Conditions: Lymphangioleiomyomatosis
Keywords: VEGF-D Imatinib mesylate Sirolimus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 18
Healthy volunteers: no

Brief summary:
This is a phase 1 clinical trial comparing imatinib mesylate to placebo for individuals with lymphangioleiomyomatosis (LAM).

Detailed description:
This is a double blind, adjusted parallel design, randomized clinical trial comparing imatinib mesylate 400 mg daily or matching placebo on the primary outcome of log transformed serum VEGF-D level in patients with LAM.

Sirolimus using patients will have co-administration of Imatinib mesylate or placebo for 28 days prior to sirolimus discontinuation.

The duration of 400 mg imatinib mesylate or placebo will be 56 days, a dose reduction is allowed for toxicity.

The primary endpoint will be the change in the log transformed VEGF-D one month after monotherapy imatinib mesylate or placebo.

Total trial duration is 2 months of drug administration.

Arms:
arm 1: 56 days of Imatinib mesylate 400 mg oral daily with or without co-administration of an mTOR inhibitor for 28 days. A dose reduction to 200 mg daily is allowed for toxicity. arm 2: 56 days of Placebo with or without co-administration of an mTOR inhibitor for 28 days. A dose reduction is allowed for toxicity.

Interventions: intervention 1: Imatinib Mesylate 400Mg Capsule intervention 2: Placebo - Capsule
Intervention descriptions: intervention 1: Sirolimus or everolimus will be withdrawn after 28 days if used at baseline intervention 2: Sirolimus or everolimus will be withdrawn after 28 days if used at baseline

Protocol document:
Prot_SAP_001.pdf: 
LAMP-1 Protocol 
LAM Pilot study with imatinib mesylate 
PI: Charlie Strange, MD 
Co-I Jeanine D’Armiento 
Protocol Version 7.0 
Date: 21 March 2018 
MUSCIRB Approved 28MAR2018


 
 
 
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PI Name:  Charlie Strange 
 
Study Title:   LAM Pilot study with imatinib mesylate (LAMP-1) 
 
TABLE OF CONTENTS 
 
1. INTRODUCTION……………………………………………………………….............. 3 
2. BACKGROUND………………………………………………………………………..... 3 
2.1 Literature and Previous Studies………………………………………………………... 3 
2.2 Rationale for the Study………………………………………………………………… 5 
2.3 Primary Hypothesis…………………………………………………………………...... 6 
3. STUDY OBJECTIVES…………………………………………………………………... 6 
3.1 Primary Aim…………………………………………………………………………..... 6 
3.2 Secondary Aims………………………………………………………………………... 6 
4. RATIONALE…………………………………………………………………………….. 6 
4.1 Study Population……………………………………………………………………….. 6 
4.2 VEGF-D………………………………………………………………………………... 7 
4.3 Spirometry, Exercise (6MWT), and Dyspnea………………………………………..…7 
4.4 Laboratory Analysis ………………………………………………………..………….. 7 
4.5 Biobank …………………………………………..……………………………………. 8 
4.6 Questionnaires …………………………….………………………………………….... 8 
4.7 Facilities ……………………………………………………………………………….. 9 
5. STUDY DESIGN AND PROCEURES……………………………………………….… 9 
5.1 Overview…………………………………………………………………….…………. 9 
5.2 Patient Recruitment and Selection……………………………………………….…….. 9 
5.3 Inclusion/Exclusion Criteria…………………………………………………………...11 
5.4 Visit Schedule………………………………………………………………………… 12 
5.5 Study Examinations…………………………………………………………………... 14 
5.6 Unblinding Considerations.............................................................................................15 
6. ETHICAL CONSIDERATIONS…………………………………………………….… 15 
6.1 Human Subjects’ Protections and Risks……………………………………………… 16 
6.2 Confidentiality………………………………………………………………………... 18 
6.3 Adverse Events……………………………………………………………………….. 18 
Medical University of South Carolina 
Protocol 


 
 
 
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6.4 Measures to Protect the Participant………………………………………..………….. 20 
7. STATISTICAL ANALYSIS…………………………………………………….……... 21 
7.1 Sample Size………………………………………………………………..………….. 21 
7.2 Statistics……………………………………………………………………….……… 21 
7.3 Endpoints……………………………………………………………………………... 22 
7.4 Study Limitations……………………………………………………………………... 22 
8. DATA HANDLING…………………………………………………………………….. 23 
8.1 Web Data Entry……………………………………………………………………….. 23 
8.2 Data Sharing………………………………………………………………...………… 23 
9. STUDY MONITORING…………………………………………………..…………… 24 
9.1 Data Fidelity and Quality Control………………………………..…………………… 24 
9.2 Biospecimen Quality Control…………………………………….…………………... 24  
9.3 Data Safety Monitoring Board………………………………………………….…….. 24 
9.4 Research Monitor………………………………………………………………………24 
10. STUDY ADMINISTRATION…………………………………………………………25 
11. REFERENCES…………………………………………………………………..…….. 26 


 
 
 
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1. INTRODUCTION 
Lymphangioleiomyomatosis (LAM) is a rare and unusual cancer that involves the lungs either as part of 
Tuberous Sclerosis Complex (TSC) or in sporadic form1. The site of origin and the reason for almost 
exclusive female predominance remain unclear. Sporadic LAM has proven difficult to study because of 
the slow rate of tumor cell (LAM cell) growth with reliance on long duration treatment studies that have 
proven problematic in rare disease populations. Lung lesions are widely present at the time of diagnosis 
in all women. LAM cells line the lymphatics and spread diffusely through the lung exhibiting tiny 
nodules on computed tomography (CT)2. Lung destruction in part occurs from the secretion of matrix 
metalloproteinases3 resulting in large cysts that are the clinical hallmark of this disease. Nevertheless, the 
rapid proliferation and growth of LAM is similar to that of other cancers, although the histologic 
appearance is benign4. The site of origin of the LAM cells remains unclear.  
 
Vascular endothelial growth factor-D (VEGF-D) is generated by LAM cells. VEGF-D at high levels is 
found in no other cystic lung diseases in women and thus is a robust biomarker for LAM activity and 
response to treatment. In patients with LAM, sirolimus (rapamycin) was shown to stabilize lung 
function, reduce serum VEGF-D levels, and was associated with a reduction in symptoms and 
improvement in quality of life. 
 
This pilot trial employs a dual agent design intended to generate safety and efficacy data sufficient to 
power and design a phase 3 study of imatinib mesylate vs placebo for Lymphangioleiomyomatosis 
(LAM). The hypothesis is that imatinib mesylate will be equivalent to sirolimus (rapamycin) in 
short term efficacy and safety. Durability of response will not be tested. Importantly, VEGF-D level 
will be used in this small clinical trial design using 20 participants. 
 
Specific Aims 
1) To determine if monotherapy imatinib mesylate suppresses serum VEGF-D in LAM compared 
to placebo. 
2) To determine if sirolimus (rapamycin) withdrawal for 1 month is associated with serum VEGF-
D elevation in patients on imatinib mesylate. 
3) To determine the safety of imatinib mesylate in patients with LAM. 
 
2. BACKGROUND 
 
2.1 Literature and Previous Studies 
 
Recently, two developments have changed the face of LAM clinical care. The first of these was the 
observation that patients with sporadic LAM often (but not always) have biallelic mutations in TSC2 in 
LAM cells. Loss of TSC functionality leads to marked activation of the mammalian target of rapamycin 
(mTOR) complex 1, a master kinase that regulates cell growth. mTOR activation is seen in a number of 
diseases prompting clinical trials of sirolimus (also known as rapamycin). In LAM, these studies showed 
that inhibition of mTOR produced growth arrest in LAM cell cultures in many laboratories. After 
sirolimus was shown to shrink renal tumors called angioleiomyomas (AML) that are associated with 
both TSC and sporadic LAM5, a trial targeting lung disease was designed and completed by the Rare 
Lung Disease Consortium of the NIH. 
 
The Multicenter International Lymphangioleiomyomatosis Efficacy and Safety (MILES) study 
compared sirolimus vs placebo in a 1:1 randomized controlled, blinded study of individuals with 
impaired lung function as defined by a forced expiratory volume in 1 second (FEV1) < 70% predicted. 


