Intravenous Immunoglobulin (IVIG, Bioven) Efficacy Assess for COVID-19 / SARS-CoV-2 Severe Pneumonia Complex Treatment

An Open-label Multicenter Randomized Trial to Evaluate the Efficacy of Bioven, Manufactured by Biopharma Plasma, LLC, in Complex Therapy of Patients With Pneumonia Induced by COVID-19 / SARS-CoV-2

Pneumonia caused by coronavirus infection COVID-19 is characterized by a combination of several dangerous factors that consistently worsen the patient's condition: viral lung damage early in the disease; a sharp increase in inflammation on the background of an unbalanced immune response ("cytokine storm"); joining a bacterial infection.

The condition of patients deteriorates significantly mostly at cytokine storm development. The damaging of a large volume of lung tissue leads to develops of respiratory failure, respiratory distress syndrome, or shock. Ventilatory support becomes ineffective and patients die.

There are reports of the effectiveness of Human Normal Immunoglobulin for Intravenous Administration (IVIG) high doses when used as part of complex therapy in patients with pneumonia caused by coronavirus COVID-19. In particular, IVIG has a positive effect on survival rates, overall disease course, duration of stay in the intensive care unit, and ventilatory support duration.

The probable mechanism of action of high-dose IVIG therapy is considered to be a regulatory effect on the immune system. Similar is the known and confirmed effectiveness of IVIG for autoimmune diseases (Kavasaky disease, Guillain Barre syndrome, Chronic inflammatory demyelinating polyradiculoneuropathy, Multifocal motor neuropathy).

This trial to assesses the Efficacy of IVIG (medication trade name - Bioven, manufactured by Biopharma Plasma LLC) in the High Immunomodulatory Dose in Complex Treatment of Severe Pneumonia Caused by COVID-19 / SARS-CoV-2

Study Overview

• Status: Completed
• Conditions: Pneumonia; Covid19
• Intervention / Treatment: Drug: IVIG

Detailed Description

The screening stage:

The patient or his legal representative must sign an informed consent. After signing the informed consent, the screening tests&procedures are performed and the compliance with the inclusion / non-inclusion criteria is assessed.

For patients who have been screened and meet the inclusion criteria and do not fall under the exclusion criteria, a blinded randomization procedure is provided.

Randomization is performed by the IVRS method, according to the blinded-block patient's randomization table.

The clinical stage of the trial:

Begins after patient randomization. At the clinical stage, among other things, provides:

• Determination of the individual dose of the study drug (in the study group)
• Administration of the drug (in the study group)
• Registration of adverse events
• registration of information about taking antiviral drugs for the treatment of COVID-19;
• registration of information on symptomatic therapy and administration of drugs for the treatment of comorbidities;
• measurement of vital signs (blood pressure, heart rate, respiratory rate, body temperature);
• Determination of SPO2 level
• Determining the need for ventilation
• Determining the need for intensive care
• Assessment of compliance with the exclusion criteria

Patients in the Control Group will receive therapy recommended by the COVID-19 coronavirus infection treatment protocol, depending on the severity of their condition according to the prescribing list, which will not include immunoglobulin preparations.

Patients of the Study Group (IVIG) receive high-dose therapy with the study drug (Bioven, 10% solution for infusions produced by Biopharma Plasma LLC, Ukraine). The dose is calculated by body weight. Patients will also receive therapy recommended by the COVID-19 coronavirus infection treatment protocol, depending on the severity of their condition according to the prescribing list.

Bioven administered intravenously, at an initial rate of 0.5 - 1.0 ml/kg body weight/hour 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/hour every 10 minutes). According to results previously accomplished clinical studies, the maximum rate of Bioven administration is up to 8.5 ml/kg body weight/hour.

Observation and completion stage:

Begins and continues from the last administration of the study drug until the discharge of the patient from the hospital, but not less than 28 days from the confirmation of the diagnosis of pneumonia caused by coronavirus infection COVID-19.

The following procedures are provided at the stage:

• registration of information about taking antiviral drugs for the treatment of COVID-19;
• registration of information on symptomatic therapy and administration of drugs for the treatment of comorbidities;
• measurement of vital signs (blood pressure, heart rate, respiratory rate, body temperature);
• determination of SPO2 level
• registration of the results of the examination of the lungs by computed tomography (or radiography)
• taking biomaterials for laboratory research:
• general blood test (erythrocytes, hemoglobin, expanded leukocyte formula, platelets, etc.);
• general analysis of urine;
• biochemical analysis of blood;
• state of the coagulation system
• determination of inflammatory factors in the dynamics (CRP, ferritin, procalcitonin; TNF-α), IL-1-beta, IL-6, complement component C3 (C3), circulating immune complexes (CIC), etc.),
• determination of IgG subclasses (G1, G2, G3, G4,);
• Determining the need for ventilation
• Determining the need for intensive care
• Adverse reactions registration
• Assessment of compliance with the exclusion criteria

The patient's condition is assessed daily till discharge; and by schedule after discharge (if it happen earlier), during 28 days period after diagnosis of severe pneumonia caused by coronavirus infection COVID-19 In case of death of the patient - the date and cause of death are fixed. The results of the study are evaluated by endpoints.

