SARS-CoV-2 Antibodies Based IVIG Therapy for COVID-19 Patients

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) Antibodies Based Intravenous Immunoglobulin (IVIG) Therapy for Severe and Critically Ill COVID-19 Patients

Severe and critically ill patients will be enrolled in the study (50 patients) after duly filled consent forms. Recipients shall be divided in to 5 groups with 10 patients per group to compare clinical efficacy and safety of patients in clinical phase I/phase II study. Each group shall receive particular single dose of Intravenously administered Immunoglobulins (IVIG) developed from convalescent plasma of recovered COVID-19 individual , an experimental drug along with standard treatment except for control group which will receive standard treatment only.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Biological: SARS-CoV-2 antibody based IVIG therapy

Detailed Description

Passive immunization using intravenous immunoglobulins (IVIG) has been tested for treating previous viral outbreaks and holds the potential to save lives in the current crisis. Recently researchers from China reported satisfactory recovery of critically ill Corona Virus Disease 2019 (COVID 19) patients when high dose intravenous immunoglobulin (IVIG) were administered.

Research team at Dow University of Health Sciences has purified immunoglobulin (both SARS-CoV 2 antibodies and existing antibodies) from convalescent plasma of COVID19 individuals and pooled to prepared IVIG formulation to treat severe and critically ill COVID-19 patients. To evaluate safety of the formulation animal (rats) safety trials and survival of all the animals were observed.

It is intended to assess safety and efficacy of experimental the IVIG treatment in severe and critically ill COVID 19 patients through phase I/phase II randomized single blinded clinical trial with fifty study participants. FDA outlined criteria for passive immunization using convalescent plasma, which will be used for recruiting participants in the study.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Pakistan
  • Sindh
    • Karachi, Sindh, Pakistan, 74200
      • Dow University of Health Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Above 18 years of age
• Have positive SARS-CoV-2 PCR on nasopharyngeal and/or oropharyngeal swabs
• Admitted in isolation ward and ICU of institutes affiliated with DUHS
• have severe or critical COVID 19 as judged by the treating physician
• Consent given by the patient or first degree relative

Exclusion Criteria:

• Pregnancy
• Previous allergic reaction to immunoglobulin treatment
• Ig A deficiency
• Patient requiring 2 inotropic agents to maintain blood pressures
• Known case of any autoimmune disorder
• Acute kidney injury or chronic renal failure
• Known case of thromboembolic disorder
• Aseptic meningitis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; Standard care only n = 10 patients.
Experimental: IVIG dose: 0.15 g/kg; Standard Care + Single dose of 0.20 g/Kg anti-COVID-19 IVIG (experimental drug prepared at DUHS) n= 10 patients	Biological: SARS-CoV-2 antibody based IVIG therapy; Patient groups will receive IVIG prepared from pooled convalescent plasma from recovered COVID-19 patients. This will be administered sequentially and in varying dosages, infused over a period of 12 hours, intravenously.Additionally, all treatment groups will receive same standard care as control group. Standard Care as per hospital protocol, which may include: Airway support, Anti-Viral medication, Antibiotics, Fluid Resuscitation, Hemodynamic Support, Steroids, Painkillers, Anti-Pyretics
Experimental: IVIG dose: 0.20 g/kg; Standard Care + Single dose of 0.25 g/Kg anti-COVID19 IVIG (experimental drug prepared at DUHS) n= 10 patients	Biological: SARS-CoV-2 antibody based IVIG therapy; Patient groups will receive IVIG prepared from pooled convalescent plasma from recovered COVID-19 patients. This will be administered sequentially and in varying dosages, infused over a period of 12 hours, intravenously.Additionally, all treatment groups will receive same standard care as control group. Standard Care as per hospital protocol, which may include: Airway support, Anti-Viral medication, Antibiotics, Fluid Resuscitation, Hemodynamic Support, Steroids, Painkillers, Anti-Pyretics
Experimental: IVIG dose: 0.25 g/kg; Standard Care + Single dose of 0.30 g/Kg anti-COVID19 IVIG (experimental drug prepared at DUHS) n= 10 patients	Biological: SARS-CoV-2 antibody based IVIG therapy; Patient groups will receive IVIG prepared from pooled convalescent plasma from recovered COVID-19 patients. This will be administered sequentially and in varying dosages, infused over a period of 12 hours, intravenously.Additionally, all treatment groups will receive same standard care as control group. Standard Care as per hospital protocol, which may include: Airway support, Anti-Viral medication, Antibiotics, Fluid Resuscitation, Hemodynamic Support, Steroids, Painkillers, Anti-Pyretics
Experimental: IVIG dose: 0.30 g/kg; Standard Care + Single dose of 0.35 g/Kg anti-COVID19 IVIG (experimental drug prepared at DUHS) n= 10 patients	Biological: SARS-CoV-2 antibody based IVIG therapy; Patient groups will receive IVIG prepared from pooled convalescent plasma from recovered COVID-19 patients. This will be administered sequentially and in varying dosages, infused over a period of 12 hours, intravenously.Additionally, all treatment groups will receive same standard care as control group. Standard Care as per hospital protocol, which may include: Airway support, Anti-Viral medication, Antibiotics, Fluid Resuscitation, Hemodynamic Support, Steroids, Painkillers, Anti-Pyretics

