Convalescent plasma in the management of moderate COVID-19 in India: An open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial)

TLDR: This trial has high generalizability and approximates real-life setting of CP therapy in settings with limited laboratory capacity and a priori measurement of neutralizing antibody titres in donors and participants may further clarify the role of CP in management of COVID-19.

Abstract: Objectives Convalescent plasma (CP) as a passive source of neutralizing antibodies and immunomodulators is a century-old therapeutic option used for the management of viral diseases. We investigated its effectiveness for the treatment of COVID-19. Design Open-label, parallel-arm, phase II, multicentre, randomized controlled trial. Setting Thirty-nine public and private hospitals across India. Participants Hospitalized, moderately ill confirmed COVID-19 patients (PaO2/FiO2: 200-300 or respiratory rate > 24/min and SpO2 ≤ 93% on room air). Intervention Participants were randomized to either control (best standard of care (BSC)) or intervention (CP + BSC) arm. Two doses of 200 mL CP was transfused 24 hours apart in the intervention arm. Main Outcome Measure Composite of progression to severe disease (PaO2/FiO2 Results Between 22nd April to 14th July 2020, 464 participants were enrolled; 235 and 229 in intervention and control arm, respectively. Composite primary outcome was achieved in 44 (18.7%) participants in the intervention arm and 41 (17.9%) in the control arm [aOR: 1.09; 95% CI: 0.67, 1.77]. Mortality was documented in 34 (13.6%) and 31 (14.6%) participants in intervention and control arm, respectively [aOR) 1.06 95% CI: −0.61 to 1.83]. Interpretation CP was not associated with reduction in mortality or progression to severe COVID-19. This trial has high generalizability and approximates real-life setting of CP therapy in settings with limited laboratory capacity. A priori measurement of neutralizing antibody titres in donors and participants may further clarify the role of CP in management of COVID-19. Trial registration The trial was registered with Clinical Trial Registry of India (CTRI); CTRI/2020/04/024775.

Figures

Table 1: Demographic and baseline characteristics of the study participants, n=464

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Title Page
Convalescent plasma in the management of moderate COVID-19 in India: An open-label
parallel-arm phase II multicentre randomized controlled trial (PLACID Trial)
Anup Agarwal, Aparna Mukherjee, Gunjan Kumar, Pranab Chatterjee, Tarun Bhatnagar, Pankaj
Malhotra and PLACID Trial Collaborators
The names and affiliations of PLACID Trial Collaborators are provided in Annexure 1
Running title: Convalescent plasma in COVID-19
Corresponding Author:
Name: Dr. Aparna Mukherjee MD, PhD
Affiliation: Scientist-E,
Clinical Trial and Health Systems Research Unit,
Indian Council of Medical Research
Full Address:
Indian Council of Medical Research
V. Ramalingaswamy Bhawan
PO Box No. 4911
Ansari Nagar, New Delhi – 110029,
India
Email:
aparna.sinha.deb@gmail.com
aparna.sinha.deb@icmr.gov.in
All rights reserved. No reuse allowed without permission.
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for thisthis version posted September 10, 2020. ; https://doi.org/10.1101/2020.09.03.20187252doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

