Angiotensin and Neuroimmune Activation in Hypertension
Phase: PHASE2
Conditions: Hypertension
Sponsor: University of Florida

 
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Study Protocol 
Project Title:  
 
 
Effect of Minocycline Treatment on Drug-Resistant Hypertensive Patients 
Subtitle: Brain-Gut Microbiome-Immune Axis in Hypertension 
NCT02133872 
Investigators:  
  
 
Principal Investigator Carl J. Pepine, MD 
Co-Investigator- Mohan, Raizada, PhD  
Co-Investigator-Eileen Handberg, PhD, ARNP-BC 
Co-Investigator – Dana Leach, DNP, ARNP-BC 
Co-Investigator-Steven Smith, PharmD, MPHCo-Investigator – Margaret Lo, MD 
Co-Investigator – Osama Dasa, MD 
 
 
Sites: 
 
University of Florida (Site 1) 
College of Medicine 
Department of Surgery 
Gainesville, Florida 
 
UF Health Shands Hospital (Site 2) 
Gainesville, Florida 
 
UF Health Springhill Cardiology Clinic (Site 3) 
Gainesville, Florida 
 
Autonomic Reflex Laboratory (Site 4) 
Jewish General Hospital  
Montreal, Canada 
 
Brain Imaging Centre (Site 5) 
Montreal Neurological Institute  
Montreal, Canada 
Abstract: 
Hypertension (HTN) is the single most modifiable risk factor for cardiovascular disease and 
stroke but also implicated in diseases such as diabetes, metabolic syndrome, dementia, and many 
other conditions. Recent statistics indicate that about one-third of all adults, and up to two-thirds 

 
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of older adults in the USA have HTN1. Despite advances in life style modification and multi-
drug therapies, ~20% of hypertensive patients may remain resistant to treatment2,3. These 
individuals exhibit autonomic dysregulation due to elevated sympathetic outflow, norepinephrine 
spillover, and low parasympathetic activity.1-6 It is generally accepted that this “treatment 
resistant” HTN is primarily “neurogenic” in origin, involving sympathetic nervous system over 
activity that initiates and sustains HTN.1-6 An invasive approach, such as the recently developed 
“Simplicity Catheter”7 assisted renal denervation remains one of the few options available to these 
patients. But several recent randomized controlled trials (Symplicity-HTN3 and Prague15) 
showed disappointing results. Thus, a mechanism-based breakthrough is imperative to develop 
novel strategies to prevent and perhaps eventually cure (treatment resistant) neurogenic 
hypertension.  
This study is designed to determine what dose of minocycline produces antihypertensive effects 
in treatment-resistant neurogenic hypertensive individuals. Minocycline was selected because it 
is a safe, time-tested, small molecule that penetrates the blood barrier to inhibit microglial 
activation.8 No other available compound appears to be safer and/or display specificity inhibiting 
microglial activation better than minocycline. Thus, the potential therapeutic benefits of this 
inexpensive, well-tolerated, long time FDA-approved (in 1971) drug that has minimal side 
effects would be enormous. 
Background and Significance: 
As many as 20% of all hypertensive patients may remain refractory to multiple hypertensive 
drugs plus life-style modification2,3. For these “treatment resistant” patients invasive intervention 
remains the only available option, but with very limited success. The proposed study will test the 
hypothesis that minocycline, a small molecule, central nervous system (CNS)-penetrable anti-
inflammatory antibiotic, inhibits activity of brain microglia attenuating sympathetic nervous 
system activity to lower blood pressure in patients with neurogenic (treatment-resistant) HTN.  
This project is extremely significant in that it seeks to investigate the hypothesis that 
neuroinflammatory processes involving activated microglial cells in the autonomic brain regions 
play a critical role in the initiation and establishment of neurogenic (treatment-resistant) HTN. In 
addition, it is further hypothesized that this is associated with a dysfunctional neural-bone 
marrow (BM) communication which perpetuates HTN pathophysiology. This study will conduct 
both fundamental physiological genomic studies in experimental models to elucidate the 
mechanism of neural-BM dysfunction and translational studies in patients with resistant HTN, to 
provide clinical validation for possible novel therapeutics for neurogenic HTN. This innovative 
hypothesis is supported by published/preliminary studies9-13: (i) High blood pressure (BP) in 
angiotensin II (Ang II)-dependent animal models of neurogenic HTN is associated with rapid 
and sustained increases in microglial activation and proinflammatory cytokines (PICs) in the 
paraventricular nucleus (PVN); (ii) Ang II, via angiotensin II type 1 receptor (AT1R), increases 
production and selection of C-C chemokine ligand 2 CCL2), that acts via its  C-C chemokine 
receptor 2 (CCR2) to stimulate microglial migration towards neurons; CCL2 levels in the PVN 
are also elevated in HTN; (iii) inhibition of brain mitochondrial reactive oxygen species (ROS) 
or microglial activation by minocycline decreases PICs in the PVN and attenuates Ang II-
induced HTN. 

