Antihypertensive Mechanisms of Minocycline in Resistant Hypertension

Antihypertensive Mechanisms of Minocycline in Resistant Hypertension: Role of the Gut Microbiota-brain-immune Axis

The goal of this clinical trial is to learn about the mechanisms by which minocycline effect blood pressure in individuals with treatment-resistant hypertension. The main questions it aims to answer are:

• To what extent does minocycline lower blood pressure?
• Are such blood pressure effects mediated through changes in gut microbiota, gut leakiness, systemic inflammation, neuroinflammation, or some combination of these?

Participants will be randomly assigned to treatment with minocycline or placebo, treated daily for 3 months, to evaluate these questions.

Study Overview

• Status: Recruiting
• Conditions: Hypertension, Resistant to Conventional Therapy
• Intervention / Treatment: Drug: Placebo; Drug: Minocycline Hydrochloride

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Joshua N Terrell; Phone Number: 352-294-8297; Email: jterrell5102@ufl.edu
• Study Contact Backup: Name: David B Smith; Phone Number: 352-294-8297; Email: dbsmith@cop.ufl.edu

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • Recruiting
      • UF Clinical Research Center (UF CRC) - CTSI
      • Principal Investigator: Carl J Pepine, MD
      • Contact: Joshua N Terrell; Phone Number: 352-294-8297; Email: jterrell5102@ufl.edu
      • Contact: David B Smith; Phone Number: 352-294-8297; Email: dbsmith@cop.ufl.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Minocycline Hydrochloride; Minocycline hydrochloride 100 mg, administered twice daily for 3 months	Drug: Minocycline Hydrochloride; Minocycline Hydrochloride 100 mg twice daily; Other Names: Minocin; Minocycline
Placebo Comparator: Placebo; Placebo administered twice daily for 3 months	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-h systolic blood pressure	Change in mean 24-hour ambulatory systolic blood pressure	3 months
Gut microbiome	Change in butyrate-producing gene abundance	3 months
Gut inflammation and leakiness	Change in gut-homing inflammatory T-helper cells	3 months
Neuroinflammation	Change in [18F]FEPPA radiotracer uptake on PET/MR imaging	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mucin-degrading gene abundance	Change in mucin-degrading gene abundance	3 months
IgA+ coated plasma cells	Change in IgA+ coated plasma cells	3 months
Gut leakiness markers	Change in gut leakiness markers, including lipocalin-2, intestinal fatty-acid binding protein (I-FABP), zonulin, and lipopolysaccharides (LPS)	3 months
24-h diastolic blood pressure	Change in mean 24-hour diastolic blood pressure	3 months
24-h heart rate	Change in mean 24-hour heart rate	3 months
Adverse Events	Incidence of treatment-related adverse events	3 months

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Emory University
• Investigators: Principal Investigator: Steven M Smith, PharmD, MPH, University of Florida

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2025
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: January 30, 2024
• First Submitted That Met QC Criteria: January 30, 2024
• First Posted (Actual): February 7, 2024

Study Record Updates

• Last Update Posted (Actual): March 6, 2026
• Last Update Submitted That Met QC Criteria: March 5, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: blood pressure; minocycline
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; cyclopia sequence; Hypertension Resistant to Conventional Therapy; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Naphthacenes; Tetracyclines; Minocycline
• Other Study ID Numbers: IRB202301939; 2R01HL132448-05A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No