Clinical trial NCT02178813: The Safety of High Dose Minocycline in the Patient Population Undergoing Carotid Revascularization
Official title: The Safety of High Dose Minocycline in the Patient Population Undergoing Carotid Revascularization. A Phase I Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Stroke
Keywords: Minocycline
Neuroprotection
Stroke
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2014-07-01
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety and tolerability of high-dose minocycline in the patient population undergoing carotid revascularization procedures, namely carotid endarterectomy (CEA) and carotid artery stenting (CAS). Establishment of safety will facilitate proceeding to a phase II trial.

During this trial, patients undergoing carotid revascularization procedures will receive high doses of minocycline with the following schedule (based on previous trials):

* Day prior to procedure: 800mg orally (p.o), 700mg p.o.
* Day of procedure: 600mg intravenously( i.v.), 500mg p.o.
* Day after procedure: 400mg p.o., 400mg p.o.

The levels of the drug in the plasma, standard blood tests (complete blood count, creatinine, liver function tests) as well as markers of neuronal injury (Neuron specific enolase, protein- S100b) and inflammation (C-reactive protein) will also be monitored. The patients will be monitored closely for the development of side effects from minocycline.

MRI imaging will be used to follow the development of small strokes as a result of the revascularization procedures and their resolution. The patients of this study, all receiving peri-operative minocycline, will be compared with historical controls with regards to development of small strokes and persistent of these strokes on subsequent MRI imaging.


Eligibility criteria: Inclusion Criteria:

1. Patients with a clinical indication for carotid revascularization (CRV) as decided by the treating physicians (the clinical indications for CRV as well as the choice of the type of CRV, either CEA or CAS, will be entirely up to the treating physicians)
2. Patients who can perform the neurocognitive tests in English
3. Women of childbearing age who are non-lactating and have a negative pregnancy test
4. Patients in the age range of 18 years - 90 years
5. Patients able to undergo MRI imaging.
6. Patients that are dependable and able to return for follow-up studies and exams.
7. Patients that will be in the hospital (inpatients) the day prior to the procedure for clinical purposes (for evaluation of side effects from the first dose and for overnight infusion of minocycline before the procedure)

Exclusion Criteria:

1. Known hypersensitivity to tetracyclines
2. Significant neurological deficit including but not limited to dense aphasia, hemi- or mono-paresis (motor strength equal or less than 3/5) or neglect.
3. Baseline abnormalities on the MRI of the brain which would preclude the detection of new DWI or FLAIR changes. (e.g large areas of acute stroke, large areas of previous encephalomalacia, existing hardware such as aneurysm clips or coil masses etc.)
4. Patients who are pregnant, breast-feeding, or lactating.
5. Patients with a contraindication to undergo MRI, including those with pacemakers, metal implants and metal fragments within their bodies.
6. Patients with abnormal liver function tests at baseline defined as a 2-fold elevation in alanine-aminotransferase.
7. Patients with significantly affected renal function at baseline (Creatinine equal or above 2mg/dL).
8. Patients on high dose isotretinoin, vitamin A, or methotrexate
9. Patients undergoing emergency carotid revascularization procedures.
10. Any clinically important known medical, surgical, psychiatric or psychological disease, which would preclude completion of the protocol (such as advanced cardiac, renal or pulmonary disease).We will screen for physical and mental capacity to undergo study procedures and will obtain proxy consent for subjects who appear decisionally impaired. The screening process will be performed by the physician co-investigator obtaining the informed consent.
11. Patients with a Mini-Mental Status Exam score (MMSE) of less than 21 (as determined by one of the co-investigators). Patients with MMSE score of 21 will be included.
12. Patients undergoing carotid revascularization in less than 36 hours from identification, or patients who are undecided about participation less than 36 hours prior to the procedure will not be eligible for the study.
13. Patients with any other factor that would make follow-up studies difficult (e.g patient is from another country, or patient is a prisoner)

Primary outcomes:
measure: Drug Safety/Tolerability (Number of patients that require discontinuation of drug because of side effects)
timeFrame: One day prior to procedure to 1 days after procedure
Secondary outcomes:
measure: Progression of procedural stroke on MRI imaging
timeFrame: 10 days before procedure, 1 day after procedure, 1 month after procedure
measure: Neuropsychological test performance
timeFrame: 10 days prior to procedure, 1 day after procedure, 1 month after procedure
measure: Myocardial Infarction
timeFrame: Days 1, 2(procedure day), 3
measure: Markers of neuronal injury
timeFrame: 1 day prior to procedure, 1 day after the procedure, 1 month after the procedure
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: Presbyterian Hospital
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh Resident in Neurosurgery
name: Georgios A Zenonos, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Casha S, Zygun D, McGowan MD, Bains I, Yong VW, Hurlbert RJ. Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain. 2012 Apr;135(Pt 4):1224-36. doi: 10.1093/brain/aws072.