 
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Specific Aims:  
The overall aim of this study is to determine if targeting brain microglial activation by 
minocycline would produce beneficial outcomes in neurogenic (treatment-resistant) HTN. This 
will be achieved by addressing the following objectives in patients with neurogenic treatment-
resistant HTN: perform an open-label dose-range study to determine the lowest effective 
minocycline dose to lower BP 
Research Plan: 
The following are the inclusion and exclusion criteria 
Inclusion: 
• Greater than 18 years of age  
• Participant is receiving a stable antihypertensive medication regimen defined as- 
o Fully-tolerated doses of 3 or more antihypertensive medications of different 
pharmacologic classes, one of which must be a diuretic. 
o  With no changes for a minimum of two months prior to screening  
o That is expected to be maintained without changes for at least 3 months. 
• The participant agrees to have all study procedures performed. 
• Patients participating in UF IRB approved protocol # IRB201400233 will be eligible to 
participate. 
Exclusion 
• Older than 85 years of age 
• Average office blood pressure less than 120 mmHg 
• eGFR <45mL/min/1.73m2, using the MDRD equation.  
•  More than one in-patient hospitalization for an antihypertensive crisis/emergency within 
the past year. 
• More than one episode(s) of orthostatic hypotension (>20mmHg systolic BP [SBP] 
reduction or, >10mmHg diastolic BP [DBP] within 3 minutes of standing). 
• Known hypersensitivity or contraindication to minocycline or another tetracycline. 
• Evidence of alcoholism or drug abuse. 
• Concurrent severe disease (such as neoplasm, HIV positive, or AIDS). 
• Women of childbearing potential, who are not using 2 forms of birth control. 
This study will determine if a low dose of minocycline is effective to reduce SBP and 
peripheral inflammation in patients with “neurogenic” or resistant HTN.  
All study procedures for this study will be performed at Sites 1-3:  
Rationale: is the dose-escalation phase with the objective of determining the potential anti-
hypertensive effects of minocycline in neurogenic (treatment-resistant) HTN by analyzing the 

 
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doses: 50mg/d, 100mg/d and 200mg/d. This is necessary because the side effects to this 
antibiotic, although infrequent, can be dose and duration dependent. Minocycline, a 
semisynthetic tetracycline derivative, has been in clinical use for ~45 years and is known for its 
excellent oral bioavailability and tissue distribution. Its efficient blood brain barrier passage 
(CNS/ plasma distribution rate in the range of 0.3-0.6) allows CNS levels up to the micromolar 
range after repeated daily standard oral doses of 100–200 mg (1–3). Thus, it is important to 
determine if a lower dose is sufficient to enter the brain, have anti- inflammatory effects, and 
result in BP lowering.  
Description: Thirty- four (34) adult patients who are resistant to hypertensive medication and 
meet all inclusion criteria and no exclusion criteria will be offered the opportunity to participate 
in this study.  Study procedure will be reviewed with the participant and once written informed 
consent has been obtained, the participant will be enrolled in the study  
Research Visits and List of Procedures: 
Visit 1 Baseline 1 
• (Screen)Medical history and medications review will be performed. 
• Brief physical exam will be performed.  
• Office Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and pulse pressure 
(PP) will be performed.  
• A total of four tablespoons of blood will be collected. Three tablespoons of blood will be 
collected and analyzed for the following: lipid panel, high sensitivity-C reactive protein, 
high sensitivity troponin, a complete metabolic profile, cystatin C and albumin.  An 
additional tablespoon of blood will be drawn for additional biomedical tests.   
• Female participants will have a pregnancy test performed to verify a negative result 
before continuing. 
• Participants will be fitted with an ambulatory blood pressure monitor (ABPM) and will 
be educated on how to take their blood pressure at home. They will also be instructed to 
start study drug after completing a 24 hour ABPM period.  Once completed, subjects will 
mail the monitor back to the research site.  Mailing material will be provided by the 
study.   
• Participants will be provided with a home blood pressure log (HBPL) and will be 
instructed to take their blood pressure at least 3 times/week.  Around the same time and 
document the results in the log.  They will be asked to bring their HBPL to every clinic 
visit.  
Visit 2 Baseline 2  
(Day 0) 
• Review of medications and hospitalizations will be performed. 
• Brief physical exam will be performed.  
Office SBP, DBP and PP readings will be performed. 
• Study drug (minocycline 50mg) will be dispensed  
• Review HBPL will be performed. 