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28 Days mortality	All cause mortality of participants will be monitored for 28 days to assess the safety and efficacy of IVIG treatment.	28 days
Requirement of supplemental oxygen support	Number of days required for invasive or non-invasive oxygen supply during hospital stay as per oxygen saturation status of patient	28 days
Number of days on assisted ventilation	Number of days a participant will be requiring assisted ventilation both invasive and noninvasive	28 days
Days to step down	Shifting from ICU to ward	28 days
Days to Hospital Discharge	Duration from day of enrollment in study to Day of hospital discharge	28 days
Adverse events during hospital stay	Kidney failure, hypersensitivity with cutaneous or hemodynamic manifestations, aseptic meningitis, hemolytic anemia, leuko-neutropenia, transfusion related acute lung injury (TRALI)	28 days
Change in C-Reactive Protein (CRP) levels	Change in C-Reactive Protein (CRP) levels from baseline will be used to monitor inflammation	28 days
Change in neutrophil lymphocyte ratio	change in neutrophil lymphocyte ratio from baseline will be used to monitor inflammation	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Ferritin levels	change in Ferritin level from baseline will be used to monitor inflammation and immune dysregulation	28 days
Change in lactate dehydrogenase (LDH) levels	change in LDH from baseline will be used to monitor infections and tissue health	28 days
Change in radiological (X-ray) findings	Any change seen in radiological chest X-ray findings	28 days
Days to negative SARS-CoV-2 Polymerase Chain Reaction (PCR) test	Time taken for participant to receive negative COVID-19 PCR test	28 days
Anti-SARS-CoV-2 Antibody	Anti-SARS-CoV-2 antibody titre from blood measured by semi-qualitative method	28 days
Change in fever	Change in body temperature from baseline will be used to monitor safety and efficacy	28 days
Change in Sodium levels	Change in electrolytes (Sodium) seen in participants	28 days
Change in Potassium levels	Change in electrolytes (Potassium) seen in participants	28 days
Change in Chloride levels	Change in electrolytes (Chloride) seen in participants	28 days
Change in Bicarbonate levels	Change in electrolytes (Bicarbonate) seen in participants	28 days

Collaborators and Investigators

• Sponsor: Dow University of Health Sciences
• Collaborators: Higher Education Commission (Pakistan)
• Investigators: Principal Investigator: Dr.Shaukat Ali, PhD, Dow University of Health Sciences, Principal Dow College of Biotechnology

