Clinical trial NCT02213575
Conditions: Hypertension
Keywords: Resistent Hypertension
Sponsor: University of Florida
Start date: 2016-03-05; Completion date: 2018-11-01
Enrollment: 5 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is a mechanistic study that will enroll 9 subjects who are participating in NCT02133872 (which is designed to evaluate minocycline to test the hypothesis that minocycline treatment would produce antihypertensive effects in drug-resistant neurogenic hypertensive individuals) to test whether the antihypertensive effect of minocycline is associated with a decrease in activated microglia in central nervous system autonomic regions as evidenced by changes in PET and MRI imaging.

Detailed description:
This study (Study 3) will recruit 9 subjects from NCT02133872 (Study1) who will agree to undergo additional autonomic testing and imaging studies at baseline and after 6 months of study treatment. Specialized imaging of the brain using magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning will be conducted at the Montreal Neurological Institute, in Montreal Canada.

For this study (Study 3) we include participants being enrolled Study 1 and/or participants who have completed participation in Study 1 and have not taken minocycline for 2 months will be approached to enroll in Study 3.

Arms: arm 1: Participants with neurogenic treatment-resistant hypertension who meet inclusion/exclusion criteria will receive minocycline at a dose determined to be most effective in lowering blood pressure (based on results from Study 1).

Participants will undergo brain imaging with MRI and PET at baseline and 26 weeks.

Intervention:

Drug: Minocycline Dose: 50, 100, or 200 mg/day (based on optimal BP-lowering dose from Study 1) Frequency: Administered orally twice daily (BID) Duration: 26 weeks arm 2: Patients without a diagnosis of neurogenic (treatment-resistant) Hypertension and have not been treated with minocycline will be recruited. These participants will undergo one-time brain imaging visit (MRI and PET)
Interventions: intervention 1: Minocycline
Intervention descriptions: intervention 1: Subjects will receive the dose of Minocycline determined to best lower BP and will undergo baseline and 26 week follow-up MRI and PET scans for changes in the paraventricular nucleus.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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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 
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 
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 


 
 
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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: (i) perform an open-label dose-range study to determine the lowest effective 
minocycline dose to lower BP, (ii) perform a double-blind, placebo-controlled cross-over study 
in a larger cohort of subjects; (iii) test whether the antihypertensive effect of minocycline is 
associated with a decrease in activated microglia in CNS autonomic region as compared to  
“control” patients without a diagnosis of neurogenic (treatment-resistant) HTN. 
Research Plan: 
The research will involve three separate studies with the same inclusion and exclusion criteria 
except for Study 3 which will recruit Two (2) “control” patients without a diagnosis of 
neurogenic (treatment-resistant) HTN for imaging comparison. 
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. 
• (For Study 3 Participants only) Willing to travel to Montreal, Canada for specialized 
imaging of the participant’s brain using magnetic resonance imaging (MRI), positron 
emission tomography (PET) scanning, Autonomic Nervous System Testing and blood 
drawing- if participant qualifies. 
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. 


 
 
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Study 1 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 Study 1 will be performed at Sites 1-3:  
Study 1 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 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.  
Study 1 Description: Thirty- five (35) 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  
Study 1 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  


 
 
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(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. 
• 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 


 
 
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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  
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. 


 
 
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• 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 
 
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 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 dose that provides with the highest number of responders will be selected for 
Study 2, the double-blind placebo controlled phase (see below).   


 
 
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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 and (3) ABPM differences 
in heart rate variability as a measure of autonomic nervous system activity.  Pseudo-resistance 
will be prospectively defined as mean ABPM SBP <130 mm Hg, despite elevated office SBP 
readings. Participants will be graded according to baseline-dipping pattern into 4 groups: 
extreme dippers (nighttime BP fall >20%, dippers (nighttime BP fall >10% and <20%), 
nondippers (nighttime BP fall <10% and >0%), and reverse-dippers (nighttime BP > daytime 
BP). The BP will be considered at target when daytime and nighttime values were <135/85 and 
<120/70 mm Hg, respectively.   
The proportion of participants who are extreme dippers (decline >20% in night to day BP), 
dippers (10-20% decline in night to day BP), non-dippers (<10% decline in BP at night), and 
reverse dippers (night BP >day BP) will be calculated at baseline and at study end-point for 
responders. Participants in each group will be further categorized according to tertiles of baseline 
ambulatory SBP. Baseline and 6 month ABPM measurements will be determined for each group.  
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 
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. Consequently, the dose that achieves a cumulative total 
of 27 responders will be used for the crossover study (Study 2). Similarly, if the 75% criteria is 
achieved using the lower dose only, then the trial will be considered as complete and no higher 
doses will be tested." The sample size carries an 8% standard error in estimating the proportion 
for a given dose.   
Study 2 will determine whether minocycline reduces BP and peripheral inflammation in 
patients with neurogenic hypertension using a double blind, placebo-controlled, crossover 
study design. 
All study procedures for Study 2 will be performed at Sites 1-3  Study 2 Rationale: A double-
blind crossover study using the dose of minocycline found to be optimal in Study 1 will be 
conducted. The “optimal” dose will be the dose resulting in the larger number of responders from 
Study 1 based on a daytime SBP reduction of ≥5 mmHg measured through ABPM. The inclusion 
and exclusion criteria will be applied to a new group of patients, along with Study 1 subjects, 
who will be screened for participation.  
Study 2 Description: Fifty-six (56) 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 


 
 
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informed consent has been obtained, the participant will be enrolled in the study.  Consented 
participants will be placed in Scheme 1 or Scheme 2 study plans.  For scheme 1, participants will 
be placed on minocycline for 16 weeks followed by 16 weeks placebo with an additional three 
week “wash out” between treatments. For Scheme 2, participants will be placed on placebo for 
16 weeks followed by 16 weeks of minocycline with a three week “wash out” period between 
treatments.  
Study 2 Research Visit and Procedures: 
Visit 1 Baseline 1 (Day 0) 
• Medical history and medication review will be performed. 
• Brief Physical exam will be performed. 
• Office SBP, DBP and PP will be performed. 
• Female participants will have a pregnancy test performed to verify a negative result 
before continuing. 
• Blood drawn (4 tablespoons approximately). 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 flow cytometry analysis and additional biomedical 
tests. 
• 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.   
• 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 14 + 3 days) 
• Review of medications and hospitalizations will be performed. 
• 24-hour ambulatory blood pressure monitor (ABPM).   
• Randomization to either Group A or Group B.   
o Group A  
▪ Minocycline (dose to be determined by Study 1) for 
16 weeks 
▪ 3 weeks of no study drug (wash out period) 
▪ Placebo (an inactive substance) for 16 weeks 
o Group B 
▪ Placebo for 16 weeks  
▪ 3 weeks of no study drug 
▪ Minocycline (dose to be determined by Study 1) 


 
 
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• Dispense study medication (depending on which group the participants are placed into)  
• Review HBPL will be performed. 
• 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 (Week 16, +7 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, 
• Review HBPL. 
• 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. 
• Blood draw (4 tablespoons approximately).  
• 24 hour ambulatory blood pressure monitor (ABPM).   
No study drug will be dispensed at this visit. 
Visit 4 (Week 19, + 7 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, 
• Review HBPL. 
• Dispense study medication (depending on which group the participants are placed into) 
• 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. 
• Blood draw (4 tablespoons approximately).  
• 24 hour ambulatory blood pressure monitor (ABPM).   
Visit 5 (Week 35, +7 days) 


 
 
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• 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, 
• Review HBPL. 
• 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.  Physical examination and vital signs.  
• Blood draw (4 tablespoons approximately).  
• 24 hour ambulatory blood pressure monitor (ABPM).  
No study drug will be dispensed at this visit. 
Visit 6 (Week 38, +7 days, Final Visit) 
• 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. 
• Review of HBPL. 
• 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. 
• Blood draw (4 tablespoons approximately). 
Sample size requirements for the cross-over study are based on a two-sided two-sample t-test 
assuming a standard deviation of 12, and with level of significance 0.05. We have greater than 
0.80 power to detect a daytime SPB difference of ≥5mmHg (from ABPM measurements) with a 
sample size of twenty-four (24) in each dose group. To allow for a 15% dropout rate, the study 
plans to randomize a total of fifty-six (56) subjects.  
Study 3 - will determine whether Minocycline decreases microglia activation in the PVN 
and other autonomic brain regions of patients with resistant NH as compared to “control” 
participants without a diagnosis of neurogenic (treatment-resistant) HTN.  
Study 3 Description: Nine (9) adult patients who are resistant to hypertensive medication and 
meet all inclusion criteria and no exclusion criteria will be offered an opportunity to participate 
in this study. Participants may have completed participation in study 1 or they are currently being 
recruited to participate in study 1. Study procedures will be reviewed with the participant and 


