Clinical trial NCT03417687
Conditions: Pulmonary Surgical Procedures
Sponsor: Polarean, Inc.
Start date: 2018-08-17; Completion date: 2020-03-10
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study compares the equivalence of hyperpolarized 129Xe MRI as compared to 133Xe scintigraphy for the evaluation of pulmonary function in patients being evaluated for lung resection.

Detailed description:
This is a multicenter, randomized, open-label, cross-over Phase 3 study evaluating hyperpolarized 129Xe gas MRI as compared to 133Xe scintigraphy for the evaluation of pulmonary function. This study will enroll subjects being evaluated for possible lung resection surgery (i.e. segmentectomy, lobectomy, or pneumonectomy). Subjects will have both a 129Xe MRI and 133Xe scintigraphy image. The vast differences in technique for obtaining hyperpolarized 129Xe MRI as compared to 133Xe scintigraphy make it impossible to blind study procedures. However, all image interpretation will be performed by personnel blinded to the subject's medical history and all study assessments.

Arms: arm 1: Subjects will undergo hyperpolarized 129Xe MRI first, followed by 133Xe scintigraphy arm 2: Subjects will undergo 133Xe scintigraphy first, followed by hyperpolarized 129Xe MRI
Interventions: intervention 1: 129Xe MRI intervention 2: 133 Xe scintigraphy
Intervention descriptions: intervention 1: Evaluation of pulmonary function intervention 2: Evaluation of pulmonary function

Protocol documents:
Prot_000.pdf: 
Hyperpolarized Xenon (129Xe) gas in the BRANDNAME device 
 
Clinical Study Protocol:  POL-Xe-001 Amendment 3 
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Clinical Trial Protocol:  POL-Xe-001 
 
Study Title: 
Evaluation of Hyperpolarized 129Xe MRI as Compared to 133Xe 
Scintigraphy for the Assessment of Pulmonary Function in Patients 
being Evaluated for Possible Lung Resection Surgery 
Study Number: 
POL-Xe-001 
Study Phase: 
3 
Product Name: 
Hyperpolarized 129Xenon (129Xe) Gas in BRANDNAME Device 
IND Number: 
075,010 
Indication: 
Diagnostic for the evaluation of pulmonary function and for imaging 
the lungs. 
Investigators: 
Multiple Centers 
 
 
Sponsor: 
Polarean, Inc.  
P.O. Box 14805 
Research Triangle Park, NC  27709-4805 
Sponsor Contact: 
Kenneth P. West 
kwest@polarean.com 
919-206-7900 ext. 102 
 
 
 
Date 
Original 
20 October 2017 
Amendment 1 
07 November 2017 
Amendment 2 
29 January 2018 
Amendment 3 
26 April 2018 
 
 
 
Confidentiality Statement 
The information contained in this protocol is confidential and is intended for the use of 
Investigators and Polarean, Inc. or its designees.  It is the property of Polarean, Inc. and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
Hyperpolarized 129Xe Gas in BRANDNAME Device unless such persons are bound by a 
confidentiality agreement with Polarean, Inc.   


Hyperpolarized Xenon (129Xe) gas in the BRANDNAME device
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SPONSOR SIGNATURES
Study Title:
Evaluation of Hyperpolarized 129Xe MRI as Compared to 133Xe 
Scintigraphy for the Assessment of Pulmonary Function in Patients being 
Evaluated for Possible Lung Resection Surgery
Study Number:
POL-Xe-001
Version:
Amendment 3
Version Date:
26 April 2018
This clinical study protocol was subject to critical review and has been approved by the Sponsor.  
The following personnel contributed to writing and/or approving this protocol:
Signature _____________________________________
Date:  
Kenneth P. West
Chief Operating Officer
Polarean, Inc.
Signature _____________________________________
Date:  
Bastiaan Driehuys, Ph.D.
Chief Technology Officer
Polarean, Inc.
26 APR 2018
26 April 2018
Bastiaan 
Driehuys
Digitally signed by Bastiaan 
Driehuys 
DN: cn=Bastiaan Driehuys, 
o=Polarean, Inc., ou, 
email=bdriehuys@polarean.com, 
c=US 
Date: 2018.04.26 10:24:04 -05'00'


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INVESTIGATOR’S SIGNATURE 
 
Study Title: 
Evaluation of Hyperpolarized 129Xe MRI as Compared to 133Xe 
Scintigraphy for the Assessment of Pulmonary Function in Patients 
being Evaluated for Possible Lung Resection Surgery 
Study Number: 
POL-Xe-001 
Version: 
Amendment 3  
Version Date: 
26 April 2018 
 
I have read the POL-Xe-001 protocol and agree to conduct the study as outlined.   
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol.   
I agree to conduct the study in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, are consistent with the Good Clinical Practices guidelines of the 
International Conference on Harmonization, and according to applicable regulatory 
requirements.  
 
