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

Abstract

Background: Observational studies suggest that immunoglobulin treatment may reduce the frequency of acute exacerbations of COPD (AECOPD).

Objective: To inform the design of a future randomised control trial (RCT) of intravenous immunoglobulin (IVIG) treatment efficacy for AECOPD prevention.

Methods: A pilot RCT was conducted. We recruited patients with COPD hospitalized for AECOPD, or from ambulatory clinics with one severe, or two moderate AECOPD in the previous year regardless of their serum IgG level. Patients were allocated in a 1:1 ratio with balanced randomisation to monthly IVIG or normal saline for 1 year. The primary outcome was feasibility defined as pre-specified accrual, adherence, and follow-up rates. Secondary outcomes included safety, tolerance, AECOPD rates, time to first AECOPD, quality of life, and healthcare costs.

Results: Seventy patients were randomized (37 female; mean age 67.7; mean FEV1 35.1%). Recruitment averaged 4.5±0.9 patients per month (range 0-8), 34 (49%) adhered to at least 80% of planned treatments, and four (5.7%) were lost to follow-up. There were 35 serious adverse events including seven deaths and one thromboembolism. None was related to IVIG. There were 56 and 48 moderate and severe AECOPD in the IVIG vs control groups. In patients with at least 80% treatment adherence, median time to first moderate or severe AECOPD was 275 vs 114 days, favoring the IVIG group (HR 0.76, 95% CI 0.3-1.92).

Conclusion: The study met feasibility criteria for recruitment and retention, but adherence was low. A trend toward more robust treatment efficacy in adherent patients supports further study, but future trials must address treatment adherence.

Trial registration number: NCT0290038, registered 24 February 2016, https://ichgcp.net/clinical-trials-registry/NCT02690038 and NCT03018652, registered January 12, 2017, https://ichgcp.net/clinical-trials-registry/NCT03018652.

Keywords: IVIG; immunoglobulin treatment; pilot RCT; recurrent AECOPD.

Conflict of interest statement

JC received grants and/or personal fees from CSL Behring, Grifols, The Ottawa Hospital Academic Medical Organization, OctaPharma, Takeda, GSK, Sanofi Genzyme, EMD Serono, and Alexion outside the submitted work. MM reports personal fees from Merck, outside the submitted work. DWC reports grants from CSL Behring Inc., Grifols Inc., during the conduct of the study; personal fees and/or non-financial support from CSL Behring, Grifols, Takeda, Celltrion, AstraZeneca Canada, Gilead Sciences outside the submitted work. The authors report no other conflicts of interest in this work.

© 2021 Cowan et al.

Figures

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.

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).

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.