 
 
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once written consent is obtained the subject will be enrolled into the study. Study 3 for patients 
taking study medication will include up to two (2) trips to Montreal, Canada to undergo 
specialized imaging of the brain.  All imaging studies will be performed at the Brain Imaging 
Centre of the Montreal Neurological Institute (MNI), in Montreal Canada, using established 
protocols. The MNI is one of only 14 centers worldwide that hosts a high-resolution research 
tomograph (HRRT) which will allow PET imaging of small brainstem nuclei and has established 
the synthesis of microglia ligands. These studies will be done to determine how the brain is 
affected by this medication and how it impacts blood pressure.  . Two (2) patients will be 
recruited as “controls” (without a diagnosis of neurogenic (treatment-resistant)HTN and have not 
been treated with Study drug. Control participants will be asked to make one(1) trip to Montreal, 
Canada to undergo specialized imaging of the brain.  All imaging studies will be performed at 
the Brain Imaging Centre of the Montreal Neurological Institute (MNI), in Montreal Canada, 
using established protocols. The MNI is one of only 14 centers worldwide that hosts a high-
resolution research tomograph (HRRT) which will allow PET imaging of small brainstem nuclei 
and has established the synthesis of microglia ligands. These studies will be done as a 
comparison with patients who have taken study medication and have a diagnosis of neurogenic 
(treatment-resistant)HTN in order to compare how the brain is affected by study medication and 
how it impacts blood pressure between the two groups. This is described in more detail below. 
Sympathetic activity in HTN patients will be done by  autonomic function tests (such as ratio of 
standing BP to supine BP, immediate HR response to standing (30:15 ratio), HR variation with 
respiration, Valsalva maneuver will be performed. The primary study endpoint will be a 
reduction in microglia activation. 
Study procedures for participants currently being recruited to participate in Study 1 and Study 3: 
AND/OR 
Study Procedures for participants who have completed participation in Study 1 and have not 
taken minocycline for 2 months will be approached to enroll in Study 3. 
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 


 
 
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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. 
Prior to starting study medication: Participants will be asked to travel to Montreal Canada to 
have specialized imaging of the brain performed.  Upon completion of the first trip to Montreal, 
Canada, participants will return to the UF site and continue study visits as outlined in study 1.  
After Study 1 Visits are complete:  After completion of study 1, or after achieving blood 
pressure lowering on Minocycline as determined by the Investigator the participant will return to 
Montreal, Canada for repeat specialized imaging of the brain.  Upon completion of the second 
trip, participant will return to the UF site for their final visit. 
Final Visit 
• 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. 
Study 3 Procedures: 
Travel:  All travel arrangements will be made by the University of Florida, Cardiology Division 
and the research staff will assist the subject in getting prepared for the trip.   There will be no 
expense to them for airfare, hotel, meals, and travel to and from the airport. Any incidentals will 
be at their own discretion. 
Informed Consent at Canadian Site:  Participants will also be asked to provide research informed 
consent for the procedures that will occur at the Canadian Sites.  This portion of the research will 
be overseen by the McGill University Faculty of Medicine Institutional Review Board, Montreal, 
Canada.   
MRI: The MRI will be performed on a 3 Tesla Siemens Trio scanner at the baseline visit and the 
final study visit. T1 weighted volumetric data-sets with 1mm resolution for co-registration with 
the PET data to localize the brain structures of interest will be acquired. 
PET: Prior to scanning, two fine needle-catheters will be inserted into the veins of the participant 
arm.  One will be used to administer small amounts of a radioactive substance, the other to take 
four blood samples of 10 mL, equal to two teaspoons each.  A portion of the blood drawn will be 


 
 
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used to determine blood levels related to the imaging and a portion of the sample will be used to 
determine if a specific genetic component is present that may affect the imaging so that all 
participants can be categorized according to the specific genotype group that they belong to.  
This will allow proper interpretation of the PET-image results.  The radioactive substance the 
participant will receive prior to commencing the study medication and then at the end of the 
study is 11C-PBR28.  This substance is labelled with the short-lived radioactive atom Carbon 11 
(physical half-life = 20 minutes). The dose of 11C-PBR28 you will receive is 600 MBq.  The 
participant will receive this dose initially at the baseline visit and then again at the end of the 
study. MBq is short for megabecquerels, a unit used to measure how much radioactivity there is 
in a sample; the quantity the participant will receive is towards the low end of what is used for 
diagnostic clinical tests performed on a regular basis in Nuclear Medicine. The substance being 
injected to perform the PET study is not currently approved for general human use in Canada; 
however, its use for research purposes is permitted by Health Canada. 
PET scanning will be performed at the baseline visit and the final study visit. The PET scans will 
be performed on a CTI/Siemens HRRT scanner in 3D mode (63 parallel planes, resolution at 
1cm from the center: 4.4mm radial, 5.1mm axial). All Participants will receive an intravenous 
injection of 600MBq of 11C-PBR28 at each scanning session for a total of 1200MBq’s over an iv 
line. Prior to injection of the tracer, the participant will be brought inside the scanner and a 
transmission scan will be performed. This transmission scan will only be used to record the 
position of the participant’s head in the scanner and is needed for attenuation correction emission 
scans. After this transmission scan of approximately 10 minutes, the participants will be injected 
with 600MBq of 11C-PBR28  and a dynamic scan will be performed over 90 minutes.  Venous 
blood samples will be taken in the steady state phase following radiotracer injection.  During the 
11C-PBR28 PET scan, four venous samples at 30, 50 ,70 and 90 minutes (about 3 tablespoons) 
will be drawn. The subject is the allowed to leave the scanner for 35 minutes. After 80 minutes, 
the subject will once again be placed in the scanner and three frames from 90-120 minutes will 
be performed followed by a transmission scan. 
Since a genetic polymorphism can influence the binding affinity of the TSPO-receptor for 
11C-PBR28, all participants will be genotyped for this polymorphism and DV/plasma ratios will 
be corrected according to the respective genotype groups. A one-time blood sample (about half a 
table spoon) is required to perform this genotyoping and will be taken when the IV line is 
inserted at the time of the baseline scan. This is only necessary at the baseline scan. This blood 
sample will be sent to the McGill University and Genome Quebec Innovation Centre for 
analysis. The blood sample will be stored there for the duration of the study. After this time, the 
blood sample will be destroyed. The sample will be used only for the purposes of this research 
protocol.   
The scanning session will take up to four hours to complete, during which time the participant 
will be asked to lie still on the mattress in the scanner.  All procedures during the PET study will 
be carried out by a qualified nuclear medicine technician, and supervised by a qualified nuclear 
medicine physician. 
Blood Draws: Blood will be drawn (3 tablespoons) during the PET scan to determine metabolite 
corrected plasma activity, and average plasma activity will be used to calculate simplified 
distribution volume (DV)/plasma ratios. Since a genetic polymorphism can influence the binding 


 
 
