A Study of the Effects of Minocycline on Cognitive Function After Carotid Endarterectomy

This protocol is a phase IIa study that will prospectively investigate whether minocycline
(an antibiotic that showed neuroprotective effects in animal models) can decrease the
cognitive deficits associated with carotid endarterectomy. This trial will be a randomized,
parallel-group design, double-blind, placebo controlled clinical trial conducted at the
Brigham and Women's Hospital.

The principal aim of this investigation is to study the effects of minocycline on cognitive
performance after carotid endarterectomy. To measure cognitive function, we will perform a
neuropsychological battery of tests (as detailed below). This battery of tests will be
carried out by a blinded rater (a neurologist) and will be performed according to the
following timetable:

Training session: before the baseline, patients will perform the tasks several times until
they reach a stable plateau (defined as a variation of less than 10% in the last three
trials) in order to eliminate the confounding effect of learning.

Baseline evaluation: the baseline evaluation will be performed in the day prior to the
surgery.

Post-treatment evaluation: post-treatment evaluation will be performed 24 hours after the
surgical procedure by the same blinded rater.

Neuropsychological battery of tests: we based our neuropsychological battery of tests on a
similar study that evaluated the cognitive deficits associated with CEA and will consist of
the following tests:

1. Trail making test - parts A and B (this test evaluates visual concept and visuo-motor
track)

2. Controlled Oral Word Association (letters C, F and L) (this test evaluates verbal
fluency)

3. The Boston Naming Test (naming of 60 pictures) (this test evaluates left hemisphere
damage)

4. Digit Span Forward and Backward (this test evaluates working memory)

5. Stroop Task (this test evaluates selective attention and mental flexibility)

6. Mini-mental state examination (this test evaluates an adult patient's level of global
cognitive functioning)

Blood sample analysis: As a secondary outcome, we will analyze subjects blood sample in
respect to two particular substances: S100B and neuron specific enolase. The rationale for
performing proteomic studies is that past research has shown that subtle cerebral injuries
after carotid endarterectomy, even in the absence of stroke, might be associated with a
significant increase in serum S100B (Connolly, 2001 - Neurosurgery, 2001 49 (5)) and also in
traumatic brain injury (Cotena, 2006, J Neurosurg 2006 104 (6)). In addition, neuron
specific enolase (NSE) also seems to be valuable to predict brain damage in patients with
brain traumatic injury (Naeimi, 2006 - Brain Inj 2006 20(5)), thus showing that these two
substances might be important biomarkers to be investigated in our study.

After eligibility screening (inclusion and exclusion criteria), consent form, medical
history and physical exam participants will be randomized to the exposure - minocycline or
placebo. The pills (minocycline and placebo) will have the same appearance and only one
person will know whether the treatment is active or placebo.

Randomization:

Because our sample size will be relatively small, participants will be randomized to
minocycline or placebo through a randomization stratification approach. This approach will
ensure that both groups will have a similar distribution regarding baseline performance in
the cognitive tests. Participants will be gathered into groups (strata) defined by their
performance in the neuropsychological tasks (baseline). Participants within each stratum
will be randomized to one of two treatment groups - minocycline and placebo - according to a
block randomization of four and using a randomization list generated by a computer that will
take into account the study entrance order. These groups are defined as follows:

Minocycline: we will use the dosage of minocycline that is currently used for clinical
indications and also used in trials employing this drug as an anti-inflammatory agent.
Minocycline will be administered in the period of 36 hrs before surgery (100 mg twice a day
and 200 mg in the morning of the surgery - total of 5 doses) and 12 hrs after surgery
(single dose of 100 mg).

The two doses of minocycline administered in the morning of the surgery will be taken with a
small sip of water.

Placebo: placebo pill will have the same appearance as the real drug (minocycline) and will
be administered using the same timetable as the active drug.