Clinical trial NCT02061397
Conditions: Lymphangioleiomyomatosis Tuberous Sclerosis Complex
Keywords: lymphangioleiomyomatosis (LAM) tuberous sclerosis complex (TSC) simvastatin sirolimus everolimus
Sponsor: University of Pennsylvania
Start date: 2014-03-01; Completion date: 2019-12-13
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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).

Arms: arm 1: 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.
Interventions: intervention 1: Simvastatin intervention 2: Sirolimus Oral Product intervention 3: Everolimus Oral Product
Intervention descriptions: intervention 1: 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 2: 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 3: 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.

Protocol documents:
Prot_SAP_000.pdf: 
 
219 Stemmler Hall ׀ 3450 Hamilton Walk ׀ Philadelphia, PA 19104-3413 ׀ 215-573-9861  ׀krymskay@pennmedicine.upenn.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVER PAGE 
 
Date: 04-October-2016 
 
TITLE: Safety of Simvastatin in LAM and TSC (SOS) 
 
Identifiers: NCT02061397 
 
Unique Protocol ID; The SOS Trial 
 
 
 
Best Regards, 
 
 
 
 
 
Vera P. Krymskaya, Ph.D., M.B.A., F.C.P.P. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vera P. Krymskaya, Ph.D., M.B.A., F.C.P.P. 
Professor of Medicine  
Laboratory of Rare Lung Diseases  
Pulmonary, Allergy and Critical Care Division 
Department of Medicine 
Perelman School of Medicine 
University of Pennsylvania  
Penn/CHOP Lung Biology Institute 
Chair, Penn Forum for Women Faculty 
Fellow, College of Physicians of 
Philadelphia 
 


 
 
 
 
 
 
 
 
A Pilot, Safety Study of Simvastatin in Patients with Sporadic 
Pulmonary Lymphangioleiomyomatosis (LAM) and  
LAM Associated with Tuberous Sclerosis Complex  
(The SOS Study) 
 
 
 
 
Version: 4 
Date: 04 October 2016 
 
 
 
 
 
 
 
 
 
 
 
IND Status:  Exempt 
 
 
 
 
 
 
 
 
This protocol is for research purposes only, and should not be copied, 
redistributed or used for any other purpose.  The procedures in this 
protocol are intended only for use by the LAM clinic investigators in 
carefully controlled settings.  The Principal Investigator of this study 
should be consulted before using or attempting any procedure in this 
protocol. 


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University of Pennsylvania Co-Investigator: Maryl Kreider, M.D., MSCE 
Contact: Maryl Kreider, M.D., MSCE 
Institution: Perelman School of Medicine,  
University of Pennsylvania 
Address: 828 Maloney Building 
Philadelphia, PA 19104 
Phone: 215-614-1939 
Email: Maryl.Kreider@uphs.upenn.edu 
 
University of Cincinnati Non-Clinical Collaborator:  Frank X. McCormack, M.D. 
Contact: Frank McCormack, M.D.  
Institution: University of Cincinnati 
Address: 231 Albert Sabin Way 
Cincinnati, OH 45267 
Phone: 513-558-4831 
Email: frank.mccormack@uc.edu 
Participating Institutions and Investigators  
 
 
University of Pennsylvania Principal Investigator: Vera P. Krymskaya, Ph.D., 
M.B.A. 
Contact: Vera P. Krymskaya, Ph.D., M.B.A. 
Institution: Perelman School of Medicine,  
University of Pennsylvania 
Address: 125 South 31st Street 
Philadelphia, PA 19104 
Phone: 215-573-9861 
Email: krymskay@mail.med.upenn.edu 
 


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PROTOCOL SUMMARY 
 
Protocol Number: 
04 
Protocol Title: 
A Pilot, Safety Study of Simvastatin in Patients 
with Sporadic Pulmonary 
Lymphangioleiomyomatosis (LAM) and LAM 
Associated with Tuberous Sclerosis Complex 
(TSC)  (The SOS Study) 
Study Chair:  
Vera P. Krymskaya 
 
 
 
Statistician: 
Kathleen J. Propert, ScD 
 
Current Status: 
Development; pre IND and Pre-IRB submission  
Sample Size:  
Up to 10 patients 
 
Target Enrollment Period: 
3-6 months 
Participating Sites: 
University of Pennsylvania 
Study Design:  
Phase II, open label, safety study 
Study Duration: 
5.5 months (approximately 164 days) 
 
OBJECTIVES: 
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 VEGF-
D serum levels. 
 
• To assess the effect of simvastatin with 
questionnaire- based assessments of dyspnea, 
fatigue, and quality of life (QOL) using the St. 
George’s Respiratory Questionnaire (SGRQ) 
and the Functional Performance Inventory 
(FPI).  
 


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• Preliminarily assess effectiveness and clinical 
benefit in this patient population. 
TREATMENT: 
 
Agent: 
Simvastatin 
 
Dosage, schedule, route 
of administration: 
 
Dose escalation from 20 mg once-daily (QD) for 
the first two months to 40 mg QD for months 3 
and 4. The study drug will be given orally. 
 
Safety Issues: 
Simvastatin, a cholesterol lowering agent, is 
effective in preventing cardiovascular diseases. 
Concomitant administration of strong CYP3A4 
inhibitors, gemfibrozil, cyclosporine, or danazol 
is contraindicated. Simvastatin is not to be used 
in patients with myopathy, hypersensitivity to 
any component of the medication, active liver 
disease, pregnant women, or nursing mothers. 
The most commonly experienced adverse events 
with simvastatin are: rhabdomyolysis, upper 
respiratory infection, headache, abdominal pain, 
constipation, and nausea.  
 
Primary Outcome 
Measures: 
Safety of simvastatin in the treatment of LAM-S 
and LAM-TS patients on a stable (for at least 3 
months) dose of sirolimus or everolimus. 
 
Secondary Outcome 
Measures: 
FEV1, FVC, DLCO, VEGF-D, and QOL; signs 
of clinical benefit. 
 
Statistical 
Considerations (sample 
size and analysis plan): 
 
Up to 10 evaluable patients will be enrolled and 
treated with increasing doses of simvastatin for 
120 days. We anticipate a 10% attrition rate. 
The analysis will be based on an intention to 
treat design. The final analysis will occur after 
the last enrolled patient has completed the 120 
day visit. 
 
Sponsors (federal, 
state, foundation and 
industry support): 
LAM Foundation  
 


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STUDY DESIGN: 
 
                                                               A Phase II, open label, safety study of up to 10 
patients with LAM-S and LAM-TS on a stable 
(for at least 3 months) dose of sirolimus or 
everolimus. Eligible patients will be assigned to 
receive 20 mg of simvastatin once daily for a 
period of two months. The dosage of simvastatin 
will be advanced to 40 mg once daily in months 3 
and 4. 
 
 
 
 
 


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STUDY POPULATION:       
 
 
                                                                        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 within 30 days of screening with 
drugs having known metabolic interactions 
with statin drugs, including: strong CYP3A4 
[cytochrome P450 3A4 metabolism] 
inhibitors (such as itraconazole, 
ketoconazole, posaconazole, voriconazole, 
fluconazole, azithromycin, erythromycin, 
clarithromycin, etc), gemfibrozil, 
cyclosporine, danazol, verapamil, diltiazem, 


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dronedarone, amiodarone, amlodipine, 
ranolazine, lomitapide, and other lipid 
lowering medications (such as niacin 
[nicotinic acid], digoxin, warfarin, sildenafil, 
etc) 
• 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 > 2X 
ULN), kidney (serum creatinine > 1.5X 
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.   
 
 
 
 
 
 


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PRIMARY ENDPOINTS:  
• Safety of simvastatin in the treatment of 
LAM-S or LAM-TS patients on a stable (for 
at least 3 months) dose of sirolimus or 
everolimus. 
 
 
SECONDARY ENDPOINTS: 
 
• Effect of simvastatin on forced expiratory 
volume in 1 second (FEV1) at days 0, 60, 
and 120. 
• Effect of simvastatin on forced vital capacity 
(FVC) at screening and at days 0, 60, and 
120. 
• Effect of simvastatin on diffusing lung 
capacity (DLCO) at screening and at days 0, 
60, and 120.  
• Effect of simvastatin on VEGF-D serum 
levels at days 0, 30, 60, 90, and 120. 
• Signs of clinical benefit. 
STUDY OBSERVATIONS: 
 
• Patients will be evaluated in person at 
baseline and at each study visit day. 
 
• Chest x-rays will be obtained at screening 
and day 120.  
 
• Laboratory tests including a complete blood 
count, routine chemistry tests (creatinine and 
transaminases) and lipid panel will be 
performed at screening and at days 30, 60, 
90, and 120. 
 
• Blood work for VEGF-D will be performed 
at days 0, 30, 60, 90 and 120 and for 
sirolimus or everolimus blood levels at 
screening and days 30, 60, 90 and 120.  
 
• Patients will have spirometry (FEV1, FVC, 
and DLCO) performed at days 0, 60, and 
day 120. 


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SAMPLE SIZE AND POWER: 
A total of up to 10 evaluable patients will be 
enrolled. As this is a safety study with a 
small number of patients, data will be 
compiled in descriptive tables of results.  
 
DATA ANALYSIS: 
All study data will be collected via systems 
that comply with all applicable guidelines 
regarding patient confidentiality and data 
integrity.  University of Pennsylvania IRB 
approval for the protocol must be on file 
before accrual can occur. Data will be 
collected on the study case report forms and 
will be stored in the research team’s office, 
which is secured and locked daily. Patients 
will be evaluated for safety if they have 
received at least one dose of simvastatin.  
The frequency, severity and duration of all 
adverse events, regardless of cause, will be 
recorded on the case report forms.  Adverse 
events will be tabulated by body system and 
by severity using the NCI Common 
Terminology Criteria for Adverse Events 
v4.0, which can be obtained from the CTEP 
Website: 
http://ctep.cancer.gov/reporting/ctc.html.  
Tables will be generated for all adverse 
events including those that are judged to be 
possibly, probably or definitely related to 
the simvastatin. All adverse events will be 
reviewed by a Data Safety Monitoring 
Board. 
 
 


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Table of Contents 
ABSTRACT.......................................................................................................................13 
1. Introduction..................................................................................................................14 
1.1. Background and Significance.............................................................................14 
1.2. Activation of mTOR signaling and increased cell growth.................................14 
1.3. Small GTPase RhoA, statins, and TSC2-null cell survival................................15 
1.3.1. Rationale for Proposed Study....................................................................16 
1.4. Study Agents......................................................................................................17 
1.4.1. Simvastatin Information, Interactions, Administration, Toxicities...........17 
1.4.2. Drug Information for Simvastatin.............................................................18 
2. Objectives and Specific Aims......................................................................................19 
2.1. Objectives...........................................................................................................19 
2.2. Specific Outcomes..............................................................................................20 
2.2.1. Primary Outcome.......................................................................................20 
2.2.2. Secondary Outcome...................................................................................20 
3. Study Design................................................................................................................20 
3.1. Identification and screening process..................................................................20 
3.2. Patient selection criteria.....................................................................................21 
3.2.1. Inclusion criteria........................................................................................21  
3.2.2. Exclusion criteria.......................................................................................21 
3.3. Recruitment........................................................................................................22 
3.4. Enrollment..........................................................................................................22 
3.5. Study drug treatment......................................................................................... 22 
3.5.1. Treatment Regimen...................................................................................23 
3.5.2. Drug and Drug Procurement......................................................................23 
4. Study Procedures and Timelines..................................................................................26 
4.1. Study and Timeline Overview...........................................................................26 
4.2. Study schedule of Procedures............................................................................26 
4.3. Study Visits.......................................................................................................27 
4.3.1. Study day - Visit 1 (Screening)..................................................................27 
4.3.2. Study day - Visit 2 (Day 0)........................................................................27 


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4.3.3. Study day - Visit 3 (30 days).....................................................................28 
4.3.4. Study day - Visit 4 (60 days).....................................................................28 
4.3.5. Study day - Visit 5 (90 days).....................................................................29 
4.3.6. Study day – Visit 6 (120 days)..................................................................29 
4.3.7. End of Study Telephone Call.....................................................................30 
5. Dose Limiting Toxicity, Dosing Delays/Dosing Modifications..................................30 
5.1. Definition of Dose Limiting Toxicity...............................................................30 
5.2. Toxicity Criteria, Dose Delays and Modifications...........................................30 
5.2.1. Toxicity Criteria........................................................................................30 
5.2.2. Dose Delays..............................................................................................31 
5.2.3. Simvastatin Dose Reduction.....................................................................32 
5.2.4. Sirolimus or Everolimus Dose Reduction................................................32 
6. Duration of Participation..............................................................................................33 
6.1. Patient retention and drug compliance.............................................................33 
6.2. Future Contact.................................................................................................34 
6.3. Consent for Continuing Data Review of Medical Records.............................34 
6.4. Consent for Storage of Blood Samples for Future Use...................................34 
7. Stopping Rules.............................................................................................................34 
7.1. Criteria for Terminating Participation on Study.............................................34 
7.2. Criteria for Terminating the Study.................................................................35 
8. Study Variables and Measuring Methods....................................................................35 
8.1. Physical Exam................................................................................................35 
8.2. Pulmonary Function Tests..............................................................................35 
8.3. Questionnaires................................................................................................35 
8.3.1. St. George’s Respiratory Questionnaire.................................................35 
8.3.2. Functional Performance Inventory.........................................................36 
8.4. Biomarker Analyses.......................................................................................36 
9. Data Management........................................................................................................36 
9.1. Registration....................................................................................................36 
9.2. Safety Monitoring and Adverse Event Reporting..........................................36 
9.3. Adverse Events..............................................................................................37 


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9.3.1. Serious Adverse Events.........................................................................37 
9.3.2. Abnormal Laboratory Test Results.......................................................39 
9.3.3. Abnormal Physical Exam Findings.......................................................39 
9.4. Investigator reporting: Notifying the Penn IRB...........................................39 
9.4.1. Adverse Events, Unanticipated Problems, Death, and Other Reportable 
Events 39 
9.4.2. Exception..............................................................................................41 
9.4.3. Deviation..............................................................................................41 
10. Ethical and Administrative Aspects.............................................................................42 
10.1. Risks and Discomforts of Testing...................................................................42 
10.2. Confidentiality................................................................................................42 
10.3. Source documents.......................................................................................... 43 
10.4. Case Report Forms..........................................................................................43 
10.5. Records Retention...........................................................................................43 
10.6. Study Monitoring, Auditing, and Inspecting..................................................44 
10.6.1. Data Monitoring Plan............................................................................44 
10.6.2. Auditing and Inspecting........................................................................44 
10.7. Ethical Considerations...................................................................................44 
10.8. Study Finances...............................................................................................44 
10.9. Conflict of Interest.........................................................................................45 
          10.10. Patient Stipends or Payments........................................................................45 
10.11. Publication Plan...........................................................................................45 
10.12. PatientWithdrawl.........................................................................................45 
11. Statistical Considerations.............................................................................................46 
11.1. Sample Size Determination............................................................................46 
11.2. Data Analysis..................................................................................................46 
REFERENCES..................................................................................................................47 
 


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ABSTRACT 
 
Pulmonary LAM, which can be sporadic (LAM-S) or associated with tuberous sclerosis 
(LAM-TS), is a rare lung disease affecting predominantly women of childbearing age 
that manifests by neoplastic growth of atypical smooth muscle-like LAM cells, lung cyst 
formation, obstruction of lymphatics, and spontaneous pneumothoraces (1). Current 
treatment with rapamycin analogs, which are not FDA-approved for treatment of LAM-S 
and LAM-TS, but are commonly used based upon published reports, stabilize lung 
function but does not prevent further disease progression (1, 2). The rapalogs are 
cytostatic agents and cessation of treatment resumes decline in lung function. Because of 
this limitation new combinational therapy targeting LAM cell death is needed.  
 
