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CTRI Number  CTRI/2020/06/025803 [Registered on: 11/06/2020] Trial Registered Prospectively
Last Modified On: 11/06/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug
Biological
Other (Specify) [Standard of care]  
Study Design  Randomized, Parallel Group, Active Controlled Trial 
Public Title of Study   Effect of convalescent plasma in COVID-19 patients 
Scientific Title of Study   Efficacy of Convalescent Plasma Therapy in Patients With COVID-19: A Randomized Control Trial  
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
COPLA Trial-II/ILBS/2020 dated 24.05.2020  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Meenu Bajpai 
Designation  Additional Professor,Transfusion Medicine 
Affiliation  Institute of Liver and Biliary Sciences 
Address  Room No:16056, Department of Transfusion Medicine, Phase I,Upper Basement, D-1, Vasant Kunj New Delhi-110070

South West
DELHI
110070
India 
Phone  01146300000  
Fax  01146300025  
Email  meenubajpai@hotmail.com  
 
Details of Contact Person
Scientific Query
 
Name  Dr Meenu Bajpai 
Designation  Additional Professor,Transfusion Medicine 
Affiliation  Institute of Liver and Biliary Sciences 
Address  Room No:16056, Department of Transfusion Medicine, Phase I,Upper Basement, D-1, Vasant Kunj New Delhi-110070

South West
DELHI
110070
India 
Phone  01146300000  
Fax  01146300025  
Email  meenubajpai@hotmail.com  
 
Details of Contact Person
Public Query
 
Name  Dr Meenu Bajpai 
Designation  Additional Professor,Transfusion Medicine 
Affiliation  Institute of Liver and Biliary Sciences 
Address  Room No:16056, Department of Transfusion Medicine, Phase I,Upper Basement, D-1, Vasant Kunj New Delhi-110070

South West
DELHI
110070
India 
Phone  01146300000  
Fax  01146300025  
Email  meenubajpai@hotmail.com  
 
Source of Monetary or Material Support  
Institute of Liver and Biliary Sciences D-1,Vasant Kunj, New Delhi-110070 
 
Primary Sponsor  
Name  Institute of Liver and Biliary Sciences 
Address  D-1,Vasant Kunj New Delhi-110070  
Type of Sponsor  Government medical college 
 
Details of Secondary Sponsor  
Name  Address 
None   
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 3  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Meenu Bajpai  Institute of Liver and Biliary Sciences  Room No:16056, Department of Transfusion Medicine, Phase I,Upper Basement, D-1, Vasant Kunj New Delhi-110070
South West
DELHI 
01146300000
01146300025
meenubajpai@hotmail.com 
Dr Suresh kumar  Maulana Azad Medical College  Room No:128,1st Floor,Department of Medicine.BL Taneja Block,Bahadur Shah Zafar Marg, Maulana Azad Medical College Campus, Balmiki Basti, New Delhi, Delhi 110002
Central
DELHI 
9891158991

drskumar31@yahoo.co.in 
Dr Vikas Dogra  Rajiv Gandhi Super Speciality Hospital  Block 4, Respiratory Intensive Care Unit, School of Medicine, Taharpur Rd, Taharpur, Taharpur Village, Dilshad Garden, New Delhi, Delhi 110093
East
DELHI 
011-22890604

vikas9949@hotmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 3  
Name of Committee  Approval Status 
IEC,MAMC  Approved 
Institutional Ethics Committee, ILBS  Approved 
Institutional Ethics Committee, ILBS  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  B972||Coronavirus as the cause of diseases classified elsewhere,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Convalescent Plasma with Standard of Care  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 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.) 
Comparator Agent  Standard of Care   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.) 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  99.00 Year(s)
Gender  Both 
Details  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 greater than or equal to 30 beats/min
Oxygen saturation level less than 90 % in resting state
Partial pressure of oxygen (PaO2)/oxygen concentration (FiO2) less than or equal to 300 mmHg
Lung infiltrates > 50% within 24 to 48 hours
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. 
 
ExclusionCriteria 
Details  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
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 
 
Method of Generating Random Sequence   Permuted block randomization, variable 
Method of Concealment   Sequentially numbered, sealed, opaque envelopes 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
efficacy of convalescent plasma in severe COVID 19 patients in time to clinical improvement (Clinical improvement: Reduction of two points in ordinal scale or live discharge from the intensive care unit, whichever is earlier)
 
Day 28 
 
Secondary Outcome  
Outcome  TimePoints 
Proportion of patients in each category according to the ordinal scale   48 hours,day 7, day 14, and day 28
 
Duration of oxygen therapy   Day 28 
Duration of hospital stay  Day 28 
Proportion of patients on mechanical ventilation   Day 7 
Mortality in both groups at day 7 and day 28  Day 7 and day 28 
Duration of Intensive Care Unit stay  Day 28 
Incidence of adverse effects in both groups  Day 28 
Presence of antibodies against SARS-CoV-2 in serum after plasma administration  days 0, 3, 7, 14, 21 & 28  
Cytokines and acute phase reactants  Day 28 
Correlation of titers in COVID-19 convalescent plasma donors and correlate with duration of illness, the severity of symptoms, duration of hospital stay, drugs used in therapy, duration between recovery, and donation  Day 28 
 
Target Sample Size   Total Sample Size="400"
Sample Size from India="400" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)   18/06/2020 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="1"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)   Not Applicable 
Recruitment Status of Trial (India)  Open to Recruitment 
Publication Details   None Yet 
Brief Summary  

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. We have recently concluded a pilot phase II open-label RCT on the efficacy of convalescent plasma in severe COVID 19 patients in which we have seen encouraging results. We plan to further study the efficacy and safety of convalescent plasma in COVID-19 severely sick patients through an RCT. We 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: We 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

 
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