 
 
 
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The randomization was intact for 1 year showing both efficacy and safety of the drug6. At the end of the 
year, the study design prompted cessation of sirolimus to determine the duration of the treatment 
response. Unfortunately, the majority of LAM affected women did not make it to the next scheduled 3 
month visit because lung function rapidly deteriorated and consent was withdrawn. 
 
The second development that has allowed the current grant to advance is the discovery that vascular 
endothelial growth factor-D (VEGF-D) is generated by LAM cells7. VEGF-D at high levels is found in 
no other cystic lung diseases in women and was added to the diagnostic criteria of the MILES study to 
facilitate study enrollment in the absence of lung biopsy. Importantly, VEGF-D was a robust biomarker 
for disease activity and response to sirolimus in the MILES study8. Historically, unlike all other cancers, 
disease activity depended on measures of lung function such as FEV1. CT scans have not been able yet 
to define an endpoint for therapy since micronodules are too small to measure and cyst volume is not 
known to correlate with disease activity. Hyperinflation, an important cause of symptoms9, is difficult to 
measure serially. Hence, a biomarker for LAM allows a path forward for LAM clinical trials. 
 
Studies in the laboratory of Dr. D’Armiento, co-investigator for this study, demonstrated that LAM and 
AML cells differentiate down several mesenchymal cell lineages, therefore she speculated that they 
possess an undifferentiated mesenchymal cell phenotype. One of the well-known characteristics of 
mesenchymal cells is the expression of the PDGF receptor. In order to confirm the fact that the LAM 
cell was of mesenchymal origin, she stained the cells for the PDGFR b receptor and demonstrated 
positive staining. Next, in order to test whether the PDGF pathway was activated in the LAM cells, she 
performed IHC and western blotting of both LAM and AML tissues. These cells were positive for 
phospho-PDGF receptor as shown in Figure 1. 
 
Figure 1. PDGFRb expression in LAM and AML. Immunohistochemistry of PDGFRb in LAM and AML tissue samples with 
a phosphor-PDGFRb antibody. Negative controls were performed after immunoabsorption of antibody. Western blot analysis 
on protein homogenates from AML tissue demonstrates expression of PDGFRb. 
 
Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor that functions by preventing the BCR-Abl 
tyrosine kinase enzyme from phosphorylating subsequent proteins and initiating the signaling cascade 
necessary for cancer development. Because the BCR-Abl tyrosine kinase enzyme exists only in cancer 
cells and not in healthy cells, imatinib is a targeted therapy that kills cancer cells through the initiation of 
apoptosis. In addition, imatinib blocks c-Kit and the platelet-derived growth factor receptor (PDGFR). 
As an inhibitor of PDGFR, imatinib mesylate has utility in other diseases. Imatinib has been reported to 
be an effective treatment for dermatologic diseases FIP1L1-PDGFR alpha+ mast cell disease, 
hypereosinophilic syndrome, and dermatofibrosarcoma protuberans10 through this mechanism. After 
identifying the reactivity of the LAM cell with the PDGF antibodies Dr. D’Armiento demonstrated that 


 
 
 
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imatinib, which targets PDGF, could completely block the growth of the LAM/AML cells resulting in 
cell death (Figure 2, 3). Cells treated with Rapamycin, although growth inhibited, did not undergo cell 
death (Figure 3, 11). These findings present Imatinib as a potential therapy in the treatment of 
Lymphangiomyomatosis. 
 
 
Figure 2. Primary human AML cells halt their growth after treatment with imatinib. Imatinib strongly inhibited the 
proliferation of primary AML cells at doses of imatinib that are achievable in the serum of humans. 
 
 
Figure 3. Cell death was achieved in the presence of fetal bovine serum (FBS) at 1μM and 0.1μM concentrations of imatinib. 
Previous studies have shown that sirolimus inhibits the cell growth but does not kill the cells as was seen in this study.11 
 
2.2 Rationale for the Study 
The proposed study design is a prospective, multicenter, randomized, stratified, double blind, placebo-
controlled, proof of principal trial to examine the effect of imatinib mesylate on intrasubject VEGF-D, a 
biomarker associated with LAM disease activity. Since imatinib mesylate has not previously been used 
in LAM, a small pilot study is needed to gather safety data, confirm biomarker efficacy data, and 
determine if a clinical efficacy signal can be obtained in a short term study.  
 
This pilot trial employs a dual agent design intended to generate safety and efficacy data sufficient to 
power and design a phase 3 study of imatinib mesylate vs placebo for LAM. Durability of response will 
not be tested. Importantly, VEGF-D level will be used in this small clinical trial design using 20 
participants. 
 
Since LAM is a rare disease a small trial is designed to assure enrollment is achievable. 


 
 
 
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This study will enable proper powering of subsequent studies. The authors believe that a proof of 
principal pilot study will be able to recruit 20 participants, the majority on rapamycin, for this study. 
 
The overarching hypothesis that imatinib mesylate kills LAM cells, while sirolimus (rapamycin) 
provides growth suppression, suggests that removal of rapamycin may be necessary for the effects of 
imatinib mesylate to be seen. Therefore, a two stage pilot study has been designed with usual doses of 
imatinib mesylate used for other indolent tumors, in an attempt to confirm the hypothesis. 
 
The findings of this pilot study are expected to enable powering of a larger clinical trial and advance 
knowledge of pathogenesis and treatment of LAM. All results will be shared at the end of the study with 
the LAM community.  
 
2.3 Primary Hypothesis 
The hypothesis is that imatinib mesylate will be equivalent to sirolimus (rapamycin) in short term 
efficacy and safety.  
 
3. STUDY OBJECTIVES  
3.1 Primary Aim 
To determine whether imatinib mesylate will be equivalent to sirolimus in short term efficacy and 
safety in patients with LAM. 
The primary efficacy analysis will be the log transformed change in intrasubject plasma VEGF-D 
before and 1 month after initiation of monotherapy imatinib mesylate. 
 
3.2 Secondary Aims  
1) To determine if monotherapy imatinib mesylate suppresses serum VEGF-D in LAM compared 
to placebo. 
2) To determine if sirolimus (rapamycin) withdrawal for 1 month is associated with serum VEGF-
D elevation in patients on imatinib mesylate. 
3) To determine the safety of imatinib mesylate in patients with LAM. 
 
3.2.1 To determine if a clinical efficacy signal can be obtained in a short term study. 
 
3.2.2 To invite biobank participation. 
With informed consent, the biosamples will be kept with study number identifiers to align with future 
clinical events. Individuals may participate in the study without agreeing to biobank participation.  
 
3.2.3 Inform about impact of imatinib mesylate treatment on quality of life. 
Quality of life questionnaire instruments are described in a later attachment as guided by the CDMRP 
Program will be administered. 
 
4. RATIONALE  
4.1 Study Population 
Adult women with definite or probable LAM and impaired lung function will be invited to participate 
and screened by study inclusion and exclusion criteria below. Definite or probable LAM is established 
by the ERS LAM guidelines modified by addition of VEGF-D criteria as defined by the MILES Trail 
(see below). 20 women with LAM and impaired lung function will be enrolled. Many participants will 
be receiving sirolimus treatment at the time of enrollment; however, sirolimus naïve patients will not be 
excluded.    
 


 
 
 
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Participation of children is not allowed in this study because LAM does not cause clinical disease in this 
population. 
 
Participation of women and minorities is encouraged, particularly since this disease only affects women. 
Sirolimus is pregnancy category C and imatinib is pregnancy category D. Pregnancy or intent to become 
pregnant or nurse during the 2 month study window and for 1 month afterwards is not allowed because 
of the safety risk of a category D medication. An adequate birth control method during these 3 months 
will be documented in all women of childbearing potential. 
 
