Study 1: Effect of Minocycline Treatment on Drug-Resistant Hypertensive Patients
| Status: | Recruiting |
|---|---|
| Conditions: | High Blood Pressure (Hypertension) |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 9/2/2018 |
| Start Date: | October 2014 |
| End Date: | May 2019 |
| Contact: | Dana Leach, DNP |
| Email: | leachdd@medicine.ufl.edu |
| Phone: | 352-273-8933 |
Angiotensin and Neuroimmune Activation in Hypertension
Hypertension (HTN) is the single most prevalent risk factor for cardiovascular disease,
diabetes, obesity and metabolic syndrome. Recent American Heart Association (AHA) statistics
indicate that one-third of all adults in the United States of America suffer from HTN.
Despite advances in life style modification and multi-drug therapies, 20-30% of all
hypertensive patients remain resistant.
These individuals exhibit autonomic dysregulation due to elevated sympathetic activity and
norepinephrine spillover, and low parasympathetic activity. It is generally accepted that
this uncontrolled, resistant HTN is primarily "neurogenic" in origin, involving over activity
of the sympathetic nervous system that initiates and sustains HTN. A surgical approach such
as the recently developed "Simplicity Catheter" assisted renal denervation remains one of the
few options available to these patients. Thus, a mechanism-based breakthrough is imperative
to develop novel strategies to prevent and perhaps eventually cure neurogenic hypertension
(NH). This study is designed to evaluate a low and high dose of minocycline to test the
hypothesis that minocycline treatment would produce antihypertensive effects in
drug-resistant neurogenic hypertensive individuals. Minocycline has been selected because of
its demonstrated effects on inhibiting microglial activation and its ability to penetrate the
blood brain barrier. There is no other compound available that is safer and displays
specificity better than Minocycline in inhibiting microglial activation. Thus, the potential
therapeutic benefits of this inexpensive, well tolerated, already FDA-approved drug that has
minimal side effects would be enormous.
diabetes, obesity and metabolic syndrome. Recent American Heart Association (AHA) statistics
indicate that one-third of all adults in the United States of America suffer from HTN.
Despite advances in life style modification and multi-drug therapies, 20-30% of all
hypertensive patients remain resistant.
These individuals exhibit autonomic dysregulation due to elevated sympathetic activity and
norepinephrine spillover, and low parasympathetic activity. It is generally accepted that
this uncontrolled, resistant HTN is primarily "neurogenic" in origin, involving over activity
of the sympathetic nervous system that initiates and sustains HTN. A surgical approach such
as the recently developed "Simplicity Catheter" assisted renal denervation remains one of the
few options available to these patients. Thus, a mechanism-based breakthrough is imperative
to develop novel strategies to prevent and perhaps eventually cure neurogenic hypertension
(NH). This study is designed to evaluate a low and high dose of minocycline to test the
hypothesis that minocycline treatment would produce antihypertensive effects in
drug-resistant neurogenic hypertensive individuals. Minocycline has been selected because of
its demonstrated effects on inhibiting microglial activation and its ability to penetrate the
blood brain barrier. There is no other compound available that is safer and displays
specificity better than Minocycline in inhibiting microglial activation. Thus, the potential
therapeutic benefits of this inexpensive, well tolerated, already FDA-approved drug that has
minimal side effects would be enormous.
One hundred seventy-five (175) subjects who will be randomized to receive either Minocycline
100 mg or 200 mg b.i.d. (twice a day). At baseline, subjects will undergo blood tests (lipid
panel, high sensitivity-C reactive protein, high sensitivity troponin, glucose, metabolic
profile, lipid panel, Cystatin C, albumin and flow cytometry). Peripheral blood mononuclear
cells will be isolated and used to generate human induced pluripotent stem cells (iPSCs)
which will be used for further mechanism studies.
In addition to blood collection, a physical exam will be conducted and office systolic blood
pressure (BP), diastolic blood pressure (DBP) and pulse pressure (PP) will be recorded.
Patients will also be fitted with an ambulatory blood pressure monitor (ABPM) system.
Patients will wear the ABPM for 24 hours at which point they will mail the monitor back to
research personnel. A week later, a second ABPM baseline reading will be conducted as
patients will return to the clinic to be fitted again with the ABPM. At this visit, the study
drug will be dispensed and patients will be instructed to start the study medication after
completing the 24- hour ABPM monitoring period. After this visit, patients will be asked to
return every month till the end of the study at 6 months.
Monthly visits (1, 2, 3, 4, 5 and 6 month visits), will include a brief physical examination
and an assessment of medication compliance and tolerance. One tablespoon of blood will be
drawn for flow cytometry analysis and iPSCs isolation at the baseline, 3 and 6 month visit
only. Study drug will be dispensed and measurement of SBP, DBP, PP and other vital signs will
also be completed. Office BP readings will be taken in a seated position after 5 minutes of
rest according to Joint National Committee VII Guidelines. At baseline, BP will be measured
at each arm, and the arm with the higher BP will be used for all subsequent readings.