 
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• Participants will be provided with a home blood pressure log (HBPL) and will be 
instructed to take their blood pressure at least 3 times/week around the same time and 
document the results in the log.  They will be asked to bring their HBPL to every clinic 
visit. Participants will be asked to bring any unused medications and bottles (including 
empty bottles) to every clinic visit. 
Visit 3, 7, and 11  
• (2 Week + 7 days, 90 + 14 days, and 150 + 14 days) Review of any unused study 
medication and bottles including empty bottles.  
• Review of medications and hospitalizations will be performed. 
• Brief physical examination will be performed.  
• Office SBP, DBP and PP readings will be performed.  
• Assessment of medication compliance and tolerance will be performed. 
• Review HBPL will be performed. 
• Study drug (Visit 3, 2 week – minocycline 50mg and Visit 7, Day 90 – minocycline 
100mg) will be re-dispensed 
• Participants will be provided with a home blood pressure log (HBPL) and will be 
instructed to take their blood pressure at least 3 times/week around the same time and 
document the results in the log.  They will be asked to bring their HBPL to every clinic 
visit. 
• Participants will be asked to bring any unused medications and bottles (including empty 
bottles) to every clinic visit. 
 
Visit 4, and 8  
(Day 60 +14 days and 120 +14 days) 
• Review of any unused study medication and bottles including empty bottles Review of 
medications and hospitalizations will be performed. 
• Brief Physical Exam will be performed.  
• Office SBP, DBP and PP readings will be performed, 
• One tablespoon of blood will be drawn for additional biomedical tests.   
• Participants will be fitted with the ABPM and instructed to complete a 24-hr reading 
cycle as performed during visit 1.     
• Review HBPL. 
• Study drug (Visit 4 Day 60 – minocycline 50mg/d / Visit 8 Day 120 – minocycline 
100mg/d) will be re-dispensed.  
• Participants will be provided with a home blood pressure log (HBPL) and will be 
instructed to take their blood pressure at least 3 times/week.  Around the same time and 
document the results in the log.  They will be asked to bring their HBPL to every clinic 
visit. 
• Participants will be asked to bring any unused medications and bottles (including empty 
bottles) to every clinic visit. 
 
Phone Calls  

 
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Visit 5 (within 10 days of visit 4) and 9 (within 10 days of visit 8) 
• Participants will be given results of their ABPM blood pressures by the study team and 
told if their participation in this study will end or continue on to the next visit. 
If they are told by the study staff that their participation is continuing, they will be asked to 
return to clinic within approximately 1 week for dose titration of their study medication. 
If they are told by the study staff that their participation has ended, they will be asked to 
return to clinic within approximately 1 week for a final visit (see Visit 12 Final Visit for 
description) 
Dose Titration  
Visit 6 (within 7 days of visit 5), and 10 (within 7 days of visit 9)  
• Review of any unused study medication and bottles including empty bottles.  Review of 
medications and hospitalizations will be performed.  Review of medications and 
hospitalizations will be performed. 
• Brief physical examination will be performed. 
• Office SBP, DBP and PP readings will be performed. 
• Review HBPL 
• Patient will be dispensed study medication (Visit 6 - minocycline 100mg/d / Visit 10 – 
minocycline 200mg/d).  
• Participants will be provided with a home blood pressure log (HBPL) and will be 
instructed to take their blood pressure at least 3 times/week around the same time and 
document the results in the log.  They will be asked to bring their HBPL to every clinic 
visit. 
• Participants will be asked to bring any unused medications and bottles (including empty 
bottles) to every clinic visit. 
Visit 12 Final Visit 
(Day 180 +14 days or at any time participation ends) 
• Review of any unused study medication and bottles including empty bottles.  Review of 
medications and hospitalizations will be performed. Review of medications and 
hospitalizations will be performed. 
• Brief Physical Exam will be performed. 
• Office SBP, DBP and PP readings will be performed. 
• Review HBPL 
• A total of approximately four tablespoons of blood will be collected, as performed in 
Visit 1. 
• Participants will be fitted with the ABPM and instructed to complete a 24-hr reading 
cycle as performed during Visit 1.5 line 
 