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affinity of the TSPO-receptor, all participants will be genotyped for this polymorphism and 
DV/plasma ratios will be corrected according to the respective genotype groups.  
Autonomic Function Testing:  
 The Autonomic Nervous System Testing will take place at the Autonomic Reflex Laboratory of 
the Jewish General Hospital.  Prior to the test, the participant’s height and weight will be 
obtained.  The participant will then be required to lie on a special table that can be tilted to a 
standing position.  Electrodes will be placed on the participant’s chest and abdomen to record 
heart function.  The participant will wear a finger cuff that continuously measures blood 
pressure.  A small device will be placed near the participant’s nose to record breathing.  An 
elastic headband will be placed around the participant’s forehead to measure brain blood flow 
and oxygen. The participant will then lie quietly for 10 minutes.  The tilt table will then be 
placed upright for 30 minutes.  After the 10 minutes of standing, the tilt table will be returned to 
the lying position.  After a few minutes of rest, the participant will be asked to take several slow 
deep breaths for about 1 minute.  The participant will then be asked to blow into a tube on 2 
separate occasions for 15 seconds each time.  During these breathing tests the medical staff will 
continue to measure blood pressure and heart function.  The tilt table test and the breathing tests 
are all routinely used in clinical practice to diagnose participants with low blood pressure or 
other autonomic nervous system disorders. 
Participants will be assessed at the autonomic lab at the Jewish General Hospital. A standard test 
battery that is used on a daily basis to assess clinical cardiovascular and sudomotor autonomic 
function will be performed using standard non-invasive techniques. The battery comprises 
cardiovascular response 40min of 80° head-up tilt, followed by response to Valsalva maneuver 
and rhythmic deep breathing. During these tests beat-to-beat BP will be measured from the 
finger using photoplathysmography, cerebral blood flow (transcranial Doppler and NIRS) and 
HR from routine 3-lead EKG. Postganglionic sympathetic sudomotor function will be assessed 
from 4 standard sites using the QSART. The total duration of testing is about 2h including 
participant preparation, device placement, calibration and actual testing.For the second part of 
the test, small capsules will be placed on the participants forearm, leg and foot.  These capsules 
will be filled with a liquid containing a drug called acetylcholine.  The capsules will be 
connected to a small battery and for 5 minutes the participant will feel a mild tingle or buzzing 
sensation over the area of the capsule.  This test causes sweating over the area covered by the 
capsule.  The sweating lasts about 15 minutes and the medical staff will measure it for 10 
minutes.  The capsules are then removed.  This test is called a QSART and is also routinely used 
to diagnose participants with autonomic nervous system disorders. 
The PET and MRI will take place at the Brain Imaging Centre of the Montreal Neurological 
Institution. These tests will take place over one or possibly two days, whichever is easier to 
schedule.   
The Autonomic Nervous System Testing will take place at the Jewish General Hospital, also in 
Montreal and will take approximately 1 ½ to 2 hours.   
Study 3 Data Analysis Plan:  T1 MR images will be used to localize the respective nuclei in the 
brain and to place volumes of interest for quantitative PET analysis. (cite Heiss WD et al 


 
 
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Metabolic Rates in Small Brain Nuclei Determined by High-Resolution PET, J Nucl Med 2004 
v45 p1811).  
PET Images will be reconstructed using a filtered back-projection algorithm (Fourier rebinning 
and 2D backprojection with Hanning filter: kernel FWHM=3 mm), supplied by the 
manufacturer, with a Hanning filter cut-off frequency of 0.4 cycles/pixel. After correction for 
scatter, attenuation and random coincidences, image volumes comprising 21 frames with matrix 
dimensions of 128x128x63 voxels and a voxel size of 2.06 x 2.06 x 2.43 mm will be obtained.  
For each participant, PET images will all be registered to the T1 weighted anatomical MRI in 
native space for localization purposes. For integration and coregistration of the different image 
modalities, a new software package (VINCI 2.55, http://www.mpifnf.de/vinci/) developed at the 
Max-Planck-Institute for Neurological Research in Cologne will be used. This tool has been 
developed for integration of multimodality imaging data sets with positioning information from 
neuronavigation systems (like the one used in this study). Using this tool, all relevant parameters 
can be measured at defined points within the coregistered imaging volumes to test the specific 
hypotheses. 
The DV/plasma ratio for all brain regions in each subject at baseline will be compared to the 
DV/plasma ration at follow up using a one-factor repeated measures ANOVA on ranks 
(Friedmann test) with respective post-hoc tests for pairwise comparisons. A similar non 
parametric repeated measures design will be used for assessing differences in the physiological 
parameters acquired during the autonomic testing. 
We expect participants will exhibit increased 11C-PBR28  binding in the autonomic brain regions 
(paraventricular nucleus (PVN), rostral ventrolateral medulla (RVLM), nucleus of the solitary 
tract (NTS), etc.) prior to treatment. This should appear as a well-defined area of increased 
radioactivity. These areas of increased 11C-PBR28  would show a decreased uptake on the 
follow-up scan 52 weeks after initiation of minocycline. We do not anticipate any difficulty in 
subject recruitment or expect any significant side effects of minocycline. 
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. “Control” patients in study 3 will not take this medication.. 
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 


 
 
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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.   
MRI: During the MRI-study, participants will be exposed to a strong magnetic field. No long-
term negative side effects have been observed from this type of study. Participants with 
transdermal patches will have to remove the patch before the procedure and replace the patch 
after the procedure. If necessary, the respective drug will be substituted orally or intravenously 
for the duration of the scan. If substitution or interruption of transdermal drug application is not 
possible, these participants will not be included in the study. The MR is very noisy and the 
subjects will wear headphones to reduce this effect. Claustrophobic subjects will not be included. 
Positron Emission Tomography (PET): 
Participants may experience some discomfort caused by the insertion of the fine needle catheter 
into their veins used to inject the radioactive substance as well as to draw blood.  Although the 
taking of the blood sample causes no serious problems for most people, it can cause some 
bleeding, bruising and/or discomfort at the site where the needle is inserted.  Also, participants 
may experience some discomfort as a result of lying on the mattress in the scanner for a long 
time without moving. 
The main risk of taking part in this study is exposure to radiation from the short-lived tracer 
substance injected for the PET scan.  The administered radioactive substance 11C-PBR28  will 
expose patients to a maximal dose of  4mSv per scan, total of 8mSv for the two scans according 
to our best scientific estimates.  This small dose of radiation 8mSv, is above that which 
participants are inevitably exposed to in daily life (natural radiation in the environment, cosmic 
rays, etc.), or to that which participants might receive for medical reasons (diagnostic x-rays, 
radiation therapy).  Nationally accepted limits on radiation doses which can be administered for 
research purposes have been defined (50 mSv/year), and in order to ensure that participants do 
not go above the recommended limit participants must make sure to let the investigators know 
about any other research protocol that participants might have been part of that would have 
involved radiation exposure, as well as to mention the current protocol, if participants do take 
part in it, to any investigator asking participants to take part in another protocol in the future.  
Most of the radioactivity participants will receive will be gone from their body in a matter of 
hours.  The risk which is alluded to when discussing risk associated with radiation exposures of 
the level seen in PET scanning (specifically in the current study, the radiation exposure is 


 
 
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estimated at  8mSv) is that of developing a cancer at some point in the future, which would not 
have happened if participants had not received that radiation dose.  Although radiation clearly 
increases the risk of developing cancer over certain doses, its ability to do so at the levels used in 
PET imaging has never been observed, is certainly at most very low and could conceivably not 
even exist. 
The substance being injected to perform the PET study is not currently approved for general 
human use in Canada.  However, its use for research purposes is allowed by Health Canada. 
Autonomic Nervous System Testing: The most important risk is the potential for syncope 
during tilt testing. As the participant is continuously monitored during the test, the prodrome to 
syncope is easily detectable and the test can terminated by returning the table to the supine 
position. Objective criteria for test termination include: decline of abrupt decline of heart rate by 
more than 20 BPM or a decline in systolic pressure or 30 mmHg. In addition continuous 
monitoring of cerebral blood flow with transcranial Doppler and NIRS ensures that cerebral 
perfusion in the up-right position is adequate at all times during the test. 
A minor skin irritation can occur from application of the EKG electrodes or during the 
iontopheresis of acetylcholine during QSART testing. 
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 
Contraindications: 
PET Study:  
The following are contraindications for this procedure: If you are pregnant or breast feeding, 
under 18 years of age, previous radiation absorbed doses received within the past (12 months) 
from other experiments that would lead with inclusion of this study, to an aggregate radiation 
absorbed dose exceeding 20 mSv. 
MRI Study:  
The following are contraindications for this procedure: The presence of a cardiac pacemaker, an 
aneurysm clip, heart / vascular clip, prosthetic valve, metal prosthesis, metal in your eye or body, 
tattoos, body piercing or dental braces, of if you suffer from acute claustrophobia. Pregnant and 
breast feeding women should not undergo an MRI. Transdermal patches are also a 
contraindication. If you need to have a patch on most of the time, you should bring one with you 
for application after the scanning session. It is imperative that you fill out a detailed 
questionnaire aimed at identifying any contraindications prior to undergoing this procedure.  
 
