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

• ClinicalTrials.gov Identifier: NCT02133872
• Recruitment Status: Recruiting
• First Posted: May 8, 2014
• Last Update Posted: May 9, 2023
• Sponsor: University of Florida
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): University of Florida

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hypertension	Drug: Minocycline dose escalation	Phase 4

Detailed Description:

One hundred seventy-five (175) subjects who will be randomized to receive either Minocycline 100 mg or 200 mg b.i.d. (twice a day). At baseline, subjects will undergo blood tests (lipid panel, high sensitivity-C reactive protein, high sensitivity troponin, glucose, metabolic profile, lipid panel, Cystatin C, albumin and flow cytometry). Peripheral blood mononuclear cells will be isolated and used to generate human induced pluripotent stem cells (iPSCs) which will be used for further mechanism studies.

After enrollment of the first two patients and observing a marked reduction in blood pressure the blind was broken and patients were on active therapy. Because these patients had CVD, for safety reasons recruitment was halted and the protocol design was modified to an 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.

A subset of responders and nonresponders were sent to Montreal as part of IRB201500594 -N to carry out novel brain imaging of sympathetic centers, and perform autonomic testing.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Intervention Model Description: Open label, dose effectiveness trial
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Angiotensin and Neuroimmune Activation in Hypertension
• Study Start Date: October 2014
• Estimated Primary Completion Date: January 30, 2024
• Estimated Study Completion Date: January 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Minocycline Dose Escalation; 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.	Drug: Minocycline dose escalation; 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.

Outcome Measures

Primary Outcome Measures :

1. Reduction in mean daytime ABPM SBP and/or down titration of antihypertensive therapy [ Time Frame: 52 weeks ]
   Reduction in anti-hypertensive medications

Secondary Outcome Measures :

1. Changes in office SBP over time [ Time Frame: 52 weeks ]
   Office BP
2. Change in 24 hr SBP by ABPM [ Time Frame: 52 weeks ]
   24 hour Systolic BP by ABPM

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion:

• 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

Contacts and Locations

Contacts

Contact: Dana Leach, DNP; 352-273-8933; leachdd@medicine.ufl.edu

Contact: Sarah Long, RN; 352-273-8933; sarah.long@medicine.ufl.edu

Locations

United States, Florida

UF Health Cardiovascular Clinic; Recruiting

Gainesville, Florida, United States, 32610

Contact: Dana Leach, DNP 352-273-8933 leachdd@medicine.ufl.edu

Sub-Investigator: Mohan Raizada, PhD

Sponsors and Collaborators

University of Florida

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Carl Pepine, MD; University of Florida

More Information

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT02133872
• Other Study ID Numbers: IRB2015005 -N; RO1HL3361028 ( Other Identifier: NHLBI ); 2013-00102 Study 1 ( Other Identifier: UF IRB ID ); 1R01HL132448-01 ( U.S. NIH Grant/Contract )
• First Posted: May 8, 2014
• Last Update Posted: May 9, 2023
• Last Verified: May 2023

Keywords provided by University of Florida:

Resistent Hypertension

Additional relevant MeSH terms:

Hypertension; Vascular Diseases; Cardiovascular Diseases; Minocycline; Anti-Bacterial Agents; Anti-Infective Agents