4.2 VEGF-D 
VEGF-D at high levels is found in no other cystic lung disease and serves as a robust biomarker for 
LAM disease activity. Sirolimus (rapamycin) was demonstrated in the MILES study to be both safe and 
effective in the treatment of LAM. Importantly, VEGF-D was added to the diagnostic criteria of the 
MILES study. Hence, a biomarker for LAM allows a path forward for LAM clinical trials. This pilot 
study to determine whether imatinib will be equivalent to sirolimus in short term efficacy and safety in 
patients with LAM will similarly utilize the biomarker VEGF-D, measured at the University of 
Cincinnati laboratory. This test has been given a Humanitarian use device (HUD) designation for the 
disease LAM. Further information is at: 
http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=470067 
 
4.3 Spirometry, Exercise (6MWT), and Dyspnea 
Traditional methods to measure LAM disease activity have depended on measures of lung function such 
as FEV1 and FVC. Hyperinflation is an important cause of symptoms. Therefore, pre and post 
bronchodilator spirometry, plethysmographic lung volumes, and diffusion capacity are needed to 
accurately provide a physiologic assessment of lung function.    
 
The ability to exercise is an important biomarker of lung disease and dyspnea. Exercise induced dyspnea 
remains a common symptom associated with the disease state. Exercise induced dyspnea correlates 
strongly to quality of life and exercise capacity correlates with mortality. Few studies of exercise 
capacity are available for LAM; however, the pathophysiology suggests that there is a high prevalence 
of hyperinflation and dynamic hyperinflation during exercise.  
Although many specific exercises have been used as a biomarker for disease severity and progression, 
the distance walked in 6 minutes (6MWT) has the most data in COPD and is part of the LAM protocol 
in order to capture an exercise biomarker. Reproducibility is improved by a second 6MWT.  
4.4 Laboratory Analysis 
Samples of whole blood serum, DNA, blood mononuclear RNA, and urine will be obtained during this 
study. These samples serve the dual purpose of allowing a robust safety analysis of study timepoints and 
populating a LAM biobank of biosamples that are available to the larger LAM community (see Data 
Resource Sharing attachment). Biosamples will be stored both at Columbia University and MUSC and 
shared between laboratories with a sample and data sharing agreement in place with this study. 
 
VEGF-D level will be measured at the beginning of the study, at one month and at the end of the study 
(56 days). For safety, all participants will also have laboratory monitoring of CBC, T4, TSH, 
Cholesterol, Sirolimus level and complete metabolic panel (CMP) at baseline, 28 days, and 56 days. 
 
 
 


 
 
 
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4.5 Biobank 
With informed consent, a portion of biosamples will be kept with study number identifiers to align with 
future clinical events. Individuals may participate in the study without agreeing to biobank participation. 
These biosamples will allow proteomic and metabalomic analysis of a rare disease population with 
samples obtained on no LAM specific therapy, sirolimus (or other mTOR inhibitor) alone, or imatinib 
alone. These samples will be used and available to the LAM community to define the metabolic 
pathways affected by these drugs in intrasubject samples. 
 
Because the LAM Foundation may in the future establish a biobank, the consent form will include an 
option of participant re-contact regarding the option moving biosamples to a LAM Foundation biobank, 
which may request identifying information. Participants in this study would be contacted prior to 
transfer of any biosample that includes identifying information and a new informed consent form for the 
LAM Foundation Biobank would be signed. Biosample requests from the LAM community will not 
receive identifying information to perform analysis on these biosamples.  
 
4.6 Questionnaires 
LAM is marked by premature disability, a shortened lifespan in most individuals, and frequent 
symptoms of disease. Disease specific quality of life, general quality of life, measures of exacerbation 
frequency, pre-existing lung function decline, and measures of dyspnea are collected by standardized 
and validated instruments. Quality of life questionnaire instruments are described in a later attachment as 
guided by the CDMRP program. Improved quality of life was determined among MILES study 
participants treated with sirolimus. Similarly, such measures will be collected in this imatinib pilot 
study.   
Designed primarily as a safety study, the likelihood of achieving statistical differences between the 
groups in lung function or quality of life remains low; therefore, the questionnaires used in the study 
should be viewed as secondary and exploratory endpoints as explained in Attachment 1. 
We will not be modifying any instrument for this study and will use the most recent validated version 
for each tool utilized. Recently, the St. Georges Respiratory Questionnaire (SGRQ) has been 
demonstrated to have longitudinal construct validity in LAM.2 Specifically, the SGRQ is a self-
administered respiratory specific health care quality of life tool. When compared to FEV1, diffusion of 
the lung for carbon monoxide (DLCO), 6 minute walk test distance, and VEGF-D levels from the 
MILES cohort, the SGRQ change scores tracked for each of these four anchors. The strongest correlates 
were with FEV1. Plots of cumulative distribution functions further supported the longitudinal validity of 
the SGRQ in LAM. 
 
The SGRQ is a 50 question examination that is available for use to academic investigators without 
charge. It is scored 1-100 with a clinically meaningful difference in obstructive lung diseases of 4 points 
change. Test to test reproducibility ranges from 0.795 to 0.9 for the American version that will be used 
for this study as a secondary variable. A copy of the questionnaire follows. 
 
Exploratory endpoints for the study include mMRC dyspnea scale, the functional Assessment Inventory, 
and the EQ-5D score that were all used in the MILES study in a LAM population. None have been 
independently validated in LAM, yet in this pilot study, will be used to define if a treatment signal exists 
with these questionnaires. All have been used in more common respiratory diseases. 
 
The modified Medical Research Council (mMRC) dyspnea scale is a four point scale that quantifies 
dyspnea and has correlations with mortality, quality of life in chronic obstructive pulmonary disease 
(COPD). The EQ-5D is a general Quality of Life scale that includes a visual analog scale to assess 
general wellbeing and may pick up non-respiratory toxicity of medications being studied. The 


 
 
 
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Functional Assessment Inventory is an instrument widely used to judge an individual's productive 
activity within 7 different domains. Copies of these 3 instruments are attached.  
 
4.7 Facilities 
University facilities at MUSC and Columbia University are available to see patients for research study 
inclusion. The pulmonary clinic in Rutledge Tower and the NEXUS center, and the clinical trials 
translational research center of the Clinical Translational Science Award (CTSA) at MUSC are available 
for this study. Personnel are available for biosample collection at the site of the CTSA biobank. The 
MUSC pulmonary clinical trials unit has 13 research coordinators working on studies at the present 
time. All are trained at time of hiring in bioethics and human subjects policy and procedures. All have 
current CITI certification through the University of Miami. 
 
Biosamples for this study that will be collected include serum, plasma, DNA and blood mononuclear 
cell RNA collected in Paxgene tubes. Biosamples will be bar coded and stored at -80oC in a dedicated 
freezer running off an emergency powered circuit. Excess biosamples that are not used by the end of the 
study will be stored for the LAM community. Aliquots of samples will be made available as described in 
data sharing agreement form. 
 
Pulmonary Division laboratories from both Universities have adequate freezer space, refrigerated 
centrifuges, and capability to isolate and store the biosamples described in the project. 
 
5. STUDY DESIGN AND PROCEDURES  
5.1 Overview 
The proposed study design is a prospective, multicenter, randomized, stratified, double blind, placebo-
controlled, proof of principal trial to examine the effect of imatinib mesylate on intrasubject VEGF-D, a 
biomarker associated with LAM disease activity. 
 
The study is designed as a 3 visit study including baseline, 1 month, and 2 month visits. Since most 
patients with impaired lung function who would be eligible for this study are already on sirolimus, the 
proposed study would simultaneously address three issues: 1) provide a biomarker rich proof of 
principle study of imatinib mesylate in LAM, 2) determine if imatinib mesylate is safe when added to 
sirolimus, and 3) determine if imatinib mesylate controls vascular endothelial growth factor-D (VEGF-
D) once sirolimus is removed. Small numbers of individuals are not on sirolimus; however, this proposal 
would not exclude them to define if there is a treatment response signal to imatinib mesylate alone. A 
stratified randomization strategy will differentially enroll participants on or off rapamycin at baseline. 
 
At the conclusion of the study, participants will be returned to clinically available LAM therapy chosen 
with their treating physician. Imatinib will not be available through the investigators after participation 
in this study. 
  
5.2 Patient Recruitment and Selection 
10 eligible patients with LAM will be recruited and enrolled at each of Columbia University Medical 
Center and Medical University of South Carolina, for a total of 20 patients in the study. Both centers 
regularly follow LAM patients with sufficient patient numbers and characteristics to fulfill recruitment 
needs. Patients who are regularly cared for by the principal investigator and co-investigator will be 
reviewed for potential eligibility. In addition, a study advertisement will be placed in the LAM 
Foundation Newsletter and Website to inform individuals with LAM of this study. Screening procedures 
for established LAM patients and others are outlined below. 
 


