Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomised Clinical Trial

Setting: Seven medical centres in China in the Hubei province.

Design: February 14, 2020, to April 1, 2020. Patients were randomly assigned via computer-generated random numbering (1:1) to receive standard treatment combined with convalescent plasma transfusion or standard treatment alone. Randomisation was stratified based on whether the infection was “severe” or “life-threatening”.

Patients:

Included: Patients with COVID-19 diagnosis based on nasopharyngeal polymerase chain reaction (PCR) testing. Patients were randomised within 72 hours of testing positive; pneumonia confirmed by chest imaging; clinical symptoms were meeting criteria for “severe” or “life-threatening” COVID-19.

Severe: Respiratory rate ≥30 breaths/min in resting-state; oxygen saturation of 93% or less on room air; or arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FIO2) of 300 or less.

Life-threatening: Respiratory failure requiring mechanical ventilation; shock; or other organ failures (apart from the lung) requiring intensive care unit (ICU) monitoring

Excluded: 1) pregnancy or lactation; (2) immunoglobulin allergy; (3) IgA deficiency; (4) pre-existing comorbidity that could increase the risk of thrombosis; (5) not expected to survive longer than 24 hours; (6) disseminated intravascular coagulation; (7) severe septic shock; (8) PaO2/ FIO2 of less than 100; (9) severe congestive heart failure; (10) detection of high titer of S protein–RBD-specific (receptor binding domain) IgG antibody (≥1:640)

Intervention: Subjects were 18–55 years old; plasma collected from donors who had COVID-19 and out of the hospital for at least two weeks. Two negative PCR test results from nasopharyngeal swabs at least 24 hours apart prior to hospital discharge. Prepared as FFP. S-RBD–specific IgG antibody (IgG antibody to the receptor-binding domain of the spike protein). Plasma with IgG titer of at least 1:640 was used for therapy. Dose: 4–13 ml/kg (300 to 900 ml). Median volume 200 mL (IQR, 200-300 mL). Single-dose in 96% of patients.

Control: Standard supportive care

Common: Antiviral medications, antibacterial medications, steroids, human immunoglobulin, Chinese herbal medicines

One hundred patients in each group, for an 8-d difference in improvement by 2 points. Assuming 20 days for improvement in the control group, and that 60% of patients will improve.

Results

Terminated early, after enrolling 103 (against the planned 200) patients as no more cases in Wuhan.

Severe: 23 vs. 22 (one patient withdrew from the plasma arm)

Life-threatening: 29 vs. 29 (one patient had plasma in the control arm)

The median interval between the onset of symptoms and randomisation was 30 days (IQR, 20-39 days)

Primary outcome: Clinical improvement as defined as patient discharge or a reduction of 2 points on a 6-point disease severity scale.

1. Hospital discharge
2. Hospitalised, not supplemental oxygen
3. Supplemental oxygen
4. HFNC or NIV
5. Invasive ventilation or ECMO
6. Death

Overall: 27/52 (51.9%) vs. 22/51 (43.1%) in the control group. (difference, 8.8% [95% CI, −10.4% to 28.0%]; HR, 1.40 [95% CI, 0.79-2.49]; P = .26). Per-protocol or intention to treat analysis were not different.

Severe disease: the primary outcome occurred in 21/23 (91.3%) vs 15/22 (68.2%) (HR, 2.15 [95% CI, 1.07-4.32]; P = .03)

Life-threatening disease: 6/29 (20.7%) vs 7/29 (24.1%) (HR, 0.88 [95% CI, 0.30- 2.63]; P = .83)

Secondary outcomes:

1. 28-d mortality: 8/51 (15.7%) vs. 12/50 (24.0%) in the control group; OR, 0.65 [95% CI, 0.29- 1.46]; P = .30).
2. Duration of hospitalisation: Time from randomisation to discharge, Time from admission to discharge, 28-day discharge rates
3. Negative conversion of nasopharyngeal PCR assessed at 24, 48, and 72 hours.

Post hoc analysis: Improvement rates at 7, 14, and 28 days. No difference except clinical improvement rate at 14 days in patients with “severe” compared to “life-threatening” disease.

Adverse events

Two patients in the plasma group. One patient suffered probable non-severe allergic transfusion reaction and possible non-severe febrile nonhemolytic transfusion reaction. The other with life-threatening disease, developed shortness of breath and cyanosis, within 6 hours of transfusion. The patient was given dexamethasone, aminophylline, and other supportive care immediately and gradually improved after 2 hours

Strengths – 

1. RCT
2. Effect size – useful for future sample size calculations
3. Assessed the effect on viral clearance along with clinical improvement

Limitations – 

1. Underpowered – Stopped early

2. Unblinded

3. Median age – 70 years and time to randomisation from symptom onset – 30 days

4. Small sample size

5. Control group – no protocolised treatment

6. Logistic issues in determining optimal “curative” dose of plasma

Summary – 

Very useful study

Need further large RCT with robust design such as protocolised treatment, early initiation of therapy in the disease process and inclusion of younger patients.

Also, it will be useful to establish a synergistic effect with other treatments such as Remdesivir.