Convalescent Plasma as Adjunct Therapy for COVID-19

COVID-19 Clinical Trial

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Official title:

Clinical Trial of Convalescent Plasma Administration as Adjunct Therapy for COVID-19 (Uji Klinik Pemberian Plasma Konvalesen Sebagai Terapi Tambahan COVID-19)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04873414
• Other study ID #: COVID-CT002
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: December 1, 2020
• Est. completion date: December 31, 2021

Study information

• Verified date: May 2021
• Source: National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
• Contact: Muhammad Karyana, MD, MKes
• Phone: 062816789813
• Email: mkaryana[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Convalescent plasma (CP) has been the subject of increasing expectation for treating coronavirus disease 2019 (COVID-19). Reports on CP transfusion have shown promising clinical improvements without serious adverse events. To date, most studies focused on reporting CP treatment in patients with severe COVID-19, but only a few addressed benefits on less severe disease. The vast majority of studies reporting COVID-19 infection and treatment have come from earlier affected countries with established health systems and research infrastructure, while very few are from low- and middle-income countries (LMICs). Nonetheless, CP therapy could be one of the few available options in LMICs where constraints may exist in the access to novel treatments, even once available. Clinical trials conducted in LMICs may differ in many respects from those in high-income countries.

This study will evaluate the safety and efficacy of convalescent plasma therapy in hospitalized with moderate and severe COVID-19, to investigate the impacts of the treatment over the course of clinical illness, including non-mortal clinical outcomes.

Description:

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly around the world, with high rates of transmission and substantial mortality.

Convalescent plasma (CP) collected from recovered patients has been evaluated in the treatment of SARS, Middle East respiratory syndrome (MERS), and Ebola, but not well further studied and with no definitive results. Preliminary studies in COVID-19 patients showed improvement in clinical status after CP transfusion. However, a multicenter, open-label, randomized clinical trial of 103 patients in China with severe or life-threatening COVID-19 found no statistical difference in clinical improvement within 28 days among patients treated with CP versus standard treatment alone.

To date, CP has not been approved as a standard of care for COVID-19. There are insufficient data from well-controlled, adequately powered, randomized clinical trials to evaluate the efficacy and safety of CP for the treatment of this disease. One randomized controlled trial (NCT04342182) was halted for redesign based on the consideration that most COVID-19 patients already have high neutralizing antibody titers at hospital admission and no difference in mortality (p=0.95), hospital stay (p=0.68), or day-15 disease severity (p=0.58) was observed between plasma treated patients and patients on standard of care. Another clinical study (NCT04345523) showed efficacy and safety of CP in preventing progression to severe disease or death. However, this study was halted early due to low enrolment. Further studies have been published and assessed in several systematic reviews that remain uncertain about the safety and effectiveness of CP treatment for COVID-19.

The vast majority of studies reporting COVID-19 trials have come from the earlier affected countries with established healthcare systems and better research infrastructure, while very few are from low- and middle-income countries (LMICs). Meanwhile, the cases in LMICs have risen considerably with critical research questions specific to the needs of are hard to answer. As an LMIC with a geographically dispersed archipelago, access to healthcare remains a challenge in remote districts that could impact the adoption of CP deployment in Indonesia. Consequently, clinical trials conducted in LMICs may differ in many respects from those in high-income countries.

This study will evaluate the safety and efficacy of CP therapy in hospitalized with moderate and severe COVID-19, to investigate the impacts of the treatment over the course of clinical illness, including non-mortal clinical outcomes. This study will involve hospitals from different places of the Indonesian archipelago, with different characteristics and community structures, social, and values. To obtain supports for the trial, the investigators will seek community engagement that allows investigators and community leaders working collaboratively.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 364
• Est. completion date: December 31, 2021
• Est. primary completion date: October 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

INCLUSION CRITERIA:

1. Patients with PCR-confirmed COVID-19

2. Minimal age:18 years

3. Agree to participate in the trial with written informed consent

4. Moderate or Severe COVID-19 at the time of enrollment

.

A. Definition of moderate disease (according to Siddiqi et al):

Moderate COVID-19 is defined as disease with fever, respiratory symptoms (dry cough, chest distress, or shortness of breath after activities), and pulmonary imaging findings, and at least one of the following findings:

i) Abnormal coagulation parameters:

• D-dimer >1 µg/mL (normal <0.5 µg/mL)

• Prothrombin time (>13.6 second) or International normalized ratio (INR) =1.8

• Thrombocyte count <100x 10^3/mL

ii) Increased pro-inflammatory markers:

• C-reactive protein (CRP) =26.9 mg/L

• Procalcitonin =0.5 ng/mL,

• Lymphocyte count <1.5x 10^9/L) or Neutrophil/Lymphocyte ratio (NLR) >3.3

iii) Presence of risk factors or comorbidities:

