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Convalescent Plasma as Adjunct Therapy for COVID-19 (PlaSenTer)

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ClinicalTrials.gov Identifier: NCT04873414
Recruitment Status : Recruiting
First Posted : May 5, 2021
Last Update Posted : June 2, 2021
Sponsor:
Collaborators:
Indonesian Red Cross
Eijkman Institute for Molecular Biology
Information provided by (Responsible Party):
National Institute of Health Research and Development, Ministry of Health Republic of Indonesia

Brief 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.


Condition or disease Intervention/treatment Phase
COVID-19 Biological: Convalescent plasma treatment Phase 2 Phase 3

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 364 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clinical Trial of Convalescent Plasma Administration as Adjunct Therapy for COVID-19 (Uji Klinik Pemberian Plasma Konvalesen Sebagai Terapi Tambahan COVID-19)
Actual Study Start Date : December 1, 2020
Estimated Primary Completion Date : October 30, 2021
Estimated Study Completion Date : December 31, 2021

Arm Intervention/treatment
Experimental: Treatment group
Subjects in the Treatment Group are given 200 ml of Plasma collected from Convalescent Patients recovered from COVID-19 at two-day intervals in addition to standard supportive treatment
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.

No Intervention: Control group
Subjects in the Control Group are given standard supportive treatment



Primary Outcome Measures :
  1. The mortality in COVID-19 patients treated with convalescent plasma [ Time Frame: From the initiation of CP treatment until hospital discharge or death, up to 28 days ]
    Number of deaths from the initiation of CP treatment until hospital discharge or death.


Secondary Outcome Measures :
  1. Change in clinical status category in CP-receiving patients [ Time Frame: From the initiation of CP treatment until hospital discharge or death, up to 28 days ]
    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

  2. Duration of hospitalization [ Time Frame: From admisstion until hospital discharge or death, up to 28 days ]
    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

  3. Duration of mechanical ventilation [ Time Frame: From the initiation of CP treatment until hospital discharge or death, up to 28 days ]
    Number of days in patients with ventilatory support

  4. Duration of ICU stay [ Time Frame: From the initiation of CP treatment until hospital discharge or death, up to 28 days ]
    Number of days from entry to release from ICU

  5. Change in lung image radiography in CP-receiving patients [ Time Frame: Days 0, 6, 14, 21, and 28 ]
    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.

  6. Change in inflammatory parameters in CP-receiving patients [ Time Frame: Days 0, 6, 14, 21, and 28 ]
    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

  7. Change in coagulation parameters in CP-receiving patients [ Time Frame: Days 0, 6, 14, 21, and 28 ]
    Measurement of D-Dimer (reference: <0.5 mcg/mL) and prothrombin time (reference range: 11.0-13.6) seconds in CP-receiving patients

  8. Change in viral load in CP-receiving patients [ Time Frame: Days 0, 3, 6, 14, 21, and 28 ]
    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.

  9. Changes in anti-SARS-CoV-2 antibody levels in CP-receiving patients [ Time Frame: Days 0, 3, 6, 14, 21, and 28 ]
    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.

  10. Systemic organ involvement in patients receiving CP treatment [ Time Frame: Days 0, 6, 14, 21, and 28 ]
    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.

  11. Time to resolution of symptoms in patients receiving CP treatment [ Time Frame: Days 0, 6, 14, 21, and 28 ]
    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.

  12. Treatment-related adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: From the initiation of CP treatment until hospital discharge or death, up to 28 days ]
    Number of participants with treatment-related adverse events as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

  13. Impact of anti-SARS-CoV-2 antibody levels in donors on the efficacy of CP therapy in CP-receiving patients [ Time Frame: Days 0, 6, 14, 21, and 28 ]
    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

  14. Impact of anti-SARS-CoV-2 antibody levels in donors on the viral clearance in CP-receiving patients [ Time Frame: Days 0, 3, 6, 14, 21, and 28 ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04873414


Contacts
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Contact: Muhammad Karyana, MD, MKes 062816789813 mkaryana@gmail.com
Contact: Retna M Indah, MD, MPH 0628990222987 retnaindah.sugiyono@ina-respond.net

Locations
Show Show 28 study locations
Sponsors and Collaborators
National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
Indonesian Red Cross
Eijkman Institute for Molecular Biology
Investigators
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Principal Investigator: David H Muljono, MD, PhD. Eijkman Institute for Molecular Biology
Principal Investigator: Irmansyah, MD, PhD National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
Study Director: Sri Idaiani, MD, PhD National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
Study Director: Tetra Fajarwati, MD,PhD National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
Additional Information:
Publications:
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.

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Responsible Party: National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
ClinicalTrials.gov Identifier: NCT04873414    
Other Study ID Numbers: COVID-CT002
First Posted: May 5, 2021    Key Record Dates
Last Update Posted: June 2, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The original datasets used for this study are not publicly available due to the existing regulation, and only can be shared upon the approval of the Sponsor on behalf of the Ministry of Health.
Supporting Materials: Study Protocol
Time Frame: January 1 - December 31, 2021
Access Criteria: The study protocol and and raw data are only shared to the ClinicalTrials.gov and/or Journal Reviewers.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institute of Health Research and Development, Ministry of Health Republic of Indonesia:
COVID-19
Moderate
Severe
Convalescent Plasma
Indonesia
Additional relevant MeSH terms:
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COVID-19
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases