). Examples of such deviations are given below. 
 
Significant deviations from the protocol: 
1) unsigned/incorrectly signed informed consent of the patient to participate in a clinical 
trial; 
2) violation/deviation from the criterion of patient selection; 
3) significant violation of the schedule of study procedures (deviation from the list of 
procedures provided by the protocol); 
4) significant violation/deviation from the schedule of treatment of patients 
(inconsistency of the therapy provided by the protocol, replacement of packaging of 
the study drug); 
5) unreasonable disclosure of the patient's code and failure to notify the company 
conducting the study; 
6) failure to report (concealment of information) about a serious adverse event that 
occurred to the patient during the study; 
7) non-compliance with the conditions of storage of the study drug. 
 
Minor violations/deviations from the protocol: 
1) violation of the schedule of study procedures on the days of the visit, slightly 
exceeding the time frame provided by the protocol; 
2) untimely (late) notification of SAE; 
3) other unforeseen deviations. 
Significant deviations include, but are not limited to, deviations that include forgery or improper 
study, increase the risk to the patient's health or distort the analysis of the main results of the study. 
All deviations from the protocol during the study should be recorded during the monitoring of the 
clinical trial and notification to the Sponsor.  
 
11.3. Audits of quality control bodies and regulatory bodies 
 
The study center may also be subject to quality assurance audits by the medicinal product 
developer or its authorized representatives. In these circumstances, the auditor appointed by the 
Sponsor will contact the Center in advance to arrange an audit visit. The auditor may want to visit the 
place where laboratory samples are collected, where the drug is stored, and any other place used 
during the study.  
In addition, if it is possible that this study will be audited by regulatory authorities, the clinical 
trials of the study drug developer should be reported immediately. 
 
 


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12.  ETHICAL AND LEGAL ASPECTS OF CLINICAL TRIAL 
 
12.1. General requirements  
 
The trial must be approved by the official regulatory authorities of the host countries. 
The study is conducted in accordance with the principles set out in the Helsinki Declaration of 
the WMA (adopted at the 18th WMA Assembly in Helsinki in June 1964, the last edition was adopted 
at the 64th WMA General Assembly, Fortaleza, Brazil, October 2013). 
Investigators involved in a clinical trial shall, prior to its initiation, provide the Sponsor with 
signed and dated resumes containing a description of the clinical trial experience, data on professional 
and scientific activities. 
 
12.2. Ethical clinical trial  
 
The approval of the trial by the Local Ethics Committee (Medical Ethics Commission) guarantees 
the observance of ethical norms during the study. 
Patient participation in the study is voluntary. The patient has the right to refuse to participate in 
the study at any stage, it is not possible to involve the patient without signing the patient's informed 
consent. 
 
Each patient will be informed that his / her personal data, including those related to the study, 
may be examined by the study monitor, the quality assurance auditor or the health inspector, in 
accordance with applicable regulations. 
 
12.3. Local Ethics Committee (LEC) 
 
Ethical examination of clinical trials of medicines is conducted by the Local Ethics Committee. 
The Local Ethics Committee (LEC) is committed to protecting the rights, safety and well-being of all 
study patients. The LEC must assess the suitability of the investigators qualifications of the proposed 
study on the basis of his scientific biography (curriculum vitae). Prior to the start of the study, the 
approval of the protocol, the Written Informed Consent Form and any other document provided to 
the patient should be obtained from the LEC of the facilities where the clinical trial will be conducted. 
The LEC opinion must be dated, signed and issued in writing. A clinical trial can only be initiated 
after approval of the appropriate LEC. The investigator, the head of the medical institution or another 
responsible person must timely submit the necessary documentation for consideration to the local 
ethics committee. The documents submitted to the LEC may differ from institution to institution, but 
must include the final version of the clinical trial protocol, the Patient's Informed Consent and the 
Written Informed Consent Form, the Investigator's Brochure with information on the investigational 
medicinal product. 
A list of all those advising the LEC, as well as the head (s) of the committee, will be included in 
the study report. 
 
12.4. Approval of the protocol by regulatory authorities 
The sponsor of the study provides a copy of this protocol, as well as other necessary documentation 
related to the study, for consideration by the regulatory authority and the commission on ethics at the 
LPZ. 
 