 
 
 
Principal Investigator: 
                           
 
(Print Name/Title) 
 
 
Signature of Principal Investigator:  
 
 
 
 
 
Date: 
 
 
Affiliation/Company:  
 
 
 
 
 
 


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SYNOPSIS 
Study Title:  Evaluation of Hyperpolarized 129Xe MRI as Compared to 133Xe Scintigraphy for the Assessment of 
Pulmonary Function in Patients being Evaluated for Possible Lung Resection Surgery 
Name of Finished Product:   
Hyperpolarized Xenon (129Xe) Gas in BRANDNAME 
Device 
Name of Active Ingredient: 
129Xe Gas 
Study Number:  POL-Xe-001 
Study Phase:  3 
Clinical Sites:  At least 2 study sites in the United States 
Primary Objective:  
The primary objective of this study is to demonstrate the equivalence of hyperpolarized 129Xe MRI as compared 
to 133Xe scintigraphy for the evaluation of pulmonary function. 
Secondary Objectives: 
The secondary objectives of this study are to: 
• 
Assess the safety and tolerability of hyperpolarized 129Xe gas; 
• 
Evaluate regional ventilation defects in each of the 6 zones, and 
• 
Demonstrate the equivalence of post-operative forced expiratory volume in 1 second (FEV1) values 
predicted using hyperpolarized 129Xe as compared to 133Xe scintigraphy.   
Study Design: 
This is a multicenter, randomized, open-label, cross-over Phase 3 study evaluating hyperpolarized 129Xe MRI as 
compared to 133Xe scintigraphy for the evaluation of pulmonary function.  This study is comprised of 4 periods:   
• 
Screening:  Subjects will be screened for study participation based on inclusion and exclusion criteria.  
Informed consent will be obtained.  
• 
Imaging:  Subjects will undergo hyperpolarized 129Xe MRI and 133Xe scintigraphy.  During the MRI 
session, one or more conventional proton MRI scans will also be collected to confirm lung anatomical 
features.  Both 133Xe scintigraphy and hyperpolarized 129Xe MRI will be quantified using commercially 
available software.  Images will be interpreted by central readers who are blinded to the subject’s 
medical history and all study assessments.  Information related to any AEs will be collected during this 
period. 
• 
Follow-up:  Subjects will be contacted by phone on the day after (+3 days) the completion of all imaging 
to collect information on any AEs. 
• 
Post-op Follow-up:  If the subject has lung surgery, approximately 3 months after surgery the subject 
will come in for a post-operative FEV1 measurement (spirometry). 
All randomized subjects will be divided between 2 treatment orders in a 1:1 ratio.     
Study Population:  
Inclusion Criteria:   
Subjects will be eligible for participation in the study only if they meet ALL of the following criteria:   
1. Male or female subjects ≥18 years of age. 
2. Subject is being evaluated for possible lung resection (e.g., segmentectomy, lobectomy, or 
pneumonectomy).   
3. Able to undergo MRI imaging and able to fit in the MRI coil. 
4. Willing and able to comply with all study procedures.   
5. Must understand and voluntarily sign an informed consent form (ICF) prior to any study-specific 
assessments or procedures.   
Exclusion Criteria:   
Subjects will not be eligible for participation in the study if they meet ANY of the following criteria:   
1. Baseline blood oxygen saturation (SpO2) <90% at rest.  For patients requiring routine supplemental 
oxygen, SpO2 measurements should be taken with the patient’s normal oxygen supplementation.   


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2. Female subjects of childbearing potential with a positive serum pregnancy test at screening, or who are 
not taking (or not willing to take) acceptable birth control measures through the Follow-up Period.  
Adequate birth control methods include with a monogamous partner who was sterilized more than 6 
months prior to screening, or measures with a Pearl index of <1 used consistently and correctly 
(including intrauterine devices, or implantable, injectable, oral, or transdermal contraceptives). 
Women are not considered to be of childbearing potential if they meet at least 1 of the following 2 
criteria as documented by the Investigator: 
• 
They have had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy at a 
minimum of 1 menstrual cycle prior to signing the ICF; or 
• 
They are post-menopausal: for women ≥55 years of age, defined as ≥1 year since their last 
menstrual period, or for women <55 years of age, defined as ≥1 year since their last menstrual 
period and have a follicle-stimulating hormone (FSH) level in the laboratory’s normal range for 
post-menopausal phase. 
3. Women who are lactating and insist on breast feeding.    
4. Subjects who have received any other investigational therapy within 4 weeks prior to Screening.  
5. Subjects who require anesthesia or heavy sedation to undergo MRI testing.  Mild sedation could be 
acceptable (i.e. a low dose oral acting anxiolytic medication such as alprazolam) as long as, in the 
opinion of the investigator, the subject meets Inclusion Criteria #4 and #5. 
Planned Number of Subjects:   
Completed:  32 subjects having both a 129Xe MRI and 133Xe scintigraphy image.   
Subjects who discontinue will be replaced in order to achieve the targeted number of completers. 
Test Product, Dose, and Mode of Administration:  
The test product is hyperpolarized 129Xe gas and will consist of a volume of hyperpolarized 129Xe inflated with 
ultra-high purity nitrogen gas to a final volume of 1 L.  Subjects will be required to inhale the 1 L of gas mixture 
and hold their breath for a maximum of 15 seconds (generally 10-15 seconds, based on the length of the scan) 
while the MRI is acquired.  
During the MRI session, one or more conventional proton MRI scans will be collected to confirm lung 
anatomical features.  Subjects will be required to take a full inhalation breath of room air and hold their breath for 
a maximum of 15 seconds while the MRI is acquired.    
Up to 750 mL hyperpolarized 129Xe gas will be administered to the subject while in the MRI scanner.  If the 
resulting scan is determined or thought to be inadequate, then a calibration dose (approximately 100 mL 
hyperpolarized 129Xe gas) will be administered followed by another full (≤750 mL) dose.  The calibration dose is 
administered to allow for adjustments of MRI parameters, as needed, to ensure best image quality. 
Reference Product, Dose, and Mode of Administration:  
The reference standard is the anterior and posterior wash-in views of a 133Xe scintigraphy scan.  133Xe is 
administered by inhalation from a closed respirator system or spirometer in accordance with the Package Insert.   
Subjects will be exposed to 133Xe gas for 3-4 minutes, as tolerated.  
Duration of Treatment:  
Depending on the number of doses required to obtain adequate images, subjects will be exposed to 
hyperpolarized 129Xe for 15-45 seconds. 
Subjects will be exposed to 129Xe gas for approximately 15 seconds per scan. 
Duration of Subject Study Participation: 
Subjects are expected to participate in this study for a maximum of 15 days unless the subject undergoes resection 
surgery.  For the sub-set of subjects undergoing surgery, the maximum duration for study participation is 
4 months.   