 
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Office blood pressure (BP) readings will be taken in a seated position after 5 minutes of rest with 
feet flat on the floor according to JNC-7 Guidelines. At the baseline visit, BP will be measured in 
each arm, and the arm with the higher SBP will be used for all subsequent readings. All BP 
recordings will be made in triplicate. The initial reading will be discarded and the second and 
third readings for SBP and DBP and HR will be averaged and used for analysis.    
Home blood pressure monitoring via the 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 (7 AM to 10 PM), and nighttime (10 PM to 7 AM).  
Participants will be assessed while adhering to their usual diurnal activity and nocturnal sleep 
routine. Antihypertensive drugs and doses taken will be recorded at each visit on standardized 
forms along with any reports of adverse experiences known to occur with the drugs used (e.g. 
lightheadedness, dizziness, syncope, etc.). 
Based on our treatment design, enrolled participants will start the study at the lowest dose of 50 
mg/d and maintained in this regimen for approximately 60 days. At Visit 4, if the participant is 
asymptomatic and average daytime SBP is not reduced by ≥5.0 mmHg measured through 
ABPM, then drug dosage will be increased to 100 mg/d until Visit 8. Similarly, if the average 
daytime SBP is not reduced (≥5.0 mmHg), then drug dosage will be increased to 200 mg/d until 
the end of the trial at Visit 12. Subjects that successfully achieve a drop of ≥5 mmHg in average 
daytime SBP by Visit 4, 8, and 12 will be classified as a responder and their study participation 
will be terminated. At Visit 12, the same blood tests performed at the baseline visit will be 
repeated and a last ABPM cycle will be recorded. 
Statistical Analysis 
The primary measure of interest will be the categorical classification of subjects into responders 
vs. non-responders upon treatment with a specific minocycline dose: 50, 100 or 200 mg/d. 
Responders are defined as subjects who achieve a drop of >5 mmHg in mean daytime SBP, 
based on daytime ABPM measurements (7 am to 10 pm). For these participants, the 
discontinuation or lowering of the dose of a concurrent anti-hypertensive drug due to excessive 
SBP reduction will also be assessed. Excessive SBP reduction is defined as an office SBP <120 
mmHg or >10 mmHg SBP decrease associated with symptom(s). On the other hand, non-
responders are defined as the participants that fail to show any change in their average daytime 
SBP measured through ABPM despite being exposed to the different minocycline doses 
evaluated. 
The secondary measures for the responders group will assess changes in the following based 
from baseline to study participation end point: (1) Evaluation of changes in office SBP 
recordings. (2) Changes in daytime and nighttime ABPM differences. 
Sample size requirements for the dose determination study are based on consideration of the 
primary measure of interest, change in SBP in response to treatment with minocycline.  In order 
to achieve our primary measure of interest (responder vs. non-responder) and assuming a 15% 
drop out rate, we will target to enroll 35 participants to participate in this study. This sample size 