2
Name
Highest
Degree
Affiliation
Full Address
Anup Agarwal
MBBS
Consultant,
Clinical Trial & Health Systems Research Unit,
Indian Council of Medical Research (ICMR)
Email – mailanupagarwal@gmail.com
Indian Council of
Medical Research.
V. Ramalingaswami
Bhawan,
P.O. Box No. 4911.
Ansari Nagar,
New Delhi - 110029,
India.
Aparna Mukherjee
PhD
Scientist E,
Clinical Trial & Health Systems Research Unit,
Indian Council of Medical Research (ICMR),
Email – aparna.sinha.deb@gmail.com
New Delhi
-
110029,
India.
Gunjan Kumar
MD
Scientist C,
Clinical Trial & Health Systems Research Unit,
Indian Council of Medical Research (ICMR)
Email - gunjan2587@gmail.com
New Delhi
-
110029,
India.
Pranab Chatterjee
MD
Scientist B,
Translational Global Health Policy and Research Cell,
Indian Council of Medical Research (ICMR)
Email - pranab.chatterjee@phi.org.in
New Delhi
-
110029,
India.
Tarun Bhatnagar
PhD
Scientist E,
ICMR School of Public Health,
Indian Council of Medical Research -National
Institute of Epidemiology
Email - drtarunb@gmail.com
Chennai, Tamil,
India
Pankaj Malhotra
MD
Professor,
Department of Internal Medicine,
Post Graduate Institute of Medical Education and
Research
Email – malhotrapankaj@gmail.com
Chandigarh, India
B Latha
MD
Department of Transfusion Medicine,
Madras
Medical College
Email - latsbalu@yahoo.co.uk
Chennai, Tamil Nadu,
India
Sunita Bundas
MD
Professor,
Department of Immunohaematology and Transfusion
Medicine,
SMS Medical College and Hospital
Email – drsunitabundas@yahoo.in
Jaipur, Rajasthan, India
Vivek Kumar
EDIC
Dept. of Critical Care Medicine,
Sir H N Reliance Foundation Hospital
Email - drvivekmd@rediffmail.com
Mumbai, India
Ravi Dosi
DNB
Professor,
Department of Respiratory Medicine,
Sri Aurobindo Institute of Medical Sciences
Email - ravi.dosi@gmail.com
Indore, Madhya
Pradesh, India
Janakkumar R
Khambholja
MD
Professor,
Department of Internal Medicine,
Smt NHL Municipal Medical College
Email - drjanak.research@gmail.com
Ahmedabad, Gujarat,
India
Rosemarie de Souza
MD
Professor,
Department of Internal Medicine,
BYL Nair Charitable Hospital & TN Medical College
Email - drrosemariedesouza@gmail.com
Mumbai, Maharashtra,
India
All rights reserved. No reuse allowed without permission.
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for thisthis version posted September 10, 2020. ; https://doi.org/10.1101/2020.09.03.20187252doi: medRxiv preprint

3
Raja Rao Mesipogu
MD
Professor,
Department of Internal Medicine,
Gandhi Medical College
Email - drmrrao@gmail.com
Hyderabad, Telangana,
India
Saurabh Srivastava
Professor,
Department of Internal Medicine, Government
Institute of Medical Sciences
Email - saurabhsrivas@gmail.com
Greater Noida, Uttar
Pradesh, India
Simmi Dube
MD
Professor,
Department of Internal Medicine,
Gandhi Medical College, Bhopal
Email - Simmi33@gmail.com
Bhopal, Madhya
Pradesh, India
Kiran Chaudhary
MCh
Department of Transfusion Medicine,
Atal Bihari Vajpayee Institute of Medical Sciences
and Ram Manohar Lohia Hospital
Email - drchaudharyk@yahoo.co.in
New Delhi, India
Subash S
MD
Professor,
Department of Transfusion Medicine,
Madras Medical College
Email - dchsub@yahoo.co.in
Chennai, Tamil Nadu,
India
S.
Anbuselvi Mattuvar
K
MD
Professor, Department of Physiology, Madras
Medical College
Email - dranbuselvimk@gmail.com
Chennai, Tamil Nadu,
India
V Rajendran
MD
Department of Internal Medicine,
Madras Medical College
Email - Rsvr2003@hotmail.com
Chennai, Tamil Nadu,
India
A Sundararajaperumal
MD
Department of Thoracic Medicine,
Madras Medical College
Email - drperumal@gmail.com
Chennai, Tamil Nadu,
India
P Balamanikandan
MD
Department of Internal Medicine,
Madras Medical College
Email - balammc@yahoo.com
Chennai, Tamil Nadu,
India
R S Uma Maheswari
MD
Department of Internal Medicine,
Madras Medical College
Email - drumamaheswari@gmail.com
Chennai, Tamil Nadu,
India
R Jayanthi
MD
Department of Internal Medicine,
Madras Medical College
Email - Rjayanthi363@gmail.com
Chennai, Tamil Nadu,
India
S Ragunanthanan
MD
Department of Internal Medic
ine,
Madras Medical College
Email - hemaragu@yahoo.com
Chennai, Tamil Nadu,
India
Sudhir Bhandari
MD
Professor,
Department of Internal Medicine,
SMS Medical College and Hospital
Email – drs_bhandari@yahoo.com
Jaipur, Rajasthan, India
Ajeet Singh
MD
Department of Internal Medicine,
SMS Medical College and Hospital
Email - Drajeetsingh2020@gmail.com
Jaipur, Rajasthan, India
Ashok Pal
MD
Department of
Immunohaematology and Transfusion
Medicine,
SMS Medical College and Hospital
Email - Dr.palashok@gmail.com
Jaipur, Rajasthan, India
Anjali Handa
MD
Department of Immunohaematology and Transfusion
Medicine,
SMS Medical College and Hospital
Jaipur, Rajasthan, India
All rights reserved. No reuse allowed without permission.
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for thisthis version posted September 10, 2020. ; https://doi.org/10.1101/2020.09.03.20187252doi: medRxiv preprint