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Efficacy Assessments: 
Primary Efficacy Endpoints:   
The primary endpoint is the scan predicted post-operative FEV1.  The scans will be quantified using 
commercially available software to report the fraction of activity arising from 6 zones.  This will be used to 
predict post-operative FEV1 by multiplying the percentage of function remaining in the non-operated zones by 
pre-operative FEV1. 
Secondary Efficacy Endpoints: 
The secondary efficacy endpoints include the post-operative FEV1 value (spirometry) and the percentage 
function contributed by each of the individual 6 lung zones.   
Safety Endpoints: 
Safety and tolerability will be assessed based on the incidence and severity of treatment emergent adverse events 
(AEs) and serious adverse events (SAEs).  Additionally, subjects will be monitored before, during, and after each 
dose to monitor for changes in vital signs. 
Statistical Methods:  
Sample Size Determination:   
The sample size required to demonstrate equivalence is driven by 2 factors: 1) the intra-subject variability of the 
difference between the predicted post-operative FEV1 from the 2 methods, and 2) the pre-specified equivalence 
margin.  From prior literature, the intra-subject variability for 133Xe scintigraphy leads to an estimated variability 
in predicted post-operative FEV1 of 0.21 L/sec.  Similarly, prior studies have suggested that the equivalence 
margin between the 2 imaging techniques currently used for resection planning is 0.3 L/sec.  Using these 
assumptions, and based on the use of a two-sided test at the alpha=0.05 level of significance, a sample size of 15 
subjects is required for 90% power.  However, given limited literature on 133Xe variability, we account for the 
possibility that it could be higher.  If true variability is 0.32 L/sec, then a sample size of 32 subjects will provide 
90% power to establish equivalence.   
Primary Analysis:   
The primary analysis for this study will be to test the mean difference in predicted post-operative FEV1 
(measured in L/sec) values as measured using hyperpolarized 129Xe gas MRI relative to 133Xe scintigraphy 
(reference standard).  The primary analysis will be conducted by estimating the 95% confidence interval (CI) for 
the mean difference in predicted FEV1 from the 2 methods.  The scans will be quantified using commercially 
available software to report the fraction of activity arising from 6 zones.  This will be used to predict post-
operative FEV1 by multiplying the percentage of function remaining in the non-operated zones by pre-operative 
FEV1.  The CI will be constructed assuming that the within-subject difference between methods is normally 
distributed.  If the 95% CI for the mean difference is contained within the interval (-0.30, +0.30 L/sec), 
equivalence will have been demonstrated. 
Secondary Analysis: 
The post-operative secondary analysis for this study will be to test the mean difference in predicted post-operative 
FEV1 (measured in L/sec) values as measured using hyperpolarized 129Xe gas MRI and 133Xe scintigraphy 
(reference standard) relative to the final post-operative FEV1 value (spirometry).  The secondary equivalence 
analysis will be conducted using the same methodology and same equivalence margin as specified for the primary 
analysis. 
The 6-zone secondary analysis for this study will be to evaluate the individual percentage function assessments 
from each of the 6 zone analyses from both the 129Xe and the 133Xe ventilation images. The equivalence margin 
will be 5 percentage points.  Thus, for each of the six zones, equivalence will have been demonstrated if the 95% 
CI for the mean difference is contained within the interval (-5%, +5%). 
Safety Analysis: 
All AEs will be summarized by system organ class (SOC), preferred term, severity and relationship to study drug.  
Aes leading to death or to discontinuation from study drug as well as the SAEs will also be tabulated.  In the by-
subject summary, a subject having the same event more than once will be counted only once and by greatest 
severity. 


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Vital sign measurements, including change from baseline, will be summarized. 
All safety analyses will be performed on the Safety population.   
Interim Analyses: 
No formal interim analyses are planned for this study.   


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TABLE OF CONTENTS 
SPONSOR SIGNATURES ........................................................................................................2 
INVESTIGATOR’S SIGNATURE ...........................................................................................3 
SYNOPSIS .................................................................................................................................4 
TABLE OF CONTENTS ...........................................................................................................8 
LIST OF TABLES ...................................................................................................................10 
LIST OF FIGURES .................................................................................................................10 
LIST OF APPENDICES ..........................................................................................................11 
LIST OF ABBREVIATIONS AND TERMS DEFINITIONS ................................................11 
1. 
INTRODUCTION ...........................................................................................................13 
1.1. 
Hyperpolarized 129Xe in BRANDNAME Device ..................................................13 
1.2. 
Mechanism of Action .............................................................................................13 
1.3. 
Pharmacokinetics ...................................................................................................14 
1.4. 
Nonclinical Evaluations .........................................................................................14 
1.5. 
Clinical Experience ................................................................................................15 
1.6. 
Rationale for Study ................................................................................................15 
2. 
STUDY OBJECTIVES ....................................................................................................15 
2.1. 
Primary Objective ..................................................................................................15 
2.2. 
Secondary Objectives.............................................................................................15 
3. 
INVESTIGATIONAL PLAN ..........................................................................................16 
3.1. 
Overall Study Design and Plan ..............................................................................16 
3.2. 
Rationale for Study Design and Control ................................................................17 
3.3. 
Study Duration and Dates ......................................................................................18 
4. 
STUDY POPULATION SELECTION ...........................................................................18 
4.1. 
Study Population ....................................................................................................18 
4.2. 
Inclusion Criteria ...................................................................................................18 
4.3. 
Exclusion Criteria ..................................................................................................18 
5. 
STUDY TREATMENTS .................................................................................................19 
5.1. 
Description of Treatments......................................................................................19 
5.1.1. 
Study Drug ...................................................................................................19 
5.1.2. 
Active Comparator .......................................................................................19 
5.2. 
Treatments Administered .......................................................................................19 
5.2.1. 
Study Drug ...................................................................................................19 
5.2.2. 
Active Comparator .......................................................................................20 
5.3. 
Selection and Timing of Dose for Each Patient .....................................................20 
5.3.1. 
Timing for Performing Scans.......................................................................20 
5.3.2. 
Hyperpolarized 129Xe Dose Selection ..........................................................20 


