Study 1: Effect of Minocycline Treatment on Drug-Resistant Hypertensive Patients

NCT ID: NCT02133872

Last Updated: 2025-10-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-10-31
• Study Completion Date: 2018-11-01

Brief Summary

Hypertension (HTN) is the single most prevalent risk factor for cardiovascular disease, diabetes, obesity and metabolic syndrome. Recent American Heart Association (AHA) statistics indicate that one-third of all adults in the United States of America suffer from HTN. Despite advances in life style modification and multi-drug therapies, 20-30% of all hypertensive patients remain resistant.

These individuals exhibit autonomic dysregulation due to elevated sympathetic activity and norepinephrine spillover, and low parasympathetic activity. It is generally accepted that this uncontrolled, resistant HTN is primarily "neurogenic" in origin, involving over activity of the sympathetic nervous system that initiates and sustains HTN. A surgical approach such as the recently developed "Simplicity Catheter" assisted renal denervation remains one of the few options available to these patients. Thus, a mechanism-based breakthrough is imperative to develop novel strategies to prevent and perhaps eventually cure neurogenic hypertension (NH). This study is designed to evaluate a low and high dose of minocycline to test the hypothesis that minocycline treatment would produce antihypertensive effects in drug-resistant neurogenic hypertensive individuals. Minocycline has been selected because of its demonstrated effects on inhibiting microglial activation and its ability to penetrate the blood brain barrier. There is no other compound available that is safer and displays specificity better than Minocycline in inhibiting microglial activation. Thus, the potential therapeutic benefits of this inexpensive, well tolerated, already FDA-approved drug that has minimal side effects would be enormous.

Detailed Description

Open-label design of dose titration for each participant beginning at 50 mg/day of minocycline, escalating to 100 mg/day and 200 mg/day if the primary outcome measure of ambulatory blood pressure monitor (ABPM) =/> to 5 mmHg decrease in mean daytime SBP was not achieved. If patients responded, participation was completed. This revised protocol was resubmitted to the IRB and approved on 1/6/16. An interim analysis was planned after 40 patients completed the revised protocol.

In addition to blood collection, a physical exam will be conducted and office systolic blood pressure (BP), diastolic blood pressure (DBP) and pulse pressure (PP) will be recorded. Patients will be fitted with an ABPM system. Patients will wear the ABPM for 24 hours at which point they will mail the monitor back to research personnel. At this visit, the study drug will be dispensed and patients will be instructed to start the study medication after completing the 24- hour ABPM monitoring period. After this visit, patients will be asked to return every month till the end of the study at 6 months.

Monthly visits (1, 2, 3, 4, 5 and 6 month visits), will include a brief physical examination and an assessment of medication compliance and tolerance. One tablespoon of blood will be drawn for flow cytometry analysis, selected cytokines, markers of gut permeability including zonulin, and iPSCs isolation at the baseline, 3 and 6 month visit only. Study drug will be dispensed and measurement of SBP, DBP, PP and other vital signs will also be completed. Office BP readings will be taken in a seated position after 5 minutes of rest according to Joint National Committee VII Guidelines. At baseline, BP will be measured at each arm, and the arm with the higher BP will be used for all subsequent readings. Averages of the triplicate measures will be calculated and used for analysis. At baseline and each followup visit, patients will be asked to wear the ABPM for 24 hours. Subjects will mail the cuff back to research personnel when completed. ABPM will be performed using an oscillometric Spacelabs 90207 monitor (Spacelabs Healthcare, Issaqua, WA) with readings taken every 30 minutes in daytime and every 60 minutes at nighttime. ABPM readings will be averaged for, daytime and nighttime. Patients will be assessed while adhering to their usual diurnal activity and nocturnal sleep routine. The antihypertensive drugs, and their doses, used at each visit will be recorded on standardized forms along with any reports of adverse experiences known to occur with the drugs used (e.g. lightheadedness, dizziness, syncope, etc.).