Averages of the triplicate measures will be calculated and used for analysis. At baseline and
each followup visit, patients will be asked to wear the ABPM for 24 hours. Subjects will mail
the cuff back to research personnel when completed. ABPM will be performed using an
oscillometric Spacelabs 90207 monitor (Spacelabs Healthcare, Issaqua, WA) with readings taken
every 30 minutes in daytime and every 60 minutes at nighttime. ABPM readings will be averaged
for, daytime (8 AM to 5 PM), and nighttime (10 PM to 7 AM). Patients will be assessed while
adhering to their usual diurnal activity and nocturnal sleep routine. The antihypertensive
drugs, and their doses, used at each visit will be recorded on standardized forms along with
any reports of adverse experiences known to occur with the drugs used (e.g. lightheadedness,
dizziness, syncope, etc.).
Only at the final visit, the same blood tests at baseline will be repeated. When the patients
complete the 6 months of treatment, come in for their final visit, and return the ABPM
monitor, their participation in the trial will be considered as complete.
100 mg or 200 mg b.i.d. (twice a day). At baseline, subjects will undergo blood tests (lipid
panel, high sensitivity-C reactive protein, high sensitivity troponin, glucose, metabolic
profile, lipid panel, Cystatin C, albumin and flow cytometry). Peripheral blood mononuclear
cells will be isolated and used to generate human induced pluripotent stem cells (iPSCs)
which will be used for further mechanism studies.
In addition to blood collection, a physical exam will be conducted and office systolic blood
pressure (BP), diastolic blood pressure (DBP) and pulse pressure (PP) will be recorded.
Patients will also be fitted with an ambulatory blood pressure monitor (ABPM) system.
Patients will wear the ABPM for 24 hours at which point they will mail the monitor back to
research personnel. A week later, a second ABPM baseline reading will be conducted as
patients will return to the clinic to be fitted again with the ABPM. At this visit, the study
drug will be dispensed and patients will be instructed to start the study medication after
completing the 24- hour ABPM monitoring period. After this visit, patients will be asked to
return every month till the end of the study at 6 months.
Monthly visits (1, 2, 3, 4, 5 and 6 month visits), will include a brief physical examination
and an assessment of medication compliance and tolerance. One tablespoon of blood will be
drawn for flow cytometry analysis and iPSCs isolation at the baseline, 3 and 6 month visit
only. Study drug will be dispensed and measurement of SBP, DBP, PP and other vital signs will
also be completed. Office BP readings will be taken in a seated position after 5 minutes of
rest according to Joint National Committee VII Guidelines. At baseline, BP will be measured
at each arm, and the arm with the higher BP will be used for all subsequent readings.
Averages of the triplicate measures will be calculated and used for analysis. At baseline and
each followup visit, patients will be asked to wear the ABPM for 24 hours. Subjects will mail
the cuff back to research personnel when completed. ABPM will be performed using an
oscillometric Spacelabs 90207 monitor (Spacelabs Healthcare, Issaqua, WA) with readings taken
every 30 minutes in daytime and every 60 minutes at nighttime. ABPM readings will be averaged
for, daytime (8 AM to 5 PM), and nighttime (10 PM to 7 AM). Patients will be assessed while
adhering to their usual diurnal activity and nocturnal sleep routine. The antihypertensive
drugs, and their doses, used at each visit will be recorded on standardized forms along with
any reports of adverse experiences known to occur with the drugs used (e.g. lightheadedness,
dizziness, syncope, etc.).
Only at the final visit, the same blood tests at baseline will be repeated. When the patients
complete the 6 months of treatment, come in for their final visit, and return the ABPM
monitor, their participation in the trial will be considered as complete.
Inclusion:
- Greater than 18 and less than 80 years of age;
- On stable medication regimen
- Full-tolerated doses of 3 or more antihypertensive medications of different classes,
one of which must be a diuretic (with no changes for a minimum of two weeks prior to
screening) that is expected to be maintained without changes for at least 3 months.
- The individual agrees to have all study procedures performed
- Willing to provide written consent
Exclusion
- eGFR of < 45mL/min/1.73m2, using the MDRD calculation.
- More than one in-patient hospitalization for an antihypertensive crisis within the
year.
- More than one episode(s) of orthostatic hypotension (reduction of SBP of ≥ 20mmHg of
diastolic blood pressure (DBP) of ≥ 10mmHg within 3 minutes of standing).
- Known hypersensitivity or contraindication to Minocycline or other tetracycline.
- Evidence of alcoholism or drug abuse;
- Concurrent severe disease (such as neoplasm or HIV positive or AIDS).
- Women of childbearing potential
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