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5.3.3. 
133Xe Dose Selection ....................................................................................21 
5.4. 
Method of Assigning Subjects to Treatment Groups .............................................21 
5.5. 
Blinding..................................................................................................................21 
5.6. 
Concomitant Therapy.............................................................................................21 
5.7. 
Restrictions ............................................................................................................21 
5.8. 
Treatment Compliance ...........................................................................................22 
5.9. 
Packaging and Labeling .........................................................................................22 
5.10. Storage and Accountability ....................................................................................22 
5.11. Investigational Product Retention at Study Site ....................................................22 
6. 
STUDY PROCEDURES .................................................................................................22 
6.1. 
Informed Consent...................................................................................................23 
6.2. 
Demographics, Medical History, and Concomitant Medications ..........................23 
6.3. 
Vital Signs ..............................................................................................................23 
6.3.1. 
Heart Rate ....................................................................................................23 
6.3.2. 
Blood Oxygen Saturation .............................................................................23 
6.4. 
Baseline Physical Exam .........................................................................................24 
6.5. 
Clinical Laboratory Tests .......................................................................................24 
6.6. 
MRI-suitable Screening .........................................................................................24 
6.7. 
Spirometry Evaluation of FEV1 ............................................................................24 
6.8. 
Image Interpretation ...............................................................................................24 
6.9. 
Dispensing Study Drug ..........................................................................................25 
6.9.1. 
Study Drug – Hyperpolarized 129Xe Gas Administration ............................25 
6.9.2. 
Anatomical Proton MRI (MRI Session Only) .............................................26 
6.9.3. 
Active Comparator – 133Xe Administration .................................................26 
6.10. Adverse Events Assessments .................................................................................26 
6.10.1. 
Adverse Events ............................................................................................26 
6.10.1.1. 
Adverse Events of Special Interest ....................................................27 
6.10.1.2. 
Serious Adverse Events .....................................................................28 
6.10.1.3. 
Unexpected Adverse Event ................................................................28 
6.10.1.4. 
Unexpected Adverse Drug Reaction ..................................................28 
6.10.2. 
Adverse Event Reporting Period .................................................................29 
6.10.3. 
Recording Adverse Events ...........................................................................29 
6.10.4. 
Assessing Adverse Event Severity...............................................................30 
6.10.5. 
Assessing Adverse Event Relationship to Study Drug ................................30 
6.10.6. 
Reporting Adverse Events ...........................................................................31 
6.10.7. 
Reporting Serious or Unexpected Adverse Events ......................................31 
6.10.8. 
Follow-Up of Adverse Events .....................................................................32 
6.11. Removal of Subjects from the Study or Study Drug .............................................32 


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6.12. Discontinuation of Study Sites...............................................................................32 
6.13. Discontinuation of the Study .................................................................................32 
6.14. Appropriateness of Measurements .........................................................................32 
7. 
QUALITY CONTROL AND ASSURANCE .................................................................32 
8. 
PLANNED STATISTICAL METHODS ........................................................................33 
8.1. 
Determination of Sample Size ...............................................................................33 
8.2. 
Analysis Populations ..............................................................................................34 
8.3. 
Demographics and Baseline Characteristics ..........................................................34 
8.4. 
Study Endpoints .....................................................................................................34 
8.4.1. 
Primary Efficacy Endpoint ..........................................................................34 
8.4.2. 
Secondary Efficacy Endpoints .....................................................................34 
8.4.3. 
Secondary Safety Endpoints ........................................................................34 
8.5. 
Study Disposition ...................................................................................................35 
8.6. 
Primary Efficacy Analysis .....................................................................................35 
8.7. 
Secondary Efficacy Analysis .................................................................................35 
8.8. 
Safety Analysis ......................................................................................................35 
8.9. 
Interim Analysis .....................................................................................................36 
9. 
ADMINISTRATIVE CONSIDERATIONS ....................................................................36 
9.1. 
Institutional Review Board Approval ....................................................................36 
9.2. 
Ethical Conduct of the Study .................................................................................36 
9.3. 
Patient Information and Consent ...........................................................................37 
9.4. 
Patient Confidentiality ...........................................................................................37 
9.5. 
Study Monitoring ...................................................................................................38 
9.6. 
Case Report Forms and Study Records .................................................................38 
9.7. 
Data Disclosure ......................................................................................................39 
9.8. 
Retention of Data ...................................................................................................39 
9.9. 
Financial Disclosure...............................................................................................40 
9.10. Publication and Disclosure Policy .........................................................................40 
10. REFERENCE LIST .........................................................................................................41 
 