• Age >65 years

• Type 1 Diabetes Mellitus or type 2 Diabetes Mellitus (with any of the following:

Fasting blood glucose =126 mg/dl, 2-h plasma glucose =200 mg/dL, or random plasma glucose =200 mg/dL, plus HbA1C >6.5%)

• Chronic kidney disease (creatinine >2.0 mg/dL) or with routine hemodialysis

• Chronic liver Disease with signs of liver cirrhosis; Child-Turcotte-Pugh (CTP) Class A (score 5-6) or Class B (score 7-9) or higher; or Model for End-Stage Liver Disease (MELD) score <39

• Heart failure (New York Health Association [NYHA] Class I or II)

• Bronchial asthma, chronic obstructive pulmonary disease (COPD), or pulmonary tuberculosis

• Cancer (particularly patients with chemotherapy or immunotherapy)

• Immunocompromised conditions, including HIV/AIDS, post-organ transplantation, or judged by attending physician (preferable after specialist consultation)

• Long-term corticosteroid use

• autoimmune disease

• Sequential Organ Failure Assessment [SOFA] score =5.65

• Body Mass Index (BMI) =35 kg/m2

B. Definition of severe COVID-19 (according to Siddiqi et al):

Severe Covid-19 is defined as disease with a respiratory rate =30 breaths/min, oxygen saturation <90% or oxygenation index (PaO2/FiO2) =300 mmHg, and/or lung infiltrates >50% within 24-48 h.

EXCLUSION CRITERIA:

• Pregnant or lactating woman

• History of transfusion reaction, blood-group incompatibility, IgA deficiency, or Allergy to Immunoglobulin-containing substances

• Concurrent participation of clinical trials of COVID-19 treatment

• Possibility of transfer to other hospital within 72 hours

• Heart Failure (NYHA Class III or higher) or other diseases with risks of volume overload

• Permanent organ failure unrelated to COVID-19, including:

• End-stage liver disease (CTP score >10 or MELD score >40)

• End stage renal disease with creatinine clearance <30% or in routine dialysis

• Multiple organ failure (SOFA score =11)

• Concomitant condition or treatment with risks of thrombosis, e.g., cryoglobulinemia, refractory hypertriglyceridemia, or monoclonal gammopathy

Related Conditions & MeSH terms

• COVID-19

Intervention

Biological:
• Convalescent plasma treatment
Convalescent Plasma collected from patients who recover from COVID-19 and have been discharged from the hospital for at least 14 days.

Locations

Country	Name	City	State
Indonesia	Aceh Tamiang Hospital	Aceh Tamiang	Aceh
Indonesia	Dr. Hasan Sadikin Central Hospital	Bandung	West Java
Indonesia	RSD Gunung Jati	Cirebon	West Java
Indonesia	Sanglah Central Hospital	Denpasar	Bali
Indonesia	Udayana University Hospital	Denpasar	Bali
Indonesia	dr. Cipto Mangunkusumo National Central General Hospital	Jakarta
Indonesia	Dr. Suyoto Pusrehab Kemenhan Hospital	Jakarta
Indonesia	Fatmawati Central Hospital	Jakarta
Indonesia	Pasar Minggu Hospital	Jakarta	DKI
Indonesia	Persahabatan Central hospital	Jakarta
Indonesia	Prof. Dr. Sulianti Saroso Infectious Disease Hospital	Jakarta
Indonesia	University Of Indonesia Hospital (RSUI)	Jakarta
Indonesia	YARSI Hospital	Jakarta
Indonesia	Emergency Hospital for COVID-19 - Wisma Atlet Kemayoran	Jakarta Pusat	Jakarta
Indonesia	Gatot Soebroto Central Army Hospital	Jakarta Pusat
Indonesia	Dr. Soeradji Tirtonegoro Hospital	Klaten	Central Java
Indonesia	Dr. Haryoto Regency Hospital	Lumajang	East Java
Indonesia	Dadi Hospital	Makassar	South Sulawesi
Indonesia	Dr. Tadjuddin Chalid Hospital	Makassar	Souh Sulawesi
Indonesia	Dr. Wahidin Sudirohusodo Central Hospital	Makassar	South Sulawesi
Indonesia	Hasanuddin University Hospital	Makassar	South Sulawesi
Indonesia	Prof. Dr. R.D. Kandou Hospital	Manado	North Sulawesi
Indonesia	Dr. Mohammad Hoesin Central Hospital	Palembang	South Sumatra
Indonesia	Waluyo Jati Kraksaan Regency Hospital	Probolinggo	East Java
Indonesia	Dr. Wongsonegoro Regency Hospital	Semarang	Central Java
Indonesia	Sidoarjo Regency Hospital	Sidoarjo	East Java
Indonesia	Dr Ramelan Navy Hospital	Surabaya	East Java
Indonesia	Dr. Soetomo Hospital	Surabaya	East Java

