MINocyclinE to Reduce inflammation and blood-brain barrier leakage in small Vessel diseAse (MINERVA): A phase II, randomized, double-blind, placebo-controlled experimental medicine trial

Abstract

Introduction: Cerebral small vessel disease (SVD) is a common cause of stroke/vascular dementia with few effective treatments. Neuroinflammation and increased blood-brain barrier (BBB) permeability may influence pathogenesis. In rodent models, minocycline reduced inflammation/BBB permeability. We determined whether minocycline had a similar effect in patients with SVD.

Methods: MINERVA was a single-center, phase II, randomized, double-blind, placebo-controlled trial. Forty-four participants with moderate-to-severe SVD took minocycline or placebo for 3 months. Co-primary outcomes were microglial signal (determined using ¹¹C-PK11195 positron emission tomography) and BBB permeability (using dynamic contrast-enhanced MRI).

Results: Forty-four participants were recruited between September 2019 and June 2022. Minocycline had no effect on ¹¹C-PK11195 binding (relative risk [RR] 1.01, 95% confidence interval [CI] 0.98-1.04), or BBB permeability (RR 0.97, 95% CI 0.91-1.03). Serum inflammatory markers were not affected.

Discussion: ¹¹C-PK11195 binding and increased BBB permeability are present in SVD; minocycline did not reduce either process. Whether these pathophysiological mechanisms are disease-causing remains unclear.

International clinical trials registry portal identifier: ISRCTN15483452 HIGHLIGHTS: We found focal areas of increased microglial signal and increased blood-brain barrier permeability in patients with small vessel disease. Minocycline treatment was not associated with a change in these processes measured using advanced neuroimaging. Blood-brain barrier permeability was dynamic but MRI-derived measurements correlated well with CSF/serum albumin ratio. Advanced neuroimaging is a feasible outcome measure for mechanistic clinical trials.

Keywords: blood‐brain barrier; cerebral small vessel disease; neuroinflammation; vascular cognitive impairment; vascular dementia.

FIGURE 1

Structured study diagram showing timeline and trial procedures.

FIGURE 2

CONSORT recruitment diagram showing flow of participants in the MINERVA study. MINERVA, minocycline to reduce inflammation and blood brain barrier leakage in small vessel disease.

FIGURE 3

Graphical representation of intention‐to‐treat cohort stratified by age, sex, and disease severity (WMH volume). WHM, white matter hyperintensity.

FIGURE 4

Representative images from two patients showing maps of hotspots of ¹¹C‐PK11195 binding (green) and BBB permeability (yellow) overlaid on FLAIR images. Overlapping voxels defined as hotposts of both processes are colored red (only present in left panel). BBB, blood‐brain barrier; FLAIR, fluid attenuated inversion recovery.

FIGURE 5

Boxplots showing between‐group comparison pre‐ and post‐treatment for (A) mean percentage of NAWM identified as ¹¹C‐PK11195 binding ‘hotspot’ tissue volume (percentage of NAWM) and (B) BBB permeability hotspot volume (percentage of NAWM). Boxes show group mean/quartiles, whiskers show maximum values within 1.5 * inter‐quartile range of upper or lower quartile, outliers beyond these values are plotted separately. BBB, blood‐brain barrier; NAWM, normal appearing white matter.