Preclinical evidence demonstrates that simvastatin acts as a pro-apoptotic agent in in vitro 
and in vivo studies in cells and tumor lesions deficient for TSC2, inactivation mutation of 
which cause LAM and TS (3, 4). HMG-CoA reductase inhibitors (statins) are very safe, 
highly effective therapies used by millions of people (5, 6). Simvastatin decreases 
cholesterol, reduces cancer incidence, stabilizes the endothelial cell layer and decreases 
inflammation. In preclinical studies the combination of rapamycin and simvastatin 
inhibited xenograft tumor growth and completely blocked the recurrence of xenograft 
tumors after treatment withdrawal (4). In mouse model of LAM, treatment with 
rapamycin and simvastatin prevented both growth of TSC2-null lesions and lung 
destruction (3). These findings have fundamental translational significance for 
combinatorial therapeutic strategies to induce the death of LAM cells, potentially 
obviating the need for continuous, life-long suppressive therapies. We have designed a 
Phase II, open label, safety trial to initiate the study of this potentially useful intervention. 
 
We propose to conduct a safety study of simvastatin treatment of patients with LAM-S 
and LAM-TS. We aim to determine the safety of simvastatin in combination with 
sirolimus or everolimus over 4 months. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Deregulated cell signaling in LAM and its therapeutic targeting.  
 


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1. Introduction 
 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 
312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures 
 
1.1 Background and Significance 
 
Pulmonary lymphangioleiomyomatosis (LAM) is a slowly progressive neoplasm that 
targets the lung, causing cystic destruction and respiratory failure over one to two 
decades (1).  LAM occurs in about 3.4–7.8 per million women (although it is likely to be 
substantially underdiagnosed) and in at least 30% of women with tuberous sclerosis 
complex.  Clinically significant LAM occurs almost exclusively in women, although 
radiographic evidence of cystic lung disease consistent with LAM and a few biopsy-
documented cases of LAM have been reported in men with and without TSC.  The 
average age at diagnosis is about 35 years, typically delayed by 3–5 years due to 
confusion with more common causes of dyspnea, including asthma or chronic obstructive 
lung disease (1). 
 
Up to 93% of patients with TSC and 32% of patients with LAM develop renal tumors 
called kidney angiomyolipomas (AML) (1).  These tumors cause significant morbidity 
and mortality, and effective systemic treatment is not currently available.  Both TSC and 
LAM are known to be caused by mutations in either of two tumor suppressor genes 
tuberous sclerosis complex 1 (TSC1), encoding hamartin protein,  or TSC2, encoding 
protein tuberin.  When either TSC1 or TSC2  gene contain inactivating mutations, tuberin 
or hamartin produced by the gene is defective or deficient, protein function is lost, 
inducing the constitutive activation of mTOR signaling pathway that deregulates cell 
growth and survival (1).  Figure 1 illustrates the deregulated TSC1/TSC2 signaling and 
its potential therapeutic targeting in LAM and TSC patients. Growth of LAM cell lesions 
in the lung and AML in kidney is partially suppressed by treatment with the FDA-
approved drugs Everolimus or Sirolimus targeting the mTOR signaling pathway.  
Cessation of therapy results in tumor regrowth.  While this therapy intervenes with tumor 
growth, none adequately addresses the tumor cell survival. 
 
1.2 Activation of mTOR signaling and increased cell growth 
 
A breakthrough in understanding neoplastic pathophysiology in TS and LAM has 
resulted from the discovery of TSC1/TSC2 tumor suppressor complex as a negative 
regulator of the mechanistic target of rapamycin (mTOR) (7), an integrator of growth 
factor, nutrient, energy and stress signaling (8, 9). TSC2 forms a tumor suppressor 
complex with TSC1 and regulates mTORC1 by directly controlling the activity of the 
small GTPase Rheb via the GTPase activating protein (GAP) domain of TSC2 (10). Rheb 
binds to raptor and controls the activity of the mTOR that phosphorylates p70 S6 kinase 
(S6K1) and 4E-BP1 (9). Importantly, TSC2-dependent S6K1 activation suppresses 


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phosphatidylinositol 3-kinase (PI3K) signaling, named a negative feedback loop, that 
may explain the benign tumorigenesis in TS and LAM (11) and has implications for the 
therapeutic targeting of mTORC1. Activity of mTORC1 is sensitive to the inhibition by 
bacterial microlide rapamycin (12), which by binding with FKBP12 (FK506-binding 
protein of 12 kDa) interacts with FKBP12-binding domain of mTOR and inhibits 
mTORC1 (13). The discovery of the TSC2 as a negative regulator of the mTORC1 (14, 
15) and inhibitory effects of rapamycin in preclinical studies (14, 16-18) provided a 
rationale for use of rapamycin analogs in the clinic.  Current rapamycin-based therapy 
stabilizes lung function in LAM (19) and slows down the disease progression that is 
resumed upon the cessation of treatment (20-22). The limitation of rapamycin as a 
cytostatic agent indicates the need for novel TS and LAM therapy targeting cell survival.  
 
1.3 Small GTPase RhoA, statins, and TSC2-null cell survival 
 
TSC1/TSC2 regulates mTOR, which forms two functionally distinct complexes 
mTORC1 and mTORC2 (9). mTORC1-independent regulation of the actin cytoskeleton 
occurs through mTORC2-dependent regulation of RhoA and Rac1 GTPases (9, 23), and 
Rac1 is required for mTOR activation (24). In TSC2-null and human LAM-derived cells, 
Rho GTPase activity is required for cell adhesion, motility, proliferation and survival (4, 25, 
26). 
 
TSC2-deficient cells may also evade apoptosis via activation of RhoA GTPase. We found 
that downregulation of RhoA in TSC2-deficient rat-derived cells increases apoptosis and 
upregulates the proapoptotic proteins Bim, Bok, and Puma (4). Importantly, the RhoA 
activation appears to be dependent on TORC2, rather than TORC1, and inhibition of 
RhoA using simvastatin induces apoptosis in vitro and in vivo. Most importantly, the 
combination is sirolimus and simvastatin inhibited xenograft tumor growth and 
completely blocked the recurrence of xenograft tumors after treatment withdrawal (4). In 
another study using mouse model of LAM, TSC2-null lesions and alveolar destruction 
were differentially inhibited by rapamycin, which inhibits TSC2-null lesion growth by a 
cytostatic mechanism, and simvastatin, which inhibits growth of TSC2-null lesions by a 
predominantly pro-apoptotic mechanism (3). Treatment with simvastatin markedly 
inhibited MMP-2, MMP-3 and MMP-9 levels in lung and prevented alveolar destruction. 
The combination of rapamycin and simvastatin prevented both growth of TSC2-null 
lesions and lung destruction by inhibiting MMP-2, MMP-3 and MMP-9 (3). The results 
thus support further investigation of the combination of rapamycin and simvastatin as a 
potential treatment for subjects with AMLs in TSC and LAM. 
 
Statins are small molecule inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-
CoA) reductase, the rate-limiting enzyme in the synthesis of mevalonate, a fatty acid 
intermediate in de novo cholesterol biosynthesis. Statins including simvastatin, 
pravastatin, lovastatin and mevastatin are derived from fungi, or made synthetically such 
as atorvastatin and fluvastatin (27). All statins are lipophilic except pravastatin (27). 
These agents are effective in preventing cardiovascular disease largely due to lowering 
cholesterol levels (5, 6) and due to their “pleiotropic” effects (independent of their lipid-
lowering properties) in non-cardiovascular diseases, including cancer (28), rheumatologic 


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(29), and neurological disorders. Pleiotropic effects of statins include among others, the 
inhibition of isoprenoid intermediates involved in oxidative stress, inhibition of L-type 
Ca2+ current (30), cell proliferation (4), invasion, metastasis, induction of apoptosis in 
leukemia, smooth muscle, prostate, and breast cancer (27). Statins (simvastatin) have 
protective effects against oxidative stress, matrix metalloproteinase and inflammation in 
preclinical studies (3, 31). Statins also show potential uses in COPD, osteoporosis, 
diabetes and depression (32).   
 
HMG-CoA inhibition in cholesterol biosynthetic pathway suppresses synthesis of 
isoprenoids such as geranyl pyrophosphate and farnesyl pyrophosphate, which are 
required for posttranslational modification of membrane-bound small GTPase including 
Rho, Rac1, and Ras (33). Geranylgeranylation and farnesylation of these proteins 
regulate their translocation to plasma membrane and activation. Inhibition of 
geranylgeranylation and/or farnesylation induces statin-dependent cell apoptosis (32). In 
some cell types inhibition of geranylgeranylation stimulates apoptosis while farnesylation 
appears to be less important (32). In our studies co-treatment of geranylgeranyl 
pyrophosphate with simvastatin rescued rat TSC2-null ELT3 cell survival, indicating that 
simvastatin effects on RhoA activity in TSC2-null cells are modulated by 
geranylgeranylation. Simvastatin had little effect on mTOR and S6K activation 
suggesting little effect of simvastatin on Rheb farnesylation. In contrast, atorvastatin 
inhibited both farnesylation of Rheb and geranylgeranylation of RhoA in TSC2-/- mouse 
embryonic fibroblasts (34). Thus, inhibition of geranylgeranylation and/or farnesylation 
may have differential effect depending on type of cell and/or statin. 
In vitro and in vivo preclinical studies using atorvastatin and simvastatin alone and in 
combination with rapamycin have been reported. Atorvastatin inhibited growth of TSC2-/-
p53-/- MEFs and TSC2-null ELT3 cells from Eker rat in vitro (34) but had little effect on 
subcutaneous tumors formed by TSC2-/-p53-/- MEFs (35). We found that downregulation 
of RhoA in TSC2-deficient rat-derived cells increases apoptosis and upregulates the 
proapoptotic proteins Bim, Bok, and Puma (4). Importantly, the RhoA activation depends 
on mTORC2, rather than mTORC1, and inhibition of RhoA using simvastatin induces 
apoptosis in vitro and in vivo. Importantly, the combination of rapamycin and simvastatin 
inhibited xenograft tumor growth and completely blocked the recurrence of xenograft 
tumors after treatment withdrawal (4). In another study using mouse model of LAM, 
TSC2-null lesions and alveolar destruction were differentially inhibited by rapamycin, 
which inhibits TSC2-null lesion growth by a cytostatic mechanism, and simvastatin, 
which inhibits growth of TSC2-null lesions by a predominantly pro-apoptotic mechanism 
(3). The combination of rapamycin and simvastatin prevented both growth of TSC2-null 
lesions and lung destruction by inhibiting MMP-2, MMP-3 and MMP-9 (3).  
 
1.3.1 Rationale for proposed study 
 
This is a pilot, safety study with plans for a multi-center Phase II once safety has been 
established.  These findings have fundamental translational significance for combinatorial 
therapeutic strategies to induce the cell death in LAM lung lesions. Pre-clinical  results 
demonstrate the beneficial effects of combinational treatment with rapamycin and 
simvastatin and support further investigation of the combination of rapamycin and statins 


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as a potential treatment for subjects with TS and TS-LAM.  While statins are very safe, 
highly effective therapies and used by millions of people to reduce the incidence of 
cancer, this study plans to better understand the mechanism and evaluate the safety of  
simvastatin when given to LAM-S and LAM-TS patients treated with everolimus or 
sirolimus. 
 
1.4 Study Agents 
 
1.4.1 Simvastatin Information, Interactions, Administration, Toxicities 
 
Simvastatin, a HMG-CoA reductase inhibitor statin, is a lipid lowering drug (36). Statins 
are commonly used in the treatment of hyperlipidemia and cardiovascular diseases. 
Simvastatin reduces the levels of LDL cholesterol, triglycerides and total cholesterol and 
raises HDL cholesterol. The metabolism of this medication may affect the occurrence of 
side effects and cause drug interactions. Simvastatin is also metabolized in the liver by 
cytochrome P450 (CYPs) CYP3A4 is specifically responsible for simvastatin metabolism 
(37). Since simvastatin is metabolized by CYP3A4, it may interact with other drugs that 
are also metabolized by the same isoform of the enzyme such as rapamycin. Some 
possible side effects of simvastatin use includes myopathy, muscle weakness, 
rhabdomyolysis (38). 
 
Rapamycin, also known as sirolimus or everolimus, is an inhibitor of mTOR and a potent 
immunosuppressive drug that is clinically used for organ transplants (39). It prevents the 
rejection of transplanted organs and tissues. Metabolism of rapamycin occurs in the liver 
and the small intestine by the CYP3A4 family of enzymes; 3A4 is most likely to be the 
main isoform of the 3A subfamily responsible for sirolimus or everolimus metabolism. 
Statistics show a significant parallel between rapamycin metabolism and P450 3A4 
activity. Inactivation of P450 3A4 inhibits metabolism of rapamycin. So, concomitant 
administration of rapamycin with other P450 3A substrates or inducers can alter the oral 
bioavailability of these drugs (40). Rapamycin is also a substrate of P-glycoprotein, a 
membrane protein in the small intestine that pumps drugs out of the cell (41). 
 
Since simvastatin and rapamycin are metabolized by the same enzyme, using them 
together can potentially increase the blood levels or add to the side effects of either 
medication. Because they bind to the same protein, the drugs compete for binding sites 
and may have antagonistic effects when used together. Competition can potentially result 
in elevated concentration of sirolimus, increasing the risk of myopathy or rhabdomyolysis 
(42). This may have a dangerous side effect on the muscles; so, patients should be 
monitored for muscle pain or weakness. There have not been many clinical reports on the 
interactions between simvastatin and rapamycin. However, one report explains the severe 
interaction between simvastatin and rapamycin which resulted in rhabdomyolysis in a 
liver transplant patient. A 56 year old man underwent liver transplantation and was 
simultaneously administered rapamycin and simvastatin. Thereafter, he experienced 
severe muscle pain and was unable to ambulate. He suffered from rhabdomyolysis and 
acute renal failure probably due to secondary drug interaction between simvastatin and 
rapamycin (43). Due to the pharmacokinetic interaction between these two agents, they 


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should be administered hours apart since co-administration can increase the risk of side 
effects. Dosage modification of sirolimus may also ameliorate the hyperlipidemic effects 
(42). 
 
