Clinical trial NCT04873414: Convalescent Plasma as Adjunct Therapy for COVID-19
Official title: Clinical Trial of Convalescent Plasma Administration as Adjunct Therapy for COVID-19 (Uji Klinik Pemberian Plasma Konvalesen Sebagai Terapi Tambahan COVID-19)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: COVID-19
Keywords: COVID-19
Moderate
Severe
Convalescent Plasma
Indonesia
Lead sponsor: National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
Sponsor class: OTHER
Collaborators: name: Indonesian Red Cross
name: Eijkman Institute for Molecular Biology
First posted: 2021-05-05
Enrollment: 364
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: The mortality in COVID-19 patients treated with convalescent plasma
timeFrame: From the initiation of CP treatment until hospital discharge or death, up to 28 days
Secondary outcomes:
measure: Change in clinical status category in CP-receiving patients
timeFrame: From the initiation of CP treatment until hospital discharge or death, up to 28 days
measure: Duration of hospitalization
timeFrame: From admisstion until hospital discharge or death, up to 28 days
measure: Duration of mechanical ventilation
timeFrame: From the initiation of CP treatment until hospital discharge or death, up to 28 days
measure: Duration of ICU stay
timeFrame: From the initiation of CP treatment until hospital discharge or death, up to 28 days
measure: Change in lung image radiography in CP-receiving patients
timeFrame: Days 0, 6, 14, 21, and 28
measure: Change in inflammatory parameters in CP-receiving patients
timeFrame: Days 0, 6, 14, 21, and 28
measure: Change in coagulation parameters in CP-receiving patients
timeFrame: Days 0, 6, 14, 21, and 28
measure: Change in viral load in CP-receiving patients
timeFrame: Days 0, 3, 6, 14, 21, and 28
measure: Changes in anti-SARS-CoV-2 antibody levels in CP-receiving patients
timeFrame: Days 0, 3, 6, 14, 21, and 28
measure: Systemic organ involvement in patients receiving CP treatment
timeFrame: Days 0, 6, 14, 21, and 28
measure: Time to resolution of symptoms in patients receiving CP treatment
timeFrame: Days 0, 6, 14, 21, and 28
measure: Treatment-related adverse events (AEs) and serious adverse events (SAEs)
timeFrame: From the initiation of CP treatment until hospital discharge or death, up to 28 days
measure: Impact of anti-SARS-CoV-2 antibody levels in donors on the efficacy of CP therapy in CP-receiving patients
timeFrame: Days 0, 6, 14, 21, and 28
measure: Impact of anti-SARS-CoV-2 antibody levels in donors on the viral clearance in CP-receiving patients
timeFrame: Days 0, 3, 6, 14, 21, and 28
Other outcomes:
Locations:
city: Aceh Tamiang
country: Indonesia
facility: Aceh Tamiang Hospital
state: Aceh
city: Denpasar
country: Indonesia
facility: Sanglah Central Hospital
state: Bali
city: Denpasar
country: Indonesia
facility: Udayana University Hospital
state: Bali
city: Klaten
country: Indonesia
facility: Dr. Soeradji Tirtonegoro Hospital
state: Central Java
city: Semarang
country: Indonesia
facility: Dr. Wongsonegoro Regency Hospital
state: Central Java
city: Jakarta
country: Indonesia
facility: Pasar Minggu Hospital
state: DKI
city: Lumajang
country: Indonesia
facility: Dr. Haryoto Regency Hospital
state: East Java
city: Probolinggo
country: Indonesia
facility: Waluyo Jati Kraksaan Regency Hospital
state: East Java
city: Sidoarjo
country: Indonesia
facility: Sidoarjo Regency Hospital
state: East Java
city: Surabaya
country: Indonesia
facility: Dr Ramelan Navy Hospital
state: East Java
city: Surabaya
country: Indonesia
facility: Dr. Soetomo Hospital
state: East Java
city: Jakarta Pusat
country: Indonesia
facility: Emergency Hospital for COVID-19 - Wisma Atlet Kemayoran
state: Jakarta
city: Manado
country: Indonesia
facility: Prof. Dr. R.D. Kandou Hospital
state: North Sulawesi
city: Makassar
country: Indonesia
facility: Dr. Tadjuddin Chalid Hospital
state: Souh Sulawesi
city: Makassar
country: Indonesia
facility: Dr. Wahidin Sudirohusodo Central Hospital
state: South Sulawesi
city: Makassar
country: Indonesia
facility: Hasanuddin University Hospital
state: South Sulawesi
city: Makassar
country: Indonesia
facility: Dadi Hospital
state: South Sulawesi
city: Palembang
country: Indonesia
facility: Dr. Mohammad Hoesin Central Hospital
state: South Sumatra
city: Bandung
country: Indonesia
facility: Dr. Hasan Sadikin Central Hospital
state: West Java
city: Cirebon
country: Indonesia
facility: RSD Gunung Jati
state: West Java
city: Jakarta Pusat
country: Indonesia
facility: Gatot Soebroto Central Army Hospital
city: Jakarta
country: Indonesia
facility: dr. Cipto Mangunkusumo National Central General Hospital
city: Jakarta
country: Indonesia
facility: YARSI Hospital
city: Jakarta
country: Indonesia
facility: Dr. Suyoto Pusrehab Kemenhan Hospital
city: Jakarta
country: Indonesia
facility: Persahabatan Central hospital
city: Jakarta
country: Indonesia
facility: Fatmawati Central Hospital
city: Jakarta
country: Indonesia
facility: Prof. Dr. Sulianti Saroso Infectious Disease Hospital
city: Jakarta
country: Indonesia
facility: University Of Indonesia Hospital (RSUI)
Study officials:
affiliation: Eijkman Institute for Molecular Biology
name: David H Muljono, MD, PhD.
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
name: Irmansyah, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
name: Sri Idaiani, MD, PhD
role: STUDY_DIRECTOR
affiliation: National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
name: Tetra Fajarwati, MD,PhD
role: STUDY_DIRECTOR
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