4
Email
-
Ahnumero29@gmail.com
Govind Rankawat
MBBS
Department of Internal Medicine,
SMS Medical College and Hospital
Email - govindrankawat@gmail.com
Jaipur, Rajasthan,
India
Ketan Kargirwar
EDIC
Dept. of Critical Care Medicine,
Sir H N Reliance Foundation Hospital
Email - ketan.kargirwar@rfhospital.org
Mumbai, Maharashtra,
India
Joyce Regi
MD
Dept. of Transfusion Medicine,
Sir H N Reliance Foundation Hospital
Email - joyce.regi@rfhospital.org
Mumbai, Maharashtra,
India
Darshana Rathod
MD
Dept. of Critical Care Medicine,
Sir H N Reliance Foundation Hospital
Email - Darshana.Rathod@rfhospital.org
Mumbai, Maharashtra,
India
Edwin Pathrose
MBBS
Dept. of Critical Care Medicine,
Sir H N Reliance Foundation Hospital
Email - Edwin.Pathrose@rfhospital.org
Mumbai, Maharashtra,
India
Nirankar Bhutaka
MBBS
Dept. of Critical Care Medicine,
Sir H N Reliance Foundation Hospital
Email - Nirankar.Bhutaka@rfhospital.org
Mumbai, Maharashtra,
India
Mayur H Patel
MD
Dept. of Critical Care and Emergency Medicine,
Sir H N Reliance Foundation Hospital
Email - Mayur.H.Patel@rfhospital.org
Mumbai, Maharashtra,
India
Rahul J Verma
MRCP
Dept. of Academics and Research,
Sir H N Reliance Foundation Hospital
Email - Rahul.j.verma@rfhospital.org
Mumbai, Maharashtra,
India
Kamal Malukani
MD
Professor,
Department of Pathology,
Sri Aurobindo Institute of Medical Sciences
Email – kamal.malukani@yahoo.com
Indore, Madhya
Pradesh, India
Shivani Patel
DM
Department of Hematology,
Sri Aurobindo Institute of Medical Sciences
Email – shivani2105@yahoo.com
Indore, Madhya
Pradesh, India
Apurv Thakur
MD
Department of Community Medicine,
Sri Aurobindo Institute of Medical Sciences
Email – apurv_thakur333@yahoo.co.in
Indore, Madhya
Pradesh, India
Satish Joshi
DCP
Department of Pathology,
Sri Aurobindo Institute of Medical Sciences
Email – drjoshi_s@yahoo.com
Indore, Madhya
Pradesh, India
Rashmi Kulkarni
PhD
Department of Forensic Medicine,
Sri Aurobindo Institute of Medical Sciences
Email - rashmiajit3@gmail.com
Indore, Madhya
Pradesh, India
Nilay N Suthar
MD
Professor,
Department of Internal Medicine,
Smt NHL Municipal Medical College
Email: nilaysuthar@gmail.com
Ahmedabad, Gujarat,
India
Nehal M Shah
MD
Department of Internal Medicine,
Smt NHL Municipal Medical College
Email: drnehalshah1929@gmail.com
Ahmedabad, Gujarat,
India
Hemang M Purohit
MSc
Department of Internal Medicine,
Smt NHL Municipal Medical College
Email: hemang.research@gmail.com
Ahmedabad, Gujarat,
India
Cherry K Shah
MD
Professor,
Department of Pathology,
Smt NHL Municipal Medical College
Email: drcherryshah@gmail.com
Ahmedabad, Gujarat,
India
All rights reserved. No reuse allowed without permission.
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for thisthis version posted September 10, 2020. ; https://doi.org/10.1101/2020.09.03.20187252doi: medRxiv preprint

