Effects of Simvastatin on Uterine Leiomyoma Size

The study is a phase II double blinded clinical trial to determine feasibility, safety and
preliminary clinical efficacy of simvastatin to reduce leiomyoma size. Women with symptomatic
fibroids planned to undergo surgical management for fibroids such as hysterectomy or
myomectomy will be screened for participation. The eligible women will undergo pre-study
evaluation to ascertain study eligibility.The study will enroll 60 participants in total,
half will receive simvastatin and the other half will receive a placebo. The study drug and
placebo will be an add on to the participants ongoing medical management of fibroids until
surgery. The participants will be monitored at intervals for the effect of the drug on
fibroid size and symptoms using ultrasound and quality of life questionnaires.

Inclusion Criteria:

- Signed informed written consent.

- Gender: female.

- Age: 18-55 years at time of signing consent.

- BMI of subjects: < 45 kg/m2.

- Uterine fibroids:

- Diagnosed by ultrasound (MRI will be used only if ultrasound is inconclusive).

- Number: any number of fibroids.

- Location: submucosal or intramural.

- At least one fibroid of diameter > 3cm.

- Symptoms: one or more of the following symptoms of heavy menstrual bleeding (HMB),
defined as: Experienced cyclic (22 to 35 days) abnormal uterine bleeding (heavy or
prolonged) in at least 3 of the last 6 menstrual periods, including menstrual bleeding
lasting 5 or more days or heavy bleeding per participant recall. Examples of heavy
bleeding may include, but are not limited to the following:

- Requires the use of double protection to manage menstrual bleeding.

- Menstrual bleeding accompanied by the sensation of "gushing" or "flooding".

- Saturates more than 1 tampon or sanitary pad per hour for 3 or more consecutive hours.

- Regularly needs to change the tampon or sanitary pad at night or regularly soils
bedclothes.

- Heavy bleeding that affects work, school, or social activities.

- Pelvic pain/ pressure likely caused by fibroids.

- Plan for surgery (hysterectomy or myomectomy).

- Normal Pap smear within the last year.

- Use of contraception during study such as non-hormonal oral contraceptives,
intrauterine devices (IUD)/ intrauterine systems (IUS), barrier contraceptives,
abstinence or sterilization.

Exclusion Criteria:

- Pregnancy or lactation.

- Previous or current uterine, cervical or ovarian cancer.

- Current endometrial hyperplasia or history of atypical endometrial hyperplasia.
Endometrial biopsy will be done during screening (if not done within last 12 months).

- Suspicion of leiomyosarcoma.

- Recent rapid growth of fibroids (i.e. doubling in size within 1-6 months period).

- Unevaluated gynecologic abnormalities (unexplained vaginal bleeding, cervical
dysplasia, or abnormal adnexal/ovarian mass).

- Menopausal status.

- Surgery is urgently indicated (< 3 months) for medical or social reasons.

- Hemoglobin ≤ 6 g/dL.

- Currently enrolled in another investigational study.

- Mental condition or other barrier preventing informed written consent.

- Allergy or hypersensitivity to simvastatin.

- Current use of simvastatin or other drugs of the same class.

- Concomitant administration of strong CYP3A4 inhibitors including itraconazole,
ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin,
HIV protease inhibitors, boceprevir, telaprevir, nefazodone, and cobicistat-containing
products.

- Concomitant administration of gemfibrozil, cyclosporine, or danazol, verapamil,
diltiazem, amiodarone, diltiazem, dronedarone, amlodipine, ranolazine, lomitapide, and
grapefruit juice.

- Active liver disease, which may include unexplained persistent elevations in hepatic
transaminase levels.( elevation of aspartate transaminase and/or alanine transaminase
> 2 s.d. above the normal range at screening visit)

- Known increased risk or diagnosis of a myopathy.