Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS

Abstract

Objective: To evaluate Bacille Calmette-Guérin (BCG) effects after clinically isolated syndromes (CIS).

Methods: In a double-blind, placebo-controlled trial, participants were randomly assigned to receive BCG or placebo and monitored monthly with brain MRI (6 scans). Both groups then entered a preplanned phase with IM interferon-β-1a for 12 months. From month 18 onward, the patients took the disease-modifying therapies (DMTs) that their neurologist considered indicated in an open-label extension phase lasting up to 60 months.

Results: Of 82 randomized subjects, 73 completed the study (33 vaccinated and 40 placebo). During the initial 6 months, the number of cumulative lesions was significantly lower in vaccinated people. The relative risks were 0.541 (95% confidence interval [CI] 0.308-0.956; p = 0.03) for gadolinium-enhancing lesions (the primary endpoint), 0.364 (95% CI 0.207-0.639; p = 0.001) for new and enlarging T2-hyperintense lesions, and 0.149 (95% CI 0.046-0.416; p = 0.001) for new T1-hypointense lesions. The number of total T1-hypointense lesions was lower in the BCG group at months 6, 12, and 18: mean changes from baseline were -0.09 ± 0.72 vs 0.75 ± 1.81 (p = 0.01), 0.0 ± 0.83 vs 0.88 ± 2.21 (p = 0.08), and -0.21 ± 1.03 vs 1.00 ± 2.49 (p = 0.02). After 60 months, the cumulative probability of clinically definite multiple sclerosis was lower in the BCG + DMT arm (hazard ratio = 0.52, 95% CI 0.27-0.99; p < 0.05), and more vaccinated people remained DMT-free (odds ratio = 0.20, 95% CI 0.04-0.93; p = 0.04).

Conclusions: Early BCG may benefit CIS and affect its long-term course.

Classification of evidence: BCG, as compared to placebo, was associated with significantly reduced development of gadolinium-enhancing lesions in people with CIS for a 6-month period before starting immunomodulating therapy (Class I evidence).

Figure 1. Flow of patients through the trial

Figure 2. Cumulative mean number of total gadolinium-enhancing lesions on MRI during the first 6 months

The p values were <0.05 at months 1, 3, 4, and 6; the difference was near-significant at months 2 (p = 0.07) and 5 (p = 0.09; Mann-Whitney U test). BCG = Bacille Calmette-Guérin; Gd = gadolinium; bars = standard error.

Figure 3. Effect of Bacille Calmette-Guérin vaccine across time

(A) Mean change in the number of total T1-hypointense lesions from baseline to months 6, 12, and 18 from vaccination or placebo in the 2 study arms. The p values were <0.05 at months 6 and 18; the difference was near-significant at month 12 (p = 0.08; Mann-Whitney U test to compare the distribution of lesion changes). (B) Kaplan-Meier estimates of the cumulative probability of the development of clinically definite multiple sclerosis (MS) according to treatment group. BCG = Bacille Calmette-Guérin; DMT = disease-modifying therapy.