The study will use generic simvastatin 20 mg and 40 mg for daily oral administration. 
Simvastatin 40 mg daily is the recommended dosage for patients at high risk for cardiac 
events, due to existing coronary heart disease, diabetes, peripheral vascular disease, 
history of stroke or other cerebrovascular disease.  Simvastatin has been extensively 
studied at the recommended dose of 40 mg per day (5).  Simvastatin is metabolized by 
cytochrome P450 isoform 3A4 (CYP3A4).  The primary indications include secondary 
prevention for coronary artery disease and for treatment of hypercholesterolemia.  Drug 
interactions include a slight potentiation of warfarin anticoagulant effect and mild 
increase in serum digoxin concentration, neither of which are clinically significant. 
 
Simvastatin has been evaluated for adverse reactions in over 21,000 patients; only 1.4% 
discontinued therapy due to adverse experience.  Rhabdomyolysis and elevations in 
serum transaminases are the two main side effects of simvastatin.  Large clinical trials 
have shown no significant differences in the incidence of elevated creatine 
phosphokinase (CPK) 4-10X the upper limit of normal (ULN) between simvastatin 
(0.19%) and placebo (0.13%) or myopathy (CPK > 10X ULN) (5).  The number of 
subjects with elevated transaminases (2-4X ULN) was also small and no different than 
placebo (1.35% for simvastatin, 1.28% for placebo, p=NS) (5).  Treatment cessation due 
to this complication was comparable between the groups (0.5% for simvastatin, 0.3% for 
placebo). 
 
Patients who are eligible will receive instructions for simvastatin and the initial one 
month supply.  Patients will be instructed to take simvastatin in the evening and advised 
to avoid grapefruit juice due to the potential for an interaction. Patients will be reminded 
about the side effects of simvastatin, and will be given a drug information sheet, 
including all adverse drug interactions.   
 
Patients will be carefully monitored at visits 3, 4, 5 and 6 for signs and symptoms of 
simvastatin side effects including upper respiratory infection, headache, abdominal pain, 
constipation, and nausea. 
 
1.4.2 Drug Information for Simvastatin 
 
Simvastatin is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive 
therapy to diet to (per package insert):  
 
• Reduce the risk of total mortality by reducing coronary heart disease (CHD) 
deaths and reduce the risk of non-fatal myocardial infarction, stroke, and the need 
for revascularization procedures in patients at high risk of coronary events. 
• Reduce elevated total-C, LDL-C, Apo B, triglycerides (TG) and increase HDL-C 
in patients with primary hyperlipidemia (heterozygous familial and nonfamilial) 
and mixed dyslipidemia. 


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• Reduce elevated triglycerides (TG) in patients with hypertriglyceridemia and 
reduce TG and VLDL-C in patients with primary dysbetalipoproteinemia. 
• Reduce total-C and LDL-C in adult patients with homozygous familial 
hypercholesterolemia. 
• Reduce elevated total-C, LDL-C, and Apo B in boys and postmenarchal girls, 10 
to 17 years of age with heterozygous familial hypercholesterolemia after failing 
an adequate trial of diet therapy.  
 
 
 
We will monitor patient lipids to ensure adequate levels of HDL.   
 
 
Limitations of Use – Simvastatin has not been studied in Fredrickson Types I and V 
dyslipidemias. 
 
The use of simvastatin is contraindicated with the administration of strong CYP3A4 
inhibitors and gemfibrozil, cyclosporine, or danazol.  It is also not to be used in patients 
with hypersensitivity to any component of this medication, active liver disease, and with 
elevations in hepatic transaminase levels.  It is also recommended that the dose of 
simvastatin not exceed 10 mg daily if patients are taking verapamil, diltiazem, and 
dronedarone.  Simvastatin should not exceed 20 mg daily if patients are taking 
amiodarone, amlodipine, and ranolazine. Women who are pregnant or may become 
pregnant or are nursing mothers should not take simvastatin.  All patients should avoid 
grapefruit juice. 
 
Most common adverse reactions (incidence ≥5.0%) are: upper respiratory infection, 
headache, abdominal pain, constipation, and nausea. 
 
Patients should be advised of the increased risk of myopathy: rhabdomyolysis has been 
seen in patients taking the 80 mg dose.   
 
Simvastatin dosing ranges from 5 mg to 40 mg once daily.  The typical starting dose is 10 
mg or 20 mg once a day in the evening.  The recommended starting dose for patients at 
high risk of CHD is 40 mg/day. 
 
2. Objectives and Specific Aims 
 
2.1 Objectives 
 
The hypothesis to be tested is whether simvastatin can be safely added to the treatment of 
LAM-S or LAM-TS patients who have been on a stable (for at least three months)  dose 
of mTOR inhibitors either sirolimus or everolimus.  Specific objectives are: 
 
Primary: 
 
• Safety of simvastatin in the treatment of LAM-S and LAM-TS patients on a stable 
(for at least 3 months) dose of sirolimus or everolimus 
 
 


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Secondary: 
 
• 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 VEGF-D serum levels. 
 
• To assess the effect of simvastatin with questionnaire-based assessments of 
dyspnea, fatigue, and quality of life (QOL) ) using the St. George’s Respiratory 
Questionnaire (SGRQ) and the Functional Performance Inventory (FPI). 
 
• To preliminarily assess effectiveness and clinical benefit in this patient population. 
 
2.2 Specific Outcomes 
 
2.2.1 Primary Outcome 
 
The primary outcome will be to determine if simvastatin can be used safely in the 
treatment of LAM-S or LAM-TS patients on sirolimus or everolimus. 
 
2.2.2 Secondary Outcome 
 
Secondary outcome measures will include effect of simvastatin addition to mTOR 
inhibitor therapy, either sirolimus or everolimus, on forced expiratory volume in one 
second (FEV1), forced vital capacity (FVC), diffusing lung capacity (DLCO), serum 
VEGF-D levels, questionnaire based assessments of dyspnea, fatigue, and quality of life 
(QOL), and clinical benefit.  The final analysis will occur after the last actively enrolled 
patient has completed the four month study visit.   
 
3. Study design 
 
This is an open label, non-randomized, dose-escalation study conducted as a pilot safety 
study.  Patients will continue on their existing background therapy of either sirolimus or 
everolimus for treatment of their LAM or LAM-TS disease.  Each patient is anticipated 
to participate in the study for approximately 5.5 months (approximately 164 days).   
 
3.1 Identification and screening 
 
Patients will be identified by the medical staff that care for patients with LAM-S and 
LAM-TS at the LAM clinic at the University of Pennsylvania Health System. Study staff  
expect to screen up to 10 patients over 3-6 months. Potentially eligible patients will be 
approached by their physician, and then by study staff.  Potential patients will be 
informed about the study, and following completion of the informed consent process, a 


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screening evaluation will be performed. The patient will provide informed consent before 
any study procedures are performed.  
 
3.2 Patient selection criteria 
 
3.2.1 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 
• 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. 
 
3.2.2 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 within 30 days of screening with drugs having known metabolic 
interactions with statin drugs, including:  
o strong CYP3A4 [cytochrome P450 3A4 metabolism] inhibitors (such as 
itraconazole, ketoconazole, posaconazole, voriconazole, fluconazole, 
azithromycin, erythromycin, clarithromycin, etc), gemfibrozil, 
cyclosporine, danazol, verapamil, diltiazem, dronedarone, amiodarone, 
amlodipine, ranolazine, lomitapide, and other lipid lowering medications 
(such as niacin [nicotinic acid], digoxin, warfarin, sildenafil, etc) 
• Participation in another clinical study(ies) of an investigational treatment or drug 
within 30 days prior to the screening visit.  
• Significant dysfunction of liver (ALT > 2X ULN), kidney (serum creatinine > 
1.5X 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.  
• 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.   
 
3.3 Recruitment 
After IRB approval has been obtained, the LAM community will be notified about the 
existence of the study by postings in public places and on the internet,.  Patients will also 
be referred by physicians and LAM support groups such as the LAM Foundation, and the 
Tuberous Sclerosis Alliance.  The study will be posted on clinicaltrials.gov.   
 
3.4 Enrollment 
Potential study patients will be contacted by the study staff to determine interest in study 
participation.  Contact may be made by postal mail, electronic mail or in person. 
Interested individuals will receive study information, including a cover letter and a 
consent form. Patients may be consented and preliminarily assessed prior to the actual 
screening visit.  
 
All patients enrolled will be female.  Up to ten evaluable patients will be enrolled. As in 
prior studies, an attrition rate of 10% is expected; appropriate adjustments will be made 
in the number of enrolled patients. 
 
3.5 Study drug treatment 
 
Patients who meet eligibility criteria, provide informed consent and and are enrolled in 
the study will receive instructions regarding simvastatin dosage, route and administration.  
A one month supply of simvastatin 20 mg will be provided at visit 2.. Patients will be 
reminded about the side effects of simvastatin, and will be given a drug information 
sheet.  Patients will be instructed to take the study medication in the evening every day.  
Patients will be carefully monitored monthly at visits 3, 4, 5 and 6 for signs and 
symptoms of simvastatin side effects including:  upper respiratory infection, headache, 
abdominal pain, constipation, myalgias, arthralgias and nausea.  Patients will be 
instructed to contact the study staff should they experience any of these side effects.  
Simvastatin doses may be held or reduced in the event of unacceptable side effects.  
 
3.5.1 Treatment Regimen 


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We have chosen an intra-patient dose escalation strategy because there is no previous 
data from human studies to demonstrate the safety of simvastatin in combination with 
sirolimus or everolimus, in patients with LAM-S and LAM-TS. Dose escalation strategy 
will be performed only for patients who tolerate 20 mg daily simvastatin. If patients do 
not tolerate  the 20 mg simvastatin dose, the dose will be down-titrated to 10 mg daily. If 
20 mg daily is well tolerated, at visit 4 the dose will be increased to 40 mg daily for 
months 3 and 4.   If 40 mg daily is not well tolerated, the dose will be reduced back to 20 
mg daily.   
Intermediate dose reductions to 15 or 30 mg/day may be undertaken if the side effect(s) is 
reasonably mild and tolerable.   
 
Patients will remain on their current dose of sirolimus or everolimus without interruption, 
as clinically indicated.   
 
3.5.2 Drug and Drug Procurement 
 
Simvastatin Description  
 
Simvastatin is a lipid-lowering agent that is derived synthetically from a fermentation 
product of Aspergillus terreus. After oral ingestion, simvastatin, which is an inactive 
lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-
hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the 
conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the 
biosynthesis of cholesterol.  
Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-
(tetrahydro-4hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl 
ester, 
[1S-
[1α,3α,7β,8β(2S*,4S*),-8aβ]]. The empirical formula of simvastatin is C25H38O5 and its 
molecular weight is 418.57. Its structural formula is:  
 
Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically 
insoluble in water, and freely soluble in chloroform, methanol and ethanol. Simvastatin’s 
inactive ingredients include: ascorbic acid, citric acid, hydroxypropyl cellulose, 


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hypromellose, iron oxides, lactose, magnesium stearate, microcrystalline cellulose, starch, 
talc, and titanium dioxide. Butylated hydroxyanisole is added as a preservative. 
 
Marketed under the trade name ZOCOR, simvastatin is available for oral administration as 
5 mg, 10 mg, 20 mg, 40 mg or 80 mg tablets.  Simvastatin is commercially available but 
will be provided to patients in this clinical study through Penn’s Investigational Drug 
Service.   
 
Everolimus Description 
 
Everolimus, an inhibitor of mTOR, is an antineoplastic agent. 
The chemical name of everolimus is 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- 
dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-
methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-
tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-  pentaone. 
The molecular formula is C53H83NO14 and the molecular weight is 958.2. The 
structural formula is: 
 
 
 
 
 
Everolimus is supplied as tablets for oral administration containing 2.5 mg, 5 mg, or 10 
mg of everolimus together with butylated hydroxytoluene, magnesium stearate, lactose 
monohydrate, hypromellose, crospovidone, and lactose anhydrous as inactive ingredients. 
 
 
 
Sirolimus Description 
 


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Sirolimus is an immunosuppressive agent. Sirolimus is a macrocyclic lactone produced 
by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as 
rapamycin) is (3S,6R ,7E,9R ,10R,12R ,14S,15E ,17E,19E ,21S,23S ,26R,27R ,34aS)-
9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-
[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-
6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] 
oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H ,31H)-pentone. Its molecular formula is 
C51H79NO13 and its molecular weight is 914.2. The structural formula of sirolimus is:  
 
Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in 
benzyl alcohol, chloroform, acetone, and acetonitrile. 
Sirolimus is available for administration as an oral solution containing 1 mg/mL 
sirolimus. Sirolimus is also available as a white, triangular-shaped tablet containing 1 mg 
sirolimus, and as a yellow to beige triangular-shaped tablet containing 2 mg sirolimus. 
The inactive ingredients in sirolimus Oral Solution are Phosal 50 
PG® (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty 
acids, and ascorbyl palmitate) and polysorbate 80. Rapamune Oral Solution contains 
1.5% - 2.5% ethanol. 
The inactive ingredients in sirolimus tablets include sucrose, lactose, polyethylene glycol 
8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium 
dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, 
glyceryl monooleate, carnauba wax, and other ingredients. The 2 mg dosage strength also 
contains iron oxide yellow 10 and iron oxide brown 70. 
Patients will remain on everolimus or sirolimus and continue to obtain those agents in the 
manner already established. 
 
 
4. Study Procedures and Timeline 
 
4.1 Study and Timeline Overview 


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The study will enroll up to 10 evaluable patients over 3-6 months.  All study patients will 
be assigned to a starting dosage of 20 mg of simvastatin daily for a period of two months. 
If patient tolerability to the 20 mg simvastatin dosage decreases, the dose will be down-
titrated to 10 mg daily.  Intra-patient dose escalation strategy will be performed only for 
patients who tolerate simvastatin 20 mg daily and the daily dosage of simvastatin will be 
escalated to 40 mg daily during months 3 and 4. .  Patients who are escalated to 40 mg 
daily who do not tolerate that dose, will be reduced back down to the previously tolerated 
20 mg daily. 
 
The patient will be given a copy of the informed consent form. Patients will be given 
ample time to read and discuss the consent form with the study staff.  The study staff will 
then answer any outstanding questions asked by the patient.  The patient will be offered 
the option of signing the consent form. Those who agree to participate will undergo the 
remainder of screening at visit 1.   
 
Prior to starting study drug, pulmonary function tests and chest X-ray will be obtained. 
The spirometry values obtained that contain the best values for FEV1, FVC and DLCO 
will constitute the baseline values. Patients will be followed with serial VEGF-D levels 
collected at each visit over a four month period.   
 
4.2 Study schedule of procedures 
 
The table below summarizes the study procedures. 
 