Publications and helpful links

General Publications

• Cunningham AC, Goh HP, Koh D. Treatment of COVID-19: old tricks for new challenges. Crit Care. 2020 Mar 16;24(1):91. doi: 10.1186/s13054-020-2818-6. No abstract available.
• Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, Wei J, Xiao H, Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, Zhang Z, Liu Y, Liu L. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020 Apr 28;323(16):1582-1589. doi: 10.1001/jama.2020.4783.
• Chen L, Xiong J, Bao L, Shi Y. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis. 2020 Apr;20(4):398-400. doi: 10.1016/S1473-3099(20)30141-9. Epub 2020 Feb 27. No abstract available.
• Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, Chan P, Wong KC, Leung CB, Cheng G. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005 Jan;24(1):44-6. doi: 10.1007/s10096-004-1271-9.
• Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, Makki S, Rooney KD, Nguyen-Van-Tam JS, Beck CR; Convalescent Plasma Study Group. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis. 2015 Jan 1;211(1):80-90. doi: 10.1093/infdis/jiu396. Epub 2014 Jul 16.
• Arabi Y, Balkhy H, Hajeer AH, Bouchama A, Hayden FG, Al-Omari A, Al-Hameed FM, Taha Y, Shindo N, Whitehead J, Merson L, AlJohani S, Al-Khairy K, Carson G, Luke TC, Hensley L, Al-Dawood A, Al-Qahtani S, Modjarrad K, Sadat M, Rohde G, Leport C, Fowler R. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus. 2015 Nov 19;4:709. doi: 10.1186/s40064-015-1490-9. eCollection 2015.
• Buchacher A, Iberer G. Purification of intravenous immunoglobulin G from human plasma--aspects of yield and virus safety. Biotechnol J. 2006 Feb;1(2):148-63. doi: 10.1002/biot.200500037.
• Hughes RA, Donofrio P, Bril V, Dalakas MC, Deng C, Hanna K, Hartung HP, Latov N, Merkies IS, van Doorn PA; ICE Study Group. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol. 2008 Feb;7(2):136-44. doi: 10.1016/S1474-4422(07)70329-0. Erratum In: Lancet Neurol. 2008 Sep;7(9):771.
• Hung IFN, To KKW, Lee CK, Lee KL, Yan WW, Chan K, Chan WM, Ngai CW, Law KI, Chow FL, Liu R, Lai KY, Lau CCY, Liu SH, Chan KH, Lin CK, Yuen KY. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest. 2013 Aug;144(2):464-473. doi: 10.1378/chest.12-2907.
• Pandey S, Vyas GN. Adverse effects of plasma transfusion. Transfusion. 2012 May;52 Suppl 1(Suppl 1):65S-79S. doi: 10.1111/j.1537-2995.2012.03663.x.
• Ali S, Uddin SM, Shalim E, Sayeed MA, Anjum F, Saleem F, Muhaymin SM, Ali A, Ali MR, Ahmed I, Mushtaq T, Khan S, Shahab F, Luxmi S, Kumar S, Arain H, Khan M, Khan AS, Mehmood H, Rasheed A, Jahangeer A, Baig S, Quraishy S. Hyperimmune anti-COVID-19 IVIG (C-IVIG) treatment in severe and critical COVID-19 patients: A phase I/II randomized control trial. EClinicalMedicine. 2021 Jun;36:100926. doi: 10.1016/j.eclinm.2021.100926. Epub 2021 Jun 4.
• Ali S, Uddin SM, Ali A, Anjum F, Ali R, Shalim E, Khan M, Ahmed I, M Muhaymin S, Bukhari U, Luxmi S, Khan AS, Quraishy S. Production of hyperimmune anti-SARS-CoV-2 intravenous immunoglobulin from pooled COVID-19 convalescent plasma. Immunotherapy. 2021 Apr;13(5):397-407. doi: 10.2217/imt-2020-0263. Epub 2021 Feb 9.
• Ali S, Luxmi S, Anjum F, Muhaymin SM, Uddin SM, Ali A, Ali MR, Tauheed S, Khan M, Bajwa M, Baig SU, Shalim E, Ahmed I, Khan AS, Quraishy S. Hyperimmune anti-COVID-19 IVIG (C-IVIG) Therapy for Passive Immunization of Severe and Critically Ill COVID-19 Patients: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020 Nov 2;21(1):905. doi: 10.1186/s13063-020-04839-5.

Helpful Links

• World Health Organization (WHO) technical guidance on COVID-19
• U.S Food and Drug Administration (FDA) Recommendations for Investigational COVID-19 Convalescent Plasma
• News story of FDA approval for use of convalescent plasma for COVID-19 patients
• list of FDA approved Intravenously administrable Immune Globulin(IVIG) along Indications
• WHO guidelines for Use of Convalescent Whole Blood or Plasma Collected from Patients Recovered from Ebola Virus Disease for Transfusion, as an Empirical Treatment during Outbreaks

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2020
• Primary Completion (Actual): January 26, 2021
• Study Completion (Actual): February 8, 2021

Study Registration Dates

• First Submitted: May 7, 2020
• First Submitted That Met QC Criteria: August 19, 2020
• First Posted (Actual): August 20, 2020

Study Record Updates

• Last Update Posted (Actual): March 24, 2021
• Last Update Submitted That Met QC Criteria: March 21, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Antibody; COVID19 ( Corona Virus Disease -2019); SARS-CoV-2 (Severe Acute respiratory syndrome Coronavirus 2); Passive Immunization; Intravenous Immunoglobulin (IVIG); Pooled convalescent Plasma; Critically ill COVID-19 patients; Severe COVID-19 patients
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Severe Acute Respiratory Syndrome; COVID-19; Physiological Effects of Drugs; Immunologic Factors; Antibodies
• Other Study ID Numbers: biotech001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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