LIST OF TABLES 
Table 1 
Reporting Requirements for Adverse Events ..............................................31 
 
LIST OF FIGURES 
Figure 1 
Illustration of Study Design for Protocol POL-Xe-001 ...............................16 
Figure 2 
Depiction of the Hyperpolarization Process and Device Components ........25 


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LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................44 
Appendix 2 
Summary of Changes from Previous Version....................................46 
 
LIST OF ABBREVIATIONS AND TERMS DEFINITIONS 
Abbreviation 
Definition 
129Xe 
non-radioactive isotope of xenon (hyperpolarized 129Xe is the drug 
product)  
ADR 
adverse drug reaction 
AE 
adverse event 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
COPD 
chronic obstructive pulmonary disease 
CRO 
Contract Research Organization 
eCRF 
electronic case report form 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
He 
helium 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization  
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
ITT 
intent-to-treat 


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Lobectomy 
Refers to the removal of a lobe (or lobes). 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
N2 
nitrogen 
Pneumonectomy 
Refers to the removal of an entire lung.   
Q 
perfusion scan  
RBC 
red blood cells 
Resection  
For this study, the definition of resection surgery includes 
segmentectomies, lobectomies, and pneumonectomies.   
SAE 
serious adverse event 
Segmentectomy 
Refers to the removal of an area of the lung that is smaller than a lobe 
SNR 
signal-to-noise ratio 
SOC 
system organ class 
SpO2 
blood oxygen saturation 
99mTc 
Metastable nuclear isomer of technetium-99 isotope 
TEAE 
treatment-emergent adverse event 
US 
United States 
V 
ventilation scan 
WHO 
World Health Organization 
Xe 
xenon 
 


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1. INTRODUCTION 
Polarean, Inc. (Polarean, the Sponsor) has developed a drug/device combination to administer 
hyperpolarized 129Xe as a diagnostic agent used in conjunction with magnetic resonance imaging 
(MRI) for the evaluation of pulmonary function and for imaging the lungs.  The proposed patient 
population includes patients requiring imaging evaluation of pulmonary function prior to a 
variety of lung surgeries.  Today, these pre-operative evaluations employ nuclear scintigraphy 
methods using 133Xe ventilation and/or Technetium (99mTc) perfusion (the so called 
ventilation/perfusion [V/Q] scan).  The primary objective for this study is to demonstrate the 
equivalence of hyperpolarized 129Xe MRI as compared to 133Xe scintigraphy.   
The population referred for such scans includes patients undergoing evaluation for possible lung 
resection surgery and transplants.  In both circumstances, regional pulmonary function 
information is used for making surgical decisions.  For this study, the population will include 
patients being evaluated for possible lung resection surgery.  The definition of lung resection 
surgery includes segmentectomies, lobectomies, and pneumonectomies.  Segmentectomies refer 
to the removal of an area of the lung that is smaller than a lobe.  A lobectomy is the removal of a 
lobe (or lobes), whereas a pneumonectomy is the removal of an entire lung (BMC website).   
1.1. 
Hyperpolarized 129Xe in BRANDNAME Device  
This device is comprised of 3 different components.  Together, these components hyperpolarize, 
measure the hyperpolarization of 129Xe gas, and permit administration to the patient.  Inhalation 
of the hyperpolarized inert gas allows for clear imaging of its distribution within the lungs when 
using any multi-nuclear capable MRI scanner.  The 3 components are the Hyperpolarizer, the 
Polarization Measurement Station, and the Gas Delivery Bag (refer to Figure 2).   
The drug product is hyperpolarized 129Xe.  It is created by passing a gas mixture of xenon (Xe), 
helium (He), and nitrogen (N2) through the Hyperpolarizer.  Once the Xe is hyperpolarized, it is 
collected in a Gas Delivery Bag and filled to volume (1 L) with with inert N2 buffer gas.  Within 
5 minutes prior to administration to the subject, the degree of hyperpolarization is measured with 
the Polarization Measurement Station (refer to Section 6.9.1).  The standard volume (dose) of 
hyperpolarized 129Xe is ≤750 mL administered (via inhalation) to the subject while in the MRI 
(refer to Section 5.2.1). 
1.2. 
Mechanism of Action 
Mechanistically, hyperpolarized 129Xe is metabolized in order to achieve its primary purpose.  
After imaging, the hyperpolarized 129Xe is exhaled from the body during normal respiration.   