 
 
 
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If a potential participant has received clinical LAM care at MUSC, authorized MUSC research 
personnel will review the potential participant’s diagnosis, demographics, and lung function results. This 
information will be documented in Part 1 (page 2) of the Eligibility Screen. Participant identifiers are 
recorded on the cover sheet (page 1), in accordance with best practice.  
Potential participants who appear eligible after Part 1 of the eligibility screen may be contacted and 
further screened by phone or in clinic. The appropriate telephone script or in-clinic script (see script 
documents) will be followed to introduce the research personnel, the research study and the option of 
engaging in the screening questions to determine eligibility. With the potential participant’s verbal 
permission, questions on Part 2 (page 3) of the Eligibility Screen will be asked and responses recorded.   
If someone is not a LAM patient at MUSC and is otherwise referred (e.g. self-referral from 
clinicaltrials.gov, advertisement response or referral from outside physician) and records do not 
accompany the request, the potential participant will be called and asked to voluntarily provide their 
records to the study team for preliminary review. When records are provided, the same procedures as 
above will be followed to screen the participant for interest and eligibility.  
The Eligibility Screen and Scripts will allow the trained research coordinators to: 
1) Verify in the records that the potential participant meets eligibility criteria (Eligibility Screen Part 1),   
2) Verify that the individual is interested in participating in the LAMP-1 study (Telephone or In-Clinic 
Script). 
3) Verify that the potential participant is preliminarily willing to perform study procedures and do not 
have contraindications (Eligibility Screen Part 2).   
A participant who is interested and eligible after scripts and screening are complete will be asked if they 
wish to schedule their first study visit. The informed consent process will occur prior to study 
procedures at Visit 1. 
 
The authorized investigator or coordinator engages in informed consent with the participant at the 
baseline visit and provides a written informed consent form for the participant to review. Following 
review of potential risks and benefits, the voluntary nature of participation, and ample opportunity to ask 
questions the consenting participant will provide signature on the informed consent document. At this 
point the participant is enrolled. The participant will be given a copy of the signed consent form to keep.    
 
Participants will be given $200 travel money for each of the 3 study visits, for a cumulative payment of 
$600 per participant who completes the study.  
 
5.2.1 Timeline  
This timeline for this study is 1 years following after study drug is obtained. Grant funding from the 
Department of Defense has been approved (see attached budget). Imatinib mesylate (Gleevec®) for this 
study will be provided by Novartis. Placebo drug will be purchased. Enrollment will commence 
following IRB approval at both MUSC and Columbia University and subsequent approval by the human 
research protection office (HRPO) of the US Army Military Department.  The anticipated enrollment 
schedule is detailed in the table below.   
 


 
 
 
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5.3 Inclusion/Exclusion Criteria 
5.3.1 Inclusion Criteria  
Signed informed consent 
- Age > 18 years* and < 65 years 
- Definite or Probable LAM** 
- FVC < 90% predicted or Postbronchodilator FEV1 <90% predicted 
- Postbronchodilator FEV1 > 30% predicted 
- DLCO > 20% predicted 
 
5.3.2 Exclusion Criteria 
- Current or planned pregnancy or lactation 
- Unwillingness to discontinue sirolimus 
- Change in the dose or use of sirolimus within the past month 
- Inability to perform spirometry 
- Other serious illness that would impact the outcome of the study 
- Current lung transplant 
- Current cigarette smoking 
- Required use of ketoconazole, itraconazole, clarithromycin, or rifampin during the 2 months of 
the study. 
- Unwillingness to avoid grapefruit juice or St. Johns Wort during the study. 
- Planned surgery during the 2 months of the study.. 
 
*Children are excluded because LAM does not affect children 
 
**Definite or Probable LAM is defined by the ERS LAM guidelines modified by addition of 
VEGF-D criteria as defined by the MILES Trail 
 
Definite LAM: 
1) Characteristic or compatible lung HRCT, and lung biopsy fitting the pathological criteria for LAM; or 
2) Characteristic lung HRCT and any of the following: angiomyolipoma (kidney); thoracic or abdominal 
chylous effusion; lymphangioleiomyoma or lymph-node involved by LAM; and definite or probable 
TSC. 
 
Probable LAM 
1) Characteristic HRCT and compatible clinical history; or 
2) Compatible HRCT and any of the following: angiomyolipoma (kidney); thoracic or abdominal 
chylous effusion; or VEGF-D >800 pg/ml at any time in the past. 
 


 
 
 
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5.4 Visit Schedule 
The Baseline Visit will begin with signing the informed consent. A history and physical examination, 
post-bronchodilator spirometry, 6 minute walk test distance, and blood samples will be obtained. 
Questionnaires will be completed and the patient will be randomized to imatinib mesylate, at an oral 
dose of 400 mg once daily, or placebo stratified on whether sirolimus has been used in the last month. A 
sirolimus level and VEGF-D level will be measured.  
 
A 1 week trough sirolimus level and telephone call will be obtained on all subjects entering the study on 
sirolimus therapy.   
 
1 Month Visit- Post-bronchodilator spirometry, 6 minute walk test distance, and blood samples will be 
obtained. Questionnaires will be completed. Sirolimus will be discontinued if used at baseline. 
 
2 Month Visit/ End of study- Post-bronchodilator spirometry, 6 minute walk test distance, and blood 
samples will be obtained. Questionnaires will be completed. A sirolimus level will be obtained to assure 
drug cessation. The participant is returned to LAM therapy of their choice. 


 
 
 
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Figure 1. Study Schedule, Stratification and Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1. Procedures by Visit 
 
Baseline (V1) 
1 Month (V2) 
2 Months (V3) 
1.Informed Consent 
X 
 
 
2.Pulmonary Function Testing  X 
X 
X 
3.Six Minute Walk Test 
X 
X 
X 
4.Blood Sample Collection* 
X 
X 
X 
5.Urine Sample Collection* 
X 
X 
X 
6.Participant Questionnaires 
X 
X 
X 
 
*Table 2. Sample Collection and Usage 
Collection 
Volume 
Sample 
Time(s)* 
Planned assays 
Blood each visit 
30ml 
Plasma 
0, 1, 2 
Cholesterol, CMP 
Sirolimus level, TSH, 
T4, VEGF-D level 
 
7 ml 
Plasma 
1 week in patients on 
sirolimus at baseline 
Sirolimus level 
 
5ml 
EDTA 
0, 1, 2 
CBC 
 
10ml 
Paxgene DNA 
0 
DNA 
 
10ml 
Paxgene RNA 
0, 2 
Blood mononuclear cell 
RNA 
Urine each visit 
10ml 
Urine 
0, 1, 2 
Urinalysis, Pregnancy 
Test 
*Time 0= Baseline, 1=1month, 2=2 months 


 
 
 
14 of 27 
5.5 Study Examinations 
5.5.1 Blood and Urine Samples 
These are collected at each study visit. 
 
Safety: Universal and Occupational Safety and Health (OSHA) and all institutional-specific (such as 
bloodborne pathogen training) precautions and training requirements should be followed when 
processing blood and urine. For more detailed safety information see 
(http://www.osha.gov/SLTC/biologicalagents/index.html).  
 
Urinalysis, pregnancy test, CBC, TSH, T4, Cholesterol, INR and CMP are performed on samples from 
each visit at the University Laboratories at MUSC and Columbia to look for adverse events and assure 
patient health and safety during the study. Trough Sirolimus level is performed on a sample from each 
visit to verify Sirolimus treated vs. naïve at baseline and that sirolimus was stopped in previous 
sirolimus receivers at the 1 month visit. This may require participants to take sirolimus at a time of the 
day that corresponds to anticipated study visit time. VEGF-D levels are performed at each visit to test 
efficacy of imatinib. 
 
All tests except the VEGF-D will be performed in the clinical laboratory of the institution where the 
patient is seen (MUSC or Columbia University) and will be performed per standard protocol in these 
trained and certified laboratories. The costs of laboratory analysis are provided for in the study budget.  
  
