Double-blinded, randomised, placebo-controlled trial of convalescent plasma for COVID-19: analyses by neutralising antibodies homologous to recipients’ variants

Figures & data

Figure 1. Study design.

Abbreviations: COVID-19 = Coronavirus Disease, CP = convalescent plasma, AE = adverse event, SAE = Serious adverse event.

¹One of these participants was administered corticosteroids before the study drug infusion but was given the infusion by mistake. A decision to exclude was made the same day.

Table 1. Baseline characteristics.

Participant characteristics^a	Randomised groups				Ad hoc groups^b
	Placebo	LCP	HCP	All	hLCP	hHCP
Number of participants, n	20	19	18	57	23	14
Female gender, n (%)	10 (50.0)	9 (47.4)	9 (47.4)	27 (47.4)	8 (34.8)	9 (64.3)
Age years, mean (SD)	54.3 (16.5)	50.6 (17.1)	50.0 (13.1)	51.7 (15.5)	52.3 (16.0)	54.1 (16.9)
BMI kg/m^2, mean(SD)	28.8 (4.8)	28.2 (5.4)	30.1 (6.2)	29.0 (5.4)	28.5 (5.7)	30.0 (6.0)
Fever ≥38.5 °C, n (%)	11 (55.0)	9 (47.4)	10 (55.6)	30(52.6)	15 (65.2)	4 (28.6)
CRP ≥100 mg/l, n (%)	2 (10.0)	3 (15.8)	3 (17.6)^c	8 (14.3)^c	3 (13.0)^c	3 (23.1)
Lymphocytes <0.50 10^9/l, n (%)^d	0 (0)	1 (5.6)	1 (6.7)	2 (3.9)	2 (10.0)	0 (0)
Any COVID-19 vaccination, n (%)	5 (25.0)	3 (15.8)	4 (22.2)	12 (21.1)	4 (17.4)	3 (21.4)
Virus variant, n (%)
Wuhan-like ancestral strain	0 (0)	2 (10.5)	0 (0)	2 (3.5)	1 (4.3)	1 (7.1)
Alpha	9 (45.0)	7 (36.8)	8 (44.4)	24 (42.1)	9 (39.1)	6 (42.9)
Beta	3 (15.0)	3 (15.8)	3 (16.7)	9 (15.8)	5 (21.7)	1 (7.1)
Delta	7 (35.0)	7 (36.8)	7 (38.9)	21 (36.8)	8 (34.8)	6 (42.9)
Omicron	1 (5.0)	0 (0)	0 (0)	1 (1.8)	0 (0)	0 (0)
CP NAb titre, median (IQR)	NA	80 (40–80)	320 (160–640)	NA	80 (40–160)	320 (80–800)
CP homologous NAb titre, median (IQR)	NA	40 (40–80)	240 (80–1280)	NA	40 (40–80)	320 (160–2240)
Symptom duration, days, median (IQR)	8 (7–9.75)	8 (6–9)	8 (5.75–9.25)	8 (6.5–9)	8 (6–9)	9 (7.75–9.25)
Delay from ER to infusion, days, median (IQR)^f	1 (1–2)	1 (1–2)	1 (1–1.25)	1 (1–2)	1 (1–2)	1 (1–2)
Systemic antibacterial medication, n (%)^g	11 (55.0)	14 (73.7)	6 (33.3)	31 (54.4)	15 (65.2)	5 (35.7)
Infusion on day of recruitment,n (%)	11 (55.0)	11 (57.9)	13 (72.2)	35 (61.4)	16 (65.2)	9 (64.3)
Diabetes, n (%)	2 (10.0)	2 (10.5)	3 (16.7)	7 (12.3)	3 (13.0)	2 (14.3)
Asthma or COPD, n (%)	3 (15.0)	7 (36.8)	3 (16.7)	13 (22.8)	6 (26.1)	4 (28.6)
Current smoker, n (%)	2 (10.5)	1 (5.6)	2 (11.1)	5 (9.1)	1 (4.5)	2 (14.3)
Dyspnoea or tightness in chest, n (%)^h	8 (42.1)	6 (33.3)	8 (44.4)	22 (40.0)	11 (50.0)	3 (21.4)
Oxygen therapy, n (%)^i	13 (65.0)	8 (42.1)	6 (33.3)	27(47.4)	11 (47.8)	3 (21.4)
Chest X-ray consistent with infection, n (%)	11 (57.9)^c	16 (84.2)	12 (70.6)^c	39 (70.9)	19 (82.6)	9 (69.2)^c
Seropositive, n (%)^j	8 (40.0)	9 (47.4)	7 (38.99)	24 (42.1)	9 (39.1)	7 (50.0)

