A Multi-Center, Open-Label, Randomized Controlled Trial to Evaluate the Efficacy of Convalescent Plasma Therapy for Coronavirus Disease 2019: A Trial Protocol (COVIPLA-RCT)
2.1. Trial Inclusion Criteria
- A patient who, or whose legal representative, has provided written consent for the participation of the patient in the trial.
- A hospitalized patient with a confirmed diagnosis of COVID-19 based on a reverse transcription-PCR (RT-PCR) or loop-mediated isothermal amplification (LAMP) assay, antigen test, or other means.
- A patient who met all of the following criteria upon admission to a hospital:
- Patients who can begin receiving study treatment within 5 d after onset.
- Patients with SpO2 ≥ 95% on room air.
- Patients aged ≥ 40 years or having at least one of the following underlying diseases: renal impairment, chronic obstructive pulmonary disease, cardiovascular disease, cerebrovascular disorder, malignant tumor, obesity, diabetes mellitus, hypertension, and an immunosuppressive state.
- A patient aged at least 20 years at the time of informed consent.
- A patient who has been infected with SARS-CoV-2 for the first time.
- Our inclusion criteria have been chosen to ensure that the patients are appropriately and ethically included in our study, have a milder form of the disease, are in the appropriate age group, and do not already have SARS-CoV-2 antibodies at the point of enrollment.
2.2. Trial Exclusion Criteria
- A patient who is pregnant or breastfeeding.
- A patient who would not undergo a blood transfusion because of their religious beliefs.
- A patient who is participating in an intervention study for the treatment of COVID-19.
- A patient who has been vaccinated against SARS-CoV-2.
- A patient who has already undergone convalescent plasma transfusion.
- A patient with a history of allergy to a blood product.
- A patient with a deficiency in a plasma protein, such as IgA.
- A patient with New York Heart Association class III or IV heart failure.
- A patient whom the principal investigator, investigator, or sub-investigator judged to be ineligible for other reasons.
- Grade A: Potent neutralizing activity. The total neutralizing capacity of 200 mL of plasma is ≥18,000 NU (Supplementary Information S2).
- Grade B: Moderate neutralizing activity. The total neutralizing capacity of 200 mL of plasma is ≥9000 but <18,000 NU.
- Grade C: Mild neutralizing activity. The total neutralizing capacity of 200 mL of plasma is ≥4500 but <9000 NU.
- Grade X: Slight neutralizing activity. The total neutralizing capacity of 200 mL of plasma is <4500 NU.
2.4. Randomization and Blinding
- Age (≥60 or <60 years old).
- The number of days from the day of onset (set as day 0) until the scheduled day of convalescent plasma transfusion (≤3 or ≥4 d).
- Trial site.
2.5. Primary and Secondary Endpoints
2.6. Dosage and Administration
2.7. Treatment and Observation Periods (Including Follow-Up)
2.8. Observation and Test Parameters
- Characteristics of each subject:
- Date of birth (age), sex, nationality/race, smoking history, complications, prior medical history, history of the current disease, and pregnancy status (premenopausal female subjects should undergo a pregnancy test).
- Information on hospitalization (dates of admission and discharge).
- Body height and weight.
- Background data related to COVID-19 and overseas travel history.
- Physical findings:
- Status of supplemental oxygen and the use of mechanical ventilation.
- Physical conditions will be examined by inspection, palpation, auscultation, and percussion.
- Vital signs:
- Level of consciousness
- Body temperature (°C)
- Blood pressure (mmHg)
- Pulse rate (beats/min)
- Respiratory rate (breaths/min)
- SpO2 (%)
- Clinical condition:The clinical condition of each subject will be assessed according to the following:
- Hospitalization and the use of invasive mechanical ventilation or ECMO.
- Hospitalization and the use of noninvasive mechanical ventilation or a high-flow oxygen device.
- Hospitalization and supplemental oxygen requirement.
- Not requiring hospitalization or supplemental oxygen but requiring the continuation of treatment (for COVID-19-related or other diseases).
- Not requiring hospitalization, supplemental oxygen, or the continuation of treatment.
- Not requiring hospitalization, but requiring the limitation of activities and/or oxygen therapy at home.
- Not requiring hospitalization or the limitation of activities.
- Laboratory tests (Table 3)
- Plain chest X-ray
2.9. Study Schedule
2.10. Participation and Follow-Up Periods
2.11. Potential Benefits and Risks of the Study Drug
2.12. Sample Size Calculation
2.13. Statistical Analysis Plan
2.14. Safety Evaluation
2.15. Data Monitoring Committee
- Changes over time in the treatment regimen in both treatment groups
- Relationship between the quality of the study drug (Grades A to C) and safety
2.16. Data Management Team
Limitations of the Trial
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
|COVID-19||coronavirus disease 2019|
|ECMO||extracorporeal membrane oxygenation|
|EDC||Electronic Data Capture|
|MERS||Middle East respiratory syndrome.|
|NIH||National Institute of Health|
|RCTs||randomized controlled trials|
|SARS||severe acute respiratory syndrome|
|WHO||World Health Organization|
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|Objective||Endpoint||Rationale for the Endpoint|
|Prevention of mechanical ventilation or death.||Use of mechanical ventilation or death by days 14 and 28.||Prognosis is an endpoint that is not subjective.|
|Prevention of death.||Mortality on days 14 and 28.||Prognosis is an endpoint that is not subjective.|
|Prevention of the need for supplemental oxygen use.||Percentage of subjects who used oxygen on days 3, 5, 7, 14, and 28.||It is an endpoint that is not subjective.|
|To assess the shortening of the duration of symptoms (the time to clinical improvement).||Clinical improvement is defined as the first day a subject meets one of the three categories on the ordinal scale shown below:||Clinical improvement is related to efficacy.|
|To assess clinical improvement on days 3, 5, 7, 14, and 28 in subjects given the convalescent plasma.||Clinical improvement on days 3, 5, 7, 14, and 28 (on an 8-point scale)||Clinical improvement is related to efficacy.|
|Time to improvement on the National Early Warning Score, UK (NEWS)||Time to discharge from the hospital or the maintenance of NEWS ≤2 for 24 h (whichever occurs first)|
NEWS on days 3, 5, 7, 14, and 28.