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1.3. 
Pharmacokinetics 
Hyperpolarized 129Xe is chemically and biologically identical to non-polarized Xe, which is a 
“perfusion-limited” gas and therefore not subject to membrane diffusion (Roughton and Forster, 
1957).  It can therefore be assumed that the Xe concentration in the venous capillary blood 
equilibrates instantaneously with the Xe concentration in the alveoli according to its Ostwald 
solubility.  Data have demonstrated that Xe concentration is diminished by more than 
1000× prior to achieving 40 breaths.  Normal humans breathe at a rate of 12-20 breaths per 
minute (Guyton and Hall, 2006), therefore the 40-breath mark would be reached at 2-3 minutes.  
Because blood and airspaces remain in close equilibrium, it is anticipated that the Xe 
concentration in blood will follow an identical decay curve; however, it will start at a lower 
concentration.  As only one breath of Xe is used for MRI imaging (rather than breathing to 
equilibrium), it is anticipated that Xe exhalation in patients with lung disease will be similar to 
that of healthy volunteers. 
Detailed information on the pharmacokinetics of Xe and 129Xe is provided in the Investigator’s 
Brochure (IB).     
1.4. 
Nonclinical Evaluations 
A single-dose toxicity study was completed in Beagle dogs under IND 075,010 by GE 
Healthcare (Report No. FY01-015).  Results from clinical observations, ophthalmologic 
examinations, body weights, food consumption, clinical pathology, and pulmonary function all 
indicated that no biologically significant adverse effects of exposure were observed.  The beagle 
dogs were observed during exposure as well as for 14 days after exposure to depolarized 129Xe.   
Expanded, single-dose toxicity studies in rats and dogs have been conducted with Xe gas 
enriched with 129Xe to 50% v/v.  No signs of toxicity, beyond the known physiological effects of 
Xe gas as an asphyxiant and anesthetic, were observed in these studies.   
Literature supports that 129Xe gas does not affect the hepatic and renal systems (Reinelt et al., 
2002), is non-reactive, and is excreted quickly via the lung.  Toxicity data from repeat-dose 
reproductive and developmental (Lane et al., 1980; Burov et al., 2002a; Burov et al., 2002b), and 
immunotoxicological (Burov et al., 2002c; Horn et al., 2001; de Rossi et al., 2001; de Rossi et 
al., 2002; de Rossi et al., 2004) studies show no evidence that inhalation of Xe gas causes any 
specific toxic effects.   
Detailed information on the nonclinical evaluation of Xe and 129Xe is provided in the IB.   


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1.5. 
Clinical Experience 
To date, the clinical development program for hyperpolarized 129Xe gas in the BRANDNAME 
device is comprised of 1 Phase 1 study (GE-141-001) and data reported in the literature.  The 
Phase 1, single-site, open-label, non-randomized study was conducted by GE Healthcare and is 
reported in the literature by Cleveland et al., 2010; Driehuys et al., 2012; Kaushik et al., 2011; 
He et al., 2014a; and Virgincar et al., 2013.  Additional literature support comes form Kirby et 
al., 2013; He et al., 2014b; Svenningsen et al., 2013; He et al., 2015; and Stewart et al., 2015.   
Across these studies, a total of 55 healthy volunteers, 20 patients with chronic obstructive 
pulmonary disease (COPD, 10 of which had radiographic evidence of emphysema), 27 patients 
with asthma, and 1 current smoker (healthy) have been administered 1 or more hyperpolarized 
129Xe scan (total exposed to 1 or more doses = 103).  No treatment-emergent adverse events 
(TEAEs) or laboratory changes were reported. 
Detailed information on the clinical evaluation of Xe and 129Xe is provided in the IB.   
1.6. 
Rationale for Study 
The investigational product is a non-radioactive, 3-dimensional MRI procedure that will allow 
physicians to clearly and accurately visualize the spatial distribution of a subject’s regional 
pulmonary function.  This study was designed to evaluate the ability of hyperpolarized 129Xe to 
provide clear images as compared to 133Xe scintigraphy for the evaluation of pulmonary 
function.   
2. STUDY OBJECTIVES 
2.1. 
Primary Objective  
The primary objective of this study is to demonstrate the equivalence of hyperpolarized 129Xe 
MRI as compared to 133Xe scintigraphy for the evaluation of pulmonary function. 
2.2. 
Secondary Objectives  
The secondary objectives of this study are to: 
• Assess the safety and tolerability of hyperpolarized 129Xe gas; 
• Evaluate regional ventilation defects in each of the 6 zones, and 
• Demonstrate the equivalence of post-operative forced expiratory volume in 1 second 
(FEV1) values predicted using hyperpolarized 129Xe as compared to 133Xe scintigraphy. 


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3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a multicenter, randomized, open-label, cross-over Phase 3 study evaluating 
hyperpolarized 129Xe gas MRI as compared to 133Xe scintigraphy for the evaluation of 
pulmonary function.  This study will enroll male and female subjects being evaluated for 
possible lung resection surgery (i.e. segmentectomy, lobectomy, or pneumonectomy).   
The planned enrollment is 32 subjects who have completed the study.  Completed subjects will 
have both a 129Xe MRI and 133Xe scintigraphy image.  Subjects who discontinue will be replaced 
in order to achieve the targeted number of completers. 
Unless required for safety reasons, all image review will be performed by central readers who are 
blinded to the subject’s medical history and all study assessments.  As is shown in Figure 1, this 
study is composed of 4 periods.  All randomized subjects will be divided between 2 treatment 
orders in a 1:1 ratio. 
Figure 1 Illustration of Study Design for Protocol POL-Xe-001 
 
The 4 study periods are defined as: 
• Screening:  Subjects will be screened for study participation based on inclusion and 
exclusion criteria.  Informed consent will be obtained and the investigator’s assessment 
of potential locations of lung resection will be recorded on the electronic case report form 
(eCRF).  
• Imaging:  Subjects will undergo hyperpolarized 129Xe MRI and 133Xe scintigraphy.  Both 
133Xe scintigraphy and hyperpolarized 129Xe MRI will be quantified using commercially 
Screening
Imaging
Imaging Follow-up
Hyperpolarized 129Xe
133Xe
Day -7 to
Day 0*
3 Months After Surgery
Post-Op Follow-up
Day 1*
* Screening and Imaging can occur on the same or different days.  However, there should be ≤48 hours 
between administration of the study drug and reference standard scans.  
** Can occur up to +3 days after completion of imaging but prior to resection surgery.  
Day 2**