5.5.2 Pulmonary Function Testing and Exercise Tests 
These are performed at each study visit. 
Comprehensive lung function testing is obtained at each visit in this study. Baseline spirometry is 
obtained by following ATS guidelines. Post bronchodilator spirometry is obtained with an aggressive 
protocol of 4 puffs of albuterol and 4 puffs of ipratroprium to allow an optimal assessment. Lung 
volumes are obtained by plethysmography and diffusion capacity by the single breath method.  
A 6MWT is performed at each of the 3 study visits. The 6MWT is performed without supplemental 
oxygen by methodology of the ATS Standards. Desaturation less than 80% has been associated with 
some adverse events and will be used to stop the test and measure the distance should that event occur. 
Oxygen saturation is determined throughout the entire test. A 10 point Borg dyspnea scale is obtained at 
rest and at the end of the 6MWT. 
 
5.5.3 Questionnaires 
Multiple questionnaires will be collected at each study visit as delineated in 4.6 above and seen in 
attachments to this study.  
 
St. George's Respiratory Questionnaire (SGRQ) 
This biomarker for COPD quantifies a patient reported outcome. 
 
Modified Medical Research Council (MRC) Dyspnea Scale 
Dyspnea is an important biomarker of disease severity and risk of death. 
 
Functional Assessment Inventory 
The FAI is widely used to judge an individual’s productive activity in 7 domains.  
 
EQ-5D Health Questionnaire 


 
 
 
15 of 27 
Quality of Life scale that includes a visual analog scale to assess general wellbeing and may pick up 
non-respiratory toxicity of medications being studied. 
 
5.5.3 Interim phone calls 
A study coordinator will call each participant by phone at 1 week +/- 3 days and  2 weeks +/- 3 days 
after the baseline visit and again 2 weeks +/- 3 days after the 1 month visit. Phone calls will serve as an 
opportunity to touch base, inquire about any side effects or adverse events, encourage adherence and 
confirm the next visit. Completion and results of the phone call will be documented in REDCap.  
 
5.6 Unblinding considerations 
An unblinded study team (prescribing health care provider +/- coordinator) will be used to monitor 
sirolimus levels at 1 week and 1 month after baseline.  Levels that increase by > 50% will lead to 
sirolimus dose reductions that will unblind the study participants.  Such unblinding events will be 
reported to the research study monitor and be part of DSMB reporting.   
 
6. ETHICAL CONSIDERATIONS 
This study will be initiated only after a thorough review by the MUSC IRB, the Columbia 
University IRB, and the Human Research Protection Office (HRPO) of the US Army Military 
Department. A written informed consent will be obtained from every participant in which known side 
effects of imatinib are described. Participants may participate in this study and request that their 
biosamples be anonymized and/or not stored after the study analysis is complete. 
 
An important consideration for this study is that sirolimus is not currently FDA approved for LAM. 
However, it is estimated that 90% of individuals with LAM and low lung function are using this drug 
and efforts are underway by Dr. Frank McCormack, principal investigator of the MILES trial and 
medical director of the LAM Foundation to obtain FDA approval via his IND for sirolimus. 
This study is submitted because no study in LAM will advance in this rare disease population unless 
individuals on sirolimus are allowed to be enrolled since the disease is so rare. A study approved by the 
CDMRP in 2010 (the TRAIL trial) failed to achieve adequate enrollment because of this issue. 
Importantly, individuals enrolled in this study are on unchanging doses of sirolimus. 
 
Subjects will be instructed at the beginning of the study to report to the investigator any adverse physical 
or mental changes they experience and they will be asked about adverse events at each visit, including 
those experienced at the baseline visit prior to, during, or immediately following treatment. All such 
adverse events reported by the subjects or observed by the investigators will be captured in the study 
forms. If the event is deemed to be Serious, the serious adverse events procedures will be followed and 
the IRB, DSMB, HRPO and Novartis notified. 
 
An independent Data Safety Monitoring Board (DSMB) composed of 3 individuals (2 pulmonary 
specialists and one regulatory/statistical clinical trial specialist) will be established to provide 
independent benefit/risk oversight during the conduct of the study. The DSMB will: 1) Review the 
protocol and consent form prior to study initiation, 2) Evaluate Serious Adverse Events on an “as 
needed” basis and all adverse events on a quarterly basis, 3) Recommend discontinuation of the study in 
the event of the occurrence of Serious or Unexpected Adverse Events that are determined by the DSMB 
to pose a significant safety concern. The Chairperson of the DSMB will notify the HRPO and Dr. 
Strange who will in turn notify the FDA or other regulatory bodies of adverse safety outcome 
information sufficient to stop the study. This information will also be reported as part of required 
regulatory progress update reports Katherine Taylor, MS, will serve as independent research monitor in 
accordance with Department of Defense requirements. The research monitor will provide study 
oversight and will have the authority to take any action necessary, including stopping the research or 


 
 
 
16 of 27 
removing a subject, to protect the safety and well-being of human subjects until the IRB has a chance to 
assess the monitor’s report.   
 
Suchit Kumbhare is a trained study coordinator who will be in charge of creating and maintaining the 
randomization list at MUSC. M. Gwen Blanton is a trained study coordinator who will count and 
package study medication and placebo for both study sites, so that 10 sets of imatinib and 10 sets of 
placebo are prepared. Haitham Al Ashry, MD will oversee the counting, packaging and sorting as a 
double check mechanism. Dr. Al Ashry will ensure appropriate sorting of correct quantities of imatinb 
and placebo into two distinct groups. After this double check is complete, Gwen Blanton will label the 
two distinct and counted groups (imatinib and placebo) as A and B and Dr. Al Ashry will ensure that the 
labels have been accurately applied to the two distinct groups. Labels compliant with pharmaceutical 
standard of care will be applied. Five sets of A and 5 sets of B will be sent by FedEx to Columbia 
University for their 10 participants. At MUSC Suchit Kumbhare will randomize the participant without 
knowledge of whether A and B are drug or placebo. According to the randomization assignment, the 
blinded assessors, PI Charlie Strange, MD or Tatsiana Beiko, MD will dispense A or B to the 
participant. The label will contain space for the authorized blinded dispensing physician to write in the 
participant’s name just prior to dispensing to the participant. 
Columbia University will name a trained study team member to perform their randomization. Blinded 
assessor and co-investigator who will dispense medication at that site is Jeanine D’Armiento, MD. The 
Columbia IRB will review and approve their plan and designation. 
 
Participation of children is not allowed in this study because LAM does not cause clinical disease in 
this population. 
 
Participation of women and minorities is encouraged, particularly since this disease only affects 
women. Sirolimus is pregnancy category C and imatinib is pregnancy category D. Pregnancy or intent to 
become pregnant or nurse during the 2 month study window and for 1 month afterwards is not allowed 
because of the safety risk of a category D medication. An adequate birth control method during these 3 
months will be documented in all women of childbearing potential. 
 
6.1 Human Subjects’ Protections and Risks 
Risks of study participation and medications are described in detail in the informed consent, as are 
protections and the participant’s right to not participate or withdraw at any time.  
 
6.1.2 Pulmonary Function Tests  
PFTs are a common medical procedure of generally low risk. Some participants may experience 
breathlessness, cough, fatigue, dizziness/lightheadedness (hyperventilation), all of which are brief and 
very rarely headache, syncope, musculoskeletal chest pain, rib fractures, or ear injury. An episode of 
stress incontinence (urine leakage) may be caused by the PFT maneuvers in susceptible individuals. A 
seated position has been specified to reduce risk related to dizziness or syncope. Transmission of 
airborne disease is rare and minimized or eliminated with single-use filters. Instructions for withholding 
bronchodilator medications prior to testing stress the continued use of rescue medication if needed. The 
use of albuterol or ipratropium generally relieves any symptoms related to the trough effect of long-
acting bronchodilators. 
• Albuterol has been reported to cause urticaria, angioedema, paradoxical bronchospasm, 
angina, arrhythmias, QT prolongation, hypertension, hypokalemia, seizures, tremor, 
nervousness, headache, tachycardia, muscle cramps, palpitations, insomnia, and dizziness. 
 