5
Monila N Patel
MD
Professor,
Department of Internal Medicine,
Smt NHL Municipal Medical College
Email: monilapatel@hotmail.com
Ahmedabad, Gujarat,
India
Sanket Shah
DM
Department of Hematology,
Smt NHL Municipal Medical College
Email: drsanket2086@gmail.com
Ahmedabad, Gujarat,
India
Smit H Shah
MBBS
Department of Internal Medicine,
Smt NHL Municipal Medical College
Email: smittusharshah@gmail.com
Ahmedabad, Gujarat,
India
Tehsim Memon
MBBS
Department of Internal Medicine,
Smt NHL Municipal Medical College
Email: tehsimemon@gmail.com
Ahmedabad,
Gujarat,
India
Vishal R Beriwala
MBBS
Department of Internal Medicine,
Smt NHL Municipal Medical College
Email: vishal.r.beriwala@gmail.com
Ahmedabad, Gujarat,
India
Kusum Jashnani
MD
Professor,
Department of Pathology,
BYL Nair Charitable Hospital & TN Medical College
Email - kasumjash@hotmail.com
Mumbai, Maharashtra,
India
Fatema Ezzy
Medical
Student
Department of Internal Medicine,
BYL Nair Charitable Hospital & TN Medical College
Email - Ezzy.fatema1998@gmail.com
Mumbai, Maharashtra,
India
Simran Agrawal
Medical
Student
Department of Internal Medicine,
BYL Nair Charitable Hospital & TN Medical College
Email - Agrawalsimran2803@gmail.com
Mumbai, Maharashtra,
India
Rakesh Bhadade
MD
Department of Internal Medicine,
BYL Nair Charitable Hospital & TN Medical College
Email - rakeshbhadade@gmail.com
Mumbai, Maharashtra,
India
Atish MN
MD
Department of Internal Medicine,
BYL Nair Charitable Hospital & TN Medical College
Email - Aathish329@gmail.com
Mumbai, Maharashtra,
India
Tushar Madke
MD
Department of Internal Medicine,
BYL Nair Charitable Hospital & TN Medical College
Email - drtusharmadke@gmail.com
Mumbai, Maharashtra,
India
Vikash Kavishwar
MD
Department of Pathology,
BYL Nair Charitable Hospital & TN Medical College
Email - kavishwarvikas@gmail.com
Mumbai, Maharashtra,
India
Ramesh Waghmare
MD
Department of Pathology,
BYL Nair Charitable Hospital & TN Medical College
Email - rameshpathmumbai@gmail.com
Mumbai, Maharashtra,
India
Nitin Valvi
MD
Department of Pathology,
BYL Nair Charitable Hospital & TN Medical College
Email - Nitinvalvi02@gmail.com
Mumbai, Maharashtra,
India
B Thrilok Chander
MD
Department of Internal Medicine,
Gandhi Medical College, Secunderabad
Email - Thrilok73@gmail.com
Secunderabad,
Telangana, India
A Vinaya Sekhar
MD
Professor,
Department of Internal Medicine,
Gandhi Medical College, Secunderabad
Email - Drvinaya31@gmail.com
Secunderabad,
Telangana, India
Akhilesh Kumar
Maurya
MBBS
Department of Internal Medicine,
Gandhi Medical College, Secunderabad
Email - Akhileshsonu1993@gmail.com
Secunderabad,
Telangana, India
K Hemanth
MBBS
Department of Internal Medicine,
Secunderabad,
All rights reserved. No reuse allowed without permission.
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for thisthis version posted September 10, 2020. ; https://doi.org/10.1101/2020.09.03.20187252doi: medRxiv preprint

Frequently asked questions

Q1. What contributions have the authors mentioned in the paper "Convalescent plasma in the management of moderate covid-19 in india: an open-label parallel-arm phase ii multicentre randomized controlled trial (placid trial)" ?

