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.