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12.5. Obtaining the written informed consent of the patient   
 
The investigator will inform each potential study participant about the study drugs, the purpose 
and nature of the study, the expected benefits, the degree of risk and the requirements that the patient 
will have to comply with during the study. 
Each patient / legal representative is also provided with written information about the 
investigational drugs and studies contained in the Patient Information. Oral and written information 
is provided to the patient in Turkish. 
The patient / legal representative should have sufficient time to consider their participation in the 
study and to ask the investigator questions of interest. The investigator is required to explain in detail 
the sections of the Informed Consent that the patient has questions about. The investigator should not 
put pressure on the patient / legal representative to influence his / her decision. 
If the patient / legal representative has decided to participate in the study, he / she must fill in and 
sign the Informed Consent Form in 2 copies. One copy of the Informed Consent is handed over to the 
patient / legal representative, the other remains in the investigator's file.  
The consent must be signed before the patient undergoes any procedures related to the study. 
Only patients who have signed the Informed Consent Form will be included in the study. 
 


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13. 
 DATA WORKING AND RECORD KEEPING 
 
13.1. Clinical trial documents 
 
The Sponsor Company provides the following key documents and materials to the study center: 
• Study protocol (and amendments to it if available); 
• Investigator's brochure; 
• IRF; 
• Information for the patient with the Informed Consent Form; 
• Scales, questionnaires, questionnaires (if any); 
• Investigator file; 
• Study drugs; 
• A copy of the insurance contract; 
• Contract; 
• A copy of the Approval of the regulatory authorities of the country in which the clinical study 
is conducted by the local ethics committee (in the presence of LEK); 
• Documents required for submission to the local ethics committee. 
 
The investigator provides the Sponsor with the following basic documents before the start of the 
study: 
• Cover letter to the local ethics committee (if there is a LEK); 
• Signed agreement on confidentiality; 
• Signed "Agreement with the principal investigator" - agreement with the terms of the protocol; 
• Contract; 
• Approval of the study and clinical trial documents by the local ethics committee (in the presence 
of LEK); 
• List of members of the local ethics committee (if available by the LEK); 
• Recently compiled scientific summaries (Curriculum Vitae) of all investigators and co-
investigators (signed and dated); 
• Laboratory standards with the date and signature of the responsible employee of the laboratory 
(when using a local laboratory), scientific resume of the head of the laboratory; 
• Certificates for medical / laboratory equipment (at the request of the Sponsor). 
The investigator must keep the documentation related to the study (primary documentation, 
copies of the IRF and the investigator's file) for 15 years after the completion of the study. 
 
13.2. Provision (supply) of study materials and documents. 
 
The Sponsor shall provide the Investigator with the study medicinal product, the Clinical Trials 
Protocol, the Investigator's Brochure, and other documents, materials and equipment (where possible) 
necessary for the investigation. 
The investigator must provide the Sponsor with a signed clinical trial agreement, a signed 
confidentiality and non-disclosure agreement, a copy of the LEC's approval, a list of LEK members, 
a current resume of the principal investigator and investigator team, unused IRF and other documents 
(where possible). 
All deliveries to the center and collection of clinical trial materials from the center will be 
documented using transfer / return forms of clinical trial materials. 
 
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The availability of primary documentation in the study center is necessary to confirm the 
existence of patients and confirm the veracity of the information collected. Primary documentation 
includes original documents that are relevant to the study, treatment, history, and description of the 
patient's condition. For example, such documents include medical history and discharge (printouts) 
with the results of laboratory tests. 
 
The following information must be reflected in the primary medical records: 
• Demographic data; 
• Information regarding inclusion and non-inclusion criteria; 
• The fact of participation in the study, indicating the study number and patient number; 
• Date and time of all visits; 
• Anamnesis and physical examination data; 
• Adverse events; 
• Preliminary therapy and concomitant treatment; 
• Results of instrumental research; 
• Results of laboratory tests; 
• Information on the intake of the investigational medicinal product; 
• Reason for premature termination of participation in the study (if any). 
 
13.4. Data collection: individual registration forms (IRF, eCRF) 
 
All data obtained, including test results, for each patient should be recorded in the IRF. For 
patients who dropped out of the study for any reason early, all the necessary documentation is 
completed, indicating the reason for the early termination of the study. 
 
The IRF can be in paper or electronic form, designed to record all the necessary protocol 
information for each patient of the study, which must be provided to the Sponsor. 
Individual registration cards are used for: 
- Ensuring data collection in accordance with the Protocol; 
- Satisfaction of the requirements of the control and permitting system for the collection of 
information; 
- Contribute to the efficient and complete processing of data, their analysis and reporting on the 
results, promote the exchange of security data among the project team and other departments 
of the organization. 
The data collected during the test at the study center must be complete and accurately reflect 
what happened to each test. 
 