Abbreviations: LCP = low-titre convalescent plasma, HCP = high-titre convalescent plasma, hLCP = low-homologous titre convalescent plasma, hHCP = high-homologous titre convalescent plasma, BMI = body mass index, CRP = C-reactive protein, CP = Convalescent plasma, NAb = neutralising antibody, COPD = chronic obstructive pulmonary disease.

^a Baseline clinical parameters and laboratory values are from the day of, and prior to infusion. If laboratory values were not taken on the day of the infusion, they are from the previous day. Symptom duration counted from the infusion day.

^b Patients regrouped based on the CP neutralising antibody titre by pseudovirus neutralization assay against the variant infecting the patient. The columns placebo and all apply also to the ad hoc groups.

^c Data missing for one patient.

^d Not taken for two in the placebo group, three in the HCP and hHCP groups and for one in the LCP and hLCP groups.

^e Neutralising antibody titre against the virus variant infecting the patient as determined by pseudovirus neutralization assay.

^f Time in days between presenting in the hospital to the intervention.

^g The difference between randomised groups is significant (p = 0.048), but not in ad hoc grouping (p = 0.22), Pearson χ².

^h Reported by participants as one of the three most difficult symptoms.

ⁱ The difference was statistically significant between the ad hoc groups (p = 0.043), but not in the randomised groups (p = 0.13), Pearson χ².

^j Baseline seropositivity was defined as ≥1:20 titre in pseudovirus neutralization assay against any variant.

Table 2. Comparison of primary and secondary outcomes between randomised and ad hoc groups.

Endpoint	Randomised groups				Ad hoc groups^a
	Placebo n = 20	LCP n = 19	HCP n = 18	p-value	hLCP n = 23	hHCP n = 14	p-value
Serious adverse event, n (%)	1 (5.0)	3 (15.8)	1 (5.6)	0.51	4 (17.4)	0 (0.0)	0.28
Intubation, n (%)	2 (10.0)	0 (0.0)^b	1 (5.6)	0.77	1 (4.3)^b	0 (0.0)	0.77
Corticosteroids for COVID-19, n (%)	8 (40.0)	6 (31.6)	4 (22.2)	0.50	9 (39.1)	1 (7.1)	0.077
Death, n (%)	0 (0)	1 (4.3)	0 (0)	0.65	1 (4.3)	0 (0)	1.0
Hositalisation length (days), median (IQR)	4 (2.25–10.75)	4 (1.0–8.0)	3 (1.0–7.25)	0.60	5 (1.0–8.0)	3 (1.0–4.0)	0.17
ICU admission, n (%)	3 (15.0)	1 (5.3)	2 (11.1)	0.77	3 (13.0)	0 (0)	0.42
ICU days, mean (SD)^c	1.5 (4.6)	0.5 (2.3)	1.4 (4.2)	0.62	1.6 (4.2)	0 (0.0)	0.34
Ventilator days, mean (SD)^c	1.4 (4.5)	0 (0.0)	0.2 (0.9)	0.18	0.2 (0.8)	0 (0.0)	0.20
DVT or pulmonary embolism, n (%)	1 (5.0)	0 (0.0)	0 (0.0)	0.39	0 (0.0)	0 (0.0)	0.39
Worst COMRF score, n (%)				0.41			0.029
4= No oxygen therapy	6 (30.0)	8 (42.1)	10 (55.6)		8 (34.8)	10 (71.4)
5 = Oxygen by mask or prongs	12 (60.0)	8 (42.1)	6 (33.3)		10 (43.5)	4 (28.6)
6 = NIV or high flow nasal cannulae	0 (0)	2 (10.5))	1 (5.6)		3 (13.0)	0 (0)
7 = IMV pO2/FiO2 ≥ 150mmHg	0 (0)	0 (0)	1 (5.6)		1 (4.3)	0 (0)
8 = IMV pO2/FiO2 < 150mmHg	2 (10.0)	0 (0)	0 (0)		0 (0)	0 (0)
9 = ECMO	0 (0)	0 (0)	0 (0)		0 (0)	0 (0)
10 = Death	0 (0)	1 (5.3)	0 (0)		1 (4.3)	0 (0)