|Clinical improvement is related to efficacy.|
|Decrease in the viral load in the convalescent plasma group after convalescent plasma transfusion.||Time-weighted average change and the numerical change in the SARS-CoV-2 virus load in nasopharyngeal swabs from day 0 to each day of assessment.||Change in the viral load has been used as the index of the therapeutic effect in many studies.|
|To assess safety after convalescent plasma transfusion.||Occurrence of adverse events.||It is necessary to evaluate safety.|
|To screen and identify variants.||Determine if variants are present in nasopharyngeal swab samples on day 0||Variants are related to efficacy because it has been reported that variants may reduce the antiviral activity of neutralizing antibodies.|
(Day of Transfusion) i
|Day 1 (1 d after Transfusion)||Day 3 (3 d after Transfusion)||Day 5 (5 d after Transfusion)||Day 7 (7 d after Transfusion)||Day 14 (14 d after Transfusion)||Day 21 (21 d after Transfusion)||Day 28 (28 d after Transfusion)||Day 90 (90 d after Transfusion)||Discontinuation of the Study|
|3 h after Start of Trans-Fusion j|
|Acceptable time window a||−3 to 0||Reference day||+1||±1||±1||±1||±3||±3||±3||+30||–|
|Confirmation of eligibility||X k|
|Registration and randomization of a subject||X|
|Characteristics of a subject||X k|
|Plasma transfusion h||X||X b|
|Vital signs d and clinical condition c||X||X h||Once daily during hospitalization and days 3, 5, 7, 14, 21, and 28 after discharge||X|
|Physical findings d||X k||X||X h||X||X||X||X||X||X||X||X|
|Pregnancy test l||X k|
|Collection of swabs (2 sticks) m||X||X||X||X||X||X||X||X||X e|
|Blood test (biochemistry, complete blood count, and coagulation) m||X k||X||X||X||X||X||X||X|
|Blood test (blood type)||X k|
|Blood test (cross-match) h||X|
|Blood test (infection screening) f||X k|
|Blood test (post-transfusion infection test) g,h||X|
|Storage of plasma m||X||X||X||X||X||X||X||X|
|Storage of serum m||X||X||X||X||X||X||X||X|
|Radiography (chest X-ray)||X k|
|Concomitant drugs c||X||Every day during hospitalization and days 3, 5, 7, 14, 21, and 28 after discharge||X|
|Adverse events c||X h||Every day during hospitalization and days 3, 5, 7, 14, 21, and 28 after discharge||X h||X|
|Hematology||Hemoglobin, Hematocrit, White Blood Cell Count with Differential, and Platelet Count|
|Coagulation||APTT, PT-INR, and D-Dimer|
|Blood biochemistry||Albumin, AST, ALT, bilirubin, CRP, blood glucose, urea nitrogen, creatinine, LDH, creatine kinase, potassium, and sodium|
|Infection screening||HBsAg, HBsAb, HCVAb, HIV-1/2Ab, Syphilis-RPR/TPHA, and HTLV-1Ab.|
|Pregnancy test||Urine or blood (HCG)|
|Blood type and cross-match||Blood type: A/O/B/AB, Rh +/−; cross-match: compatible/incompatible|
|SARS-CoV-2 viral load||Nasopharyngeal swabs|
|Samples for storage||Serum (1.5 mL) and plasma (1.5 mL)|
|Post-transfusion infection test||HBV-DNA quantification, HCV core protein, and HIV-1/2Ab|
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Tomita, N.; Saito, S.; Terada-Hirashima, J.; Mikami, A.; Uemura, Y.; Kutsuna, S.; Nomoto, H.; Fujisawa, K.; Nagashima, M.; Terada, M.; et al. A Multi-Center, Open-Label, Randomized Controlled Trial to Evaluate the Efficacy of Convalescent Plasma Therapy for Coronavirus Disease 2019: A Trial Protocol (COVIPLA-RCT). Life 2022, 12, 856. https://doi.org/10.3390/life12060856
Tomita N, Saito S, Terada-Hirashima J, Mikami A, Uemura Y, Kutsuna S, Nomoto H, Fujisawa K, Nagashima M, Terada M, et al. A Multi-Center, Open-Label, Randomized Controlled Trial to Evaluate the Efficacy of Convalescent Plasma Therapy for Coronavirus Disease 2019: A Trial Protocol (COVIPLA-RCT). Life. 2022; 12(6):856. https://doi.org/10.3390/life12060856Chicago/Turabian Style
Tomita, Noriko, Sho Saito, Junko Terada-Hirashima, Ayako Mikami, Yukari Uemura, Satoshi Kutsuna, Hidetoshi Nomoto, Kyoko Fujisawa, Maki Nagashima, Mari Terada, and et al. 2022. "A Multi-Center, Open-Label, Randomized Controlled Trial to Evaluate the Efficacy of Convalescent Plasma Therapy for Coronavirus Disease 2019: A Trial Protocol (COVIPLA-RCT)" Life 12, no. 6: 856. https://doi.org/10.3390/life12060856