Trial of Sirolimus for Cognitive Impairment in Sturge-Weber Syndrome

Sirolimus will be administered as an adjunct to all current medications. The impact of
sirolimus upon cognitive functioning in Sturge-Weber syndrome is the primary outcome measure.
This outcome will be assessed using a panel of testing selected based upon extensive
experience in testing cognitive function in adults and children with SWS at the Kennedy
Krieger Sturge-Weber Center. Changes in a quantitative EEG before and after the trial,
Sturge-Weber syndrome clinical neuroscore, port-wine birthmark score, and the impact of
sirolimus upon seizures will be assessed.

Inclusion Criteria:

1. Male or female patients ages 3 to 31 years of age, inclusive.

2. Cognitive impairment as defined by the following:

SWS cognitive neuroscore of ≥ 1

3. Ability to participate in direct neuropsychological and developmental testing.

4. English as primary language.

5. Stable anti-epileptic drugs (no changes in medications except dose for >3 months).

6. Adequate renal function. GFR must be greater than 50 ml/min/m2 as determined by the
Schwartz Formula for children and MDRD for adults:
http://www.nkdep.nih.gov/professionals/gfr_calculators/index.htm

7. If female and of child bearing potential, documentation of a negative pregnancy test
prior to enrollment determined by a urine test is required. Sexually active
pre-menopausal female patients (and female partners of male patients) must use
adequate contraceptive measures, excluding estrogen containing contraceptives, while
on the study drug. Abstinence will be considered an adequate contraceptive measure.

8. INR ≤1.5 (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin
or on a stable dose of LMW heparin for >2 weeks.)

9. Adequate liver function as shown by:

- Serum bilirubin ≤ 1.5x ULN

- ALT and AST ≤ 2.5x ULN

10. Written informed consent according to local guidelines. Local guidelines for subject
assent will also be followed.

11. Stable dose of medications affecting the cytochrome P 450 3A4 (CYP3A4) and p
glycoprotein (P gp) systems for at least 3 months prior to consent.

Exclusion Criteria:

1. Allergy to sirolimus or other rapamycin analogues.

2. Patients with seizures secondary to metabolic, toxic, infectious or psychogenic
disorder, drug abuse or current seizures related to an acute medical illness.

3. Inability to keep follow-up appointments, maintain close contact with Principal
Investigators, and/or complete all necessary studies to maintain safety.

4. Patients in need of immediate major surgical intervention.

5. Concurrent severe and/or uncontrolled medical disease, which could compromise
participation in the pilot study (e.g. uncontrolled diabetes, uncontrolled
hypertension, severe infection, severe malnutrition, chronic liver or renal disease,
active upper GI tract ulceration, impaired or restrictive pulmonary function,
pneumonitis or pulmonary infiltrates).

6. Chronic treatment with systemic steroids or another immunosuppressive agent. Patients
with endocrine deficiencies are allowed to receive physiologic or stress doses of
steroids if necessary. Inhaled steroids are allowed.

7. Known history of HIV seropositivity or known immunodeficiency. Testing is not required
unless a condition is suspected.

8. Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of sirolimus (e.g. ulcerative disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A
gastric tube or nasogastric tube is allowed.

9. Patients with an active, bleeding diathesis.

10. Patients with uncontrolled hyperlipidemia: fasting serum cholesterol > 300 mg/dL AND
fasting triglycerides > 2.5 x ULN.

11. Patients who have had a major surgery or significant traumatic injury within four
weeks of study entry. Patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia) or patients that may require
major surgery during the course of the pilot study.

12. Patients with a prior history of organ transplant.

13. Patients who have received live attenuated vaccines within one week of start of
sirolimus and during the pilot study.

14. Patients who have a history of malignancy.

15. Patients who are currently part of or have participated in any clinical investigation
with an investigational drug within one month prior to enrollment.

16. Patients being treated with felbamate, unless treatment has been continuous for ≥ one
year.

17. Patients currently receiving anticancer therapies or who have received anticancer
therapies within four weeks of study entry (including chemotherapy, radiation therapy,
antibody based therapy, etc.).