Safety of Simvastatin in LAM and TSC

After providing written informed consent, study related tests/procedures will be done to
ensure eligibility for the study. If found to be eligible, the participant will be given
simvastatin at a starting dose of 20 mg, to be taken each evening by mouth. If after 2 months
the simvastatin 20 mg dose is tolerated, the dose of simvastatin will be increased to 40 mg
each evening by mouth. Doses may be adjusted as needed, should the participant experience
side effects from simvastatin. The participant's dose of everolimus or sirolimus is not
expected to change, as this is a dose that has been previously tolerated. If side effects
occur as a result of the combination of drugs, the dosages may be adjusted by the study
physician (investigator).

Inclusion Criteria:

- Female, age 18 and older with clinically definitive diagnosis (biopsy proven or
compatible chest CT/MRI scan) of sporadic LAM (LAM-S) or LAM associated with TS
(LAM-TS).

- Treated with a stable (at least 3 months) dose of sirolimus or everolimus

- Negative pregnancy test (women of child bearing potential) at screening.

- Women of childbearing potential must be using barrier, medically acceptable
contraceptive precautions.

- Signed and dated informed consent.

Exclusion Criteria:

- Age < 18 years

- Known allergy to simvastatin or currently taking simvastatin, or therapy with a
medication in the same class as simvastatin within the past 30 days.

- Allergy to sirolimus or everolimus.

- Current use of other than sirolimus or everolimus investigational drug for TSC or LAM
within the past 30 days.

- Use of estrogen containing medications, including birth control pills, within the 30
days prior to enrollment.

- Treatment with drugs having known metabolic interactions with statin drugs (e.g.
cytochrome P450 3A4 metabolism), including ketoconazole, itraconazole, fluconazole,
erythromycin, clarithromycin, azithromycin, niacin (nicotinic acid), digoxin,
warfarin, sildenafil or use of strong CYP3A4 inhibitors including gemfibrozil,
cyclosporine, danazol, verapamil, diltiazem, and dronedarone. amiodarone, amlodipine,
and ranolazine.

- Participation in another clinical study(ies) of an investigational treatment or drug
within 30 days prior to the screening visit.

- Amiodarone; within the past 30 days.

- Significant dysfunction of liver (ALT > 2 times upper limit of normal-ULN), kidney
(serum creatinine > 1.5 times ULN), or blood (leucopenia (ANC<2000), anemia, Hgb < 11
gm/dl).

- History of inflammatory muscle disease or myopathy.

- Bleeding diathesis or anticoagulant therapy.

- Uncontrolled hyperlipidemia or diabetes.

- Pregnant, breast feeding, or plan to become pregnant within the next 6 months

- Inadequate contraception (must agree to barrier method)

- History of organ transplant.

- Active on transplant list.

- Severe or uncontrolled medical conditions which would cause an unacceptable safety
risk or compromise compliance with the protocol.

- Unstable seizures (recent changes in pattern or anti-epileptics).

- Mental illness or cognitive deficit precluding informed consent..

- Inability to attend scheduled clinic visits or comply with study procedures.