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Health Research and Development, Ministry of Health Republic of Indonesia	Eijkman Institute for Molecular Biology, Indonesian Red Cross

Country where clinical trial is conducted

Indonesia, 

References & Publications (20)

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Cholongitas E, Papatheodoridis GV, Vangeli M, Terreni N, Patch D, Burroughs AK. Systematic review: The model for end-stage liver disease--should it replace Child-Pugh's classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther. 2005 Dec;22(11-12):1079-89. Review. — View Citation

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Focosi D, Anderson AO, Tang JW, Tuccori M. Convalescent Plasma Therapy for COVID-19: State of the Art. Clin Microbiol Rev. 2020 Aug 12;33(4). pii: e00072-20. doi: 10.1128/CMR.00072-20. Print 2020 Sep 16. Review. — View Citation

Janiaud P, Axfors C, Schmitt AM, Gloy V, Ebrahimi F, Hepprich M, Smith ER, Haber NA, Khanna N, Moher D, Goodman SN, Ioannidis JPA, Hemkens LG. Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA. 2021 Mar 23;325(12):1185-1195. doi: 10.1001/jama.2021.2747. — View Citation

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Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, Esteban I, Caballero MT, Wood C, Berrueta M, Rondan A, Lescano G, Cruz P, Ritou Y, Fernández Viña V, Álvarez Paggi D, Esperante S, Ferreti A, Ofman G, Ciganda Á, Rodriguez R, Lantos J, Valentini R, Itcovici N, Hintze A, Oyarvide ML, Etchegaray C, Neira A, Name I, Alfonso J, López Castelo R, Caruso G, Rapelius S, Alvez F, Etchenique F, Dimase F, Alvarez D, Aranda SS, Sánchez Yanotti C, De Luca J, Jares Baglivo S, Laudanno S, Nowogrodzki F, Larrea R, Silveyra M, Leberzstein G, Debonis A, Molinos J, González M, Perez E, Kreplak N, Pastor Argüello S, Gibbons L, Althabe F, Bergel E, Polack FP; Fundación INFANT-COVID-19 Group. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med. 2021 Feb 18;384(7):610-618. doi: 10.1056/NEJMoa2033700. Epub 2021 Jan 6. — View Citation

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. Review. — View Citation

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Ng JJ, Luo Y, Phua K, Choong AMTL. Acute kidney injury in hospitalized patients with coronavirus disease 2019 (COVID-19): A meta-analysis. J Infect. 2020 Oct;81(4):647-679. doi: 10.1016/j.jinf.2020.05.009. Epub 2020 May 8. — View Citation

Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020 May;39(5):405-407. doi: 10.1016/j.healun.2020.03.012. Epub 2020 Mar 20. — View Citation

Szakó L, Farkas N, Kiss S, Váncsa S, Zádori N, Vörhendi N, Eross B, Hegyi P, Alizadeh H. Convalescent plasma therapy for COVID-19 patients: a protocol of a prospective meta-analysis of randomized controlled trials. Trials. 2021 Feb 1;22(1):112. doi: 10.1186/s13063-021-05066-2. — View Citation

WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020 Aug;20(8):e192-e197. doi: 10.1016/S1473-3099(20)30483-7. Epub 2020 Jun 12. Review. Erratum in: Lancet Infect Dis. 2020 Oct;20(10):e250. — View Citation

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Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Oct 15;62(16):e147-239. doi: 10.1016/j.jacc.2013.05.019. Epub 2013 Jun 5. — View Citation