 
Effects of participation in this study on your health:  


 
 
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Both the PET and MRI scans should not interfere with any treatment or other diagnostic test you 
may require. 
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 
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. 


 
 
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Conflict of Interest: 
None. 
 
 


 
 
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References: 
1. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, 
Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, 
Kissela BM, Kittner SJ, Lackland  DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus 
GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter 
NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, 
Turner MB; American Heart Association Statistics Committee and Stroke Statistics 
Subcommittee. Executive summary: heart disease and stroke statistics--2012 update: a 
report from the American Heart Association. Circulation. 2012; 125(1): 188-97. 
2. Roberie DR, Elliott WJ. What is the prevalence of resistant hypertension in the United 
States? Curr Opin Cardiol. 2012;27(4):386-91.  
3. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G et al. 2007 
Guidelines for the Management of Arterial Hypertension: The Task Force for the 
Management of Arterial Hypertension of the European Society of Hypertension (ESH) and 
of the European Society of Cardiology (ESC). J Hypertens. 2007;25(6):1105-87.  
4. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD et al. Resistant 
hypertension: diagnosis, evaluation, and treatment. A scientific statement from the 
American Heart Association Professional Education Committee of the Council for High 
Blood Pressure Research. Hypertension. 2008;51(6):1403-19.  
5. Fisher JP, Paton JF. The sympathetic nervous system and blood pressure in humans: 
implications for hypertension. J Hum Hypertens. 2012;26(8):463-75.  
6. Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci. 2006;7(5):335-
46. 
7. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton 
A, Sievert H,Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic 
denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort 
study. Lancet 2009; 373:1275-1281. 
8. Yellowlees Douglas J, Bhatwadekar AD, Li Calzi S, Shaw LC, Carnegie D, Caballero S, 
Li Q, Stitt AW, Raizada MK, Grant MB. Bone marrow-CNS connections: implications in 
the pathogenesis of diabetic retinopathy. Prog Retin Eye Res. 2012; 31(5):481-94. 
9. Shi P, Raizada MK, Sumners C. Brain cytokines as neuromodulators in cardiovascular 
control. Clin Exp Pharmacol Physiol 2010; 37(2):e52-7. 
10. Shi P, Diez-Freire C, Jun JY, Qi Y, Katovich MJ, Li Q, Sriramula S, Francis J, Sumners 
C, Raizada MK. Brain microglial cytokines in neurogenic hypertension. Hypertension 
2010; 56:297-303. 
11. Zubcevic J, Waki H, Raizada MK, Paton JF. Autonomic-immune-vascular interaction: an 
emerging concept for neurogenic hypertension. Hypertension 2011; 57:1026-1033. 
12.  Jun JY, Zubcevic J, Qi Y, Afzal A, Carvajal JM, Thinschmidt JS, Grant MB, Mocco J, 
Raizada MK. Brain mediated dysregulation of the bone marrow activity in angiotensin II-
induced hypertension. Hypertension 2012; 60(5):1316-23. 
13. Shi P, Zhou G, Desland FA, Shan Z, Raizada MK, Sumners C. Elevated brain MCP-1 
contributes to neuroinflammation in hypertension. HBPR Conference, 2012, Abstract # 
226. 

ICF_001.pdf: 
Patients who have completed study 1
IRB Project #:  201500594
Page 1 of 21
IRB Version: 10/19/2011
Study 3
PI Version: 12/18/2018
INFORMED CONSENT FORM
to Participate in Research, and
AUTHORIZATION
to Collect, Use, and Disclose 
Protected Health Information 
(PHI)
INTRODUCTION
Name of person seeking your consent:
Place of employment & position: 
Please read this form which describes the study in some detail. A member of the research 
team will describe this study to you and answer all of your questions.  Your participation is 
entirely voluntary.  If you choose to participate you can change your mind at any time and 
withdraw from the study.  You will not be penalized in any way or lose any benefits to which 
you would otherwise be entitled if you choose not to participate in this study or to withdraw.  
If you have questions about your rights as a research subject, please call the University of 
Florida Institutional Review Board (IRB) office at (352) 273-9600.   
GENERAL INFORMATION ABOUT THIS STUDY
1.
Name of Participant ("Study Subject")
___________________________________________________________________ 
2.
What is the Title of this research study?
Effect of Minocycline Treatment on Drug-Resistant Hypertensive Patients-Study 3
3.
Who do you call if you have questions about this research study?
Principal Investigator: Dr. Carl J. Pepine (352) 273-9082 (during office hours)
Other research staff: 
Study ID:IRB201500594   Date Approved: 5/15/2019
NCT02213575


Patients who have completed study 1
IRB Project #:  201500594
Page 2 of 21
IRB Version: 10/19/2011
Study 3
PI Version: 12/18/2018
Dana Leach, DNP, ARNP (352) 273-8933 during office hours
Evenings, weekends, and holidays: call (352) 265-0111 and ask for the Cardiology 
Fellow on call.
4.   Who is paying for this research study? 
The sponsor of this study is the National Institutes of Health.
5.   In general, what do you need to know about this Research Study?
Agreeing to become involved in any research is always voluntary.  By signing this 
form, you are not waiving any of your legal rights.  If you decide not to participate in 
this research, you will not be penalized in any way and you will not lose any benefits 
to which you are entitled. If you have questions about your rights as a research 
subject, please call the University of Florida Institutional Review Board (IRB) office at 
(352) 273-9600.    
a.) In general, what is the purpose of the research, how long will you be involved?
The purpose of this study is to observe the effects the drug, minocycline, and how it 
works with the chemicals in your brain and to determine the best dose to use in future 
studies.  Your participation will last 180 days. 
b.)  What is involved with your participation, and what are the procedures to be 
followed in the research?
This study involves specialized imaging of the brain, and you must be willing to travel 
to Montreal, Canada for these tests, which will be done at the Montreal Neurological 
Institute (McConnell Brain Imagine Centre) and the Jewish General Hospital.  These 
images will be collected before taking study medication and will be performed again 
between two to six months after treatment. 
c.)  What are the likely risks or discomforts to you?
The study drug is a well-tolerated antibiotic but can have some side effects, which are 
described in full detail later in this form.
You may experience some discomfort caused by the insertion of the fine needle 
catheter into your veins used to inject the radioactive substance as well as to draw 
blood.  The main risk of taking part in this study is exposure to radiation from the short-
lived tracer substance injected for the PET scan.  
Study ID:IRB201500594   Date Approved: 5/15/2019