Serious adverse events and deep venous thrombosis/pulmonary embolism recorded for 360 days. Death recorded separately for 360 and 21 days post-infusion, but only one death occurred (in less than 21 days). Hospital stay was until death or discharge to either home or aftercare in a non-HUS hospital. Other parameters recorded for 21 days after infusion: maximum stay ICU or on ventilator was thus 21 days.

Abbreviations: LCP = low-titre convalescent plasma, HCP = high-titre convalescent plasma, hLCP = low-homologous titre convalescent plasma, hHCP = high-homologous titre convalescent plasma, DVT = deep venous thrombosis, COMRF = core outcome measure for respiratory failure, NIV = non-invasive ventilation, IMV = invasive mechanical ventilation, ECMO = extracorporeal membrane oxygenation.

^a Placebo group the same as in randomised groups, therefore not presented here. The p-value concerns that as well.

^b One patient got DNI (do-not-intubate) order after the intervention.

^c p-value from Kruskall-Wallis, but since medians were 0, values are presented as mean (SD) to allow more informative interpretation.

Table 3. Adverse (AE) and severe adverse events (SAE) for hospitalised COVID-19 patients receiving convalescent plasma containing a high (HCP) or low (LCP) titre of anti-SARS-CoV-2 neutralising antibodies, or placebo.

Group	AE/SAE	Description	Time of onset^a	AE/SAE outcome	Causality^b
HCP	SAE	Increasing dyspnoea and worsening hypoxaemia	4	Oxygen supplement by mask for two days. Possible (secondary) bacterial pneumonia. Discharged five days after infusion.	Unlikely
LCP	AE	Fever (38 °C)	3	Resolved with acetaminophen. Discharged three days after infusion.	Possible
LCP	SAE	Worsening hypoxaemia	1	Hypoxaemia deepened rapidly after infusion. Due to advanced age and obesity, ICU care was withheld. Died of COVID-19 pneumonitis eight days after infusion.	Possible
LCP	SAE	Dyspnoea and worsening hypoxaemia	8	Admitted to ICU three days after infusion, non-invasive ventilation. Discharged after nine days in ICU and ten days on regular ward.	Unlikely
LCP	SAE	Tachypnea and worsening hypoxaemia	5	Nasal high flow oxygen therapy. Discharged eight days after infusion.	Possible
Placebo	SAE	Worsening hypoxaemia	7	Intubated and transferred to ICU three days after infusion. Treated 31 days in ICU. Finally discharged after 105 days in various hospitals. Sequelae of COVID-19 resulted in chronic dyspnoea.	Possible
Placebo	AE	Pain and paresthaesia of non-infusion arm	0	Resolved within hours. Discharged the following day.	Unlikely
Placebo	AE	Nausea and dizziness after study infusion	0	Resolved spontaneously within 12 h. Discharged five days after infusion.	Possible

^a Hours after initiation of study infusion.

^b Probability that adverse event was caused by study infusion, as judged by investigators at the time (before unblinding).