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available software.  Images will be interpreted by central readers who are blinded to the 
subject’s medical history and all study assessments.  Information related to any AEs will 
be collected during this period. 
• Imaging Follow-up:  Subjects will be contacted by phone on the day after (+3 days) the 
completion of all imaging to collect information on any adverse events (AEs). 
• Post-op Follow-up:  If the subject has lung surgery, approximately 3 months after surgery 
the subject will return for a post-operative FEV1 measurement (spirometry). 
Following completion of screening and baseline eligibility assessments, all subjects will receive 
both a hyperpolarized 129Xe MRI and 133Xe scintigraphy.  During the MRI session, one or more 
proton MRI scans will also be collected to confirm lung anatomical features.  Subjects will 
receive standard of care at the discretion of the investigator, including appropriate therapies, 
unless otherwise specified in this protocol.  If a subject undergoes resection surgery, an 
additional study visit to record post-operative FEV1 levels (spirometry) will be required 
approximately 3 months after surgery.   
Safety will be monitored after the administration of both hyperpolarized 129Xe and 133Xe (Day 1) 
and again on Day 2 during the Imaging Follow-up period. 
The Schedule of Assessments is provided in Appendix 1.  The study endpoints are provided in 
Section 8.4. 
3.2. 
Rationale for Study Design and Control  
Study Design:  This is a multicenter, randomized, open-label, Phase 3 study designed to 
demonstrate that hyperpolarized 129Xe gas MRI is equivalent to 133Xe scintigraphy for the 
evaluation of pulmonary function.  The vast differences in technique for obtaining 
hyperpolarized 129Xe MRI as compared to 133Xe scintigraphy make it impossible to blind study 
procedures.  However, all image interpretation will be performed by personnel blinded to the 
subject’s medical history and all study assessments (Section 5.5).   
Dose:  Dose justification is provided in Section 5.3.2 for hyperpolarized 129Xe and in 
Section 5.3.3 for 133Xe.   
Population Choice: The proposed study population includes subjects requiring imaging 
evaluation of pulmonary function prior to lung resection surgery.  Subjects being considered for 
surgery normally undergo a full pulmonary evaluation to provide regional lung function 
information used for surgical decisions.  
Control:  Regional lung function information is used for making decisions regarding the need 
for, and predicted success of, resection surgery.  Current practice for pre-operative evaluation 
employs nuclear scintigraphy methods using 133Xe ventilation and/or Technetium (99mTc) 


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perfusion (the V/Q scan). This permits the patient’s post-operative FEV1 to be estimated based 
on the amount of function that will be removed by resection surgery.  For the purposes of this 
study, 133Xe will be used as the comparator to evaluate the performance of hyperpolarized 129Xe 
in patients being considered for lung resection surgery.      
3.3. 
Study Duration and Dates 
Subjects are expected to participate in this study for a maximum of 15 days unless the subject 
undergoes resection surgery.  For the subset of subjects undergoing surgery, the maximum study 
participation is expected to be 4 months.   
4. STUDY POPULATION SELECTION 
4.1. 
Study Population 
This study will include subjects who are being evaluated for possible lung resection surgery.  For 
the purposes of this study, lung resection surgery will include segmentectomies, lobectomies, 
and pneumonectomies.  Specific inclusion and exclusion criteria are provided below.   
At least 32 subjects will be enrolled in the study.  Subjects will be recruited primarily via cardio-
thoracic surgeons for enrollment at 2 clinical sites in the US.   
4.2. 
Inclusion Criteria 
Subjects will be eligible for participation in the study only if they meet ALL of the following 
criteria:   
1. Male or female subjects ≥18 years of age. 
2. Subject is being evaluated for possible lung resection (e.g., segmentectomy, lobectomy, 
or pneumonectomy).   
3. Subject is able to undergo MRI imaging and able to fit in the MRI coil. 
4. Subject is willing and able to comply with all study procedures.   
5. Subject must understand and voluntarily sign an informed consent form (ICF) prior to 
any study-specific assessments or procedures. 
4.3. 
Exclusion Criteria 
Subjects will not be eligible for participation in the study if they meet ANY of the following 
criteria:   
1. Baseline blood oxygen saturation (SpO2) <90% at rest (refer to Section 6.3.2).  For 
patients requiring routine supplemental oxygen, SpO2 measurements should be taken 
with the patient’s normal oxygen supplementation. 


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2. Female subjects of childbearing potential with a positive serum pregnancy test at 
screening, or who are not taking (or not willing to take) acceptable birth control measures 
through the Follow-up Period.  Adequate birth control methods include with a 
monogamous partner who was sterilized more than 6 months prior to screening, or 
measures with a Pearl index of <1 used consistently and correctly (including intrauterine 
devices, or implantable, injectable, oral, or transdermal contraceptives).  Women are not 
considered to be of childbearing potential if they meet at least 1 of the following 2 criteria 
as documented by the Investigator: 
• They have had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy 
at a minimum of 1 menstrual cycle prior to signing the ICF; or 
• They are post-menopausal: for women ≥55 years of age, defined as ≥1 year since 
their last menstrual period, or for women <55 years of age, defined as ≥1 year 
since their last menstrual period and have a follicle-stimulating hormone (FSH) 
level in the laboratory’s normal range for post-menopausal phase. 
3. Women who are lactating and insist on breast feeding.    
4. Subjects who have received any other investigational therapy within 4 weeks prior to 
Screening.  
5. Subjects who require anesthesia or heavy sedation to undergo MRI testing.  Mild sedation 
could be acceptable (i.e. a low dose oral acting anxiolytic medication such as alprazolam) 
as long as, in the opinion of the investigator, the subject meets Inclusion Criteria #4 and 
#5. 
5. STUDY TREATMENTS 
5.1. 
Description of Treatments 
5.1.1. 
Study Drug 
The study drug is hyperpolarized 129Xe gas generated from gas cylinders containing Xe/He/N2 
(Section 6.9.1).   
5.1.2. 
Active Comparator 
The active comparator (reference standard) is 133Xe gas.    
5.2. 
Treatments Administered 
5.2.1. 
Study Drug 
Up to 750 mL hyperpolarized 129Xe gas will be inflated with ultra-high purity nitrogen (N2) gas 
to a final volume of 1 L.  To ensure that each dose has sufficient polarization (>10%), the 
polarization level will be measured at the Polarization Measurement Station within 5 minutes 
prior to administration.   


