Convalescent Plasma as Adjunct Therapy for COVID-19

Phase 2

• Conditions: COVID-19
• Interventions: Biological: Convalescent plasma treatment

• Registration Number: NCT04873414
• Lead Sponsor: 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.

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.

Study Timeline

• Study Start: 2020-12-01
• Study First Submitted: 2021-04-26
• Status Verified: 2021-05
• Study First Submitted QC: 2021-05-03
• Study First Posted: 2021-05-05
• Last Update Submitted: 2021-05-31
• Last Update Posted: 2021-06-02
• Primary Completion: 2021-10-30
• Study Completion: 2021-12-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 364

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment group	Convalescent plasma treatment	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

Primary Outcome Measures

Name	Time	Method
The mortality in COVID-19 patients treated with convalescent plasma	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

Name	Time	Method
Change in clinical status category in CP-receiving patients	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
Duration of hospitalization	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
Duration of mechanical ventilation	From the initiation of CP treatment until hospital discharge or death, up to 28 days	Number of days in patients with ventilatory support
Duration of ICU stay	From the initiation of CP treatment until hospital discharge or death, up to 28 days	Number of days from entry to release from ICU
Change in lung image radiography in CP-receiving patients	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.
Change in inflammatory parameters in CP-receiving patients	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
Change in coagulation parameters in CP-receiving patients	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
Change in viral load in CP-receiving patients	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.
Changes in anti-SARS-CoV-2 antibody levels in CP-receiving patients	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.
Systemic organ involvement in patients receiving CP treatment	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.
Time to resolution of symptoms in patients receiving CP treatment	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.
Treatment-related adverse events (AEs) and serious adverse events (SAEs)	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.
Impact of anti-SARS-CoV-2 antibody levels in donors on the efficacy of CP therapy in CP-receiving patients	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
Impact of anti-SARS-CoV-2 antibody levels in donors on the viral clearance in CP-receiving patients	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.

Trial Locations

Locations (28)

Aceh Tamiang Hospital; 🇮🇩 Aceh Tamiang, Aceh, Indonesia

Udayana University Hospital; 🇮🇩 Denpasar, Bali, Indonesia

Dr. Wongsonegoro Regency Hospital; 🇮🇩 Semarang, Central Java, Indonesia

Sidoarjo Regency Hospital; 🇮🇩 Sidoarjo, East Java, Indonesia

Dr Ramelan Navy Hospital; 🇮🇩 Surabaya, East Java, Indonesia

Waluyo Jati Kraksaan Regency Hospital; 🇮🇩 Probolinggo, East Java, Indonesia

Dr. Soetomo Hospital; 🇮🇩 Surabaya, East Java, Indonesia

Emergency Hospital for COVID-19 - Wisma Atlet Kemayoran; 🇮🇩 Jakarta Pusat, Jakarta, Indonesia

Prof. Dr. R.D. Kandou Hospital; 🇮🇩 Manado, North 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

Dr. Suyoto Pusrehab Kemenhan Hospital; 🇮🇩 Jakarta, Indonesia

Dadi Hospital; 🇮🇩 Makassar, South Sulawesi, Indonesia

Dr. Mohammad Hoesin Central Hospital; 🇮🇩 Palembang, South Sumatra, Indonesia

dr. Cipto Mangunkusumo National Central General Hospital; 🇮🇩 Jakarta, Indonesia

YARSI Hospital; 🇮🇩 Jakarta, Indonesia

Gatot Soebroto Central Army Hospital; 🇮🇩 Jakarta Pusat, Indonesia

Persahabatan Central hospital; 🇮🇩 Jakarta, Indonesia

Fatmawati Central Hospital; 🇮🇩 Jakarta, Indonesia

Prof. Dr. Sulianti Saroso Infectious Disease Hospital; 🇮🇩 Jakarta, Indonesia

University Of Indonesia Hospital (RSUI); 🇮🇩 Jakarta, Indonesia

Sanglah Central Hospital; 🇮🇩 Denpasar, Bali, Indonesia

Pasar Minggu Hospital; 🇮🇩 Jakarta, DKI, Indonesia

Dr. Haryoto Regency Hospital; 🇮🇩 Lumajang, East Java, Indonesia

RSD Gunung Jati; 🇮🇩 Cirebon, West Java, Indonesia

Dr. Hasan Sadikin Central Hospital; 🇮🇩 Bandung, West Java, Indonesia

Dr. Soeradji Tirtonegoro Hospital; 🇮🇩 Klaten, Central Java, Indonesia