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* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The mortality in COVID-19 patients treated with convalescent plasma	Number of deaths from the initiation of CP treatment until hospital discharge or death.	From the initiation of CP treatment until hospital discharge or death, up to 28 days
Secondary	Change in clinical status category in CP-receiving patients	Change in clinical status category will be scored daily based on the modified WHO six-point ordinal scale. The six-point scale is as follows: 1, non-hospitalized; 2, hospitalized, without supplemental oxygen; 3, hospitalized, with supplemental oxygen; 4, hospitalized, with nasal high-flow oxygen therapy, non-invasive mechanical ventilation, or both; 5, hospitalized, with invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO), or both; and 6, death	From the initiation of CP treatment until hospital discharge or death, up to 28 days
Secondary	Duration of hospitalization	Number of days from the admission to the date of discharge or death. Patients who are not discharged and remain in the hospital at the end of study period will be censored on the study's end date, while those who are lost to follow-up will be censored on the last encounter date	From admisstion until hospital discharge or death, up to 28 days
Secondary	Duration of mechanical ventilation	Number of days in patients with ventilatory support	From the initiation of CP treatment until hospital discharge or death, up to 28 days
Secondary	Duration of ICU stay	Number of days from entry to release from ICU	From the initiation of CP treatment until hospital discharge or death, up to 28 days
Secondary	Change in lung image radiography in CP-receiving patients	The lung radiological image will be assessed using the Brixia chest X-ray scoring (Morghesi and Maroldi, 2020). Each lung is divided into three zones, marked by letters A, B, and C for the right lung, and D, E, and F for the left lung. The letters divide the lungs into three levels: upper level (A and D), above the inferior wall of the aortic arch; middle level (B and E), below the inferior wall of the aortic arch and above the inferior wall of the right inferior pulmonary vein; and lower level (C and F), below the inferior wall of the right inferior pulmonary vein. A score (from 0 to 3) is assigned to each zone based on the detected lung abnormalities: 0, no lung abnormalities; 1, interstitial infiltrates; 2, interstitial and alveolar infiltrates (interstitial pre-dominance); and 3, interstitial and alveolar infiltrates (alveolar predominance). The overall CXR score is the sum of points from the six lung zones with a range from 0 to 18.	Days 0, 6, 14, 21, and 28
Secondary	Change in inflammatory parameters in CP-receiving patients	Measurement of C-reactive protein (reference: <5.0 mg/L); neutrophil/lymphocyte ratio reference range: male, 0.43~2.75; female,0.37~2.87), procalcitonin (reference: <0.15 ng/mL), and IL-6 (reference range: (5-15 pg/ml) levels in CP-receiving patients	Days 0, 6, 14, 21, and 28
Secondary	Change in coagulation parameters in CP-receiving patients	Measurement of D-Dimer (reference: <0.5 mcg/mL) and prothrombin time (reference range: 11.0-13.6) seconds in CP-receiving patients	Days 0, 6, 14, 21, and 28
Secondary	Change in viral load in CP-receiving patients	Measurement of viral load by nasopharyngeal swab PCR in CP-receiving patients. Additional test on day 3 will be performed to identify the early clearance of the virus.	Days 0, 3, 6, 14, 21, and 28
Secondary	Changes in anti-SARS-CoV-2 antibody levels in CP-receiving patients	Plasma/serum titer of anti-SARS-CoV-2 antibodies in CP-receiving patients by the plaque reduction neutralization test or enzyme-linked immunosorbent assay. Additional test on day 3 will be performed to identify the early changes in antibody levels.	Days 0, 3, 6, 14, 21, and 28
Secondary	Systemic organ involvement in patients receiving CP treatment	Systemic organ involvement measured by the Sequential Organ Failure Assessment (SOFA) score. It is used for calculation of both the number and the severity of organ dysfunction in six organ systems (respiratory, coagulatory, liver, cardiovascular, renal, and neurologic), and can measure individual or aggregate organ dysfunction. Each organ system is assigned a point value from 0 (normal) to 4 (high degree of dysfunction/failure). The SOFA score ranges from 0 to 24. An increasing or unchanged SOFA score is associated with a higher mortality rate than patients with a decreasing score.	Days 0, 6, 14, 21, and 28
Secondary	Time to resolution of symptoms in patients receiving CP treatment	Patients whose symptoms are not resolved and remain in the hospital at the end of study period will be censored on the study's end date, while those are lost to follow-up will be censored on the last encounter date.	Days 0, 6, 14, 21, and 28
Secondary	Treatment-related adverse events (AEs) and serious adverse events (SAEs)	Number of participants with treatment-related adverse events as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.	From the initiation of CP treatment until hospital discharge or death, up to 28 days
Secondary	Impact of anti-SARS-CoV-2 antibody levels in donors on the efficacy of CP therapy in CP-receiving patients	Correlation between anti-SARS-CoV-2 antibody levels in donors and the clinical status of CP-receiving patients according to the modified WHO 6-point ordinal scale	Days 0, 6, 14, 21, and 28
Secondary	Impact of anti-SARS-CoV-2 antibody levels in donors on the viral clearance in CP-receiving patients	Correlation between anti-SARS-CoV-2 antibody levels in the donors and the viral clearance in CP-receiving patients. Additional test on day 3 will be performed to identify the early clearance of the virus.	Days 0, 3, 6, 14, 21, and 28

External Links

•   Clinical management of COVID-19: Interim guidance
•   Convalescent Plasma for COVID-19. A randomized clinical trial
•   Coronavirus Disease 2019 (COVID-19) Treatment Guidelines
•   NCI Common Terminology Criteria for Adverse Events (CTCAE)
•   Recommendations for Investigational COVID-19 Convalescent Plasma
•   WHO R & D. COVID-19 Therapeutic Trial Synopsis