Currently, no effective treatments are available for the COVID-19. Scientists and Researchers are working on many aspects of treatment options for the development of vaccination and medication to combat this life-threatening problem. Convalescent plasma from recovered COVID-19 patients contains antibodies against COVID-19 which may be beneficial to severely sick COVID-19 patients. Investigator have recently concluded a pilot phase II open-label RCT on the efficacy of convalescent plasma in severe COVID 19 patients in which encouraging results were seen. Investigator plan to further study the efficacy and safety of convalescent plasma in COVID-19 severely sick patients through an RCT. Investigator will collect up to 500 ml Convalescent Plasma from the COVID-19 recovered persons after 14 days of clinical recovery with two consecutive SARS CoV-2 negative tests by PCR at least 24 hours apart. This plasma will be tested and frozen and stored. On requisition it will be thawed and sent to the treating center. Two doses of 250 ml convalescent plasma each will be transfused on two consecutive days to patients who fit the eligibility criteria (Severely sick COVID-19 patients) and are randomized to the convalescent plasma group along with the standard of care and the other group will receive standard of care alone. Data will be collected to study the benefits and adverse events related to convalescent plasma transfusion.
Study Centres:
Institute of Liver and Biliary Sciences Sector D-1, Vasant Kunj New Delhi -110070
- Collection and testing of Convalescent Plasma
Treatment Centres
Lok Nayak Jai Prakash Hospital (LNJP)
Rajiv Gandhi Super-speciality Hospital (RGSSH)
Methodology Donor Plasmapheresis COVID-19 recovered patients will be counseled and informed
regarding convalescent plasma donation. The contact information of those who agree will be
sent to the coordinator at ILBS Blood Centre.
- The prospective donor will be contacted and if willing to come for donation, the donor
will be provided conveyance if required, to come to ILBS Blood centre for Plasma
Donation
- At ILBS the donor will be counseled and the doctor in-charge will explain the procedure
to the Donor.
- The donor will be given a Donor Information Sheet and Informed consent will be taken on
the document
- The eligibility for plasma donation will be ascertained through Medical History,
Physical Examination, and laboratory tests.
Donor Eligibility for Plasmapheresis
- Virologically documented (PCR positive by nasopharyngeal swab) who is recovered and free
of symptoms for 14 days.
- Has tested negative for SARS CoV 2 on two consecutive tests 24 hrs apart.
- Fulfill all criteria of donor eligibility for donor Plasmapheresis under the Drugs &
Cosmetics Act 1940 and Rules 1945, amended 11.03.2020
- Females who have been pregnant may be tested for anti-HLA antibodies and eligible if
negative for the same.
The following Donors will be excluded
- Do not fulfill all criteria of donor eligibility for donor Plasmapheresis under
- the Drugs & Cosmetics Act 1940 and Rules 1945, amended 11.03.2020
- Females who have been pregnant and have not been tested for HLA antibodies or are HLA
antibody positive if tested and previously transfused donors (to prevent TRALI)
- Donors who have taken steroids during treatment for COVID-19 Donor Selection Process
- A detailed medical history of the donor will be taken and documented
- Physical examination ( Height, Weight, Blood Pressure, Temperature, adequate veins for
phlebotomy)
- Laboratory Testing: complete Blood count, Testing for hepatitis B virus, hepatitis C
virus, HIV, malaria, and syphilis) by serology, blood grouping, and antibody screening.
Serum protein will be done in repeat donors ( Ref: D&C Act and Rules)
- Serum COVID-19 specific IgG antibody positive (with an IgG titre higher than 80).
- All Results Evaluated & Clinically Correlated The donor is deemed eligible/non-eligible
Plasmapheresis Procedure
- Determine Volume to be collect-approx. 500 ml
- As per the Drugs & Cosmetics Act 1940 and Rules 1945, amended 11.03.2020
- Start Donor Plasmapheresis Procedure(As per SOP)
- Collect Convalescent Plasma The convalescent plasma will be properly labeled and frozen
at -80o C in a separate Deep Freezer. It will not be issued to other patients who are
with non-COVID.
- Label Details: As per the Drugs & Cosmetics Act 1940 and Rules 1945, amended 11.03.2020.
- Storage condition- Below -30oC
- Shelf life: - 1 Year
Other Sources of Convalescent Plasma:
Convalescent Plasma collected during a CP donation drive by Delhi Govt. following all rules
and regulations of the Drugs& Cosmetics Act 1940 and Rules 1945, amended 11.03.2020 is stored
at ILBS and will be used in this trial.
The tests for Donors:
1. Real-time PCR for SARS-CoV-2: Nasal swab samples will be taken prior to donation and
tested for SARS-CoV-2 by real-time PCR method it the donor does not have two negative reports
24 hrs apart.
Antibody Titers of Convalescent Plasma and Patients Plasma by ELISA
For Donors:
The titre of serum neutralizing antibody which is the spike protein antibody, directed
against the SARS-CoV-2 RBD (receptor binding domain) proteins. The titre will be done by IgG
ELISA or by Rapid IgG antibody titre. The minimum titre of 80 is needed for the use of
convalescent in patients.
For recipients:
1. Real-time PCR for SARS-CoV-2:
Nasal swab samples will be taken prior to transfusion and tested for SARS-CoV-2 by
real-time PCR method. The test should be positive for eligibility of the recipient along
with clinical criteria for COVID-19.
2. Antibody titre: The serum of each recipient will be obtained and IgG antibody titre by
enzyme-linked immune-sorbent assay (ELISA) or Rapid IgG antibody method will be tested
one day prior to the convalescent plasma transfusion. Changes of IgG antibody titre
before and after convalescent plasma transfusion in patients will be studied. The serum
will be stored for neutralizing antibody titers by plaque reduction will be done subject
to availability.
Study Population:
Adult patients with severe COVID -19 infections defined as WHO Interim Guidance and the
Guideline of Diagnosis and Treatment of COVID-19 of National Health Commission of China
(version 5.0) with confirmation by real-time RT-PCR assay with severe disease i.e. meeting
any 2 of the following criteria
1. Patients on ventilator (in last 24 hours)
2. Respiratory distress, RR ≥30 beats/min
3. Oxygen saturation level less than 90% in resting state
4. Partial pressure of oxygen (PaO2)/oxygen concentration (FiO2) ≤ 300 mmHg
5. Lung infiltrates > 50% within 24 to 48 hours
Study Design:
An open label randomized controlled trial. The study group will comprise of 400 adult
patients with severe COVID -19 as detailed above.
Randomization will be done in the ratio of 1:1 in with 200 patients in the treatment arm and
200 patients in the control arm. Allocation concealment will be done by Sequentially Numbered
Opaque Sealed Envelopes (SNOSE) method.
Intervention Arm: Two doses of 250 ml Convalescent plasma from recovered COVID-19 patients +
Standard of Care will be given to severely sick COVID-19 patients in the treatment arm
Control Arm: Standard of Care will be given to severely sick COVID-19 patients in the control
arm Details of Standard of Care The Ministry of Health and Family Welfare has issued detailed
guidelines for the management of sCOVID-19 based on varying grades of severity which may be
periodically updated. For the management of ARDS or sepsis the respective guidelines issued
by ARDSNet and Surviving Sepsis campaign will be followed. Other institutional protocols for
supportive management will be implemented. (Ref: Guidelines on Clinical Management of
COVID-19. MoHFW, GoI.2020.) Monitoring and Assessment: Daily until clinical improvement
Adverse Effects: Will be documented Stopping rule: None (C) The expected outcome of the
project: Investigator expect convalescent plasma therapy to be a safe and efficacious therapy
based on our pilot RCT. This study will determine if there is a clinical improvement
/mortality benefit and further elaborate on its safety in patients with severe COVID-19
Biological: Convalescent Plasma
Dose-250 ml Frequency - 2 doses on consecutive days Duration -Start by day 3 of symptom onset (of severe COVID-19 as in inclusion criteria) in eligible patients
Other: Standard of Care
The Ministry of Health and Family Welfare has issued detailed guidelines for the management of sCOVID-19 based on varying grades of severity which may be periodically updated. For the management of ARDS or sepsis the respective guidelines issued by ARDSNet and Surviving Sepsis campaign will be followed. Other institutional protocols for supportive management will be implemented. (Ref: Guidelines on Clinical Management of COVID-19. MoHFW, GoI.2020.)
Recipient Inclusion Criteria:
- Patients with severe COVID-19 will be considered for randomization and will be transfused
convalescent plasma within 3 days of symptom onset (Severe COVID-19) Severe COVID -19
defined by WHO Interim Guidance and the Guideline of Diagnosis and Treatment of COVID-19 of
National Health Commission of China (version 5.0) along with confirmation by real-time
RT-PCR assay with severe disease i.e. meeting any 2 of the following criteria-
- Patients on ventilator (in last 24 hours)
- Respiratory distress, RR ≥30 beats/min
- Oxygen saturation level less than 90 % in resting state
- Partial pressure of oxygen (PaO2)/oxygen concentration (FiO2) ≤ 300 mmHg
- Lung infiltrates > 50% within 24 to 48 hours
Recipient Exclusion Criteria:
- Patient/ family members who do not give consent to participate in the study.
- Patients with age less than 18 years
- Patients presenting with multi-organ failure
- Pregnancy
- Individuals with HIV and Viral Hepatitis and Cancer
- Extremely moribund patients with an expected life expectancy of less than 24 hours
- Hemodynamic instability requiring vasopressors
- Previous history of allergy to plasma
- Cirrhosis
- Severe renal impairment with GFR< 30ml/min or recipients of RRT, peritoneal dialysis
- Patients with uncontrolled diabetes mellitus, hypertension, arrhythmias and unstable
Angina
Donor Inclusion Criteria for Plasmapheresis
- Virologically documented (PCR positive by nasopharyngeal swab) who is recovered and
free of symptoms for 14 days.
- Has tested negative for SARS CoV 2 on two consecutive tests 24 hrs apart.
- Fulfill all criteria of donor eligibility for donor Plasmapheresis under the Drugs &
Cosmetics Act 1940 and Rules 1945, amended 11.03.2020
- Females who have been pregnant may be tested for anti-HLA antibodies and eligible if
negative for the same.
Donors Exclusion Criteria:
- Do not fulfill all criteria of donor eligibility for donor Plasmapheresis under
- the Drugs & Cosmetics Act 1940 and Rules 1945, amended 11.03.2020
- Females who have been pregnant and have not been tested for HLA antibodies or are HLA
antibody positive if tested and previously transfused donors (to prevent TRALI)
- Donors who have taken steroids during treatment for COVID-19
Maulana Azad Medical College
New Delhi, Delhi, India
Institute of Liver & Biliary Sciences
New Delhi, Delhi, India
Rajiv Gandhi Super Speciality Hospital
New Delhi, Delhi, India