Patients who have completed study 1
IRB Project #:  201500594
Page 3 of 21
IRB Version: 10/19/2011
Study 3
PI Version: 12/18/2018
The conditions imposed by the use of magnetic resonance imaging can cause a 
certain amount of discomfort due to the fact that you may have to remain completely 
still during the examination and the noise generated by the scanner while it is 
capturing images could cause you some discomfort as well, however, you will be 
provided with earplugs to reduce this effect.
For the Autonomic Nervous System Testing you will be positioned in a head-up tilt 
which may cause lightheadedness or fainting.  
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.
The risks of drawing blood from vein and/or intravenous catheter (small plastic tubing 
inserted into your vein to obtain blood samples) include discomfort at the site of 
puncture; possible bruising and swelling around the puncture site; rarely an infection 
and uncommonly faintness from the procedure.
d.)  What are the likely benefits to you or to others from the research?
You may or may not benefit from participating in this study.  You may potentially benefit 
from taking minocycline and see improvement in your hypertension. Information 
generated from this study may help others in the future with hypertension.
e.)  What are the appropriate alternative procedures or courses of treatment, if any, 
that might be helpful to you?
The alternative treatment would be to continue your normal clinical care as directed by 
your physician. 
Twenty to thirty percent of patients with high blood pressure (BP) have difficulty keeping it 
controlled with medications. This is because their high BP is controlled by the brain and 
most known blood pressure medications do not cross the blood-brain barrier to affect the 
responsible cells in the brain.  The purpose of this study is to observe the effects the drug 
minocycline and how it works with the chemicals in your brain and to determine the best 
dose to use in future studies.  Minocycline is an FDA approved drug used to treat infections.  
You are being asked to be in this research study because you have been diagnosed with 
high blood pressure that is difficult to control and you have participated in the first study for 
the project and it was determined that your blood pressure was responsive to minocycline.
Additional and more detailed information is provided within the remainder of this 
Informed Consent form, please read before deciding if you wish to participate in this 
study
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6.  What will be done as part of your normal clinical care (even if you did not 
participate in this research study)?
Your normal clinical care will continue as previously determined by your physician. 
There will be no changes to your normal clinical care if you decide to participate in this 
study.
7.  What will be done only because you are in this research study? 
To participate in this study, you must meet certain qualifications, which the study staff 
will discuss with you.  You are being asked to participate because you qualify for and 
have already participated in the first study of this project. If you decide to take part in 
this study, we will ask you to provide written informed consent. This study involves 
specialized imaging of the brain, and you must be willing to travel to Montreal, Canada 
for these tests, which will be done at the Montreal Neurological Institute (McConnell 
Brain Imagine Centre) and the Jewish General Hospital.  These images will be 
collected before taking study medication and will be performed again between two to 
six months after treatment. 
In order to participate you will have a baseline visit where a complete medical history 
will be taken and a brief physical examination and ambulatory monitor will be 
performed.
Visit 1 Baseline 1 (Screen)
•
You will have a medical history taken and will be asked about the medication you 
are currently taking.
•
You will have a physical examination:  Your study doctor will listen to your heart 
and lungs, your vital signs (temperature, blood pressure, heart rate, and breathing 
rate) will also be measured.  Your height and weight will be recorded.
•
You will have your office blood pressure measured
•
The “office” blood pressure (BP) measurement (meaning your blood pressure 
while at the study doctor’s office). At each visit, office BP will be recorded as an 
average of 3 BP readings after you have rested for 5 minutes in a quiet room..  In 
preparation for your office blood pressure measurements you will be asked to try 
to follow the below guidelines:
•
Take all prescribed medications at your usual times on the day of these office BP 
measurements.  If you have not taken your medications as usual, you will be asked 
to return for another office BP visit when you have taken your medications.
•
At least thirty minutes before you go in for your study visit, avoid caffeine, smoking 
and exercising.
WHAT CAN YOU EXPECT IF YOU PARTICIPATE IN THIS STUDY?
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•
During the measurements you will be asked to sit quietly in a chair with both of 
your feet flat on the ground for at least 5 minutes before multiple BP readings are 
taken.
•
If you are a woman able to become pregnant, you will be asked to take a pregnancy 
test that must have a negative result before you can continue in this study.  If 
sexually active, you must agree to use two 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 
and discontinue the use of Minocycline immediately.
•
You will be instructed to begin recording your home blood pressure monitor 
readings if you are not currently doing so. You will need to record your blood 
pressure readings at least 3 times a week. These recordings will need to be 
brought with you to your clinic visits.
•
You will be fitted with a 24 hour ambulatory blood pressure monitor (ABPM).  This 
is described under “Visit 1
•
You will be scheduled to go to Montreal for Baseline Imaging as noted below. 
•
You will have blood drawn (3 tablespoons)
Travel to Montreal:
Prior to starting study medication you will be asked to undergo specialized imaging of 
your brain using magnetic resonance imaging (MRI) and positron emission 
tomography (PET) scanning to determine how the brain is affected by this medication 
and how it impacts your blood pressure.   In addition, you will also undergo Autonomic 
Nervous System Testing.  The PET and MRI will take place at the Montreal 
Neurological Hospital. These will take place either over one or possibly two days, 
whichever is easier to schedule.  Each scan takes approximately one to one and half 
hours.  The Autonomic Nervous System Testing will take place at the Jewish General 
Hospital, also in Montreal and will take approximately 1 ½ to 2 hours.  
During the PET scan, a blood sample will be taken from you for genetic analysis, 
approximately (3 tablespoons).  The purpose of this genetic analysis is only to enable 
the investigators to properly analyze your PET images.  If you agree to participate in 
this study, your blood sample will be sent to the McGill University and the Genome 
Quebec Innovation Centre for analysis.  The sample will be stored here for the duration 
of this study, after this time the blood sample will be destroyed.  Your sample will be 
used only for the purposes of this research project.  
Positron Emission Tomography (PET):
Positron Emission Tomography or PET, is a nuclear medicine imaging technique 
which produces 3D images or pictures of the brain (specific to this study).
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Prior to scanning, two fine needle-catheters will be inserted into the veins of your arm.  
One will be used to administer small amounts of a radioactive substance, the other to 
take four blood samples of 10 mL, equal to two teaspoons each.  A portion of the blood 
drawn will be used to determine blood levels related to the imaging and a portion of 
the sample will be used to determine if a specific genetic component is present that 
may affect the imaging so that all patients can be categorized according to the specific 
genotype group that they belong to.  This will allow us to properly interpret the PET-
image results.  The radioactive substance you will receive prior to commencing the 
study medication and then at the end of the study is 11C-PBR28 .  This substance is 
labelled with the short-lived radioactive atom Carbon 11 (physical half-life = 20 
minutes). The dose of 11C-PBR28  you will receive is 1200 MBq.  You will receive this 
dose initially at the baseline visit and then again at the end of the study. MBq is short 
for megabecquerels, a unit used to measure how much radioactivity there is in a 
sample; the quantity you will receive is towards the low end of what is used for 
diagnostic clinical tests performed on a regular basis in Nuclear Medicine. The 
substance being injected to perform the PET study is not currently approved for 
general human use in Canada; however, its use for research purposes is permitted by 
Health Canada.
The scanning session will take approximately one and a half hour for each scan, 
during which time you will be asked to lie still on the mattress in the scanner.  All 
procedures during the PET study will be carried out by a qualified nuclear medicine 
technician, and supervised by a qualified nuclear medicine physician.
Magnetic Resonance Imaging (MRI):
A magnetic resonance examination is a medical technique that provides high quality 
images of the brain. This technique uses a natural force around us; magnetism.  This 
intense magnetic field is created by a magnet.  For the MRI session, you will lie on a 
mattress that will slowly slide into a large cylindrical tube where pictures of your head 
will be taken during a period of 45 to 60 minutes.  The tube is open at both ends; it 
has excellent air circulation, and is well lit.  An intercom system will enable you to talk 
with the technician, if necessary.  For your comfort you will be asked to wear protective 
earplugs, this is in order to cut out the large amount of noise made by the scanner.  It 
is important that you remain completely still when the instrument is capturing images.  
To this end, a small cushion will be placed around your head to hold it still during the 
scan.  
You will not be injected with any substances during this examination.  
Autonomic Nervous System Testing:
The Autonomic Nervous System Testing will take place at the Autonomic Reflex 
Laboratory of the Jewish General Hospital.  Prior to the test, your height and weight 
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will be obtained.  You will then be required to lie on a special table that can be tilted 
to a standing position.  Electrodes will be placed on your chest and abdomen to record 
heart function.  You will wear a finger cuff that continuously measures blood pressure.  
A small device will be placed near your nose to record breathing.  An elastic headband 
will be placed around your forehead to measure brain blood flow and oxygen.  You 
will then lie quietly for 10 minutes.  The tilt table will then be placed upright for 30 
minutes.  After the 10 minutes of standing, the tilt table will be returned to the lying 
position.  After a few minutes of rest, you will be asked to take several slow deep 
breaths for about 1 minute.  You will then be asked to blow into a tube on 2 separate 
occasions for 15 seconds each time.  During these breathing tests we will continue to 
measure blood pressure and heart function.  The tilt table test and the breathing tests 
are all routinely used in clinical practice to diagnose patients with low blood pressure 
or other autonomic nervous system disorders.
For the second part of the test, small capsules will be placed on your forearm, leg and 
foot.  These capsules will be filled with a liquid containing a drug called acetylcholine.  
The capsules will be connected to a small battery and for 5 minutes you will feel a mild 
tingle or buzzing sensation over the area of the capsule.  This test causes sweating 
over the area covered by the capsule.  The sweating lasts about 15 minutes and we 
measure it for 10 minutes.  The capsules are then removed.  This test is called a 
QSART and is also routinely used to diagnose patients with autonomic nervous 
system disorders.
The cardiology research team will assist you in getting prepared for the trips to 
Montreal, Canada.  More information about the costs of the travel can be found below 
in the “If you participate in this study, what will it cost you” section.
When you return, you will then be followed and treated as outlined in the Study 1 
consent. 
Between two and six months, you will be scheduled to return to Canada for repeat 
imaging, depending on when your blood pressure normalizes. 
Tests done only for research purposes will not be evaluated or used to diagnose or 
treat any of your medical problems. This/these test(s) may need to be repeated if 
required for your medical care in the future.
When you return you will be scheduled for study visits as outlined below and restarted 
on the dose of minocycline that lowered your blood pressure during your previous 
participation. After you are considered a responder to minocycline, you will be 
scheduled to return to Montreal for repeat imaging.
Visit 2 (Day 0- ±3 days)
•
You will be dispensed study medication (the dose of minocycline you responded 
to previously)
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
Your home blood pressure monitor readings that you recorded will be reviewed 
and you will be given a new home blood pressure log.
•
You will have your office blood pressure measured. This is described under “Visit 
1”.
Visit 3 (2 week + 7 days)
•
Bring any unused study medication and bottles including empty bottles to this visit.
•
You will have an updated medical history taken and will be asked about the 
medication you are currently taking.
•
You will have a brief physical examination and vital signs. This is described under 
“Visit 1”.
•
You will have your office blood pressure measured. This is described under “Visit 
1”.
•
Your home blood pressure monitor readings that you recorded will be reviewed 