If patients respond to treatment, by protocol defined drop in daytime ABPM and/or the need for down titration of hypertensive therapy they will be considered a responder, complete the final visit and complete study participation. At the final visit, the same blood tests at baseline will be repeated. When the patients complete the 6 months of treatment or are considered a responder at a lower dose, they will come in for their final visit, and return the ABPM monitor, their participation in the trial will be considered as complete.

Conditions

Hypertension

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Minocycline (50 mg/d)

Subjects received minocycline 50mg/d.

Group Type: EXPERIMENTAL

Minocycline 50mg/d

Intervention Type: DRUG

Subjects will receive minocycline 50mg if no mean daytime ABPM SBP decline =/\> 5mm Hg; subjects will receive minocycline 100mg, if no mean daytime ABPM SBP decline =/\> 5mm Hg BP subjects will receive minocycline 200 mg.

Minocycline (100 mg/d)

Subjects received minocycline 50mg escalating to 100 mg/d.

Group Type: EXPERIMENTAL

Minocycline 100mg/d

Intervention Type: DRUG

Subjects will receive minocycline 50mg if no mean daytime ABPM SBP decline =/\> 5mm Hg; subjects will receive minocycline 100mg, if no mean daytime ABPM SBP decline =/\> 5mm Hg BP subjects will receive minocycline 200 mg.

Minocycline (200 mg/d)

Subjects received minocycline 50mg escalating to 100 mg then 200 mg/d.

Group Type: EXPERIMENTAL

Minocycline 200mg/d

Intervention Type: DEVICE

Subjects will receive minocycline 50mg if no mean daytime ABPM SBP decline =/\> 5mm Hg; subjects will receive minocycline 100mg, if no mean daytime ABPM SBP decline =/\> 5mm Hg BP subjects will receive minocycline 200 mg.

Interventions

Minocycline 50mg/d

Subjects will receive minocycline 50mg if no mean daytime ABPM SBP decline =/\> 5mm Hg; subjects will receive minocycline 100mg, if no mean daytime ABPM SBP decline =/\> 5mm Hg BP subjects will receive minocycline 200 mg.

Intervention Type: DRUG

Minocycline 100mg/d

Subjects will receive minocycline 50mg if no mean daytime ABPM SBP decline =/\> 5mm Hg; subjects will receive minocycline 100mg, if no mean daytime ABPM SBP decline =/\> 5mm Hg BP subjects will receive minocycline 200 mg.

Intervention Type: DRUG

Minocycline 200mg/d

Subjects will receive minocycline 50mg if no mean daytime ABPM SBP decline =/\> 5mm Hg; subjects will receive minocycline 100mg, if no mean daytime ABPM SBP decline =/\> 5mm Hg BP subjects will receive minocycline 200 mg.

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

• Greater than 18 and less than 86 years of age;
• On stable medication regimen
• Full-tolerated doses of 3 or more antihypertensive medications of different classes, one of which must be a diuretic (with no changes for a minimum of two months prior to screening) that is expected to be maintained without changes for at least 3 months.
• The individual agrees to have all study procedures performed
• Willing to provide written consent

Exclusion

• eGFR of < 45mL/min/1.73m2, using the MDRD calculation.
• More than one in-patient hospitalization for an antihypertensive crisis within the year.
• More than one episode(s) of orthostatic hypotension (reduction of SBP of ≥ 20mmHg of diastolic blood pressure (DBP) of ≥ 10mmHg within 3 minutes of standing).
• Known hypersensitivity or contraindication to Minocycline or other tetracycline.
• Evidence of alcoholism or drug abuse;

• Concurrent severe disease (such as neoplasm or HIV positive or AIDS).
• Women of childbearing potential

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Carl Pepine, MD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

UF Health Cardiovascular Clinic

Gainesville, Florida, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

RO1HL3361028

Identifier Type: OTHER

Identifier Source: secondary_id

2013-00102 Study 1

Identifier Type: OTHER

Identifier Source: secondary_id

1R01HL132448-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB2015005 -N

Identifier Type: -

Identifier Source: org_study_id