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 3

Contacts and Locations

Study Locations

• Ukraine
  • Kyiv, Ukraine, 03110
    • Site 01 - "Kyiv City Clinical Hospital №17"
  • Kyiv, Ukraine, 03110
    • Site 05 - "Kyiv City Clinical Hospital №4"
  • Ivano-Frankivs'k Region
    • Ivano-Frankivs'k, Ivano-Frankivs'k Region, Ukraine, 76018
      • Site 08 - "Central City Clinical Hospital of Ivano-Frankivsk City Council"
  • Kyiv Region
    • Bila Tserkva, Kyiv Region, Ukraine, 09112
      • Site 02 - "Bila Tserkva City Hospital №3"
  • Lviv Region
    • Lviv, Lviv Region, Ukraine, 79010
      • Site 03 - "Lviv Regional Infectious Diseases Clinical Hospital"
  • Odesa Region
    • Odesa, Odesa Region, Ukraine, 65021
      • Site 04 - "City Clinical Infectious Diseases Hospital", Odesa
  • Ternopil' Region
    • Ternopil', Ternopil' Region, Ukraine, 46006
      • Site 07 - "Ternopil City Municipal Ambulance Hospital"
  • Vinnitsia Region
    • Vinnitsia, Vinnitsia Region, Ukraine, 21021
      • Site 06 - "Vinnytsia City Clinical Hospital №1"
  • Volyn Region
    • Luts'k, Volyn Region, Ukraine, 43000
      • Site 09 - "Volyn Regional Clinical Hospital"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men and women 18 years of age and older;
• COVID-19 documentary confirmed by PCR lab test;

• severe pneumonia caused by COVID-19 according to the criteria below:

  • - fever or suspicion of respiratory infection;
  • - the number of respiratory movements 30 per 1 min and above;
  • - severe respiratory failure or SpO2 <90% with spontaneous breathing indoors;
  • - the presence of foci of inflammation in the lungs according to the results of computed tomography, which is documented.

  • or if any of the conditions listed below have developed on the background of previously diagnosed coronavirus pneumonia:

    • - severe respiratory failure required mechanical ventilation (ALV);
    • - acute respiratory distress syndrome according to WHO diagnostic criteria (development within one week after the manifestation of disease clinical symptoms or emergence of new ones or deterioration of respiratory syndromes. Chest visualization (lung X-ray, CT or ultrasound); bilateral opacities not fully explaining the gravity of condition or lung collapse or nodules);
    • - sepsis according to WHO diagnostic criteria (life-threatening organ dysfunction caused by disturbance of host reaction to suspected or proven infection. The features of organ dysfunction include the following: mental change, labored or shallow breathing, low oxygenation, oliguria or anuria, rapid heart palpitation, weak pulse, cold extremities or low blood pressure, skin blotching or lab-proven coagulopathy, thrombocytopenia, acidosis, high level of lactic acid or hyperbilirubinemia);
    • - endotoxic shock according to WHO diagnostic criteria (persisting hypotension despite extensive resuscitation requiring vasoconstrictors for maintaining mean arterial pressure ≥ 65 mmHg and serum lactate level > 2 mmol/l);
• the signed patient's informed consent to participation in the trial;
• the negative pregnancy test (for female patients of reproductive age), readiness to use reliable contraception methods during the whole duration of the trial.
• the ability, according to the researcher, to follow all requirements of the research protocol.
• this study allows you to take into account the results of examinations related to the disease, conducted within 10 days before signing the Informed Consent. Such data are transferred from the primary documentation to the CRF.

Exclusion Criteria:

• known intolerance to plasma or immunoglobulin drugs;
• drug allergy or hypersensitization to immunoglobulin drugs;
• any known counter-indication to immunoglobulin drugs according to the instruction for medical application of the tested drug;
• pneumonia not associated with COVID-19 infection;
• pregnancy, lactation period;
• any clinically significant impairment of liver function (elevation of serum transaminase levels more than 3 times the upper limit of normal);
• serum creatinine levels more than 2 times the upper limit of normal for a given age and gender;
• established diagnosis of primary immunodeficiency;
• verified HIV-infection;
• immune diseases (blood immune diseases, rheumatic diseases, nephritis, etc.)
• severe cardiovascular failure (Stage III);
• mental illness in anamnesis;
• the need for prescribing medicines or procedures that are incompatible with the administration of the drug within the scope of this study: monoclonal antybodies;
• known drug addiction;
• participation in any other clinical trial presently or within the last 30 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Study Group (IVIG); Patients receive IVIG (trade name - Bioven) with base therapy	Drug: IVIG; Patients in the study group receive the drug Bioven, 10% solution for infusions produced by LLC Biopharma Plasma 0,8-1,0 g/kg once a day for 2 days (total course dose - 1.6-2.0 g/kg) as well as base treatment recommended by the protocol of COVID-19 coronavirus infection treatment depending on the severity of their condition according to the prescription sheet.; Other Names: Human normal immunoglobulin for intravenous administration; Bioven
No Intervention: Control group; Patients receive base therapy only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Period duration (in days) to clinical improvement	Number of days post-onset of severe pneumonia to the moment of normalization at least two from following primary outcomes: O2 saturation with self-breathing, respiratory movements rate with self-breathing, body temperature without antipyretics use, lymphocyte count (targeted levels set in the description each of these primary outcomes)	From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days
O2 saturation (SPO2 percentage), with self-breathing	The target level of SPO2 percentage - 95% and above with self-breathing, is used as one of the clinical improvement criteria	From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days
Respiratory movements rate (amount per minute), with self-breathing	The target level of respiratory movements - 28 per minute or less with self-breathing, is used as one of the clinical improvement criteria	From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days
Body temperature without antipyretics use	Measured in degrees Celsius. Fever absence (body temperature no more 37 degrees Celsius) during at least 24 hours without antipyretics, is used as one of the clinical improvement criteria.	From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days
Lymphocyte count	The target level 1000 cells / mm3 and above is used as one of the clinical improvement criteria (applicable for patients with lymphocytes count lower 1000 cells / mm3 at screening moment)	From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from the onset of the disease to discharge, in days	Period duration (in days)	28 days
Duration of the need for ventilatory support, in days	Number of days with ventilatory support	28 days
Duration of the need for intensive care, in days	Number of days in the intensive care unit	28 days
Duration of need for oxygenation in days (SPO2 ≤ 93% with self-breathing)	Number of days with necessery of oxygenation support	28 days
The C-reactive protein (CRP) level	Measuring the analyte concentration in plasma (mg/L)	Day 0 (screening), day 5, day 14, day 28
The tumor necrozis factor alpha (TNF-α) level	Measuring the analyte concentration in plasma (pg/mL)	Day 0 (screening), day 5, day 14, day 28
The interleukin-1β (IL-1β) level	Measuring the analyte concentration in plasma (pg/mL)	Day 0 (screening), day 5, day 14, day 28
The interleukin-6 (IL-6) level	Measuring the analyte concentration in plasma (pg/mL)	Day 0 (screening), day 5, day 14, day 28
The D-dimer level	Measuring the analyte concentration in plasma (µg FEU/mL)	Day 0 (screening), day 5, day 14, day 28
The Complement (C3 component) level	Measuring the analyte concentration in plasma (g/L)	Day 0 (screening), day 5, day 14, day 28
The Circulating immune complexes level	Measuring the analyte concentration in plasma (U/mL)	Day 0 (screening), day 5, day 14, day 28
The ferritin level	Analyte concentration in plasma (ng/mL)	Day 0 (screening), day 5, day 14, day 28
The procalcitonin level	Analyte concentration in plasma (ng/mL)	Day 0 (screening), day 5, day 14, day 28
IgG subtypes	The IgG-subtypes (IgG1-IgG4) concentration in plasma (mg/dL)	Day 0 (screening), day 5, day 14, day 28
Survival assessment for a 28-day follow-up period since the onset of severe pneumonia	Survivealance estimation	28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of side effects	Number of participants with adverse reactions related by investigational drug as assessed by CTCАЕ v 4.0	28 days
Frequency of serious side effects	Number of participants with serious adverse reactions related by investigational drug as assessed by CTCАЕ v 4.0	28 days

Collaborators and Investigators

• Sponsor: Biopharma Plasma LLC
• Collaborators: Lviv National Medical University; Vinnitsa National Medical University

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2020
• Primary Completion (Actual): September 15, 2020
• Study Completion (Actual): September 15, 2020

Study Registration Dates

• First Submitted: July 15, 2020
• First Submitted That Met QC Criteria: August 4, 2020
• First Posted (Actual): August 5, 2020

Study Record Updates

• Last Update Posted (Actual): October 14, 2020
• Last Update Submitted That Met QC Criteria: October 12, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Pneumonia; Coronavirus; COVID-19; IVIG; Immunoglobulin for Intravenous Administration; Bioven
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; COVID-19; Pneumonia; Physiological Effects of Drugs; Immunologic Factors; Immunoglobulins
• Other Study ID Numbers: 2020-BV-BP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: After completion of the trial, results will be published. Access to parts CSR planned after the release of scientific publications
• IPD Sharing Time Frame: After trial result publication 3 months later
• IPD Sharing Access Criteria: For specialists in medicine, pharmacy, scientists
• IPD Sharing Supporting Information Type: Clinical Study Report (CSR)

Drug and device information, study documents

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