The monitor should check the information entered in the IRF for compliance with the primary 
documentation, which will confirm the absence of discrepancies in the various documents when 
registering data. If the monitor detects inconsistencies, the necessary changes will be made to the IRF. 
The monitor should monitor the completeness and correctness of the IRF. The monitor doesn’t 
have the right to make corrections to the IRF itself. 
The investigator or other person authorized to complete the IRF must enter the data into the IRF 
during or immediately after each visit, but no later than 5 working days after the visit, according to 
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13.5. Data processing and changes in the IRF 
 
Data processing will be coordinated by the Sponsor or CRO. All information about each patient 
is recorded in accordance with the protocol, must be entered in a timely manner in the IRF, which 
was developed in accordance with the protocol. 
 
To ensure the most efficient process of data collection and transmission to the investigator or the 
authorized employee of the study center, it is necessary to enter information into the IRF as soon as 
possible, immediately after the patient's visit. IRF and other documents (such as primary 
documentation) should be available for verification by the monitor. 
 
Any changes or corrections are made to the IRF after the verification of the primary 
documentation and will reflect: 
- The value to be corrected - crossed out, but with the ability to read; 
- Correct value; 
- Date and data of the person who made changes to the IRF data. 
After verification of the data and changes in the IRF, requests for clarification will be addressed. 
The investigator is obliged to respond to requests for clarification of data within 5 working days after 
their generation / sending to the center. In rare cases, permission is allowed for requests for 
clarification of data before the next scheduled monitoring visit. 
 
13.6. Confidentiality of patient data 
 
The patient's personal medical information obtained during the study is considered confidential 
and may not be disclosed to third parties. This information may be communicated to the patient's 
physician or other health care professional responsible for the patient's health (with the patient's 
consent only). 
 
Each patient will be assigned an identification number, which will be used instead of the patient's 
last name to maintain the confidentiality of personal data when transmitting information about AEs 
or other data related to the study. 
 
Complete identification information about each patient will be kept only by the investigator, who 
must provide it at the request of the auditor, insurance company or other official bodies. This 
information should be kept confidential. To this end, the study center will fill in and keep a Patient 
Identification Journal, which contains information about the patient (name, date of birth, outpatient 
card number in the institution, etc.) and the code assigned to him. The identification journal or its 
copy is not transferred to the Sponsor / CRO and must be kept in the archives of the study center after 
the end of the study. This journal provides the identification of coded information about the study 
participant with his personal data and ambulatory card. 
 
All those involved in clinical trials should ensure the confidentiality of patients, not allowing the 
use of any information that could identify the patient (eg name or address). 
 
 
13.7. Investigator file 
 
The investigator is required to keep all records to ensure complete documentation of the study 
process in accordance with the standards of Good Clinical Practice. The investigator must keep all 


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necessary clinical trial documentation for 15 years, unless otherwise required by the Sponsor; The 
investigator must take steps to prevent accidental or premature destruction of this document. 
The investigator is required to maintain a confidential journal of patient identification codes, 
which provides a unique link between the original records containing the name and anonymous IRF 
data intended for the Sponsor. The investigator must organize the storage of this confidential code for 
15 years (at least) after the completion or termination of the study. 
It isn’t allowed to destroy clinical trial documents without the prior written permission of the 
Sponsor and the Investigator. If the Investigator wishes to transfer the documentation to a third party 
or move it to another location, the Investigators is obliged to notify the Sponsor. 
The Investigator file includes (required for detailed reference): 
• Investigator's brochure; 
• Clinical trial protocol; 
• Patient Information and Written Informed Consent Form; 
• Reports on the progress of the clinical trial; 
• Printout of individual registration form (IRF); 
• Form of division of responsibilities; 
• Patient identification journal; 
• Forms of accounting for SD / issuance of SD; 
• Forms of accounting screening. 
 
13.8. Archive data storage. 
 
Copies of the eCRF and primary documentation relevant to the study, the patient identification 
list and the Written Informed Consent Form must be kept by the investigator for 15 years. In the event 
of relocation, retirement or other changes related to the retention of the archive for a specified period 
(at least 15 years), the Sponsor must be notified of who will be responsible for maintaining the eCRF 
and other information of the study. A description of the data stored will be kept by the Investigator, a 
copy will be provided to the Sponsor. The clinical trial protocol and amendments to the Protocol, all 
editions of the Investigator's Brochure, eCRF, copies of regulatory approvals, all correspondence and 
reports and other documents relevant to the study will be kept by the Sponsor or his authorized 
representative for 15 years. 
 