 
 
 
17 of 27 
• Ipratropium has been reported to cause cough, nausea, dry mouth, dizziness, headache, 
dyspnea, atrial fibrillation, tachycardia, paradoxical bronchospasm, laryngospasm, 
angioedema, anaphylaxis, hypersensitivity, and exacerbate narrow-angle closure glaucoma. 
 
• The dose used in testing is twice the usual dose of albuterol (one dose every four hours) or 
ipratropium (one dose every six hours) used chronically. However, home management of 
exacerbations includes increasing the dose and/or frequency of bronchodilator therapy. Doses 
in patients hospitalized or visiting the Emergency Department for exacerbations may be ten 
times the usual dose. Repeat dosing after at least three hours, is unlikely to result in any 
additional side effects, if necessary for the scheduling of the computed tomography. 
 
The six-minute walk test is self-paced, but participants are encouraged to cover as much distance as they 
can in six-minutes. As with any walk, the participant may stumble or fall. It is expected that more severe 
participants will become short of breath and may need to stop to recover before six minutes have 
elapsed. The walk test will be stopped if the participant’s SaO2 falls below 80%. 
6.1.3 Imatinib side effects 
The most common side effects of imatinib include nausea, diarrhea, headaches, leg cramps, fluid 
retention, visual disturbances, rash, weight gain, and reduced number of blood cells (any cell line can be 
affected). Imatinib is an immune suppressant and increases risks of common and uncommon infections. 
 
Severe systolic congestive heart failure is an uncommon but recognized side effect of imatinib and mice 
treated with large doses of imatinib show toxic damage to myocardiocytes.  Hypoxemia has been noted 
in one individual with LAM..  
 
Since imatinib is mainly metabolised via the liver enzyme CYP3A4, substances such as ketoconazole, 
itraconazole, clarithromycin, and grapefruit juice can increase the plasma concentration of the drug. 
Conversely, CYP3A4 inducers like rifampin and St. John's Wort reduce the drug's activity. These 
medications will be prohibited during the study. A known interaction between imatinib and sirolimus in 
which sirolimus levels rise will be monitored during the study.  
 
Imatinib also acts as an inhibitor of CYP3A4, 2C9 and 2D6, increasing the plasma concentrations of 
simvastatin, cyclosporin, pimozide, warfarin, and metoprolol. Imatinib also reduces plasma levels of 
levothyroxin via an unknown mechanism. INR, Cholesterol, T4, and TSH will be measured during the 
study for all individuals. 
 
An imatinib dose reduction to 200 mg daily will be permitted should a participant experience persistent 
side effects.  
 
6.1.4 Sirolimus side effects 
The most common side effects of sirolimus are immune suppression, thrombocytopenia and impaired 
wound healing. For these reasons, individuals planning surgery (including oral surgery) during the study 
interval are excluded. 
 
Lung toxicity is a serious complication associated with sirolimus therapy although it usually occurs 
shortly after beginning therapy. The mechanism of the interstitial pneumonitis is not clear. The toxicity 
does not appear to be dose dependent, but is more common in patients with underlying lung 
disease13. 
 


 
 
 
18 of 27 
Sirolimus also acts on a related complex known as mTORC2. Disruption of mTORC2 produces the 
diabetes-like symptoms of decreased glucose tolerance and insensitivity to insulin also associated with 
sirolimus. As with all immunosuppressive medications, in theory sirolimus and imatinib may decrease 
the body's inherent anticancer activity. However, both of these medications have data that sirolimus can 
enhance the immune response to tumor targeting and promote tumor regression in clinical trials14,15. 
 
6.1.5 Vaccinations 
Because both of these agents are immunosuppressants, live vaccinations are contraindicated because the 
microorganisms in the vaccine could multiply and infect the patient. Vaccines that are inactivated and 
toxoid vaccines do not hold this risk, but may not be effective during imatinib or sirolimus therapy. 
 
6.2 Confidentiality 
There is a risk to confidentiality. Source data at each center will be kept electronically under password 
protected systems. Questionnaires or paper documents will be kept in secure areas. Data transmission 
will be encrypted with a 128-bit VPN approach. The PFT software is designed to be HIPAA compliant 
for clinical use. Collection of DNA and RNA can lead to identification of patients. 
 
All study personnel are certified in the ethical conduct of human biomedical and genetics research and 
HIPAA information security.  
 
Longer descriptions of human subjects protections are provided in the consent form template. 
 
6.3 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a study subject. This may include 
symptom(s), illness, clinically significant abnormal laboratory value or change in value, or worsening in 
a subject during a clinical study. Since one of the specific aims of the study is to establish the safety of 
imatinib in LAM affected individuals, it is the goal of the investigators to capture every AE. 
 
6.3.1 Procedures for Adverse Events 
Event, date of onset, severity, duration, and relationship to sirolimus or imatinb (if it can be determined) 
will be recorded on the study AE forms. All adverse events will be followed until they are adequately 
resolved or stabilized, or for 1 month following study completion, whichever comes first. 
 
If an adverse event occurs during a study visit the study coordinator should first insure the participant 
receives any needed medical attention. If the study coordinator is notified by phone, the coordinator 
should confirm that the participant has received medical attention. The study coordinator should then 
notify the site Principal Investigator and complete the Adverse Event Form within seven days of 
learning of the event. Study coordinators will comply with local regulations and policies when notifying 
the institutional IRB.   
 
The following general definitions for rating severity should be used for this study: 
Mild: Awareness of signs or symptoms, but easily tolerated and transient; causing no loss of time from 
normal activities; symptoms would not require medication or a medical treatment; signs and symptoms 
are transient. 
Moderate: Marked symptoms and discomfort severe enough to cause moderate interference with the 
subject’s usual activities. Symptomatic treatment is possible. 
Severe: Incapacitating with inability to do work or usual activities; signs and symptoms may be of 
systemic nature or require medical intervention and/or treatment. Hospitalization may be required or 
prolonged. 


 
 
 
19 of 27 
The relationship of an AE or SAE to the underlying disease or to the procedure will be attributed using 
the following definitions: 
Not Related: There is no evidence that the event has a relationship to the drug(s). 
Possibly Related: The event has a timely relationship to the drug(s) used. However, a potential 
alternative etiology may be responsible for the adverse event. 
Probably Related: The event has a timely relationship to the drug(s) used and the causative relationship 
can clearly be established. No potential alternative etiology is apparent. 
The number of subjects and observation time in this pilot study is insufficient to develop a composite 
index or statistical plan for the evaluation of safety endpoints for this study. Therefore, all adverse 
events, their timing, severity, and attribution will be reported in study reports. 
 
6.3.2 Serious Adverse Events 
The FDA (2009) defines a serious adverse event as an adverse event that: results in the participant’s 
death, is life-threatening, results in hospitalization (initial or prolonged), results in significant, persistent, 
or permanent change, impairment, damage, disruption, or disability in the participant's body 
function/structure, physical activities or quality of life, results in a congenital anomaly, or requires 
intervention to prevent permanent impairment or damage. 
 
6.3.3 Procedures for Serious Adverse Events 
There are no expected serious adverse events (SAE) in this study. In accordance with 21 CFR Parts 
803 and 812, an SAE is defined as any untoward medical occurrence that: results in death, is 
lifethreatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or requires 
intervention to prevent permanent impairment or damage. All SAE will be reported to Dr. Strange and 
the Data Safety Monitoring Board Chair in 24 hours after knowledge of the occurrence. 
 
If a serious adverse event (SAE) occurs during a study visit the study coordinator should first insure the 
participant receives any needed medical attention. If the study coordinator is notified by phone, the 
coordinator should confirm that the participant has received medical attention. The study coordinator 
should then notify the site Principal Investigator and complete the adverse event form.  All SAE will be 
reported to Dr. Strange and the Data Safety Monitoring Board in 24 hours after knowledge of the 
occurrence. Study coordinators should comply with local regulations and policies when notifying the 
institutional IRB. The DSMB will review all SAEs and the Chairperson of the DSMB will notify the 
HRPO and principal investigator of adverse safety outcome information sufficient to stop the study.  
 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, and 
Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E).  All events reported to 
the FDA by the investigator are to be filed utilizing the Form FDA 3500A (MedWatch Form), if 
applicable  
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has 
provided informed consent and until at least 30 days after the patient has stopped study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. Information about all SAEs is 
collected and recorded on a Serious Adverse Event Report Form. The investigator must assess and 
record the relationship of each SAE to each specific study treatment (if there is more than one study 
treatment), complete the SAE Report Form in English, and send the completed, signed form along with 
the Novartis provided fax cover sheet to the Novartis Oncology Drug Safety and Epidemiology (DS&E) 
department by fax (fax: 877-778-9739) within 24 hours. 


