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Safety of Simvastatin in LAM and TSC (SOS)

Primary Purpose

Lymphangioleiomyomatosis, Tuberous Sclerosis Complex

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Simvastatin
Sirolimus Oral Product
Everolimus Oral Product
Sponsored by
University of Pennsylvania
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphangioleiomyomatosis focused on measuring lymphangioleiomyomatosis (LAM), tuberous sclerosis complex (TSC), simvastatin, sirolimus, everolimus

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Pennsylvania

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

simvastatin treatment arm

Arm Description

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.

Outcomes

Primary Outcome Measures

Safety of Simvastatin in the Treatment of LAM-S and LAM-TS Patients
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
Lung function will be measured by FEV1: forced expiratory volume in 1s mean and calculated as % predicted +_ SD (standard deviation).

Full Information

First Posted
January 23, 2014
Last Updated
August 12, 2020
Sponsor
University of Pennsylvania
Collaborators
The LAM Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT02061397
Brief Title
Safety of Simvastatin in LAM and TSC
Acronym
SOS
Official Title
The Safety of Simvastatin (SOS) in Patients With Pulmonary Lymphangioleiomyomatosis (LAM) and With Tuberous Sclerosis Complex (TSC)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
March 2014 (undefined)
Primary Completion Date
December 13, 2019 (Actual)
Study Completion Date
December 13, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Pennsylvania
Collaborators
The LAM Foundation

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphangioleiomyomatosis, Tuberous Sclerosis Complex
Keywords
lymphangioleiomyomatosis (LAM), tuberous sclerosis complex (TSC), simvastatin, sirolimus, everolimus

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
simvastatin treatment arm
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Simvastatin
Other Intervention Name(s)
trade name Zocor
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Sirolimus Oral Product
Other Intervention Name(s)
Rapamune
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Everolimus Oral Product
Other Intervention Name(s)
Afinitor
Intervention Description
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.
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vera P Krymskaya, PhD, MBA
Organizational Affiliation
University of Pennsylvania
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Maryl Kreider, MD, MSCE
Organizational Affiliation
University of Pennsylvania
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Frank McCormack, MD
Organizational Affiliation
University of Cincinnati
Official's Role
Study Chair
Facility Information:
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22550272
Citation
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. No abstract available.
Results Reference
background
PubMed Identifier
23035046
Citation
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.
Results Reference
background
PubMed Identifier
23947572
Citation
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.
Results Reference
background
PubMed Identifier
21482669
Citation
Goncharova EA, Goncharov DA, Li H, Pimtong W, Lu S, Khavin I, Krymskaya VP. mTORC2 is required for proliferation and survival of TSC2-null cells. Mol Cell Biol. 2011 Jun;31(12):2484-98. doi: 10.1128/MCB.01061-10. Epub 2011 Apr 11.
Results Reference
result

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Safety of Simvastatin in LAM and TSC

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