13.9. Direct access to primary documentation 
 
Primary data is all the information contained in the original records and certified copies of clinical 
data, observations, and other activities within the study, and which is necessary for the reconstruction 
and evaluation of the study. The investigator provides the opportunity to monitor trial, audit (s), 
expertise by the Ethics Council and regulatory authorities, provides direct access to primary data / 
records. 
Primary data should be stored for the maximum period allowed by local rules. For each 
participant included, the investigator shall indicate in the primary records the fact of participation in 
this study, as well as record at least the following information: individual identification code, personal 
data of patients (name, address), dates of medication, indicators of vital signs, any AR, dates of 
completion of the study and the main reasons for stopping treatment (if any). 
 
It is the investigator's responsibility to provide direct access to the primary data and 
documentation to the sponsor's clinical trial specialist and / or his / her authorized representatives 
(CRO), the competent authority auditor, the insurance company's representatives, and the ethics 
committees. 
 


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14. 
 FINANCING AND INSURANCE 
 
This clinical trial will be organized and conducted at the expense of the Sponsor. The financial 
aspects of the trial will be documented in the form of an agreement between the Sponsor and the study 
center. 
If the patient follows the investigator’s instructions and he/she is harmed by the medication or 
procedures performed in accordance with the study plan, the Sponsor shall pay all medical expenses 
for the treatment. No other compensation from the Sponsor is provided, except for compensation for 
the transport costs of patients (if possible). 
Prior to the start of the study, there is a procedure for ensuring the health of patients and civil 
liability of persons conducting clinical trials. In the event of harm to the health of a patient related to 
a clinical trial, the Insurance Company through which the Sponsor has concluded an insurance 
contract undertakes to reimburse all costs for necessary medical examination and treatment required 
because of direct exposure to the study drug and / or procedures carried out in accordance with the 
Clinical Trial Protocol. 
The sponsor of the clinical study is the company LLC "BIOPHARMA PLASMA", UKRAINE. 
The Sponsor assumes responsibility for the insurance of each subject, in accordance with the 
requirements for clinical trials. The company-representative of the Sponsor will conclude an 
agreement on life and health insurance of patients participating in the study of drugs for medical use, 
in accordance with current legislation of Ukraine. 
All discussions (if any) will be governed by the terms of the local insurance policy signed by the 
Sponsor and the Insurance Company. 
 
 
 


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15. 
ISSUES OF PUBLICATION AND USE OF RESEARCH RESULTS 
 
Information regarding the study drug and / or the conditions of the study or the results of the 
study, as well as unpublished scientific data on the study drug is considered confidential and owned 
by the Sponsor of the study. This information may be disclosed only to the authorities that authorize 
the study or to those who participate in the study in confidence. The researcher should use this 
information only for the purpose of conducting this study, unless otherwise provided by separate 
written permission of the Sponsor. 
The researcher agrees that the Sponsor may use the information obtained during the clinical trial 
for publication and thus may make it available to other researchers or regulators. 
The results of this study can be published or presented at scientific conferences. Publication or 
presentation of research results by the Researcher is possible only after consultation with the Sponsor. 
In this case, the Researcher must provide all manuscripts and abstracts of the planned publication to 
the Sponsor for approval for submission to the editorial board or scientific expert council. This will 
allow the Sponsor to protect information that is his property and to supplement the message with 
comments based on information that may not yet be available to the Researcher. 
In accordance with the standards of publishing practice, the Sponsor is usually in favor of 
publishing the results of multicenter research in its entirety, rather than in the form of data from 
individual research centers. Any publication of the results of a study in which the Sponsor's specialist 
was more involved than the performance of standard monitoring should be considered as a joint 
publication of the Researcher and this person. 
Before presenting the results (written or oral), the material of the clinical study must be submitted 
for consideration and approval by LLC "BIOPHARMA PLASMA". The authorship of materials for 
an oral report or article is determined by agreement between the Sponsor and the Researcher. 
 
