Statistical Analysis Plan: Using live vaccines to induce beneficial innate immune training and reduce systemic inflammation in COPD patients (COPD-LIVE, EU CT: 2023-504519-34-01)

Design: A randomized, single-blinded clinical pilot study to assess whether vaccination with live attenuated vaccines can induce trained immunity and cause beneficial changes in patients with specialist-verified, spirometry-confirmed COPD. Study population: 60 adult patients with chronic obstructive pulmonary disease (COPD). Single center study at Department of Internal Medicine, Section of Respiratory Medicine, Herlev-Gentofte Hospital, University of Copenhagen. Methods and interventions: Single-blinded 1:1:1 block randomized study with varying block sizes of 3-6, stratified by sex. Treatment arm:s 1. MMR vaccine (M-M-R VaxPro) 2. BCG vaccine (Danish strain 1331) 3. Saline (placebo). Participants received two doses of one of the three treatment arms; one dose at enrollment (day 0) and one dose 3 months (day 90). Peripheral mononuclear blood cells (PBMC) will be used to measure innate immune triaining. The primary outcome is detection of fold-changes in cytokine production capacity of innate immune cells for cytokines IL-1β, IL-6, IL-10, TNF-α and IFN-γ, following pro-inflammatory stimulation from inclusion to 4 months (~day 120) post-inclusion. Based on more recent experiences, an overall significant increase in cytokine production capacity of >1.3 fold post-vaccination with BCG or MMR, when compared with placebo, will be considered as indicative of innate immune training. We expect 30-40% of the population to be BCG non-responders. Fold-changes will be calculated at the individual level (day 120 / day 0); due to skewed cytokine distributions, analyses will be performed on log-transformed values and results presented as medians with interquartile ranges and geometric mean fold-changes.