SOS: Safety of Simvastatin in LAM and TSC
Study Details
Study Description
Brief Summary
The purpose of this research study is to see if simvastatin can be taken safely in patients with either LAM or TSC, who are already being treated with everolimus or sirolimus. This is the first step in looking at simvastatin as a drug that may help patients, by impacting the growth and survival of cells that make up the lung lesions that cause problems in LAM and TSC patients. The study also seeks to learn more about how simvastatin works, when given to patients being treated with everolimus or sirolimus, and to evaluate the safety and any potential benefit to patients taking this 2-drug combination.
The primary objective of this study is to determine the safety of simvastatin in the treatment of LAM-S or LAM-TS in patients on a stable (for at least 3 months) dose of sirolimus or everolimus.
Secondary objectives include:
-
To assess the effect of simvastatin on forced expiratory volume in 1 second (FEV1).
-
To assess the effect of simvastatin on forced vital capacity (FVC).
-
To assess the effect of simvastatin on diffusing lung capacity (DLCO).
-
To assess the effect of simvastatin on vascular endothelial growth factor -D (VEGF-D) serum levels.
-
To assess the effect of simvastatin with questionnaire- based assessments of dyspnea, fatigue, and quality of life (QOL).
-
Assess signs of clinical benefit.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
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).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: simvastatin treatment arm Eligible patients on sirolimus or everolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4. |
Drug: Simvastatin
Eligible patients on sirolimus or everolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.
Other Names:
Drug: Sirolimus Oral Product
Eligible patients on sirolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.
Other Names:
Drug: Everolimus Oral Product
Eligible patients on everolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Safety of Simvastatin in the Treatment of LAM-S and LAM-TS Patients [5 months]
Safety is a primary outcome measure which will be assessed by any major changes or deterioration in patient health.
Secondary Outcome Measures
- Percent Predicted FEV1 [5 months]
Lung function will be measured by FEV1: forced expiratory volume in 1s mean and calculated as % predicted +_ SD (standard deviation).
Eligibility Criteria
Criteria
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.
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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.
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Uncontrolled hyperlipidemia or diabetes.
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Pregnant, breast feeding, or plan to become pregnant within the next 6 months
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Inadequate contraception (must agree to barrier method)
-
History of organ transplant.
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Active on transplant list.
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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..
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Inability to attend scheduled clinic visits or comply with study procedures.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Pennsylvania | Philadelphia | Pennsylvania | United States | 19104 |
Sponsors and Collaborators
- University of Pennsylvania
- The LAM Foundation
Investigators
- Principal Investigator: Vera P Krymskaya, PhD, MBA, University of Pennsylvania
- Study Director: Maryl Kreider, MD, MSCE, University of Pennsylvania
- Study Chair: Frank McCormack, MD, University of Cincinnati
Study Documents (Full-Text)
More Information
Publications
- Atochina-Vasserman EN, Goncharov DA, Volgina AV, Milavec M, James ML, Krymskaya VP. Statins in lymphangioleiomyomatosis. Simvastatin and atorvastatin induce differential effects on tuberous sclerosis complex 2-null cell growth and signaling. Am J Respir Cell Mol Biol. 2013 Nov;49(5):704-9. doi: 10.1165/rcmb.2013-0203RC.
- Goncharova EA, Goncharov DA, Fehrenbach M, Khavin I, Ducka B, Hino O, Colby TV, Merrilees MJ, Haczku A, Albelda SM, Krymskaya VP. Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). Sci Transl Med. 2012 Oct 3;4(154):154ra134. doi: 10.1126/scitranslmed.3003840.
- Krymskaya VP. Treatment option(s) for pulmonary lymphangioleiomyomatosis: progress and current challenges. Am J Respir Cell Mol Biol. 2012 May;46(5):563-5. doi: 10.1165/rcmb.2011-0381ED.
- The SOS Trial
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Single Simvastatin Treatment Arm |
|---|---|
| Arm/Group Description | Simvastatin 20 mg oral daily for 2 months; if tolerated, followed by simvastatin 40 mg oral daily for 2 months Simvastatin: Eligible patients will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4. |
| Period Title: Simvastatin 20 mg Oral Daily for 2 Month | |
| STARTED | 10 |
| COMPLETED | 10 |
| NOT COMPLETED | 0 |
| Period Title: Simvastatin 20 mg Oral Daily for 2 Month | |
| STARTED | 10 |
| COMPLETED | 10 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Single Simvastatin Treatment Arm |
|---|---|
| Arm/Group Description | Simvastatin 20 mg oral daily for 2 months; if tolerated, followed by simvastatin 40 mg oral daily for 2 months Simvastatin: Eligible patients will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4. |
| Overall Participants | 10 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
50.4
(9.5)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
10
100%
|
| Male |
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
0
0%
|
| White |
10
100%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
| Region of Enrollment (participants) [Number] | |
| United States |
10
100%
|
| Rate of change in FEV1 (%) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [%] |
68.7
(23.8)
|
Outcome Measures
| Title | Safety of Simvastatin in the Treatment of LAM-S and LAM-TS Patients |
|---|---|
| Description | Safety is a primary outcome measure which will be assessed by any major changes or deterioration in patient health. |
| Time Frame | 5 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Single Simvastatin Treatment Arm |
|---|---|
| Arm/Group Description | Simvastatin 20 mg oral daily for 2 months; if tolerated, followed by simvastatin 40 mg oral daily for 2 months Simvastatin: Eligible patients will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4. |
| Measure Participants | 10 |
| Number [participants] |
0
0%
|
| Title | Percent Predicted FEV1 |
|---|---|
| Description | Lung function will be measured by FEV1: forced expiratory volume in 1s mean and calculated as % predicted +_ SD (standard deviation). |
| Time Frame | 5 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Single Simvastatin Treatment Arm |
|---|---|
| Arm/Group Description | Simvastatin 20 mg oral daily for 2 months; if tolerated, followed by simvastatin 40 mg oral daily for 2 months Simvastatin: Eligible patients will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4. |
| Measure Participants | 10 |
| Mean (Standard Deviation) [percent predicted FEV1] |
-2.9
(3.7)
|
Adverse Events
| Time Frame | 5 months | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Single Simvastatin Treatment Arm | |
| Arm/Group Description | Simvastatin 20 mg oral daily for 2 months; if tolerated, followed by simvastatin 40 mg oral daily for 2 months Simvastatin: Eligible patients will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4. | |
All Cause Mortality |
||
| Single Simvastatin Treatment Arm | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/10 (0%) | |
Serious Adverse Events |
||
| Single Simvastatin Treatment Arm | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/10 (0%) | |
Other (Not Including Serious) Adverse Events |
||
| Single Simvastatin Treatment Arm | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/10 (30%) | |
| Blood and lymphatic system disorders | ||
| Peripheral adema | 1/10 (10%) | 4 |
| Cardiac disorders | ||
| Tachycardia | 1/10 (10%) | 1 |
| Gastrointestinal disorders | ||
| Diarrhea | 1/10 (10%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Vera Krymskaya |
|---|---|
| Organization | University of Pennsylvania |
| Phone | 215-573-9861 |
| krymskay@pennmedicine.upenn.edu |
- The SOS Trial