 
 
 
20 of 27 
Any additional information for the SAE including complications, progression of the initial SAE, and 
recurrent episodes must be reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information. An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one should be reported separately as 
a new event.  
Any SAEs experienced after a 30 day safety evaluation follow-up period should only be reported to 
Novartis if the investigator suspects a causal relationship to the study treatment.  
Follow-up information is submitted in the same way as the original SAE Report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has resolved 
or continues, if and how it was treated, whether the blind was broken or not, and whether the patient 
continued or withdrew from study participation.  
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis Drug 
Safety and Epidemiology (DS&E) department associate may urgently require further information from 
the investigator for Health Authority reporting. Novartis may need to issue an Investigator Notification 
(IN), to inform all investigators involved in any study with the same drug that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as 
per national regulatory requirements in participating countries. 
6.3.4 Pregnancy Procedures and Reporting  
 
Any participant who becomes pregnant during the study will discontinue study medication and 
procedures for pregnancy follow-up and reporting will be followed: 
 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.  
Pregnancy should be reported by the investigator to the Novartis Oncology Drug Safety and 
Epidemiology Department (DS&E) by fax (fax: 877-778-9739). Pregnancy follow-up should include an 
assessment of the possible relationship of the pregnancy outcome to the study treatment. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Because males will not be enrolled in this study, there is no risk of pregnancy in partners of male 
participants.  
6.4 Measures to Protect the Participant 
All participants will have laboratory monitoring of CBC, T4, TSH, Cholesterol, INR, Sirolimus level 
and complete metabolic panel (CMP) at baseline, 28 days, and 56 days. Side effects may receive 
imatinib dose reduction to 200 mg daily if persistent. Study withdrawal for side effects is permitted. 
All side effects will be graded and followed. Side effects suggestive of an infection will prompt 
cessation of subsequent doses of rapamycin and imatinib mesylate/placebo for 1 week until such 
symptoms are improved. Any worsening of symptoms would prompt evaluation. Decline in FEV1 or 
FVC of 10% would prompt end of study, study unblinding, and transition to usual clinical care. A study 


 
 
 
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coordinator will call each participant to check on how they are doing 1 week +/- 3 days and  2 weeks +/- 
3 days after the baseline visit and  2 weeks +/- 3 days after the 1 month study visits.  
 
Study related injuries are addressed in the MUSC Statements of the informed consent form. In the event 
of a study related injury, the participant should go immediately to the emergency room of the Medical 
University Hospital, or in case of an emergency go to the nearest hospital, and tell the physician on call 
that they are in a research study. The doctor should call the study doctor to make arrangements for 
treatment. If the study sponsor does not pay for treatment, the Medical University Hospital and the 
physicians who render treatment will bill the participant’s insurance. If the insurance company denies 
coverage or insurance is not available, the participant will be responsible for payment of all services 
rendered.  
 
6.4.1 Withdrawal 
A participant may withdraw from the study at any time for any reason. Study withdrawal for side effects 
is permitted. At the time of withdrawal the participant may 1) decline to provide any more data or 
specimens to the study but allow use of previously collected data and/or specimens, 2) request 
withdrawal of all his/her data from study databases and request that any stored samples be destroyed, or 
3) withdraw some portion of the data collected (i.e., participants may withdraw specimens but not exam 
or questionnaire data or vice versa).  
If a participant chooses to withdraw from the study, the research coordinator at the clinical site conducts 
an exit interview to determine the disposition of the participant’s study data. The coordinator also 
provides the participant with any clinically relevant study results or establishes how the participant 
would like to be contacted if relevant results become available in the future. If the participant declines an 
exit interview, the consent form in place at the time of study withdrawal is used to determine the status 
of the participant’s data.  
Participants may be removed from the study if the clinical center PI determines that it is unsafe or 
unethical for the participant to continue in the study. Situations that might result in this kind of 
withdrawal include physical impairment such that the participant cannot complete the study protocol, 
institutionalization (e.g., long-term care facility, prison), or aggressive or antagonistic behavior towards 
clinical center staff. Any deterioration in symptoms or a 10% decline in either postbronchodilator FEV1 
or FVC would end the study and participants can resume previous therapy. 
 
7. STATISTICAL ANALYSIS 
7.1 Sample Size 
Since this is a pilot study, the estimate of sample size to determine a biologic signal in patients with 
LAM is extrapolated from other studies in which serial samples of VEGF-D has been measured. Since 
LAM is a rare disease a small trial is designed to assure enrollment is achievable. This study will enable 
proper powering of subsequent studies. The authors believe that a proof of principal pilot study will be 
able to recruit 20 participants, the majority on rapamycin, for this study. A larger study is not possible 
given the limitations of funding.  
 
7.2 Statistics 
Statistical analysis of the primary endpoint will compare the VEGF-D before and one month after 
imatinib montherapy by intrasubject testing. VEGF-D has been shown to be logarithmically expressed 
and log transformation of the data is planned. It is unlikely that data will be normal between the imatinib 
and placebo groups. Therefore, the intrasubject difference (log pg/ml) in VEGF-D between imatinib and 
placebo groups will be subjected to non-parametric analysis with Wilcoxen rank sum tests. All statistical 
tests will be 2-sided at a 0.05 level of significance. 


 
 
 
22 of 27 
 
Statistical analysis of secondary endpoints will be performed in identical manner using the % change in 
FEV1 and FVC for these analyses. Use of ml change disproportionately shows effects in this 
bronchodilator responsive disease for those with preserved lung function. All secondary endpoints will 
be reported in study manuscripts with adjustment for multiplicity testing. Data will be presented in 
spaghetti plots to allow an assessment for responder analysis. 
 
Exploratory analyses are designed to not miss a biologic signal if present. The impact of any significant 
difference between groups will require additional study and will be presented as question generating and 
will not use adjustments for multiplicity testing. 
 
7.3 Endpoints 
7.3.1 The primary efficacy analysis will be the log transformed change in intrasubject plasma VEGF-D 
before and 1 month after initiation of monotherapy imatinib mesylate. Log transformation was needed in 
the MILES study because this serum concentration can often go quite high in some patients. VEGF-D 
will be obtained at baseline and at 28 and 56 days after initiation of imatinib. Note that this analysis will 
allow the use of sirolimus using and sirolimus naïve participants.  
 
7.3.2 Secondary endpoints are obtained to test both efficacy and inform about quality of life. Quality of 
life questionnaire instruments are described in a later attachment as guided by the CDMRP program. 
Importantly, respiratory specific and general quality of life scores will be used in the study. Recently, 
the St Georges Respiratory Questionnaire (SGRQ) was retrospectively validated against four anchors in 
the MILES study12 and will be used as a secondary efficacy endpoint in the combined analysis of both 
stratified randomization populations. To minimize multiplicative analysis, 3 endpoints are chosen for 
combined population secondary endpoints: Intrasubject Change in FEV1 (ml), Intrasubject Change in 
FVC (ml), and Intrasubject Change in SGRQ (points) between the timepoints of Baseline and 1 month 
after initiation of monotherapy imatinib/placebo. The last secondary endpoint compares a 2 month 
treatment with imatinib/placebo in sirolimus naive participants on intrasubject change in log VEGF-D 
(pg/ml). 
 
7.3.3 Exploratory endpoints 
The table below lists the exploratory endpoints that will be collected to define if there is a difference 
between the 4 populations in the study. All change variables are measured intrasubject. 
 