Table 1: Study Procedures  
 
Event 
Screen 
Day 0 
Day 30 
 
Day 60 
Day 90 
Day 
120 
Visit number 
1 
2 
3 
4 
5 
6 
Informed consent  
X 
 
- 
- 
- 
- 
History and physical 
X 
 
X 
X 
X 
X 
Chest X-ray 
X 
 
 
 
 
X 
Blood levels of sirolimus 
(target range 3-20 ng/ml) 
or everolimus (target 
range of 3-20 ng/ml)  
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
CBC, CPK, CMP * 
X 
 
X 
X 
X 
X 
Lipid profile** 
X 
 
X 
X 
X 
X 
VEGF-D 
 
X 
X 
X 
X 
X 
Saved serum and plasma 
 
X 
X 
X 
X 
X 
Urine pregnancy test 
X 
X 
X 
X 
X 
X 
Spirometry (FEV1, FVC 
DLCO)   
 
X 
 
X 
 
X 


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Review concomitant 
medications 
X 
X 
X 
X 
X 
X 
Review adverse events 
 
 
X 
X 
X 
X 
Study drug (simvastatin) 
management 
 
X 
X 
X 
X 
X 
SGRQ and  FPI 
  
 
X 
X 
X 
X 
X 
*CMP to include BUN, creatinine, ALT, AST, Alk Phos, total bilirubin 
**Lipid Panel to include total cholesterol, LDL, HDL and triglycerides. 
  
4.3 Study Visits 
 
4.3.1 Visit 1 - Screening 
 
At the screening, the consent form will be presented to the potential patient. If the patient 
is competent to understand the risks, agrees to participate and provides informed consent 
and HIPAA release, the patient will undergo screening.  
 
During this visit, the following will be performed: 
• review the inclusion/exclusion criteria 
•  obtain a urine pregnancy test (for women of childbearing potential) 
• review current medications 
• review medical history and conduct a physical examination 
• obtain clinical labs including: CBC, CPK, Complete Metabolic Panel (CMP), 
lipid panel, and sirolimus or everolimus drug level 
• obtain a chest x-ray    
 
4.3.2 Visit 2 - Day 0 (< 14 days of Visit 1) 
 
After review of screening tests and confirmation the patient continues to meets eligibility 
criteria, the patient will return to the clinic where the following will be performed: 
 
• obtain a urine pregnancy test (for women of childbearing potential) 
• review current medications 
• obtain blood for VEGF-D measurement and, if the patient has consented obtain an 
additional sample to be stored on-site for potential future use 
• perform spirometry with appropriate safety procedures. All spirometry tests 
during all visits will be performed after supervised administration of 
bronchodilator in the pulmonary function laboratory.  
• administer the SGRQ and FPI instruments for dyspnea, fatigue and quality of life  
• dispense simvastatin 20 mg with instructions regarding dosing and potential side 
effects 
•  provide a study calendar to document drug compliance.  The patient should bring 
the completed calendar back at Visit 3.  


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4.3.3 Visit 3 – Day 30 ( 7 days) 
 
The patient will return 30 days  (+/- 7 days) after Visit 2.  During this visit, the following 
will be performed: 
 
• obtain a urine pregnancy test (for women of childbearing potential) 
• review current medications 
• review the interval medical history and conduct a physical examination 
• assess for adverse events 
• obtain clinical labs including: CBC, CPK, Complete Metabolic Panel, lipid panel, 
and sirolimus or everolimus drug level 
• obtain blood for VEGF-D measurement and, if the patient has consented obtain an 
additional sample to be stored on-site for potential future use 
• administer the SGRQ and FPI instruments for dyspnea, fatigue and quality of life 
• assess for simvastatin drug compliance 
• as necessary, perform simvastatin down-titration and manage drug dispensing 
• provide a study calendar to document drug compliance.  The patient should bring 
the completed calendar back at Visit 4. 
  
4.3.4 Visit 4 – Day 60  ( 7 days) 
 
The patient will return 30 days  (+/- 7 days) after Visit 3.  During this visit, the following 
will be performed: 
 
• obtain a urine pregnancy test (for women of childbearing potential) 
• review current medications 
• review the interval medical history and conduct a physical examination 
• assess for adverse events 
• obtain clinical labs including: CBC, CPK, Complete Metabolic Panel, lipid panel, 
and sirolimus or everolimus drug level 
• obtain blood for VEGF-D measurement and, if the patient has consented obtain an 
additional sample to be stored on-site for potential future use 
• perform spirometry with appropriate safety procedures. All spirometry tests 
during all visits will be performed after supervised administration of 
bronchodilator in the pulmonary function laboratory. 
• administer the SGRQ and FPI instruments for dyspnea, fatigue and quality of life 
• assess for simvastatin drug compliance 
• dispense simvastatin 40 mg (if not contraindicated) with instructions regarding 
dosing and a reminder regarding potential side effects 
• provide a study calendar to document drug compliance.  The patient should bring 
the completed calendar back at Visit 5. 
 
4.3.5 Visit 5 – Day 90 ( 7 days) 


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The patient will return 30 days  (+/- 7 days) after Visit 4.  During this visit, the following 
will be performed: 
 
• obtain a urine pregnancy test (for women of childbearing potential) 
• review current medications 
• review the interval medical history and conduct a physical examination 
• assess for adverse events 
• obtain clinical labs including:   CBC, CPK, Complete Metabolic Panel, lipid 
panel, and sirolimus or everolimus drug level 
• obtain blood for VEGF-D measurement and, if the patient has consented obtain an 
additional sample to be stored on-site for potential future use 
• administer the  SGRQ and FPI instruments for dyspnea, fatigue and quality of life 
• assess for simvastatin drug compliance 
• as necessary, perform simvastatin down-titration and manage drug dispensing 
• provide a study calendar to document drug compliance.  The patient should bring 
the completed calendar back at Visit 6. 
 
4.3.6     Visit 6 - Day 120 ( 7 days) 
 
The patient will return 30 days  (+/- 7 days) after Visit 5.  During this visit, the following 
will be performed: 
 
• obtain a urine pregnancy test (for women of childbearing potential) 
• review current medications 
• review the interval medical history and conduct a physical examination 
• assess for adverse events 
• obtain clinical labs including:   CBC, CPK, Complete Metabolic Panel, lipid 
panel, and sirolimus or everolimus drug level 
• obtain blood for VEGF-D measurement and, if the patient has consented obtain an 
additional sample to be stored on-site for potential future use 
• obtain a chest x-ray 
• perform spirometry with appropriate safety procedures. All spirometry tests 
during all visits will be performed after supervised administration of 
bronchodilator in the pulmonary function laboratory. 
• administer the SGRQ and FPI instruments for dyspnea, fatigue and quality of life 
• assess for simvastatin drug compliance  
• advise women of childbearing potential that they should continue to use their 
method of birth control for at least 30 days after the study ends 
• remind patients they will be contacted by phone in approximately 30 days as a 
follow-up. 
• remind the patient  to follow up with her regular physician for routine care.   
 
If at visit 6, it is determined there has been clinical benefit, the patient and her regular 
physician will decide how to proceed after the conclusion of the clinical study.   


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4.3.7 End of Study Telephone Call – Day 150 (+/- 7 days) 
 
An end of study phone call will be conducted at 30 days (+/- 7 days) after the study visit 
6.  The purpose of the call is to follow up on any open or unresolved adverse events. 
 
5. Dose Limiting Toxicity Rules, Dose Delays, and Dosing Modifications 
 
5.1  Definition of Dose Limiting Toxicity (DLT) 
 
DLTs will be defined by toxicity occurring during the first 5 weeks of this study. A DLT 
will be any non-pulmonary AE of Grade 3 or higher that is at least possibly treatment-
related with the exception of nausea and vomiting which have not been treated with 
optimal anti-emetic therapy. Any DLT that causes a patient to miss > 28 consecutive days 
of simvastatin will result in the patient being taken off treatment. 
 
A DLT is defined as a toxicity considered at least possibly related to simvastatin.  In this 
regard, it is important to consider the possibility that co-administration of simvastatin 
may increase the toxicity of sirolimus or everolimus.  Conversely, sirolimus or 
everolimus might influence the toxicity profile of simvastatin.  Thus, it may be difficult 
to confidently attribute certain observed toxicities solely to either simvastatin and 
sirolimus, or simvastatin and everolimus. With this potential complication in mind, an 
attempt will be made to define dose-limiting toxicities (DLTs), which apply specifically 
to simvastatin.  In this study, DLTs will include any possibly, probably, or definitely 
simvastatin-related Grade 3 or 4 toxicity.  Known toxicities specific to sirolimus and 
everolimus such as mucositis will not be considered dose limiting unless the treating 
physician considers the toxicity to be exacerbated by simvastatin. Toxicities that will be 
attributable to simvastatin include but are not limited to abdominal pain, nausea, diarrhea, 
headache, and infectious complications.   
 
The target DLT rate is ≤ 33%.  The maximum tolerated dose (MTD) will be defined as a) 
the dose producing DLT in 2 out of 6 patients, or b) the dose level below the dose which 
produced DLT in ≥ 2 out of 3 patients, or in ≥ 3 out of 6 patients.  Patients will be 
evaluable for a DLT if they have finished 5 weeks of combined therapies. Patients who 
are removed from study due to clinical progression prior to the 5 week period will be 
replaced. Patients will be evaluable for response if they have completed 90% of their 
expected dose of simvastatin for the 8 weeks. Patients will be evaluated for toxicity if 
they received at least one dose of simvastatin. 
 
5.2 Toxicity Criteria, Dose Delays, and Modifications 
 
5.2.1 Toxicity Criteria 
 
This study will utilize the CTCAE version 4.0 for toxicity  and Adverse Event Reporting.  
A copy  of the CTCAE version 4.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov). All appropriate treatment areas should have access to a copy of 


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the CTCAE version 4.0.  
 
           5.2.2 Dose Delays 
 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the patient on study drug. If administration of 
sirolimus or everolimus must be interrupted because of unacceptable toxicity, drug 
dosing will be interrupted or modified according to rules described in Section 6.4. Major 
Events are non-treatment-related grade 3 and 4 pulmonary and non-pulmonary toxicities. 
Treatment should be delayed for major events if simvastatin may further complicate the 
non-treatment related event.  If a major event requires a delay of treatment, treatment 
must be delayed until toxicity is resolved (≤ Grade 1 or ≤ Baseline). For treatment-related 
toxicities and major events, if toxicity is not resolved in  4 weeks, patient will be taken 
off the treatment that is most likely to be related to the toxicity. While this most likely 
will result in coming off study, at the investigator’s discretion patients may continue on 
single agent therapy, if toxicities are <  grade 2 and there is some evidence of clinical 
benefit to the patient.    
                
Table 2A: Approach to overlapping toxicities of simvastatin and sirolimus* 
 
Overlapping Toxicity  
Dose Reduce First   
Dose Reduce Second  
Mucositis 
sirolimus 
simvastatin 
Nausea 
sirolimus 
simvastatin 
Abdominal pain 
simvastatin 
sirolimus 
Infections 
sirolimus 
simvastatin 
Diarrhea 
sirolimus 
simvastatin 
Headache 
simvastatin 
sirolimus 
   
Table 2B: Approach to overlapping toxicities of simvastatin and everolimus* 
 
Overlapping Toxicity  
Dose Reduce First   
Dose Reduce Second  
Mucositis 
everolimus 
simvastatin 
Nausea 
everolimus 
simvastatin 
Abdominal pain 
simvastatin 
everolimus 
Infections 
everolimus 
simvastatin 
Diarrhea 
everolimus 
simvastatin 
Headache 
simvastatin 
everolimus 
 
*At the discretion of the treating physician. 
 
            
5.2.3 Simvastatin Dose Reduction 


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Any AE of ≥ Grade 3 and attributed as possibly, probably or definitely related to 
simvastatin will result in the dose being held until the AE has resolved to ≤ grade 1 or 
baseline, while sirolimus dosing may continue uninterrupted. If the AE resolves, 
reinstitution of treatment can occur but at a reduced dose as described in Table 3. If the 
AE recurs at the reduced dose, treatment will be held until the AE has resolved to ≤ grade 
1 and when resolved treatment can be reinstituted at the next lower dose level. No more 
than 2 dose reductions are allowed during the maintenance cycles.    
  
  
Table 3: Simvastatin Dose Reduction Schema 
  
Dose mg/day 
Reduce to 
20 mg daily 
15 mg daily 
15 mg daily 
10 mg daily 
40 mg daily 
30 mg daily 
30 mg daily 
20 mg daily 
 
Toxicities that may attributable to simvastatin include nausea, abdominal pain, diarrhea, 
upper respiratory infections, headache, and diarrhea.  If any of these AEs occur at grade ≤ 
2, simvastatin may be continued and the AE managed with supportive care. For any AE 
with a grade ≥ 3, the rules outlined in Sections 5.3 apply for holding of dose, dose 
reduction, removal from study and reporting requirements.   
 
The main laboratory abnormalities which may result from simvastatin include increased 
CPK and liver transaminases. Patients who develop increased CPK levels (> 2X ULN) 
will be followed with weekly CPK levels until the abnormalities return to normal. 
Simvastatin will be continued if CPK values are decreasing on the following week’s 
blood sample. If persistent elevations (> 2X ULN) occur over two weeks (three 
assessments), or symptoms such as muscle pain are present, the simvastatin study drug 
will be stopped. The simvastatin study drug will be stopped immediately if myositis 
(CPK > 10 x ULN) is documented at any time. 
 
5.2.4 Sirolimus or Everolimus Dose Reduction 
 
Known sirolimus and everolimus toxicities will not be attributed to simvastatin but will 
only be attributed to sirolimus or everolimus and will result in the following sirolimus or 
everolimus dose modifications. Pulmonary toxicity of unexpected severity may be 
attributed to simvastatin (in addition to sirolimus or everolimus) at investigator 
discretion.  Non-pulmonary toxicities of possible, probable or definite  anddefinite and 
having an attribution to sirolimus or everolimus will result in the following sirolimus or 
everolimus dose modifications.   Blood counts will be evaluated weekly.  Within -3 days 
prior to sirolimus or everolimus dosing, the patient must have an ANC > 1.0 x 109/L and 
platelet count > 75 x 109/L. All non-pulmonary toxicity grade 3 or 4 (except for 
mucositis, diarrhea, nausea, and acneiform rash) must have resolved to CTCAE grade ≤ 
2.  If toxicity persists, treatment should be delayed by one week for up to 3 consecutive 


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weeks. If after 3 weeks of delay, all toxicity has still not resolved, then any further 
treatment with sirolimus or everolimus should be stopped. Simvastatin may be continued 
after sirolimus or everolimus has been stopped.  
 
If any non-pulmonary toxicity observed Grade ≥ 3 (except for mucositis, diarrhea, 
nausea, acneiform rash, and swelling of extremities) and/or if platelets < 75 x 109/L 
and/or ANC < 1 x 109/L, causing delay of two weeks of sirolimus then the dose should be 
reduced by one dose level (Table 5). For patients requiring more than 2 dosage  
reductions, sirolimus or everolimus will be stopped. If any non-pulmonary toxicity 
observed was CTCAE Grade 4 (except for mucositis, diarrhea, nausea, acneiform rash, 
and swelling of extremities) then sirolimus or everolimus should be stopped. 
 
Table 4: Sirolimus or Everolimus dose level modification guidelines 
 
 
 
 
 
 
6. Duration of Participation 
 
6.1 Patient retention and drug compliance 
 
Patient retention will be encouraged in several ways. Extensive contact information will 
be captured for each patient, at the time of study enrollment. This will include home, 
work, and cellular telephone numbers. Prior to each study visit, the study staff will 
contact the patient to remind her about the upcoming study visit.  Patients will receive a 
stipend in the amount of $25 per study visit, for their participation in the study. A check 
for the reimbursement of expenses will be issued after each study visit.  
 
