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

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ClinicalTrials.gov Identifier: NCT02133872
Recruitment Status : Recruiting
First Posted : May 8, 2014
Last Update Posted : March 30, 2021
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
University of Florida

Brief Summary:

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

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


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

Detailed Description:

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

After enrollment of the first two patients and observing a marked reduction in blood pressure the blind was broken and patients were on active therapy. Because these patients had CVD, for safety reasons recruitment was halted and the protocol design was modified to an open-label design of dose titration for each participant beginning at 50 mg/day of minocycline, escalating to 100 mg/day and 200 mg/day if the primary outcome measure of ambulatory blood pressure monitor (ABPM) =/> to 5 mmHg decrease in mean daytime SBP was not achieved. If patients responded, participation was completed. This revised protocol was resubmitted to the IRB and approved on 1/6/16. An interim analysis was planned after 40 patients completed the revised protocol.

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

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

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

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description: Open label, dose effectiveness trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Angiotensin and Neuroimmune Activation in Hypertension
Study Start Date : October 2014
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Minocycline Dose Escalation
Subjects will receive minocycline 50mg if no mean daytime ABPM SBP decline =/> 5mm Hg; subjects will receive minocycline 100mg, if no mean daytime ABPM SBP decline =/> 5mm Hg BP subjects will receive minocycline 200 mg.
Drug: Minocycline dose escalation
Subjects will receive minocycline 50mg if no mean daytime ABPM SBP decline =/> 5mm Hg; subjects will receive minocycline 100mg, if no mean daytime ABPM SBP decline =/> 5mm Hg BP subjects will receive minocycline 200 mg.




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


Secondary Outcome Measures :
  1. Changes in office SBP over time [ Time Frame: 52 weeks ]
    Office BP

  2. Change in 24 hr SBP by ABPM [ Time Frame: 52 weeks ]
    24 hour Systolic BP by ABPM



Information from the National Library of Medicine

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

Inclusion:

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

Exclusion

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

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02133872


Contacts
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Contact: Dana Leach, DNP 352-273-8933 leachdd@medicine.ufl.edu
Contact: Sarah Long, RN 352-273-8933 sarah.long@medicine.ufl.edu

Locations
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United States, Florida
UF Health Cardiovascular Clinic Recruiting
Gainesville, Florida, United States, 32610
Contact: Dana Leach, DNP    352-273-8933    leachdd@medicine.ufl.edu   
Sub-Investigator: Mohan Raizada, PhD         
Sponsors and Collaborators
University of Florida
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Carl Pepine, MD University of Florida
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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT02133872    
Other Study ID Numbers: IRB2015005 -N
RO1HL3361028 ( Other Identifier: NHLBI )
2013-00102 Study 1 ( Other Identifier: UF IRB ID )
1R01HL132448-01 ( U.S. NIH Grant/Contract )
First Posted: May 8, 2014    Key Record Dates
Last Update Posted: March 30, 2021
Last Verified: March 2021
Keywords provided by University of Florida:
Resistent Hypertension
Additional relevant MeSH terms:
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Hypertension
Vascular Diseases
Cardiovascular Diseases
Minocycline
Anti-Bacterial Agents
Anti-Infective Agents