Efficacy Endpoints 
Difference in baseline 
and 1 month after 
initiation of 
monotherapy 
imatinib/placebo 
Difference in 
baseline and 1 
month in patients on 
sirolimus 
Difference in 
baseline and 2 
months in imatinb 
naive participants 
Change in VEGF-D 
(log pg/ml) 
X (Primary) 
X (Exploratory) 
X (Secondary) 
Change in FVC (%) 
X (Secondary) 
X (Exploratory) 
X (Exploratory) 
Change in FEV1 (%) 
X (Secondary) 
X (Exploratory) 
X (Exploratory) 
Change in mMRC 
Dyspnea (score) 
X (Exploratory) 
X (Exploratory) 
X (Exploratory) 
Change in 6MWT 
distance (M) 
X (Exploratory) 
X (Exploratory) 
X (Exploratory) 
EQ-5D (score) 
X (Exploratory) 
X (Exploratory) 
X (Exploratory) 
Functional Assessment 
X (Exploratory) 
X (Exploratory) 
X (Exploratory) 


 
 
 
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Inventory (score) 
SGRQ (score) 
X (Secondary) 
X (Exploratory) 
X (Exploratory) 
 
7.4 Study Limitations 
Study limitations include that the exact mechanism by which imatinib kills LAM cells remains 
unknown. The Bcr-Abl pathway has many downstream pathways including the Ras/MapK pathway, 
which leads to increased proliferation due to increased growth factor-independent cell growth. It also 
affects the Src/Pax/Fak/Rac pathway that affects the cytoskeleton leading to increased cell motility and 
decreased adhesion. The PI/PI3K/AKT/BCL-2 pathway is also affected altering mitochondrial stability. 
The JAK/STAT pathway, responsible for cellular proliferation is also affected by imatinib. While 
further laboratory studies on LAM/AML cells with alternative agents and mechanisms will continue, the 
current safety profile for imatinib use in humans is sufficient to begin a clinical trial in LAM prior to 
definitive mechanism of its effect on LAM cells is known. 
 
The study is small and of short duration. The time interval for LAM cells in vivo to grow once removed 
from the influence of sirolimus is unknown. The study design in this rare disease is based on experience 
from LAM patients that remains anecdotal. However, in balancing safety and the potential to see a 
signal of efficacy in a pilot study, the current design is advanced. 
 
8. DATA HANDLING 
8.1 Web Data Entry 
Clinical data and research questionnaires will be captured through REDCap, an encrypted, password 
protected database developed for the purpose of clinical research. REDCap has been embraced by the 
CTSA program of the NIH. Data entry is performed via REDCap by trained study coordinators at each 
clinical site. An electronic copy of the REDCap submission is available at the end of the entry session 
and serves as the source document kept at the clinical site. Lung function data are entered by the clinical 
coordinators, but source documents are saved electronically according to Good Clinical Practice. 
 
8.2 Data Sharing 
All data collected in this study will be published in a peer reviewed medical journal to support access of 
imatinib mesylate to patients if it is effective in LAM. This study also allows for the collection of 
plasma, blood mononuclear cell RNA and DNA and urine from patients on sirolimus and on imatinib 
mesylate that will allow a large community of researchers to study these biosamples for differences in 
biologic activity of these two medications. When distributing these unique resources, the PI would 
include pertinent information on the nature, quality, or characterization of the materials. In addition, the 
PI will submit unique biological information, if samples are measured, to the appropriate data banks so 
that they can be made available to the broad scientific community. 
 
At the end of the study the PI will share data with any interested party via a data-sharing agreement to 
impose a minimum of limitations on users. First publication rights and acknowledgement of original 
investigators in future secondary publications would be necessary for data access. Privacy and 
confidentiality standards will ensure data security at the recipient site, and prohibitions for manipulating 
data for the purposes of identifying subjects will be put in place. 
 
8.2.1 Biobank  
Biosamples will remain at MUSC, Columbia University, or the University of Cincinnati during the study 
until study parameters are complete. With informed consent, samples that are left after study completion 
will be kept in biorepositories at the respective institutions and will be available for sharing with 
qualified researchers. The informed consent form explains that samples may be transferred to qualified 


 
 
 
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researchers with coded participant information, but without use of protected health information (PHI).  
Biosamples will not be sent to researchers with attached PHI.   
 
Biosamples will be available at the end of study for the larger number of LAM researchers to access the 
biosamples through a data and biosample sharing agreement with MUSC and/or Columbia University. 
Although the number of biosamples will be small, the ability to study active disease pathways between 
two medications used in humans is an attractive resource that would be advertised to the researcher 
community through the LAM Foundation and CDMRP resource listings. Shipping and laboratory costs 
would be paid by the requesting parties. 
 
The biosamples will be collected under an informed consent that asks optional permission to re-contact 
the participant in order to link biosamples with future clinical events and introduce future LAM-related 
research opportunities. With effort ongoing to develop a LAM Registry through the University of 
Cincinnati, future research opportunities include the possibility of sample transfer if a larger biobank 
specific to LAM develops. If the LAM Foundation establishes such a biorepository, participants in this 
study who have given permission for biobanking of sample(s) and for recontact would be contacted 
prior to transfer of any biosample and consented with the new LAM biorepository consent form from the 
new site. 
 
9. STUDY MONITORING 
9.1 Data Fidelity and Quality Control 
The clinical and biospecimen output data linked to a study ID will be archived and stored in the secure 
study database for a period of no less than 5 years after conclusion of the study. Data is password 
protected and secured by physical and firewall protected means. 
9.2 Biospecimen Quality Control 
Samples for study analysis related to clinical safety and efficacy are obtained, transported and processed 
through protocols of clinical laboratories at each institution. Samples for storage and biobank use, as 
expressly indicated in the participant’s informed consent, are kept in dedicated repositories with all 
sample use logged. Quality control to define stability of all freezer temperatures and sample integrity is 
performed regularly. 
9.3 Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) composed of 3 individuals (2 pulmonary 
specialists and one regulatory/statistical clinical trial specialist) will be established to provide 
independent benefit/risk oversight during the conduct of the study. The DSMB will: 1) Review the 
protocol and consent form prior to study initiation, 2) Evaluate Serious Adverse Events on an “as 
needed” basis and all adverse events on a quarterly basis, 3) Recommend discontinuation of the study in 
the event of the occurrence of Serious or Unexpected Adverse Events that are determined by the DSMB 
to pose a significant safety concern. The Chairperson of the DSMB will notify the HRPO and Dr. 
Strange who will in turn notify the FDA or other regulatory bodies of adverse safety outcome 
information sufficient to stop the study. This information will also be reported as part of required 
regulatory progress update reports. 
 
9.4 Research Monitor 
A qualified research monitor, Katherine Taylor, is appointed in accordance with the Department of 
Defense (DoD) requirements. The research monitor will observe recruitment and enrollment procedures, 
the informed consent process and may oversee study visits and interactions. The research monitor will 
review monitoring plans and any unanticipated problem involving risks to subjects or others (UPIRTSO) 
reports. The research monitor will oversee data collection and analysis. The research monitor may 


 
 
 
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discuss the research protocol with the investigators, interview human subjects and consult with others 
outside of the study about the research. The research monitor will have the authority to stop the research 
in progress, remove individual human subjects from the research protocol, and take whatever steps are 
necessary to protect the safety and well-being of human subjects until the IRB can assess the monitor’s 
report. The research monitor is responsible for promptly reporting their observations and findings to the 
IRB and HRPO.     
 
10. STUDY ADMINISTRATION 
The Principal Investigator, Charlie Strange, MD, oversees study design and implementation. Dr. Strange 
additionally oversees study administration and study personnel, including co-investigator, study 
coordinator (TBD) and other trained research personnel who will be involved in coordination and 
execution of this study. Under the auspices of Dr. Strange and institutional regulatory bodies trained 
study staff will coordinate meetings, conference calls, and web-conferences as needed; determine and 
delegate needs for administrative support (e.g. scheduling, minutes) for committees and subcommittees; 
ensure fidelity of all data management activities, including form design, regular reports, reimbursing, 
including contracts, identifying milestones for payment, and generating invoices and payments, 
maintaining directories and distribution lists, preparing reports, creating recruitment materials and 
assisting with recruitment, creating and updating the Manual of Operations, training and certification of 
study personnel, organizing in-person meetings, and coordinating and overseeing the publication 
process. Consultant funds (see attached budget) will be used for the formation of a Data Safety 
Monitoring Board, a research monitor and statistical analysis.  
 


 
 
 
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