Preprint ( which was not certified by peer review ) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Q2. What have the authors stated for future works in "Convalescent plasma in the management of moderate covid-19 in india: an open-label parallel-arm phase ii multicentre randomized controlled trial (placid trial)" ?

Areas of future research could include effectiveness of CP among NAb naïve patients and the use of CP with high NAb titres. The Corresponding Author grants on behalf of all authors a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats and media ( whether known now or created in the future ), to i ) publish, reproduce, distribute, display and store the Contribution, ii ) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii ) create any other derivative work ( s ) based on the Contribution, iv ) to exploit all subsidiary rights in the Contribution, v ) the inclusion of electronic links from the Contribution to third party material where-ever it may be located ; and, vi ) licence any third party to do any or all of the above. Whilst the observational studies suggested clinical benefits in recipients of convalescent plasma, the trials were stopped early, and they failed to ascertain any mortality benefit associated with convalescent plasma therapy in COVID-19 patients. The effectiveness of convalescent plasma as a potential therapeutic modality for moderately ill COVID-19 patients is limited. 

Q3. What are other mechanisms through which CP may exert its therapeutic effect in COVID-19 patients?

Other immune pathways such as antibody-dependent cellular cytotoxicity, complement activation, or phagocytosis are putative mechanisms through which CP may exert its therapeutic effect in COVID-19 patients. 

Q4. What was the protocol used to allocate participants in a 1:1 ratio to receive CP?

medRxiv preprintblock randomization strategy was used to allocate participants in a 1:1 ratio to receive either CP with the best standard of care (BSC) (intervention arm) or BSC alone (control arm). 

Q5. What is the role of CP in the management of COVID-19?

CP is a passive immunization strategy which has been used on several occasions in the past century, inspiring clinical expectations that it could emerge as a potential therapy for a disease with no proven, effective interventions. 

Q6. How did Wu et al determine the level of NAb in COVID-19 patients?

Wu et al documented that 30% of patients generated very low levels of NAb with titres correlating to increasing age and disease severity. 

Q7. What did the investigators do to ensure the safety of the study?

After obtaining written, informed consent from an eligible patient, the site investigators screened the participant for recruitment, and called a member of the central trial coordinating team to receive the randomization sequence, ensuring concealment of allocation. 

Q8. How many patients were randomized into the intervention or BSC arm?

A total of 1210 patients admitted across 39 trial sites were screened between 22nd April to 14th July 2020; 464 patients were randomized into intervention or CP +BSC arm (n=235) and control or BSC arm (n=229). 

Q9. What was the majority of the patients who were encouraged to donate plasma?

While all COVID-19 survivors were encouraged to donate plasma, an overwhelming majority of the donors were only mildly sick, young survivors. 

Q10. What is the role of CP in reducing mortality?

Since the publication of the first case series from China, multiple observational studies have been published, some on pre-print servers, highlighting the usefulness of CP in reducing mortality, hospital stay and viral load in COVID-19 patients. 

Q11. how many participants received a unit of CP with detectable NAb?

Titres of NAb in transfused CP were available in 224 out of 235 participants in the intervention arm; 160 (71.4%) participants received at least one unit of CP with detectable NAb. 

Q12. What was the definition of a patient who had received a diagnosis of COVID-19?

Eligible donors were either males or nulliparous females aged between 18-65 years, weighing over 50 kg, who had received a diagnosis of COVID-19 confirmed with a positive RT-PCR test, suffered from symptomatic COVID-19 with at least fever and cough, which had completely resolved for a period of 28 consecutive days prior to donation or a period of 14 days prior to donation with two negative SARS-CoV-2 RT-PCR tests from nasopharyngeal swabs collected 24 hours apart. 

Q13. How many hospitals were involved in the PLACID trial?

; https://doi.org/10.1101/2020.09.03.20187252doi: medRxiv preprintThe PLACID trial was an open-label, parallel-arm, phase II, multicentre, randomized, controlled trial conducted in 39 tertiary care hospitals across India. 

Q14. What is the main difference between the PLACID trial and the other studies?

While this approach could have impacted the internal comparability across sites, the authors feel this lends the trial more generalizability, approximates real-world scenarios more closely and places their study closer to the pragmatic trials across the methodological spectrum of clinical trials.