and you will be given a new home blood pressure log.
•
You will be re-dispensed study medication (minocycline). You will be instructed to 
continue to take study medication (minocycline  by mouth once a day).
Visit 4 (Day 60 + 14 days)
•
Bring any unused study medication and bottles including empty bottles to this visit
•
You will have an updated medical history taken and will be asked about the 
medication you are currently taking.
•
You will have a brief physical examination and vital signs. This is described under 
“Visit 1”.
•
You will have your office blood pressure measured. This is described under “Visit 
1”.
•
Your home blood pressure monitor readings that you recorded will be reviewed 
and you will be given a new home blood pressure log.
•
You will have blood drawn (1 tablespoon approximately) for analysis and additional 
biomedical tests. 
•
You will be re-dispensed study medication (minocycline ). You will be instructed to 
continue to take study medication (minocycline  by mouth once a day).
•
You will be fitted with a 24 hour ambulatory blood pressure monitor (ABPM).  This 
is described under “Visit 1”.
Visit 5 Phone Call (within 10 days of Visit 4)
•
You will be given results of your ABPM blood pressures by the study team and told 
if your participation in this study will end or continue on to the next visit.
•
If you are told by the study staff that your participation is continuing, you will be 
asked to return to clinic within approximately 1 week to increase your study 
medication dose  mouth once a day.
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•
If you are told by the study staff that your participation has ended, you will be asked 
to have your final visit scheduled to have repeat imaging in Montreal. When you 
return you will be asked to return to clinic within approximately 1 week for a final 
visit (see Visit 12 Final Visit for description).
Visit 6 (within 7 days of Visit 5)
•
Bring any unused study medication and bottles including empty bottles to this visit
•
You will have an updated medical history taken and will be asked about the 
medication you are currently taking.
•
Your home blood pressure monitor readings that you recorded will be reviewed 
and you will be given a new home blood pressure log.
•
You will have a brief physical examination and vital signs. This is described under 
“Visit 1”.
•
You will have your office blood pressure measured. This is described under “Visit 
1”.
•
You will be dispensed study medication (minocycline). You will be instructed to 
continue to take study medication (minocycline by mouth once a day).
Visit 7 (Day 90 + 14 days)
•
Bring any unused study medication and bottles including empty bottles to this visit
•
You will have an updated medical history taken and will be asked about the 
medication you are currently taking.
•
You will have a brief physical examination and vital signs. This is described under 
“Visit 1”.
•
You will have your office blood pressure measured. This is described under “Visit 
1”.
•
Your home blood pressure monitor readings that you recorded will be reviewed 
and you will be given a new home blood pressure log.
•
You will be re-dispensed study medication (minocycline). You will be instructed to 
continue to take study medication (minocycline by mouth once a day).
Visit 8 (Day 120 + 14 days)
•
Bring any unused study medication and bottles including empty bottles to this visit
•
You will have an updated medical history taken and will be asked about the 
medication you are currently taking.
•
You will have a brief physical examination and vital signs. This is described under 
“Visit 1”.
•
You will have your office blood pressure measured. This is described under “Visit 
1”.
•
Your home blood pressure monitor readings that you recorded will be reviewed 
and you will be given a new home blood pressure log.
•
You will have blood drawn (1 tablespoon approximately). This is described under 
“Visit 4”.
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•
You will be re-dispensed study medication (minocycline). You will be instructed to 
continue to take study medication (minocycline by mouth once a day).
•
You will be fitted with a 24 hour ambulatory blood pressure monitor (ABPM). This 
is described under “Visit 1”.
Visit 9 Phone Call (within 10 days of Visit 8)
•
You will be given results of your ABPM blood pressures by the study team and told 
if your participation in this study will end or continue on to the next visit.
•
If you are told by the study staff that your participation is continuing, you will be 
asked to return to clinic within approximately 1 week to increase your study 
medication dose  mouth once a day.
•
If you are told by the study staff that your participation has ended, you will be asked 
to have your final visit scheduled to have repeat imaging in Montreal. When you 
return you will be asked to return to clinic within approximately 1 week for a final 
visit (see Visit 12 Final Visit for description).
Visit 10 (within 7 days of Visit 9)
•
Bring any unused study medication and bottles including empty bottles to this visit
•
You will have an updated medical history taken and will be asked about the 
medication you are currently taking.
•
You will have your office blood pressure measured. This is described under “Visit 
1”.
•
You will have a brief physical examination and vital signs. This is described under 
“Visit 1”.
•
Your home blood pressure monitor readings that you recorded will be reviewed 
and you will be given a new home blood pressure log.
•
You will be dispensed study medication (minocycline). You will be instructed to 
continue to take study medication (minocycline by mouth twice a day).
Visit 11 (Day 150 +14 days)
•
Bring any unused study medication and bottles including empty bottles to this visit
•
You will have an updated medical history taken and will be asked about the 
medication you are currently taking.
•
You will have a brief physical examination and vital signs. This is described under 
“Visit 1”.
•
Your home blood pressure monitor readings that you recorded will be reviewed 
and you will be given a new home blood pressure log.
•
Your home blood pressure monitor readings that you recorded will be reviewed
•
You will be re-dispensed study medication (minocycline). You will be instructed to 
continue to take study medication (minocycline by mouth twice a day).
Final Visit (Day 180 +14 days or at any time your participation ends)
•
Bring any unused study medication and bottles including empty bottles to this visit
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•
You will have an updated medical history taken and will be asked about the 
medication you are currently taking.
•
You will have a brief physical examination and vital signs. This is described under 
“Visit 1”.
•
You will have your office blood pressure measured. This is described under “Visit 
1”.
•
Your home blood pressure monitor readings that you recorded will be reviewed
•
You will have blood drawn (4 tablespoons approximately). This is described under 
“Visit 1”.
•
You will be fitted with a 24 hour ambulatory blood pressure monitor (ABPM). This 
is described under “Visit 1”.
Once this research study is completed, any information that could identify you might 
be removed from any identifiable private information or identifiable biospecimens 
collected and that, after such removal, the information or biospecimens could be used 
for future research studies or distributed to another investigator for future research 
studies without additional informed consent from you or your legally authorized 
representative
If you have any questions now or at any time during the study, please contact one of 
the research team members listed in question 3 of this form.
8. How long will you be in this research study?
Your participation could last up to 180 days.
9. How many people are expected to take part in this research study?
Nine (9) subjects will need to complete this protocol.
WHAT ARE THE RISKS AND BENEFITS OF THIS STUDY AND 
WHAT ARE YOUR OPTIONS?
10. What are the possible discomforts and risks from taking part in this research 
study?
Minocycline 
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The study medication is an FDA approved drug and is a well-tolerated antibiotic used 
every day to treat many different types of infections.  Side effects of this drug may 
include abdominal cramping, diarrhea, nausea, dry mouth, headache or 
hypersensitivity (skin sensitivity after sun exposure, dizziness or mild skin rashes).  
Please inform the study doctor if you experience any of these side effects. 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.
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.  
Positron Emission Tomography (PET):
You may experience some discomfort caused by the insertion of the fine needle 
catheter into your veins used to inject the radioactive substance as well as to draw 
blood.  Although the taking of the blood sample causes no serious problems for most 
people, it can cause some bleeding, bruising and/or discomfort at the site where the 
needle is inserted.  Also, you may experience some discomfort as a result of lying on 
the mattress in the scanner for a long time without moving.
The main risk of taking part in this study is exposure to radiation from the short-lived 
tracer substance injected for the PET scan.  The administered radioactive substance 
11C-PBR28   will expose you to a maximal dose of 4 mSv per scan, total of 8 mSv for 
the two scans according to our best scientific estimates.  This small dose of radiation 
8mSv, is above that which you are inevitably exposed to in daily life (natural radiation 
in the environment, cosmic rays, etc.), or to that which you might receive for medical 
reasons (diagnostic x-rays, radiation therapy).  Nationally accepted limits on radiation 
doses which can be administered for research purposes have been defined (50 
mSv/year), and in order to ensure that you do not go above the recommended limit 
you must make sure to let the investigators know about any other research protocol 
that you might have been part of that would have involved radiation exposure, as well 
as to mention the current protocol, if you do take part in it, to any investigator asking 
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you to take part in another protocol in the future.  Most of the radioactivity you will 
receive will be gone from your body in a matter of hours.  The risk which is alluded to 
when discussing risk associated with radiation exposures of the level seen in PET 
scanning (specifically in the current study, the radiation exposure is estimated at 8 
mSv) is that of developing a cancer at some point in the future, which would not have 
happened if you had not received that radiation dose.  Although radiation clearly 
increases the risk of developing cancer over certain doses, its ability to do so at the 
levels used in PET imaging has never been observed, is certainly at most very low 
and could conceivably not even exist.
The radiation exposure in this study is thought to be minor. However, the effects of 
radiation add up over your lifetime. Repeated exposures may increase your risk of 
injury or disease. When deciding to enter this study you should consider previous and 
future potential exposures. Examples would include x-rays taken for a broken bone 
or radiation therapy treatments for cancer.
The substance being injected to perform the PET study is not currently approved for 
general human use in Canada.  However, its use for research purposes is allowed by 
Health Canada.
Magnetic Resonance Imaging (MRI):
The conditions imposed by the use of magnetic resonance imaging can cause a 
certain amount of discomfort due to the fact that you may have to remain completely 
still during the examination and the noise generated by the scanner while it is 
capturing images could cause you some discomfort as well, however, you will be 
provided with earplugs to reduce this effect.
Based on current knowledge, your participation in a MRI examination will not pose 
any medical risks to you, as long as you do not have any contraindications.  
Autonomic Nervous System Testing:
Head-up tilt may cause lightheadedness or fainting.  The tilt will be stopped if you feel 
lightheaded, or if we feel that your blood pressure has become too low or that your 
heart is beating too quickly.  After the QSART, your skin may become slightly red 
around the area where the capsules had been placed, however, this will disappear 
after a few hours.  The exercise test may cause leg discomfort, shortness of breath 
or lightheadedness.  The exercise test will be stopped if you find it to be too tiring or 
if for any reason it is felt that it would be unsafe for you to continue.
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 
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irritate the skin. Careful monitoring of the arm and removal during nonrecording periods 
can alleviate any irritation.
Risk of Blood Collection  
The risks of drawing blood from vein and/or intravenous catheter (small plastic tubing 
inserted into your vein to obtain blood samples) include discomfort at the site of 
puncture; possible bruising and swelling around the puncture site; rarely an infection 
and uncommonly faintness from the procedure.  Blood drawn for this study will be 
approximately 15 tablespoons over the year of the study.  
Potential Risks and the Genetic Information Non-Discrimination Act (GINA): 
There is a potential risk of loss of confidentiality. Every effort will be made to protect 
your confidential information, but this cannot be guaranteed. The genetic information 
obtained as a result of your participation in this research will not be included in your 
medical record. Information from which you may be personally identified will be 
maintained in a confidential, secure location, accessible only by authorized members 
of the study team, and will not be disclosed to third parties except as described in this 
consent form, with your permission, or as may be required by law.
The Genetic Information Nondiscrimination Act (GINA) is a Federal law that will 
protect you in the following ways:

Health insurance companies and group plans may not request genetic 
information from this research;

Health insurance companies and group plans may not use your genetic 
information when making decisions regarding your eligibility or premiums;

Employers with 15 or more employees may not use your genetic information 
when making a decision to hire, promote, or fire you or when setting the terms 
of your employment.
GINA does not protect you against genetic discrimination by companies that sell life 
insurance, disability insurance, or long-term care insurance. GINA also does not 
protect you against discrimination based on an already-diagnosed genetic condition 
or disease.
Samples collected as part of this study may be valuable for scientific, research, or 
teaching purposes or for the development of a new medical product. The sponsor 
and/or the developers will assert all rights of ownership in the samples and all rights 
arising from use of the samples and may profit from this. In this event, there is no plan 
to compensate you.
Confidentiality:  
There is a potential risk of loss of confidentiality.  Every effort will be made to protect 
your confidential information but this cannot be guaranteed.  Study records that 
identify you will be kept confidential, as required by law. 
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Researchers will take appropriate steps to protect any information they collect about 
you.  However, there is a slight risk that information about you could be revealed 
inappropriately or accidentally.  Depending on the nature of the information, such a 
release could upset or embarrass you, or possibly affect your insurability or 
employability.  Questions 17-21 in this form discuss what information about you will be 
collected, used, protected, and shared.
This study may include risks that are unknown at this time.
Participation in more than one research study or project may further increase the risks 
to you.  If you are already enrolled in another research study, please inform one of the 
research team members listed in question 3 of this form or the person reviewing this 
consent with you before enrolling in this or any other research study or project.
Throughout the study, the researchers will notify you of new information that may 
become available and might affect your decision to remain in the study. 
If you wish to discuss the information above or any discomforts you may experience, 
please ask questions now or call one of the research team members listed in question 
3 in this form.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify 
you.  At most, the Web site will include a summary of the results. You can search 
this Web site at any time. The NCT number for this study is NCT02213575.
11a. What are the potential benefits to you for taking part in this research study?
You may or may not benefit from participating in this study.  You may potentially benefit 
from taking minocycline and see improvement in your hypertension.
11b. How could others possibly benefit from this study?
Information generated from this study may help others in the future with hypertension.
11c. How could the researchers benefit from this study?
In general, presenting research results helps the career of a scientist. Therefore, the 
Principal Investigator listed in question 3 of this form may benefit if the results of this 
study are presented at scientific meetings or in scientific journals.
12. What other choices do you have if you do not want to be in this study? 
You are free not to participate in this study.  The alternative to being in this study 
includes standard of care medical treatment for hypertension which includes blood 
pressure medications and lifestyle changes.  If you do not want to take part in this 
study, tell the Principal investigator and do not sign this Informed Consent Form.
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13a. Can you withdraw from this study?
You are free to withdraw your consent and to stop participating in this study at any time.  
If you do withdraw your consent, you will not be penalized in any way and you will not 
lose any benefits to which you are entitled.  
If you decide to withdraw your consent to participate in this study for any reason, please 
contact one of the research team members listed in question 3 of this form.  They will 
tell you how to stop your participation safely.
If you have any questions regarding your rights as a research subject, please call the 
Institutional Review Board (IRB) office at (352) 273-9600.
13b.If you withdraw, can information about you still be used and/or collected?
If you withdraw, the investigators will report the results of the testing that you have
completed, but only as part of the overall study results.  Your individual results will not 
be reported.
13c. Can the Principal Investigator withdraw you from this study? 
You may be withdrawn from the study without your consent for the following reasons:

If it is medically necessary;

the sponsor stops the study;

you become pregnant;

if you do not follow the instructions given to you by the investigator;
WHAT ARE THE FINANCIAL ISSUES IF YOU PARTICIPATE?
14. If you choose to take part in this research study, will it cost you anything?
Study Drugs, Devices
The study drug Minocycline and an ambulatory blood pressure monitoring device will 
be provided at no cost to you while you are participating in this study.
Study Services
The Sponsor will pay for all medical services required as part of your participation in 
this study and travel to Montreal Neurological Institute, in Montreal Canada for the 
specialized imaging of the brain and the autonomic nervous system testing. 
There will be no cost to you. If you receive a bill related to this study, please contact Dr. 
Carl J. Pepine (352) 273-9082 (during office hours).
Items/Services Not Paid for by the Sponsor 
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All other medical services provided to you that are not directly required by this study 
will be billed to you or your insurance company in the usual manner.
15. Will you be paid for taking part in this study?
All costs and arrangements for travel to the Canadian study center for imaging will be 
provided by the study. You will receive a stipend, in the form of a pre-paid cash card, 
of $300.00 to compensate you for loss of wages during your time off of work and 
incidentals.  You will receive this compensation prior to your departure to Canada on 
both occasions.  You will also be paid $25.00 for the cost of mileage and parking 
expenses for all study related visits that require you to come to clinic here at UF to 
complete the visit. You will be paid with a pre-paid debit card at the conclusion of the 
visit.  The total amount of money you could be paid for your participation in this study 
will not exceed $850.00. You will not be paid for phone call visits (Visit 5 and Visit 9).
16. What if you are injured because of the study?  
If you are injured as a direct result of your participation in this study, only the 
professional services that you receive from any University of Florida Health Science 
Center healthcare provider will be provided without charge.  These healthcare providers 
include physicians, physician assistants, nurse practitioners, dentists or psychologists. 
Any other expenses, including Shands hospital expenses, will be billed to you or your 
insurance provider. 
You will be responsible for any deductible, co-insurance, or co-payments. Some 
insurance companies may not cover costs associated with research studies or 
research-related injuries. Please contact your insurance company for additional 
information.
The Principal Investigator will determine whether your injury is related to your 
participation in this study. 
This study requires international travel to Montreal Canada.  Medicare, 
Medicaid and most U.S. medical insurance plans do not pay for healthcare 
costs outside the United States. If you are injured and require medical care in 
Canada you will be responsible for these expenses.  
No additional compensation is routinely offered. The Principal Investigator and others 
involved in this study may be University of Florida employees. As employees of the 
University, they are protected under state law, which limits financial recovery for 
negligence.
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Please contact one of the research team members listed in question 3 of this form if 
you experience an injury or have questions about any discomforts that you experience 
while participating in this study.
17. How will your health information be collected, used and shared?
If you agree to participate in this study, the Principal Investigator will create, collect, and 
use private information about you and your health. This information is called protected 
health information or PHI. In order to do this, the Principal Investigator needs your 
authorization  The following section describes what PHI will be collected, used and 
shared, how it will be collected, used, and shared, who will collect, use or share it, who 
will have access to it, how it will be secured, and what your rights are to revoke this 
authorization. 
Your protected health information may be collected, used, and shared with others to 
determine if you can participate in the study, and then as part of your participation in 
the study.  This information can be gathered from you or your past, current or future 
health records, from procedures such as physical examinations, x-rays, blood or urine 
tests or from other procedures or tests.  This information will be created by receiving 
study treatments or participating in study procedures, or from your study visits and 
telephone calls.  More specifically, the following information may be collected, used, 
and shared with others: 

Complete past medical history

Laboratory, x-ray imaging reports and other test results

Records about medications

Ability or potential to conceive a child, or document pregnancy
This information will be stored in locked filing cabinets or on computer servers with 
secure passwords, or encrypted electronic storage devices. 
Some of the information collected could be included in a "limited data set" to be used 
for other research purposes.  If so, the limited data set will only include information that 
does not directly identify you.  For example, the limited data set cannot include your 
name, address, telephone number, social security number, photographs, or other 
codes that link you to the information in the limited data set.  If limited data sets are 
created and used, agreements between the parties creating and receiving the limited 
data set are required in order to protect your identity and confidentiality and privacy.
18. For what study-related purposes will your protected health information be 
collected, used, and shared with others?
Your PHI may be collected, used, and shared with others to make sure you can 
participate in the research, through your participation in the research, and to evaluate 
the results of the research study.  More specifically, your PHI may be collected, used, 
and shared with others for the following study-related purpose(s):
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
to observe the effects the drug minocycline and its interaction with the chemicals 
in your brain and its ability to inhibit the activation of these brain cells
Once this information is collected, it becomes part of the research record for this study.  
19. Who will be allowed to collect, use, and share your protected health information?
Only certain people have the legal right to collect, use and share your research records, 
and they will protect the privacy and security of these records to the extent the law 
allows. These people include:

the study Principal Investigator (listed in question 3 of this form) and research 
staff associated with this project.

other professionals at the University of Florida or Shands Hospital that provide 
study-related treatment or procedures.

the University of Florida Institutional Review Board (IRB; an IRB is a group of 
people who are responsible for looking after the rights and welfare of people 
taking part in research). 

McGill University (the IRB residing over the procedures performed at the 
Montreal Neurological Institute)
20.  Once collected or used, who may your protected health information be shared 
with?
Your PHI may be shared with:

the study sponsor (listed in Question 4 of this form).

United States and foreign governmental agencies who are responsible for 
overseeing research, such as the Food and Drug Administration, the 
Department of Health and Human Services, and the Office of Human Research 
Protections
.

Government agencies who are responsible for overseeing public health 
concerns such as the Centers for Disease Control and federal, state and local 
health departments.

Montreal Neurological Institute
Otherwise, your research records will not be released without your permission unless 
required by law or a court order. It is possible that once this information is shared with 
authorized persons, it could be shared by the persons or agencies who receive it and 
it would no longer be protected by the federal medical privacy law.  
21. If you agree to take part in this research study, how long will your protected 
health information be used and shared with others?
Your PHI will be used and shared with others until the study is completed.
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You are not required to sign this consent and authorization or allow researchers to 
collect, use and share your PHI. Your refusal to sign will not affect your treatment, 
payment, enrollment, or eligibility for any benefits outside this research study. However, 
you cannot participate in this research unless you allow the collection, use and sharing 
of your protected health information by signing this consent and authorization.
You have the right to review and copy your protected health information.  However, we 
can make this available only after the study is finished.
You can revoke your authorization at any time before, during, or after your participation 
in this study.  If you revoke it, no new information will be collected about you.  However, 
information that was already collected may still be used and shared with others if the 
researchers have relied on it to complete the research.  You can revoke your 
authorization by giving a written request with your signature on it to the Principal 
Investigator.
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), makes 
it illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information.  Additional information 
can be obtained at: http://irb.ufl.edu/gina.html or call 1-800-669-3362.  If you think 
this law has been violated, it will be up to you to pursue any compensation from the 
offending insurance company and/or employer.
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SIGNATURES
As an investigator or the investigator’s representative, I have explained to the participant 
the purpose, the procedures, the possible benefits, and the risks of this research study; the 
alternative to being in the study; and how the participant’s protected health information will 
be collected, used, and shared with others: 
Signature of Person Obtaining Consent and 
Authorization
Date
You have been informed about this study’s purpose, procedures, possible benefits, and 
risks; the alternatives to being in the study; and how your protected health information will 
be collected, used and shared with others.  You have received a copy of this Form.  You 
have been given the opportunity to ask questions before you sign, and you have been told 
that you can ask   questions at any time.  
You voluntarily agree to participate in this study. You hereby authorize the collection, use 
and sharing of your protected health information as described in sections 17-21 above.  By 
signing this form, you are not waiving any of your legal rights.
Signature of Person Consenting and Authorizing
Date
 
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