A Randomized Double-Blind Placebo-Control Feasibility Trial of Immunoglobulin Treatment for Prevention of Recurrent Acute Exacerbations of COPD

Figures & data

Table 1 Baseline Characteristics

Parameter	IVIG	Control
Male:Female, n	20:15	13:22
Age, yrs	66.7 ± 7.4	68.7 ± 8.7
Body mass index, kg・m^−2	28.1 ± 6.7	27.6 ± 7.4
Smoking history, pack years	56.8 ± 27.5	51.3 ± 29.8
COPD Gold stage, I:II:III:IV	0:7:10:18	0:4:8:13
COPD Grade, A:B:C:D	0:3:0:32	0:1:0:34
Absolute eosinophils, 10^9・L^−1	0.16 ± 0.20	0.15 ± 0.21
Creatinine, µmol・L^−1	71.1 ± 19.8	68.4 ± 25.0
Total protein, g・L^−1	72.2 ± 5.9	69.7 ± 4.8
Pulmonary function
FEV1, L (%)	0.90 ± 0.39 (34±13)	0.87 ± 0.4 (35±14)
FEV1/FVC, %	42 ± 12	43 ± 16
Rate of AECOPD
Total number of AECOPD, number・year^−1	2.7 ± 1.3	2.5 ± 1.3
Moderate AECOPD (managed as outpatient), number・year^−1	1.37 ± 1.44	0.86 ± 1.04
Moderate AECOPD (ED visit), number・year^−1	0.34 ± 0.68	0.26 ± 0.56
Severe AECOPD (hospitalization), number・year^−1	1.1 ± 0.8	1.4 ± 0.81
Health status and quality of life
SGRQ score, out of 100	65.8 ± 15.0	68.4 ± 15.6
CAT score, out of 40	22.4 ± 8.8	26.2 ± 7.1
EQ-5D-5L UI	0.56 ± 0.26	0.51 ± 0.27
EG-5D-5L VAS, out of 100	57 ± 23	49 ± 16
Immunoglobulins
IgG total, g・L^−1	8.94 ± 2.83	7.34 ± 1.64
IgM, g・L^−1	0.85 ± 0.76	0.79 ± 0.56
IgE, mg・L^−1	0.96 ± 1.52	0.35 ± 0.57
IgA, g・L^−1	2.69 ± 1.15	2.17 ± 1.27
Comorbidities
Hypertension, %	57	51
Coronary artery disease, %	26	43
Congestive heart failure, %	11	3
Cardiomyopathy, %	8	8

Abbreviations: FEV1, forced expiratory volume in one second; FVC, forced vital capacity; AECOPD, acute exacerbation of COPD; SGRQ, St. George’s respiratory questionnaire; CAT, COPD assessment test; UI, utility index; VAS, visual analogue scale.

Figure 1 Consort diagram of the study population. Eligible patients were recruited from in- and out-patient settings. Seventy patients were randomized to IVIG or control group in a 1:1 ratio. Number of deaths, all-cause hospitalization, severe and moderate AECOPD were reported in the flow-chart for both ITT and PP analysis.

Abbreviations: IVIG, intravenous immunoglobulin; ITT, intention-to-treat; PP, per-protocol.

Figure 2 Study recruitment, adherence and retention. Number of patients recruited each month by recruitment settings from September 2016 to November 2018 is shown (A). Recruitment from ambulatory care clinics started in March 2018 while prespecified number of patients with hypogammaglobulinemia recruited from inpatient units was reached by March 2018. The horizontal dashed lines represent mean recruitment rate over the actual recruitment period. The combined recruitment rate was 4.5±0.9 patients/month. Proportion of allocated treatments received in patients by assigned treatment group (B). Arrows indicate numbers of patients who were adherent greater (↑) or less (↓) than 80%. Adherence was low, and more so in the control group. Retention rate by treatment group over 48 weeks was high despite low adherence (C).

Table 2 Rates of Acute Exacerbation of COPD (AECOPD) by Treatment Allocation

Analysis	AECOPD Outcome Events	IVIG	Control	Ratio Rate^a (95% CI)
ITT Analysis	Total number of AECOPD	56 (25)	48 (21)	0.91
N = 35 per group	(number of patients with events)			(0.59 to 1.41)
	AECOPD requiring	16 (13)	20 (12)	0.78
	Hospitalization			(0.37 to 1.65)
	(number of patients with events)
	AECOPD requiring ED visit	12 (9)	2 (2)	3.16
	(number of patients with events)			(0.64 to 15.60)
	AECOPD managed as outpatients	28 (15)	26 (12)	0.69
	(number of patients with events)			(0.37 to 1.30)
PP Analysis	Total number of AECOPD	24 (12)	24 (11)	0.98
N = 16 for control, N = 18 for IVIG	(number of patients with events)			(0.50 to 1.93)
	AECOPD requiring hospitalization	4 (4)	4 (3)	0.43
	(number of patients with events)			(0.07 to 2.49)
	AECOPD requiring ED visit	5 (4)	1 (1)	2.52
	(number of patients with events)			(0.23 to 27.7)
	AECOPD managed as outpatient	15 (9)	19 (9)	0.88
	(number of patients with events)			(0.39 to 1.97)

Note: ^aAdjusted for age, sex, baseline IgG, FEV1 predicted value, and AECOPD rates.

Abbreviations: CI, confidence interval; ITT, intention-to-treat; PP, per-protocol.

Figure 3 Kaplan–Meier curve of cases remaining without moderate or severe AECOPD, (A) regardless of non-adherence (ITT), (B) in cases with >80% adherence (PP) to study treatments.