The study staff and physician will explain the importance of compliance with the study 
protocol at each patient contact. If a patient fails to comply with a study visit, the study 
staff will contact her by telephone. If the study staff is unsuccessful in reaching the 
patient, a follow up letter will be sent by Federal Express, on two consecutive weeks, 
seeking follow-up. 
 
Compliance with the protocol and drug administration will be strongly emphasized.  Pill 
counts will be performed at visits and episodes of medication noncompliance will be 
recorded, including the reason for noncompliance. Patients will receive a calendar to 
document medication and any side effects experienced that day.   If a patient wishes to 
withdrawal from the treatment phase of the study or has a serious adverse event (SAE) 
(whether related to study drugs or not),  patient follow-up assessments will continue for 
safety monitoring and to avoid problems associated with missing data. The inclusion of 
such follow-up data will allow for analysis by intention-to-treat. 
 
Dose reduction  
Dose and schedule 
            Starting dose 
10 mg daily 
1 
5 mg daily 
2 
5 mg every other day 


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If a patient is withdrawn from the treatment portion of the study for any reason, the 
patient will be strongly encouraged to continue with and complete the remainder of the 
study assessments, as scheduled.   
 
6.2 Consent for Future Contact   
 
During the consent process, patients will have the option to provide permission for future 
contact.  This permission allows for patient contact information, including their full 
name, address and telephone number, to be collected. The permission for future contact 
also allows for possible patient contact regarding  future IRB-approved studies.  If the 
patient denies permission, no future contact will be made. 
 
6.3 Consent for Continuing Data Review of Medical Records 
 
During the consent process, patients will have the option to provide permission for future 
data review of their medical records. This permission allows for study staff to contact the 
patient (or the patient’s caregiver(s)) to obtain medical records and other information for 
a period of up to two years after the patient has withdrawn from or completed the study.  
The purpose of this data review is to capture information including but not limited to 
clinical, radiographic, pathologic, laboratory and pulmonary function data, after the 
patient has exited the study. 
 
6.4 Consent for Storage of Blood Samples for Future Use 
 
Patients will be asked to consent to the storage of leftover blood and serum samples for 
future use related to LAM.  Patients can refuse without impacting their care or ability to 
participate in this study.  
 
7. Stopping Rules 
 
7.1 Criteria for Terminating Participation on Study 
 
An intent-to-treat approach will be used in this study.  All data acquired prior to patient 
termination for the following reasons will be included in the primary analysis.   
 
• Withdrawal of patient consent 
• Withdrawal by the patient 
• Withdrawal by the investigator 
• Intercurrent illness or event that precludes further administration of treatment or 
ability to evaluate lung function (e.g.-mental status change, large pleural 
effusion).  
• Pregnancy or failure to comply with adequate contraception 
• Continuing patient non-compliance 
 


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Every effort will be made to conduct a final study visit and patients will be followed 
clinically until all study-related adverse events resolve, the patient’s condition stabilizes 
or the adverse events are determined to be permanently ongoing. 
 
7.2 Criteria for Terminating the Study 
 
Up to ten patients will be enrolled in this study.  The maximum duration of patient 
participation is up to 164 days, including a follow-up phone contact one month after the 
last study visit.  In the event of any death, or Grade III SAE attributable to the study 
agent, enrollment and treatment will be suspended, pending Data Safety Monitoring 
Board (DSMB) review.   
 
8. Study Variables and Measuring Methods 
 
8.1 Physical Exams 
 
Exams will be performed in a routine manner, consistent with the standard of care. 
 
8.2 Pulmonary Function Testing  
 
Pulmonary function testing (PFT) including FEV1, FVC, and DLCO, will be performed 
in a standardized manner according to American Thoracic Society (ATS criteria) for 
acceptability and repeatability.  The study site will attempt to have the same respiratory 
therapist administer testing to patients for consistency in the study.  All PFTs during 
visits 2, 4 and 6 will be performed post bronchodilator only, regardless of whether 
bronchodilator responsiveness is demonstrated. Although, plethysmography is the 
preferred method, lung volumes may be obtained by plethysmography or gas dilution. All 
spirometry data will be assessed for quality by the attending pulmonary physicians at the 
Penn Lung Center  
 
 
8.3 Questionnaires 
 
8.3.1 St. George’s Respiratory Questionnaire (SGRQ) 
 
The SGRQ is a disease-specific instrument designed to measure impact on overall health, 
daily life, and perceived well-being.  It has been developed to be used by patients with 
fixed or reversible airway obstruction.  It has been shown to correlate well with 
physiologic parameters and to show changes with time, as the lung disease progresses 
(44).  The administration is performed by face to face or telephone interview; completion 
takes approximately 10 minutes.  The questionnaire consists of 76 items divided into 3 
domains:  symptoms (frequency and severity); activity (activities that cause or are limited 
by breathlessness); and impacts (social functioning, psychological disturbances resulting 
from airways disease).  The questionnaire has been translated into many languages, 
including Spanish and Japanese.  
 
8.3.2 Functional Performance Inventory (FPI) 


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The FPI includes many domains that are particularly relevant to women, including body 
care, maintaining the household, physical exercise, recreation, spiritual and social 
interaction.  The inventory is short, containing only 16 items, and is easy to use.  The 
instruments do not require licenses.   
 
8.4 Biomarker Analyses 
 
VEGF-D biomarker analysis will be conducted on blood samples collected from each 
study patient at scheduled times.  Samples will be sent to the central laboratory in 
Cincinnati, where the assays will be performed.  Serum VEGF-D has been shown to be 
elevated in LAM and TSC patients and is diagnostically specific to these diseases (45, 
46).   
 
9. Data Management 
 
9.1 Registration 
 
All study data will be collected via systems that comply with all applicable guidelines 
regarding patient confidentiality and data integrity.  University of Pennsylvania IRB 
approval for the protocol must be on file before patient enrollment and accrual can occur. 
 
The investigators will use a system of coded identifiers to protect patient confidentiality 
and safety.  Each patient enrolled will be assigned a unique identifier.  Access to the 
linkage between the coded identifier and the patient identity will be limited to the study 
team.   The file containing the linkage between the coded identifiers and patient names 
will be stored in a location separate from the data collection forms and analysis 
spreadsheet and will be maintained on a secure server. 
 
9.2 Safety Monitoring and Adverse Event Reporting 
 
Patients will be evaluated for safety if they have received at least one dose of simvastatin.  
The frequency, severity and duration of all adverse events, regardless of cause, will be 
recorded on the case report forms.  The frequency and severity of adverse events will be 
calculated by patient.  The most severe grade of adverse event experienced by patient will 
be counted once.  The duration of adverse events will be calculated by the number of 
days each event persisted.  Adverse events will be tabulated by body system and by 
severity using the NCI Common Terminology Criteria for Adverse Events v4.0, which 
can be obtained from the CTEP Website: http://ctep.cancer.gov/reporting/ctc.html.  
Tables will be generated for all adverse events including those that are judged to be 
possibly, probably or definitely related to the simvastatin. 
 
All adverse events will be reviewed by a DSMB created for this study and composed of 
pulmonologists Vivek Ahya, M.D., Reynold A. Panettieri, Jr., M.D., and John Hansen-
Flaschen, M.D. Any serious AE (generally grade 3 or 4 toxicity or defined by lead 
pulmonologist) will result in patient discontinuation of simvastatin until the DSMB 


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reviews the case and make a recommendation made regarding re-institution of the study 
drug.   
 
As this is a safety study with a small number of patients, data will be compiled in 
descriptive tables of results.  A study participation summary will be written for each 
patient and for trends in the data.  Special attention will be given to adverse reactions to 
the simvastatin and any changes in the pulmonary function testing or the laboratory 
values outside of normal ranges. 
 
9.3. Adverse Events 
 
The investigator must grade AEs according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0) and provide an 
opinion regarding the causal relationship of the AE to study drug.  
 
Patients will be carefully monitored for adverse events from the initial dose of study 
medication through the 30 day post telephone call. 
 
All observed or volunteered adverse events, regardless of treatment group or suspected 
causal relationship to study drug, will be recorded on the adverse event page(s) of the 
case report form. 
 
Events involving adverse drug reactions, illnesses with onset during the study, or 
exacerbations of pre-existing illnesses will be recorded.  Exacerbation of pre-existing 
illness, including the disease under study, is defined as a manifestation (sign or symptom) 
of the illness that indicates a significant increase in the severity of the illness, as 
compared to the severity noted at the start of the study. 
 
9.3.1 Serious Adverse Events 
 
A serious adverse event is any adverse drug experience occurring at any dose that: 
• Results in death; 
• Is life-threatening; 
• Results in inpatient hospitalization or prolongation of existing hospitalization; 
• Results in congenital anomaly or birth defect;  
• Results in a persistent or significant disability/incapacity; or 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious adverse drug experiences when, 
based upon appropriate medical judgment, they may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. 
 


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A life-threatening adverse event is any adverse drug experience that places the patient at 
immediate risk of death from the reaction as it occurred; ie, it does not include a reaction 
that, had it occurred in a more severe form, might have caused death. 
 
Initial hospitalization is defined as any inpatient admission (even if less than 24 hours).  
For chronic or long-term inpatients, inpatient admission also includes transfer within the 
hospital to an acute/intensive care inpatient unit (eg, from the psychiatric wing to a 
medical floor, from a medical floor to the coronary care unit, from the neurological floor 
to the tuberculosis unit). 
 
Inpatient admission in the absence of a precipitating, treatment-emergent, clinical adverse 
event may meet criteria for “seriousness” but is not an adverse experience and thus is not 
subject to immediate reporting. For example: 
• Admission for treatment of a pre-existing condition not associated with the 
development of a new adverse event or with a worsening of the pre-existing 
condition (eg, for work-up of persistent pretreatment lab abnormality) 
• Social admission (eg, patient has no place to sleep) 
• Administrative admission (eg, for yearly physical exam) 
• Protocol-specified admission during the clinical study (eg, for a procedure 
required by the study protocol) 
• Optional admission not associated with a precipitating clinical adverse event (eg, 
for elective cosmetic surgery) 
• Hospitalization for what is clearly progressive disease 
 
However, if a hospitalization for an unknown event occurs, it should be considered as a 
serious adverse event. 
 
Prolongation of hospitalization is defined as any extension of an inpatient hospitalization 
beyond the stay anticipated/required in relation to the original reason for the initial 
admission, as determined by the investigator or treating physician.   
 
Preplanned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient. 
 
Disability is a substantial disruption of a person’s ability to conduct normal life functions. 
 
Any serious adverse event or death must be reported to the IRB immediately, 
independent of the circumstances or suspected cause, if it occurs or comes to the attention 
of the investigator at any time during the study, through 30 days after the last 
administration of study drug.  Any serious adverse event occurring beyond 30 days after 
the last administration of study drug must be promptly reported, if a causal relationship to 
study drug is suspected.  The only exception to these reporting requirements are serious 
adverse events that occur during a pre-randomization/washout run-in period, during 
which either placebo alone is administered, or no active study drug or protocol-specified 
background drug is administered. 


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9.3.2 Abnormal Laboratory Test Results 
 
Laboratory results will be assessed for adverse events as described in CTCAE v4.0 using 
normal ranges specified for the institution’s laboratory.  
 
The results of all laboratory tests required by the protocol will be recorded in the patient’s 
case report form.  All clinically important abnormal laboratory tests occurring during the 
study will be repeated at appropriate intervals until they return either to baseline or a 
level deemed acceptable by the investigator or until a diagnosis that explains them is 
made.  The criteria for determining whether an abnormal laboratory test result should be 
reported as an adverse event are as follows: 
• Test result is associated with accompanying symptoms, and/or 
• Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment or other therapy, and/or 
• Test result leads to any of the outcomes included in the definition of a serious 
adverse event, and/or 
• Test result is considered to be an adverse event by the investigator or sponsor. 
 
Merely repeating an abnormal test, in the absence of any of the above conditions, does 
not meet Condition 2 above for reporting as an adverse event. 
9.3.3 Abnormal Physical Examination Findings 
 
Clinically significant changes, in the judgment of the investigator, in physical 
examination findings (abnormalities) will be recorded as adverse events. 
 
9.4 Investigator reporting: Notifying the Penn IRB 
 
This section describes the requirements for safety reporting by investigators who are 
Penn faculty, affiliated with a Penn research site, or otherwise responsible for safety 
reporting to the Penn IRB. The University of Pennsylvania IRB (Penn IRB) requires 
expedited reporting of those events related to study participation that are unforeseen and 
indicate that patients or others are at increased risk of harm.  The Penn IRB will not 
acknowledge safety reports or bulk adverse event submissions that do not meet the 
criteria outlined below.  The Penn IRB requires researchers to submit reports of the 
following problems within 10 working days from the time the investigator becomes 
aware of the event: 
 
9.4.1 Adverse Events, Unanticipated Problems Death, and Other Reportable Events 
 
Adverse Events 
 
Any adverse event (regardless of whether the event is serious or non-serious, on-site or 
off-site) that occurs any time during or after the research study, which in the opinion of 
the principal investigator is: 
 


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Unexpected (An event is “unexpected” when its specificity and severity are not 
accurately reflected in the protocol-related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, the current IRB-approved 
informed consent document and other relevant sources of information, such as product 
labeling and package inserts.) 
 
AND 
 
Related to the research procedures (An event is “related to the research procedures” if in 
the opinion of the principal investigator or sponsor, the event was more likely than not to 
be caused by the research procedures.) 
 
Unanticipated Problems 
 
Unanticipated problems posing risks to patients or others as noted above will be reported 
to the Penn IRB using the form: “Unanticipated Problems Posing Risks to Subjects or 
Others Including Reportable Adverse Events” or as a written report of the event 
(including a description of the event with information regarding its fulfillment of the 
above criteria, follow-up/resolution and need for revision to consent form and/or other 
study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in 
the Clinical Investigator’s study file. 
 
Death 
 
Concerning deaths that occur during the course of a research study, the following 
describes the more rapid reporting requirement of the Penn IRB for specific situations: 
 
Report the event within 24 hours when the death is unforeseen (unexpected) and indicates 
patients or others are at increased risk of harm. 
 
Report the event within 72 hours, for all other deaths, regardless of whether the death is 
related to study participation. 
 
For reportable deaths, the initial submission to the Penn IRB may be made by contacting 
the IRB Director or Associate Director. The AE/Unanticipated Problem Form is required 
as a follow up to the initial submission. 
 
Other Reportable Events 
 
For clinical drug studies, the following events are also reportable to the Penn IRB: 
• Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 


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• Any adverse event that would cause the sponsor to modify the investigators 
brochure, protocol or informed consent form, or would prompt other action by the 
IRB to assure protection of human subjects. 
• Information that indicates a change to the risks or potential benefits of the 
research, in terms of severity or frequency. For example:  
• An interim analysis indicates that participants have a lower rate of response to 
treatment than initially expected. 
• Safety monitoring indicates that a particular side effect is more severe, or more 
frequent than initially expected. 
• A paper is published from another study that shows that an arm of your research 
study is of no therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, 
or biologic used in a research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research participant. 
• Incarceration of a participant when the research was not previously approved 
under Subpart C and the investigator believes it is in the best interest of the 
subject to remain on the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that, in the opinion of the investigator, placed one or more 
participants at increased risk, or affects the rights or welfare of subjects. 
 
