Antihypertensive Mechanisms of Minocycline in Resistant Hypertension

One hundred twenty patients with treatment-resistant hypertension will be enrolled. A total of 34 patients (17 from each treatment arm), who are participants in the main study, will also be enrolled in a substudy that includes neuroimaging. The study will last 3 months, and will include 3 visit time points (screening, randomization visit, 3-month follow-up visit).

Participants will be randomly assigned, in a 1:1 allocation, to minocycline 100 mg twice per day, or matching placebo, each provided by the study, and investigators will be blinded to treatment assignment.

At the baseline and 3-month follow-up visit, subjects will undergo:

• A comprehensive medical history and examination, including assessment of antihypertensive treatment history
• A series of behavioral activity questionnaires
• Blood tests (plasma renin activity, aldosterone, catecholamines, serum creatinine, lipid panel, hemoglobin a1c, as well as various biomarkers of immune and inflammatory activity, and gut leakiness markers)
• Urine/saliva tests for antihypertensive adherence
• Gut microbiota profiling via whole metagenomic sequencing of stool samples
• Blood pressure (BP) measurement, including unattended office BP and 24-hour ambulatory BP

Subjects enrolled in the neuroimaging substudy will also have PET/MR imaging performed at each visit. Neuroimaging activities will take place at Emory University in Atlanta, GA.

At the final visit (3-month follow-up), participants will also have blood tests to measure study drug concentration, as a measure of adherence to the assigned treatment.

Inclusion criteria

• Age ≥18 years
• Uncontrolled TRH, defined as uncontrolled blood pressure (mean 24-hour ambulatory systolic BP ≥125 mm Hg or diastolic BP ≥80 mm Hg) while being adherent to a stable (no changes in ≥14 days prior) antihypertensive regimen of 3 or more drugs, including an adequately dosed diuretic or unable to tolerate a diuretic.
• The participant agrees to have all study procedures performed

Exclusion criteria

• Known hypersensitivity or contraindication to minocycline or other tetracyclines
• Recent (≤3 months prior), ongoing, or expected use of oral antibiotics
• Estimated glomerular filtration rate (eGFR) of <45mL/min/1.73m2, using the MDRD equation
• Known secondary hypertension
• History of hypertensive crisis, defined as any in-patient hospitalizations for hypertensive crisis/emergency within the past year
• History of orthostatic hypotension, defined as two or more episode(s) of orthostatic hypotension (reduction of SBP of >20 mm Hg or DBP of >10 mm Hg within 3 minutes of standing) in the past year
• History of myocardial infarction, unstable angina, syncope, or cerebrovascular accident in prior 6 months
• Evidence of alcoholism or drug abuse
• Severe comorbid conditions (i.e., neoplasms or HIV positive or AIDS)
• Current pregnancy or anticipated pregnancy during the study.