 
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estimation is based on our interest to target a dose where 75% (27/35) of all participant’s 
response to treatment and are therefore classified as responders. For this purpose, we will use a 
cumulative response approach where participants who respond to the lower doses will be 
assumed to also respond to higher doses. 
Possible Discomforts and Risks: 
Minocycline is a well-tolerated antibiotic, which has been in continuous use in the USA since 
1971 when approved by the FDA, and adverse effects are anticipated to be infrequent. Side 
effects in some subjects may be gastrointestinal (abdominal cramping, diarrhea, nausea and dry 
mouth), central nervous system (CNS) (headache, vestibular reaction) or hypersensitivity e.g. 
rash, itching; sun sensitivity, new signs of infection e.g. fever, chills, persistent sore throat, oral 
thrush or new yeast infection; ringing in the ears. The drug can cause fetal harm when taken 
during pregnancy. The drug treatment will immediately be discontinued with the experience of 
any of these side effects. 
Blood draws may cause pain, bruising, lightheadedness, or, on rare occasions, infection. 
Varying amounts of blood will be collected for each study (3 tablespoons at each draw).  
Special note to women.  Being part of this study while pregnant may expose the unborn child to 
significant risks, some of which may be currently unforeseeable.  Therefore, pregnant women 
will be excluded from the study.  If you are a woman able to become pregnant, a pregnancy test 
will be done and it must be negative before you can continue in this study.  If sexually active, 
you must agree to use appropriate contraceptive measures while taking part in this study.  
Medically acceptable contraceptives include: (1) surgical sterilization (such as tubal ligation or 
hysterectomy), 2) approved hormonal contraceptives (such as birth control pills, patches, 
implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a 
spermicide, or (4) intrauterine device (IUD).  If you become pregnant while taking part in this 
study or if you have unprotected sex, you must inform the study doctor immediately.  A 
pregnancy test will be repeated at the 6-month visit.  Due to the possible drug interaction of 
minocycline with oral contraceptives, women of child bearing age who are using oral 
contraceptives will be required to utilize a second form of birth control while participating 
in this study.   
Risks of twenty-four-hour ambulatory blood pressure cuff 
The risks to the ambulatory blood pressure monitoring generally relate to the annoyance of the 
repeated inflations and may become uncomfortable and/or could irritate the skin. Careful 
monitoring of the arm and removal during non-recording periods can alleviate any irritation 
Study Monitoring: 
This study will be conducted to meet strict requirements approved by the Institutional Review 
Board (IRB-01) of the University of Florida. It will be conducted according to the ethical 
principles stated in the Declaration of Helsinki (2008).  IRB approval will be obtained before 
initiating the study.  The consent forms will take into consideration the well-being, free-will and 
respect of the participants, including respect of privacy.  We agree to respect the requirements of 
the McGill University Faculty of Medicine Institutional Review Board, the Tri-Council Policy 

 
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Statement:  Ethical Conduct for Research Involving Humans, 2010.  The IRB will also monitor 
the lab performance during the approved period.  In addition, the IRB committee performs 
annual reviews of all human studies for safety related issues. An independent DSMB will be 
formed and operate under a pre-specified set of rules for monitoring.   
Data Safety: 
Each subject will be assigned a code when they are recruited into the study. Copies of case report 
forms, original test results, participants’ medical records, correspondence, participant informed 
consent and any other documentation relevant to the study collected from the subjects will be 
coded and secured in a safe place (in a locked filing cabinet inside a locked office).  Access will 
only be granted to investigators and study coordinators involved in the study. All electronic files 
will be encrypted.  Data recorded with computers, will be transferred and kept on computer disks 
with limited access.  This information will be kept for a maximum of 10 years after the study is 
completed, after which they will be destroyed.  The research data will appear only in the form of 
a scientific presentation or publication, without the participant’s name, or any potentially 
identifying information being disclosed.  These measures will protect subject confidentiality.  
All information obtained about the participant during this research study at the Canada sites will 
be performed under the oversight of the McGill University Faculty of Medicine Institutional 
Review Board.  The participant will sign an informed consent which will describe the safety plan 
for all research data.  The data collected from all study procedures performed at the Canada sites 
will be de-identified and transferred on to computer disks with limited access.  A copy of each 
participant’s de-identified data will be shipped to the University of Florida site.  The study code 
key, study documents and these disks will be kept for a maximum of 10 years at the Canada site 
following per policy after which they may be destroyed. 
Possible Benefits: 
Subjects may or may not benefit from participating in this study.  They could potentially benefit 
from taking minocycline and see improvement in their hypertension. 
Incidental Findings: 
Research scans are not subject to clinical review.  However, any incidental finding will be 
communicated with the participant and if requests the participants primary physician. 
Conflict of Interest: 
None. 
 
 

 
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