9.4.2 Exception 
 
An exception is defined as a one time, intentional action or process that departs from the 
IRB approved study protocol, intended for one occurrence. If the action disrupts the 
study progress, such that the study design or outcome (endpoints) may be compromised, 
or the action compromises the safety and welfare of study subjects, advance documented 
IRB and DSMB approval is required.  
 
For in-house studies with a Medical Monitor or Safety Monitoring Committee (not 
DSMB), approval must be obtained from the Medical Monitor or Safety Monitoring 
Committee prior to submitting your exception request to the DSMB. 
 
9.4.3 Deviation 
 
A deviation is defined as a one time, unintentional action or process that departs from the 
IRB and DSMB approved study protocol, involving one incident and identified 
retrospectively, after the event occurred. If the impact on the protocol disrupts the study 
design, may affect the outcome (endpoints) or compromises the safety and welfare of the 
subjects, the deviation must be reported to the DSMB within 5 business days and the IRB 
within 10 business days.  


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Examples of Exceptions/Deviations that must be submitted (not meant to be inclusive): 
 
May/can/have affects/affected subject safety. So, a subject missing a visit is not an issue 
unless a critical/important treatment or procedure was missed and must have been done at 
that specific time.  
 • Violate eligibility 
 • Dose adjustment 
 • Stopping criteria 
 • Affect sample size (adding more subjects, decreasing number of subjects, changing the 
number of subject in a specific arm/cohort) 
Other deviations should be explained in a memo to file or on a deviation log. 
 
 
10.  Ethical and Administrative Aspects 
 
10.1 Risks and Discomforts of Testing 
 
Occasional shortness of breath or light-headedness can occur while performing 
pulmonary function tests.   
 
Rarely after blood drawing, the vein in which the needle has been inserted to draw blood, 
may become sore and red.  A temporary “black and blue mark” may develop, and rarely 
fainting may occur.   
 
As part of routine care while participating in this study, patients will undergo 2 chest x-
rays.  There is a level of radiation exposure from these x-rays that is considered low, 
when compared with other everyday risks of radiation exposure. 
 
10.2 Confidentiality 
 
Information about study patients will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed patient authorization informing the patient 
of the following:  
 
• What protected health information (PHI) will be collected from patient in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research patient to revoke their authorization for use of their PHI.  
 
In the event a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
patient authorization.  For patients who have revoked authorization to collect or use PHI, 


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43 
 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
patient is alive) at the end of their scheduled study period. 
 
Several mechanisms will be in place to maintain confidentiality. Patient names will not 
be abstracted and all of the data will be reported in aggregate. Each patient in all phases 
of the study will be assigned a unique study code number to be used on all data forms, 
study records, and blood samples. A list of patient names and code numbers will be 
maintained separately, in a locked office or on password protected computers. Only the 
investigators and study staff will have access to this information. No other personally 
identifiable information will be available.  
 
10.3 
Source Documents 
 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study.  
Source data are contained in source documents.  Examples of these original documents, 
and data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, patient diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, patient files, and records kept at the pharmacy, at 
the laboratories, and at medico-technical departments involved in the clinical study. 
 
10.4 
Case Report Forms 
 
Data will be collected on the study case report forms and will be stored in the research 
team’s office, which is secured and locked daily.  Data will be entered onto a case report 
form or into an Excel spreadsheet using the patient identifier described above.  Any data 
set leaving the University of Pennsylvania site will be de-identified. 
 
10.5 
Records Retention 
 
It is the investigator’s responsibility to retain study essential documents for at least 2 
years after the last approval of a marketing application in their country and until there are 
no pending or contemplated marketing applications in their country or at least 2 years 
have elapsed since the formal discontinuation of clinical development of the 
investigational product.  These documents should be retained for a longer period if 
required by an agreement with a sponsor.  In such an instance, it is the responsibility of 
the sponsor to inform the investigator/institution as to when these documents may be 
discarded.  
 
 
10.6 Study Monitoring, Auditing, and Inspecting 
 
10.6.1 Data Monitoring Plan 
 


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44 
 
Data will be reviewed and recorded in a timely manner.  The PI or their designee will be 
responsible for ensuring protocol compliance and appropriate reporting.   
 
10.6.2 Auditing and Inspecting 
 
The investigator will permit study-related monitoring, audits, and inspections of all study 
related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.) by the IRB, government regulatory bodies, and University 
compliance and quality assurance groups.  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality 
assurance offices. 
 
10.7 Ethical Considerations 
 
This study will be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to the Penn IRB in agreement with 
local legal prescriptions for formal approval of the study conduct.  The decision of the 
IRB concerning the conduct of the study will be made in writing to the investigator and 
retained before commencement of this study.   
 
All patients for this study will receive a consent form describing this study and providing 
sufficient information for them to make an informed decision about their participation in 
this study.  See a copy of the Patient Informed Consent Form.  This consent form will be 
submitted with the protocol for review and approval by the IRB.  The formal consent of a 
patient, using the IRB-approved consent form, must be obtained before that patient 
undergoes any study procedure.  The consent form must be signed by the patient or 
legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent.  
 
10.8 Study Finances 
 
This study will be funded through a grant from the LAM Foundation. 
10.9 Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must have the conflict reviewed by a properly constituted Conflict of Interest Committee 
with a Committee-sanctioned conflict management plan that has been reviewed and 


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45 
 
approved by the study sponsor prior to participation in this study.  All University of 
Pennsylvania investigators will follow the University conflict of interest policy. 
 
10.10 Patient Stipends or Payments 
 
Patients may receive a stipend of up to $25 per study visit for participating in this study. 
 
10.11 Publication Plan 
 
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided by the sponsor for the purposes of 
performing the study, will be published or passed on to any third party without the 
consent of the study sponsor.  Any investigator involved with this study is obligated to 
provide the sponsor with complete test results and all data derived from the study. 
 
10.12 Patient withdrawal  
 
A patient has the right to withdraw from the study entirely, at any time, for any reason, 
without prejudice to future medical care by the investigator or other physicians. The 
investigator also has the right to withdraw patients from the study in the event of 
concurrent illness, AEs, or other reasons deemed to be in the patient’s best interest. 
 
A patient should be withdrawn from the study if there is: 
 
• Withdrawal of consent 
• Termination of the study by the funding agency  
 
In order to preserve the integrity of the intention-to-treat analysis, even if the patient is 
withdrawn from the treatment portion of the protocol (either due to patient, physician, or 
investigator decision), it is imperative to continue with the scheduled follow-up 
assessments, both for the safety of the patient and for completeness of data collection. 
This will be explained to potential patients at the time of informed consent. The 
importance of compliance with study visits will be reinforced throughout the study. If the 
treatment is permanently withdrawn, the patient will return to the LAM clinic for safety 
assessment (history, physical examination, and clinical laboratories, if necessary). 
 
 
 
 
 
11.0 
Statistical Considerations 
 
11.1 
Sample Size Determination 
 
A total of up to 10 evaluable patients will be enrolled. As this is a safety study with a 
small number of patients, data will be compiled in descriptive tables of results. 


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46 
 
Assuming a 10% rate of attrition, this will yield 9 evaluable patients for the entire 120 
days of follow-up.  The table below shows the exact 95% confidence interval (CI) for the 
true probability of dose-limiting toxicity (DLT), given the observed rates out of 9 patients 
and the probability of failing to observe at least one DLT among 9 patients for various 
underlying dose-limiting toxicity rates. 
Table 5: Dose-limiting toxicity rates 
Observed DLT 
1/9 (11%) 
2/9 (22%) 
3/9 (33%) 
4/9 (44%) 
5/9 (56%) 
95% CI 
(3%, 48%) 
(3%, 60%) 
(7%, 70%) 
(13%, 9%) (22%, 87%) 
Probability fail to 
observe at least one 
DLT if true rate is 
equal to the above 
35.0% 
10.7% 
2.7% 
<1.0% 
<1.0% 
 
11.2 Data Analysis 
 
All study data will be collected via systems that comply with all applicable guidelines 
regarding patient confidentiality and data integrity. Patients will be evaluated for safety if 
they have received at least one dose of simvastatin.  The  frequency, severity and duration 
of all adverse events, regardless of cause, will be recorded on the case report forms.  
Adverse events will be tabulated by body system and by severity using the NCI Common 
Terminology Criteria for Adverse Events v4.0, which can be obtained from the CTEP 
Website: http://ctep.cancer.gov/reporting/ctc.html.  Tables will be generated for all 
adverse events, including those judged to be possibly, probably, or definitely related to 
the simvastatin.  
 
 
 
 
 
 
 
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47 
 
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H. L. Kenerson, L. D. Aicher, L. D. True, R. S. Yeung, Activated mammalian 
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E. A. Goncharova et al., Abnormal smooth muscle cell growth in LAM: role for 
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L. Lee et al., Efficacy of a rapamycin analog (CCI-779) and IFN-g in tuberous 
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V. P. Krymskaya, E. A. Goncharova, PI3K/mTORC1 activation in hamartoma 
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F. X. McCormack et al., Efficacy and Safety of Sirolimus in 
Lymphangioleiomyomatosis. N. Engl. J. Med. 364, 1595 (2011). 
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J. J. Bissler et al., Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex 
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21. 
D. M. Davies et al., Sirolimus Therapy for Angiomyolipoma in Tuberous 
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22. 
J. J. Bissler et al., Everolimus for angiomyolipoma associated with tuberous 
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E. Jacinto et al., Mammalian TOR complex 2 controls the actin cytoskeleton and 
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A. Saci, Lewis C. Cantley, Christopher L. Carpenter, Rac1 Regulates the Activity 
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E. A. Goncharova, D. A. Goncharov, P. N. Lim, D. Noonan, V. P. Krymskaya, 
Modulation of cell migration and invasiveness by tumor suppressor TSC2 in 
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A. J. Dirks, K. M. Jones, Statin-induced apoptosis and skeletal myopathy. 
American Journal of Physiology - Cell Physiology 291, C1208 (December 2006, 
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33. 
A. Hall, The cytoskeleton and cancer. Cancer and Metastasis Reviews 28, 5 
(2009). 
34. 
G. A. Finlay et al., Selective Inhibition of Growth of Tuberous Sclerosis Complex 
2 Null Cells by Atorvastatin Is Associated with Impaired Rheb and Rho GTPase 
Function and Reduced mTOR/S6 Kinase Activity. Cancer Res 67, 9878 (October 
15, 2007, 2007). 
35. 
N. Lee et al., Rapamycin weekly maintenance dosing and the potential efficacy of 
combination sorafenib plus rapamycin but not atorvastatin or doxycycline in 
tuberous sclerosis preclinical models. BMC Pharmacol 9, 8 (2009). 
36. 
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K. I. E. L. R. Eugene Ramsay, P. Emilio, Eds. (Academic Press, 2007), vol. 
Volume 81, pp. 235-251. 
37. 
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Pharmacokinetics and Metabolism of Sirolimus. Therapeutic Drug Monitoring 
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P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin 
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G. Ingle, T. Sievers, C. Holt, Sirolimus: continuing the evolution of transplant 
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Transplant Patient. Transplant. Proc. 41, 1021 (2009). 
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Journal of Heart and Lung Transplantation 26, 1293 (12//, 2007). 
45. 
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Distinguishes Lymphangioleiomyomatosis From Other Diseases. Chest 138, 674 
(September 1, 2010, 2010). 
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ICF_001.pdf: 
 
219 Stemmler Hall ׀ 3450 Hamilton Walk ׀ Philadelphia, PA 19104-3413 ׀ 215-573-9861  ׀krymskay@pennmedicine.upenn.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVER PAGE 
 
Date: 04-October-2016 
 
TITLE: Safety of Simvastatin in LAM and TSC (SOS) 
 
Identifiers: NCT02061397 
 
Unique Protocol ID; The SOS Trial 
 
 
 
Best Regards, 
 
 
 
 
 
Vera P. Krymskaya, Ph.D., M.B.A., F.C.P.P. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vera P. Krymskaya, Ph.D., M.B.A., F.C.P.P. 
Professor of Medicine  
Laboratory of Rare Lung Diseases  
Pulmonary, Allergy and Critical Care Division 
Department of Medicine 
Perelman School of Medicine 
University of Pennsylvania  
Penn/CHOP Lung Biology Institute 
Chair, Penn Forum for Women Faculty 
Fellow, College of Physicians of 
Philadelphia 
 


SOS STUDY 
Version: 6 Date: 04 October 2016 
  
1 of 18 
UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT  
INFORMED CONSENT AND  
HIPAA AUTHORIZATION FORM 
 
Protocol Title:   
The Safety of Simvastatin in Patients with 
Pulmonary Lymphangioleiomyomatosis and with 
Tuberous Sclerosis Complex (The SOS Trial) 
Principal 
Investigator: 
Vera P. Krymskaya, Ph.D., M.B.A. 
Pulmonary, Allergy & Critical Care Division,  
219 Stemmler Hall 
3450 Hamilton Walk, Philadelphia, PA 19104 
Phone (office): 215-573-9861 
E-mail: krymskay@mail.med.upenn.edu 
Emergency 
Contacts: 
Maryl Kreider, M.D. 
Phone (office): 215-662-3202 
Email: Maryl.Kreider@uphs.upenn.edu 
 
Why am I being asked to volunteer? 
 
You are being invited to participate in a research study because you have either 
pulmonary lymphangioleiomyomatosis (LAM) or tuberous sclerosis complex (TSC) and 
the investigators of this study want to look at how safe it is to use a drug called 
simvastatin in subjects like you with LAM or TSC.  Your participation is voluntary, which 
means you can choose whether or not you want to participate. If you choose not to 
participate, there will be no loss of benefits to which you are otherwise entitled.  Before 
you can make your decision, you will need to know what the study is about, the possible 
risks and benefits of being in this study, and what you will have to do in this study.  The 
research team is going to talk to you about the research study, and they will give you 
this consent form to read.  You may also decide to discuss it with your family, friends, or 
family doctor.  You may find some of the medical language difficult to understand. 
Please ask the study doctor and/or the research team about this form. If you decide to 
participate, you will be asked to sign this form. 
 
 


SOS STUDY 
Version: 6 Date: 04 October 2016 
  
2 of 18 
What is the purpose of this research study? 
 
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 benefit or risk to patients taking this 2-drug combination.   
Simvastatin is a member of a group of drugs called HMG CoA reductase inhibitors, or 
"statins." These drugs reduce levels of "bad" cholesterol (low-density lipoprotein, or 
LDL) and triglycerides in the blood, while increasing levels of "good" cholesterol (high-
density lipoprotein, or HDL).  Simvastatin is used by millions of people to lower the risk 
of stroke, heart attack, and other heart complications, in people with diabetes, coronary 
heart disease, or other risk factors.  Simvastatin is approved by the US Food and Drug 
Administration (FDA) for this purpose.  It is considered experimental in this study.   
 