 
 


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16. 
 FINAL REPORT 
 
The final report on the study is written after the closure of databases and statistical data 
processing in case of completion of the study in accordance with the protocol. 
Whether the study was completed on a protocol or early basis, the Sponsor ensures that the 
clinical trial report is prepared and submitted to the regulatory authorities and the LEC in accordance 
with the ICH guidelines "Structure and content of effects in a clinical trial". Abbreviated reports may 
be acceptable in some cases. 
The final report must be prepared in accordance with the requirements of the clinical trial report 
set out in ICH E3 STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTS. 
The final report and its annexes should provide information on the dates of all stages of the study 
to ensure that the work can be traced. 
The report should clearly state the efficacy, safety, and tolerability of the investigational 
medicinal product. Conclusions and recommendations should be consistent with the results obtained. 
In addition to the report, the Sponsor must be provided with the original IRF and, at the request of 
the Sponsor, copies of primary data with the results of research that are not included in the report 
prepared in accordance with the established procedure. 
The final report is submitted to the Research Sponsor for approval. The final report, as well as 
other research documents, is confidential information that cannot be disclosed by researchers without 
the appropriate permission of the Sponsor. 
 
 
 


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17. 
 CONFIDENTIALITY 
 
The information contained in this document is the property of the Sponsor and its transfer to third 
parties is permitted only with the written permission of the Sponsor. The right to access this 
information is granted only to the Researcher (s) and the staff of the research center (s) participating 
in the study, the members of the independent ethics committee (s) and the staff of the authorized 
health authorities. to exercise control over the conducted research. Information about the study, to the 
extent necessary to decide on the consent to participate, is provided to patients whom the Researcher 
plans to include in the study. 
 
18. 
 AMENDMENTS TO THE PROTOCOL AND / OR UPDATED VERSION 
OF THE PROTOCOL 
 
Any changes will be agreed between the Researcher and the Sponsor prior to its entry into force. 
Any changes to the study that occurred after the puncture was approved should be documented as 
appendices or changes to the protocol and / or an updated version of the protocol. Depending on the 
nature of the amendment, approval or notification from the Ethics Committee and regulators will be 
required, except when there is an imminent threat to the life or health of patients participating in a 
clinical trial, or when changes to the protocol concern only administrative aspects or issues. supply. 
 
19. 
 TERMS OF THE STUDY 
 
Estimated start date of the study: 2022. 
Estimated completion date: 2024. 
The Researcher and the Sponsor reserve the right to terminate the study at any time. If 
necessary, the procedures will be agreed after consultation with both parties. If the study is 
prematurely stopped or suspended, the Sponsor must immediately notify the Researchers / 
Organizations and the Authorized Bodies of the stop or suspension, as well as the reasons for the stop 
or suspension. The Local Ethics Committee should also be immediately informed by the Sponsor or 
the Researcher / organization (as required by regulatory requirements), including the reasons for 
terminating or suspending the study. At the end of the study, the Sponsor and the Researcher will 
ensure compliance with the provisions to best protect the interests of patients. 


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20. 
LIST OF REFERENCES  
 
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7. Pottier L., Sapir T., Bendaoud B. Et al Intravenous immunoglobulin, and cytokines: focus 
on tumor necrosis factor family members BAFF and APRIL// Ann.NY Acad Sci. – 2007. 
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8. Seite J.F., Shoenfeld Y., Youinou P., Hillion S. What are the contents of the magic draft 
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9. Lemieux R., Bazin R., Neron S. Therapeutic intravenous immunoglobulins// Mol. 
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11. Kessel A., Ammuri H., Peri R. et al. Intravenous immunoglobulin therapy affects T 
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12. Nimmerjahn F, Ravetch JV. Anti-inflammatory actions of intravenous immunoglobulin// 
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13. S.C.  Chow, J. Shao, H.Wang. Sample Size Calculations in Clinical Research. London: 
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14. Anurag Singh, Günalp Uzun, Tamam Bakchoul / Primary Immune Thrombocytopenia: 
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15. Gelfand E.W. Differences between IGIV products impact on clinical outcome// Int. 
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16. Guideline on the clinical investigation of human normal immunoglobulin for intravenous 
administration (IVIg). EMA/CHMP/BPWP/94033/2007. rev.2 (22.07. 2010) 
17. Godeau B., Caulier M-T. Decuypere L. et al. Intravenous immunoglobulin for adults with 
autoimmune thrombocytopenic purpura: results of a randomized trial comparing 0´5 and 1 
g/kg b.w. // British Journal of Haematology, 1999, 107, 716-719 
18. Ruqayyah J. Almizraq, Donald R. Branch Efficacy and mechanism of intravenous 
immunoglobulin treatment for immune thrombocytopenia in adults // Ann Blood 2021 
19. Drew Provan, Roberto Stasi, Adrian C. Newland et al. International consensus report on 
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