Effects of Simvastatin on Uterine Leiomyoma Size

Study Overview
=================
Brief Summary
-----------------
The study aims to study the effect of simvastatin on the size of uterine fibroids.

Detailed Description
-----------------
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.

Official Title
-----------------
A Double-blinded, Phase II, Randomized Control Trial to Study the Effects of Simvastatin in Patients With Uterine Leiomyoma

Conditions
-----------------
Fibroid Uterus, Fibroid Tumor, Leiomyoma, Fibromyoma, Leiomyoma, Uterine

Intervention / Treatment
-----------------
* Drug: Simvastatin 40mg
* Drug: Placebo 40 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group<br>The 30 participants randomized in this group will intake Simvastatin 40mg / day of orally at the same time in the evening, every day for the study duration of 12 weeks prior to undergoing hysterectomy/ myomectomy. The fibroid samples will be collected after the surgery to evaluate the effects of the study medication on the fibroid tissue. | Drug: Simvastatin 40mg<br>* The Treatment Group subjects will orally intake encapsulated Simvastatin 40 mg tablets daily for the 12 weeks duration with water in the evening.<br>* Other names: Simvastatin;|
| Placebo Comparator: Placebo Group<br>The 30 participants randomized in this group will intake Placebo 40mg / day orally at the same time in the evening every day for the study duration of 12 weeks prior to undergoing hysterectomy/ myomectomy. The fibroid samples will be collected after the surgery to evaluate the effects of the study medication on the fibroid tissue. | Drug: Placebo 40 mg<br>* The Placebo group will orally intake encapsulated Starch 1500, 40 mg Placebo for 12 weeks duration with water in the evening.<br>* Other names: Starch 1500 encapsulated;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Tumor size volume pre and post study intervention | Tumor size measured by ultrasound imaging comparing tumor volume using ultrasound imaging. The volume will be reported in Centimeter cubes. The largest radius of the tumor will be used to calculate the volume, this will be measured in centimeters. | Change from baseline to 12 weeks post intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical symptom improvement as determined by the Uterine Fibroid Symptom and Health Related Quality of Life Questionnaire. | The questionnaire used is the Uterine Fibroid Symptom and Health Related Quality of Life Questionnaire. This questionnaire is an effective and validated tool for detecting differences in symptom severity and health-related quality of life among patients with uterine fibroids. The scale for this questionnaire denotes symptom severity with lowest and highest possible scores of 8 and 40 respectively. Higher scores indicate greater severity of symptoms. | At visit 1 (Screening), At visit 2 (start of the study drug intake), visit 3 (6 weeks after start of the study drug), visit 4( 12 weeks after start of the study drug), and follow up visit at 2 and 6 weeks post hysterectomy | 
| Adherence to the recommended treatment dosing | Based on review of patient diaries and counting of left over medications bought back by the subject. This will be reported as an overall percentage. | At Visit 3 (6 weeks after start of study drug), and Visit 4 (12 weeks after start of the study drug) | 
| Subject retention | Based on presence at follow up visits to the study site. This will be determined as a simple percentage of subjects that stay in the study until the last visit. | At visit 2 (start of the study drug intake), visit 3 (6 weeks after start of the study drug), visit 4 (12 weeks after start of the study drug), and follow up visit at 2 and 6 weeks post hysterectomy. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
simvastatin, fibroids, medical management, uterine fibroids, leiomyoma