How long will I be in the study?  
 
You will be one of ten evaluable patients in the study.  The study involves 6 scheduled 
visits occurring approximately every 30 days, over a 5 month period (approximately 164 
days).   You will receive simvastatin as part of this study for four months.  At the end of 
five month period, you will complete your final set of surveys and questioning. One 
month after completing the final study visit, you will be contacted by telephone to see 
how you are doing.  The total number of days for this study (including all visits and 
telephone contacts) is approximately 164.  All participants in this study will be from the 
University of Pennsylvania.   
 
What am I being asked to do? 
 
Once you have signed this consent form, study related tests/procedures will be done to 
ensure that you qualify for the study.  If found to be eligible and you agree to participate, 
you will be given simvastatin at a starting dose of 20 mg, to be taken each evening by 
mouth.   If after 2 months, you tolerate the simvastatin 20 mg dose, the dose of 
simvastatin will be increased to 40 mg each evening by mouth.  Doses may be 
adjusted, as needed, should you experience side effects from simvastatin.  The dose of 
everolimus or sirolimus that you have been taking is not expected to change, as this is a 
dose that you have shown to tolerate.  If however, you experience side effects from the 
combination of drugs, the dosages may be adjusted by the study physician 
(investigator).  
 
Please note, you should not drink grapefruit juice or eat grapefruit or grapefruit products 
while taking simvastatin, because it could create an unwanted interaction with 
simvastatin. 


SOS STUDY 
Version: 6 Date: 04 October 2016 
  
3 of 18 
 
At screening, Visit 1, the following tests and evaluations will be performed (however, if 
done recently, some of these tests may not need to be repeated):   
• Medical history review and a physical examination 
• Review of the medications you are currently taking 
• A urine pregnancy test, if there is a possibility you could become pregnant 
• Three (3) tablespoons of blood will be drawn and the following tests will be 
performed on the blood: 
• CBC: a complete blood count provides important information about the 
kinds and numbers of cells in the blood 
• Chemistry (CMP):  a blood test that looks at kidney function, liver 
function and electrolytes like potassium and calcium.  
• CPK: creatine phosphokinase (CPK) is an enzyme found mainly in the 
heart, brain, and skeletal muscle. This test will monitor the health 
status of muscle.  
• Lipid Profile: a panel of blood tests that serves as an initial broad 
screening tool for abnormalities in lipids, such as cholesterol (including 
LDL and HDL) and triglycerides 
• Sirolimus or everolimus test: a measurement of the amount of 
sirolimus or everolimus (whichever medicine you take) in your blood. 
• Any remaining blood from the sample will be stored for LAM research. 
• A chest x-ray  will be performed 
 
Visit 2 will happen within 14 days of your screening visit; this will be day 0, since it will 
be the first day of treatment with simvastatin. During this visit, the following tests and 
evaluations will be performed: 
• Review of the medications you are currently taking 
• A urine pregnancy test, if there is a possibility you could become pregnant 
• One (1) tablespoon of blood will be drawn as research for VEGF-D.  VEGF-D is a 
marker frequently found in the blood of patients with LAM and/or TSC  
• Spirometry testing (breathing test) performed before and after using a 
bronchodilator  inhaler 
• Completing questionnaires about your overall health, daily life and your sense of 
well-being (approximately 20 minutes to complete)  
 
You will be given a 30-day supply of simvastatin 20 mg, which you will take each 
evening.  You will also be given a calendar to write down when you took the simvastatin 
each day; you will be asked to bring the calendar and the pill bottle back with you, at the 
next scheduled study visit. 
 


SOS STUDY 
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Visit 3 (day 30) will occur one month after Visit 2.  During this visit, the following tests 
and evaluations will be performed: 
• Medical history review and a physical examination 
• Review of the medications you are currently taking 
• Review of any side effects you may have experienced since the last visit 
• A urine pregnancy test, if there is a possibility you could become pregnant 
• Four (4) tablespoons of blood will be drawn and the following tests will be 
performed on the blood: 
• CBC: a complete blood count provides important information about the 
kinds and numbers of cells in the blood 
• Chemistry (CMP):  a blood test that looks at kidney function, liver 
function and electrolytes like potassium and calcium.  
• CPK: creatine phosphokinase (CPK) is an enzyme found mainly in the 
heart, brain, and skeletal muscle. This test will monitor the health 
status of muscle.  
• Lipid Profile: a panel of blood tests that serves as an initial broad 
screening tool for abnormalities in lipids, such as cholesterol (including 
LDL and HDL) and triglycerides 
• Sirolimus or everolimus test: a measurement of the amount of 
sirolimus or everolimus (whichever medicine you take) in your blood. 
• VEGF-D:  a marker frequently found in the blood of patients with LAM 
and/or TSC  
• Any remaining blood from the sample will be stored for LAM research. 
• Completing questionnaires about your overall health, daily life and your sense of 
well-being (approximately 20 minutes to complete)  
 
You will be given a 30-day supply of simvastatin 20 mg, which you will take each 
evening.  You will be given a calendar to write down when you took the simvastatin 
each day; you will be asked to bring the calendar and the pill bottle back with you, at the 
next scheduled study visit. 
 
Visit 4 (day 60) will occur one month after Visit 3.  During this visit, the following tests 
and evaluations will be performed: 
• Medical history review and a physical examination 
• Review of the medications you are currently taking 
• Review of any side effects you may have experienced since the last visit 
• A urine pregnancy test, if there is a possibility you could become pregnant 
• Four (4) tablespoons of blood will be drawn and the following tests will be 
performed on the blood: 


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• CBC: a complete blood count provides important information about the 
kinds and numbers of cells in the blood 
• Chemistry (CMP):  a blood test that looks at kidney function, liver 
function and electrolytes like potassium and calcium.  
• CPK: creatine phosphokinase (CPK) is an enzyme found mainly in the 
heart, brain, and skeletal muscle. This test will monitor the health 
status of muscle.  
• Lipid Profile: a panel of blood tests that serves as an initial broad 
screening tool for abnormalities in lipids, such as cholesterol (including 
LDL and HDL) and triglycerides 
• Sirolimus or everolimus test: a measurement of the amount of 
sirolimus or everolimus (whichever medicine you take) in your blood. 
• VEGF-D:  a marker frequently found in the blood of patients with LAM 
and/or TSC  
• Any remaining blood from the sample will be stored for LAM research. 
• Spirometry testing (breathing test) performed before and after using a 
bronchodilator  inhaler 
• Completing questionnaires about your overall health, daily life and your sense of 
well-being (approximately 20 minutes to complete)  
 
If you have tolerated the simvastatin 20mg dose without any problems, you will be given 
a 30-day supply of simvastatin 40 mg, which you will take each evening.  You will be 
given a calendar to write down when you took the simvastatin each day; you will be 
asked to bring the calendar and the pill bottle back with you, at the next scheduled study 
visit. 
 
Visit 5 (day 90) will occur one month after Visit 4.  During this visit, the following tests 
and evaluations will be performed: 
• Medical history review and a physical examination 
• Review of the medications you are currently taking 
• Review of any side effects you may have experienced since the last visit 
• A urine pregnancy test, if there is a possibility you could become pregnant 
• Four (4) tablespoons of blood will be drawn and the following tests will be 
performed on the blood: 
• CBC: a complete blood count provides important information about the 
kinds and numbers of cells in the blood 
• Chemistry (CMP):  a blood test that looks at kidney function, liver 
function and electrolytes like potassium and calcium.  
• CPK: creatine phosphokinase (CPK) is an enzyme found mainly in the 
heart, brain, and skeletal muscle. This test will monitor the health 
status of muscle.  


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• Lipid Profile: a panel of blood tests that serves as an initial broad 
screening tool for abnormalities in lipids, such as cholesterol (including 
LDL and HDL) and triglycerides 
• Sirolimus or everolimus test: a measurement of the amount of 
sirolimus or everolimus (whichever medicine you take) in your blood. 
• VEGF-D:  a marker frequently found in the blood of patients with LAM 
and/or TSC  
• Any remaining blood from the sample will be stored for LAM research. 
• Completing questionnaires about your overall health, daily life and your sense of 
well-being (approximately 20 minutes to complete)  
 
If you have continued to tolerate the simvastatin 40mg dose without any problems, you 
will be given a 30-day supply of simvastatin 40 mg, which you will take each evening.  
You will be given a calendar to write down when you took the simvastatin each day; you 
will be asked to bring the calendar and the pill bottle back with you, at the next 
scheduled study visit. 
 
Visit 6 (day 120) will occur one month after Visit 5.  During this visit, the following tests 
and evaluations will be performed: 
• Medical history review and a physical examination 
• Review of the medications you are currently taking 
• Review of any side effects you may have experienced since the last visit 
• A urine pregnancy test, if there is a possibility you could become pregnant 
• Four (4) tablespoons of blood will be drawn and the following tests will be 
performed on the blood: 
• CBC: a complete blood count provides important information about the 
kinds and numbers of cells in the blood 
• Chemistry (CMP):  a blood test that looks at kidney function, liver 
function and electrolytes like potassium and calcium.  
• CPK: creatine phosphokinase (CPK) is an enzyme found mainly in the 
heart, brain, and skeletal muscle. This test will monitor the health 
status of muscle.  
• Lipid Profile: a panel of blood tests that serves as an initial broad 
screening tool for abnormalities in lipids, such as cholesterol (including 
LDL and HDL) and triglycerides 
• Sirolimus or everolimus test: a measurement of the amount of 
sirolimus or everolimus (whichever medicine you take) in your blood. 
• VEGF-D:  a marker frequently found in the blood of patients with LAM 
and/or TSC 
•  Any remaining blood from the sample will be stored for LAM research. 


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• Spirometry testing (breathing test) performed before and after using a 
bronchodilator  inhaler 
• Completing questionnaires about your overall health, daily life and your sense of 
well-being (approximately 20 minutes to complete)  
• A chest x-ray  will be performed 
 
You will kindly bring the calendar and empty pill bottle back with you for this final study 
visit.  You should bring the calendar and the pill bottle back with you at this last face-to-
face visit. 
 
A telephone call will occur one month (day 150) after Visit 6.  During this call, the study 
coordinator will ask how you are doing, review any adverse events, and give you a 
chance to give feedback. 
 
The chart below indicates which procedures are performed at each visit: 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
Event 
Screen 
Day 0 
Day 30 
 
Day 60 
Day 90 
Day 
120 
30 day 
follow-
up 
Informed consent  
X 
 
 
 
 
 
 
History and physical exam 
X 
 
X 
X 
X 
X 
 
Chest X-ray 
X 
 
 
 
 
X 
 
Blood levels of sirolimus 
(target range 3-20 ng/mL) or 
everolimus (target range of 
3-20 ng/ml)  
X 
 
X 
X 
X 
X 
 
CBC, CPK, CMP, Lipid 
profile 
X 
 
X 
X 
X 
X 
 
VEGF-D 
 
X 
X 
X 
X 
X 
 
Saved serum and plasma 
from blood sample 
 
X 
X 
X 
X 
X 
 
Urine pregnancy test 
X 
X 
X 
X 
X 
X 
 
Spirometry (breathing test) 
 
X 
 
X 
 
X 
 
Review medications 
X 
X 
X 
X 
X 
X 
 
Review adverse events 
 
 
X 
X 
X 
X 
X 
Study drug (simvastatin) 
management 
 
X 
X 
X 
X 
X 
 
Complete health 
questionnaires 
 
X 
X 
X 
X 
X 
 
 
What are the possible risks or discomforts?  
There may be unknown or unforeseen risks associated with study participation.  
There is also the possibility of previously unknown side effects occurring from 
simvastatin alone or from combining it with everolimus or sirolimus.  It is important that 
you inform your study team should you experience any of these side effects, or any 


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other effects you think might be related to study treatment.   You will be monitored for 
side effects and if indicated, treatment for the side effect will be offered.     
 
Side effects of Simvastatin include: 
 
More common 
• 
Dizziness 
• 
Fainting 
• 
Fast or irregular heartbeat 
Less common 
• 
Bladder pain 
• 
Bloody or cloudy urine 
• 
Blurred vision 
• 
Body aches or pain 
• 
Chills 
• 
Cough 
• 
Dark-colored urine 
• 
Difficult, burning, or painful urination 
• 
Difficulty with breathing 
• 
Difficulty with moving 
• 
Dry mouth 
• 
Ear congestion 
• 
Fever 
• 
Flushed, dry skin 
• 
Frequent urge to urinate 
• 
Fruit-like breath odor 
• 
Headache 
• 
Increased hunger 
• 
Increased thirst 
• 
Increased urination 
• 
Joint pain 
• 
Loss of consciousness 
• 
Lower back or side pain 


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• 
Muscle cramps, spasms, or stiffness 
• 
Muscular pain, tenderness, wasting, or weakness 
• 
Nasal congestion 
• 
Nausea 
• 
Runny nose 
• 
Sneezing 
• 
Sore throat 
• 
Stomachache 
• 
Sweating 
• 
Swelling 
• 
Swollen joints 
• 
Troubled breathing 
• 
Unexplained weight loss 
• 
Unusual tiredness or weakness 
• 
Vomiting 
Less common 
• 
Acid or sour stomach 
• 
Belching 
• 
Burning feeling in the chest or stomach 
• 
Dizziness or lightheadedness 
• 
Excess air or gas in the stomach or intestines 
• 
Feeling of constant movement of self or surroundings 
• 
Full feeling 
• 
Heartburn 
• 
Lack or loss of strength 
• 
Pain or tenderness around the eyes and cheekbones 
• 
Passing gas 
• 
Sensation of spinning 
• 
Skin rash, encrusted, scaly, and oozing 
• 
Stomach discomfort, upset, or pain 
• 
Tenderness in the stomach area 


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• 
Trouble sleeping 
 
Simvastatin has been extensively studied at the doses you will be taking during this 
study. Currently, simvastatin is not FDA approved for use in treating LAM and TSC 
patients.  There has been a possibility of a slight risk of bleeding.  If you take digoxin, 
there is a slight risk of raising your digoxin levels in your blood when taking simvastatin.  
(Digoxin is a type of medicine used to treat certain heart problems. Too much digoxin in 
your blood can be harmful or even toxic.) 
 
Possible symptoms you may experience also include an upper respiratory infection, 
headache, abdominal pain, constipation and nausea.  There is an increased risk of 
muscle weakness, including rhabdomyolysis (breakdown of muscle fibers into the 
bloodstream) with acute renal (kidney) failure.  However, this has been seen in patients 
who have certain predisposing factors (such as advanced age of 65 years or older, are 
female, are taking Lomitapide for high cholesterol, have uncontrolled hypothyroidism, 
and have renal impairment) AND are taking a higher dose (80 mg) of simvastatin.  The 
highest simvastatin dose used in this study is 40 mg.   
 
If you wish to discuss the information above or any other discomforts you may 
experience, you may ask questions now or call the study doctor listed on the front of this 
form. 
   
Side effects of everolimus or sirolimus have been previously discussed with you, when 
you starting one of these drugs, prior to enrolling in this study.   Please talk to your 
doctor if you have any additional questions about side effects of everolimus or sirolimus. 
 
Reproductive risks:  The effects of simvastatin may result in serious harm to unborn 
children or children who are breast-feeding.  This medication can cause birth 
defects. Do not take simvastatin if you are pregnant.  If you become pregnant 
during this study, stop taking simvastatin and tell your doctor right away.  Use 
effective birth control to avoid pregnancy while you are taking simvastatin.  Simvastatin 
may pass into breast milk and could harm a nursing baby. Do not breast-feed while you 
are taking simvastatin. 
 
It is also possible that harmful side effects that are not yet known could happen to both 
the mother and unborn or breast-feeding child.  If you are currently pregnant, it is 
important that you inform the investigator, because you will not be able to participate in 
this study.  If you are able to become pregnant, you will be given a urine pregnancy test 
before entering the study and at each study visit, to confirm you are not pregnant.  You 
are required to use a medically accepted barrier method of birth control while you 
participate in the study. You should not become pregnant while you are taking 
simvastatin.  If you do become pregnant, you must tell the investigator immediately and 
consult an obstetrician or maternal-fetal specialist immediately.  You will be removed 
from the study promptly.   


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Risks of Chest x-rays: The radiation dose of a chest x-ray will be equivalent to the 
background radiation experienced by a person living in the Philadelphia area,  over 
approximately an eight day period of time. The risk from this level of radiation exposure 
is too small to be measured directly and is considered to be very low, when compared 
with other everyday risks. The amount of radiation received in this study is unlikely to 
cause any side effects or problems. 
Risks of Questionnaires: The risks of completing the questionnaires include fatigue; you 
may also feel that the questions are too personal. You may skip any questions you wish 
and may take as long as you need to complete the questionnaires.  A staff member will 
be available to assist you.   
Risks of Pulmonary Function Testing: The risk of performing a pulmonary function test 
is occasional shortness of breath or light-headedness. Occasionally after receiving the 
salbutamol, a temporary sensation of a racing heart, nervousness, or jitteriness may 
develop.  
Risks of Blood Collection: Blood collection for laboratory tests involves removing blood 
from a vein with a needle. Risks associated with blood draws include soreness, 
bruising, and in rare instances, an infection at the site of the blood draw or fainting. 
 
What if new information becomes available about the study? 
During the course of this study, we may find more information that could be important to 
you.  This includes information that, once learned, might cause you to change your mind 
about being in the study.  We will notify you as soon as possible, if such information 
becomes available. 
 
What are the possible benefits of the study?  
 
If you agree to take part in this research study, there may not be a direct medical benefit 
for you.  However, it is possible that your lung function may improve with the addition of 
simvastatin, but there is no guarantee.  The information learned from this research 
study may benefit other patients with LAM or TSC in the future. 
 
What other choices do I have if I do not participate?  
 
You have the option of not participating in this research study.  If you choose not to 
participate, you may continue to receive your usual medical care through the University 
of Pennsylvania. 
 
Simvastatin is a commercially available drug. It is possible for you to receive this drug 
without participating in this study.  
 
Will I be paid for being in this study? 
 
You will receive a stipend (small payment) for your participation in this study.  This 
stipend is intended to help offset any inconvenience associated with your participation in 


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this study.  The stipend is $25 per completed study visit. In addition to the stipend, 
reimbursement for travel related to the study (such as gas, parking, hotel costs, etc.) is 
available for participants. This compensation will be made only after proper 
documentation has been provided to the study coordinator. Please speak with the study 
coordinator prior to study initiation for details, forms, and eligibility restrictions.   
 
Will I have to pay for anything? 
 
Study-related tests, study visits and the simvastatin drug will be provided free of charge.  
Tests that are performed only because of the study will be covered (paid for) by the 
study.  These tests include the lipid panel, CPK measurement, VEGF-D, sirolimus or 
everolimus measurement and urine pregnancy test. 
 
As a participant in this research study, you or your insurance company will have to pay 
for the costs of standard procedures (procedures or tests that are part of normal care for 
your condition) for your disease, that are also used as part of this the study.   These 
include physician visits, hospital costs, physicians’ fees for surgery, laboratory tests 
(blood counts, etc.), and radiologic studies (x-rays, CT Scans, etc.).  Every effort will be 
made to establish which costs will or will not be covered by your insurance policy, prior 
to study enrollment and this information will be discussed with you. 
 
There may be extra costs with this treatment.  Some of the costs may not be covered by 
the study or your health insurance company.  We encourage you to work closely with 
your insurance company, to find out exactly what is covered for this research study.  
You will also be responsible for any co-pays or deductibles required by your insurance 
company.  
 
What happens if I am injured from being in the study?  
 
We will offer you the care needed to treat injuries directly resulting from taking part in 
this research study.  We may bill your insurance company or other third parties, if 
appropriate, for the costs of the care you get for the injury, but you may also be 
responsible for some of them. 
 
There are no plans for the University of Pennsylvania to pay you or give you other 
compensation for an injury.  You do not give up your legal rights by signing this form.   
 
If you think you have been injured as a result of taking part in this research study, tell 
the investigator or study coordinator as soon as possible.  The investigator and 
physician names and phone numbers are listed on the front of this consent form. 
 
When is the Study over?  Can I leave the Study before it ends? 
This study is expected to end after all participants have completed all visits, and all 
information has been collected.  This study may also be stopped at any time by your 
physician, the study Sponsor, or the Food and Drug Administration (FDA) without your 
consent because: 


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• 
The Principal Investigator feels it is necessary for your health or safety.  Such 
an action would not require your consent, but you will be informed if such a 
decision is made and the reason for this decision. 
• 
You have not followed the study instructions. 
• 
 The sponsor, the Principal Investigator, or the Food and Drug Administration 
(FDA) has decided to stop the study. 
If you decide to participate, you are free to leave the study at anytime; your participation 
is voluntary.  Withdrawing from the study will not interfere with your future care.   
 
Who can see or use my information?  How will my personal 
information be protected?   
 
If you decide to participate in this study, the study doctor and staff will collect medical 
and personal information about you as part of completing the study.  We will do our best 
to make sure that the personal information in your medical record is kept private.  
However, we cannot guarantee total privacy.  Your personal information may be given 
out if required by law.  If information from this study is published or presented at 
scientific meetings, your name and other personal information will not be used. This 
study is being overseen by the Food and Drug Administration (FDA).  The FDA may 
review your research records.  Please refer to the information below, which explains 
more specifically how your personal information will be protected. 
 
What information about me may be collected, used or shared with 
others?   
 
The following personal health information will be collected and used for the purposes of 
this study.  
• 
The history and diagnosis of your 
disease 
• 
Specific information about the 
treatments you are receiving and  
previous treatment(s) you may 
have had and your response to 
them 
• 
Medical data generated during this 
study- including physical exams, 
laboratory test results, radiology 
and pulmonary scan results and 
results of any other 
tests/procedures performed during 
the study  
• Information on side effects you may 
experience, and how these were 
treated 
• 
Other conditions that may affect 
your treatment 
• 
Information related to study visits 
and other tests/procedures 
performed while you are 
participating in this study 
• 
Date of birth 
• 
Name 
• 
Medical Record Number 
• 
Telephone Number 
 
 
You will be assigned a unique subject registration number upon enrollment.  This 
number and your initials will be used to identify you throughout the course of this study, 
so that your identity is protected.   


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Electronic Medical Records and Research Results  
  
What is an Electronic Medical Record?  
 
An Electronic Medical Record (EMR) is an electronic version of the record of your care 
within a health system. An EMR is simply a computerized version of a paper medical 
record.  
  
If you are receiving care or have received care within the University of Pennsylvania 
Health System (UPHS) (outpatient or inpatient) and are participating in a University of 
Pennsylvania research study, results of research-related procedures (i.e. laboratory 
tests, imaging studies and clinical procedures) may be placed in your existing EMR 
maintained by UPHS.  
  
If you have never received care within UPHS and are participating in a University of 
Pennsylvania research study that uses UPHS services, an EMR will be created for you, 
for the purpose of maintaining any results of procedures performed as part of this 
research study.  The creation of this EMR is required for your participation in this study.  
In order to create your EMR, the study team will need to obtain basic information about 
you that would be similar to the information you would provide the first time you visit a 
hospital or medical facility (i.e. your name, the name of your primary doctor, the type of 
insurance you have). Results of research procedures performed as part of your 
participation in the study (i.e. laboratory tests, imaging studies and clinical procedures) 
may be placed in this EMR.  
 
Once placed in your EMR, these results are accessible to appropriate UPHS workforce 
members that are not part of the research team.  Information within your EMR may also 
be shared with others who are determined by UPHS to be appropriate to have access to 
your EMR (e.g. health insurance company, disability provider, etc).  
 
Will I be able to access my research records? 
 
You have the right to see and get a copy of your medical records kept by the University 
of Pennsylvania.  However, you will not be able to review or receive some of your 
records related to the study until after the entire study has been completed. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify you. At 
most, the website will include a summary of the results. You can search this website at 
any time. 
 
 
 
 
 


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Why is my information being used? 
 
Your personal contact information is used by the research team to contact you during 
the study. Your information and results of tests and procedures are used to: 
• do the research 
• oversee the research 
• to see if the research was done right 
• to evaluate and manage research functions.   
 
Who may use and share information about me?   
The following individuals may use or disclose your personal health information for this 
research study: 
• The Principal Investigator and the study team  
• Authorized members of the workforce of the UPHS and the School of Medicine, 
and University of Pennsylvania support offices, who may need to access your 
information in the performance of their duties (for example: for research oversight 
and monitoring, to provide treatment as part of this study or as part of your routine 
care, to manage accounting or billing matters, etc.). This includes members of the 
Institutional Review Board (IRB), an Ethics Committee at the University of 
Pennsylvania, which is responsible for reviewing and overseeing research studies 
to ensure that they are safe and well managed.  
 
Who, outside of the School of Medicine, might receive my 
information?  
 
As part of the study, the Principal Investigator, the study team and others listed above, 
may disclose your study-related records, including the results of the research study 
tests and procedures, to those listed below.  In all disclosures sent outside of the 
University of Pennsylvania Health System and School of Medicine, you will not be 
identified by name, social security number, address, telephone number, or any other 
direct personal identifier, unless disclosure of the direct identifier is required by law. In 
records and information sent outside of the University of Pennsylvania Health System 
and School of Medicine, you will be assigned a unique code number.  
 
Individuals or organizations outside of Penn who might see your personal health 
information:  
• 
The physician and laboratory staff at the University of Cincinnati, where some of 
the blood specimens will be analyzed.   
 
Regulatory and safety oversight organizations who might see your personal health 
information: 
• The Food and Drug Administration 
• DHHS (Department of Health and Human Services) 
• Other regulatory agencies and/or their designated representatives in the United 
States and other countries 


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Once your personal health information is disclosed to others outside of UPHS or the 
School of Medicine, it may no longer be covered by federal privacy protection 
regulations.   
 
The Principal Investigator or study staff will inform you if there are any additions to the 
list above during your active participation in the trial. Any additions will be subject to 
University of Pennsylvania procedures, developed to protect your privacy. 
 
How long may the School of Medicine be able to use or disclose my 
personal health information?   
 
Your authorization for use of your personal health information for this specific study 
does not expire. If you sign this form, we will collect your health information until the end 
of the research study.  We may collect some information from your medical records, 
even after you finish taking part in this study. We will keep all of the information forever, 
in case we need to look at it again. We will protect this information and keep it 
confidential.  
 
Your information may be held in a research database.  However, UPHS and the School 
of Medicine may not re-use or re-disclose information collected in this study for a 
purpose other than this study unless: 
• You have given written authorization to do so  
• The University of Pennsylvania’s Institutional Review Board grants permission 
after ensuring that appropriate privacy safeguards are in place  
• As permitted or required by law  
 
The data from this study may be published or used for teaching purposes, but you will 
not be personally identified in any publication.  Your identity will remain confidential, 
unless disclosure is required by law. 
 
Can I change my mind about giving permission for use of my 
information? 
 
You have the right to withdraw your permission for the use of your personal health 
information, but if you do so, you must stop taking part in this study. You must withdraw 
your permission in writing to the Principal Investigator, at the address on the first page.  
Even if you withdraw your permission, your personal health information that was 
collected before we received your written request may still be used and disclosed, as 
necessary for the study.  If you withdraw your permission to use your personal health 
information, you will also be withdrawn from the research study and no new information 
will be collected. 
 


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What if I decide not to give permission to use and give out my health 
information? 
 
Then you will not be able to participate in this research study. 
 
Who can I call with questions, complaints or if I’m concerned about 
my rights as a research subject? 
 
If you have questions, concerns or complaints regarding your participation in this 
research study or if you have any questions about your rights as a research participant, 
you should speak with the Principal Investigator listed on page one of this form.  If a 
member of the research team cannot be reached or you want to talk to someone other 
than the study staff, you may contact the Office of Regulatory Affairs with any questions, 
concerns or complaints at the University of Pennsylvania by calling (215) 898-2614. 
 
When you sign this form, you are agreeing to take part in this research study. 
This means that you have read the consent form, your questions have been 
answered and you have decided to volunteer.  Your signature also means that 
you are permitting the University of Pennsylvania to use your personal health 
information collected about you for research purposes within our institution. You 
are also allowing the University of Pennsylvania to disclose that personal health 
information to outside organizations or people involved with the operations of this 
study. 
A copy of this consent form will be given to you.  
 
Please check ‘yes’ or ‘no’ if you would like to participate in the 
following options: 
 
1. The study team would like to keep some of your blood and store it for future use.  The 
precise tests to be performed are not known at this time, but the samples would only be 
used to help better understand LAM and/or TSC.  If you agree to allow storage of your 
samples for future use, please indicate below.  This is voluntary and may decide not to 
allow samples to be used for future use.  This decision will in no way impact your care 
or your ability to participate in this clinical trial. 
 Yes, I agree to allow some of my blood to be stored for future use.   
 No, I do NOT agree to allow some of my blood to be stored for future use.    
 
 
 
 


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2. The study team would like your permission to continue to access and look at your 
medical records, after the study has ended.  Your records may be reviewed for up to 2 
years, in order to check, clarify and/or confirm information about your condition, 
treatment or any tests or procedures that have been done.   
 Yes, I agree to allow my medical records to be accessed and reviewed for up to 2   
years after the study has ended.   
 No, I do NOT agree to allow my medical records to be accessed or reviewed after 
the study has ended. 
 
3. The study team would like your permission to contact you after your participation in 
the study has ended.  The team would contact you about other research studies for 
which you may qualify and want to participate. 
 Yes, I agree to be contacted regarding potential new studies, after this study has 
ended.   
No, I do NOT agree to be contacted regarding potential new studies, after this study 
has ended.   
 
Informed Consent Signature 
 
 
 
________________________       ____________________________________ 
Name of Subject (Please Print)    Signature of Subject  
 
          Date 
 
 
 
 
________________________ 
_____________________________________ 
Name of Person Obtaining  
  Signature                                   
Date 
Consent (Please Print)