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The hyperpolarized 129Xe gas (in N2) will be administered to the subject while in the MRI 
scanner.  Subjects will be required to inhale the 1 L of gas mixture and hold their breath for a 
maximum of 15 seconds (generally 10-15 seconds, based on the length of the scan) while the 
MRI is administered.  
If the resulting scan is determined, or thought to be, inadequate, then a calibration dose 
(approximately 100 mL hyperpolarized 129Xe gas) will be administered followed by another full 
(≤750 mL) dose.  The calibration dose will be administered to allow for adjustments of MRI 
parameters, as needed, to ensure best image quality.  If calibration is required, subjects will be 
exposed to hyperpolarized 129Xe for a maximum of 45 seconds.   
During the MRI session, one ore more conventional proton MRI scans will be collected to 
confirm lung anatomical features.  Subjects will be required to take a full inhalation breath of 
room air and hold their breath for a maximum of 15 seconds while the MRI is acquired.    
Detailed information for preparation and administration of hyperpolarized 129Xe gas is provided 
in the IMP Handling and Labeling Instruction Manual for this study.   
5.2.2. 
Active Comparator 
The active comparator, 133Xe, will be administered by inhalation from a closed respirator system 
or spirometer in accordance with the Package Insert.  Subjects will be exposed to 133Xe gas for 
3-4 minutes as tolerated. 
Detailed information for preparation and administration of 133Xe is provided in the IMP 
Handling and Labeling Instruction Manual for this study as well as the 133Xe Package Insert.   
5.3. 
Selection and Timing of Dose for Each Patient 
5.3.1. 
Timing for Performing Scans 
Imaging should be performed within the established 48 hour window (refer to the Schedule of 
Events in Appendix 1).   
5.3.2. 
Hyperpolarized 129Xe Dose Selection 
Since this is a diagnostic drug-device combination, dosing is performed only at the time of 
imaging.  To ensure that each dose has sufficient polarization (>10%) for imaging, the 
polarization will be measured within 5 minutes prior to administration.   
The dose range for hyperpolarized 129Xe for this study was calculated based on a typical fast 
gradient echo image acquisition signal-to-noise ratio (SNR) and voxel volumes from studies 
conducted to date.  The calculated hyperpolarized 129Xe dose equivalent is 75 mL in order to 
provide scans with adequate SNR.  This dose equivalent represents the product of Xe volume, 


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isotopic enrichment, and polarization.  Assuming polarization levels >10% and isotopically 
enriched 129Xe at ~85%, the calculated Xe volume for evaluation is ≤750 mL.   
Information regarding safety and nonclinical evaluations of hyperpolarized 129Xe is provided in 
the IB.   
5.3.3. 
133Xe Dose Selection 
133Xe will be dosed according to the Package Insert.  Please refer to the IMP Handling and 
Labeling Instuction Manual for additional details.   
5.4. 
Method of Assigning Subjects to Treatment Groups 
All randomized subjects will be divided between 2 treatment orders in a 1:1 ratio.  Subjects will 
be randomized to receive either 129Xe followed by 133Xe, or 133Xe followed by 129Xe.  All 
subjects will receive at least 1 dose of hyperpolarized 129Xe and 1 dose of 133Xe during study 
participation.    
5.5. 
Blinding 
This is an open-label study (refer to Section 3.2 for rationale).   
Images generated from this study will be interpreted by central readers blinded to the subject’s 
medical history and all study assessments.  The images will be uploaded in a blinded manner to a 
computer for review.  Both 133Xe scintigraphy and hyperpolarized 129Xe MRI will be quantified 
using commercially available software.   
5.6. 
Concomitant Therapy 
There are no restrictions with respect to concomitant therapies for this study.  All concomitant 
medications should be listed in the electronic case report form (eCRF) along with the date 
therapy was initiated, and if applicable, terminated.   
For patients taking inhalers, there are no restrictions with respect to timing of dose and imaging.  
However, the last dose administered prior to imaging should be recorded on the eCRF. 
For patients requiring supplemental oxygen, there are no restrictions with respect to timing of 
dose and imaging.  However, the oxygen flow rate should be recorded on the eCRF.   
5.7. 
Restrictions 
There are no restrictions for this protocol with respect to prior therapies, or food and fluid intake.   


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5.8. 
Treatment Compliance 
Site personnel will administer both hyperpolarized 129Xe and 133Xe while the subject is at the 
site.  All administration information will be recorded on the eCRF.  
5.9. 
Packaging and Labeling 
Polarean will provide each of the 3 components of the device (Hyperpolarizer, Polarization 
Measurement Station, and Gas Delivery Bag) to the site.  Gas cylinders containing the Xe/He/N2 
gas blend and the ultra-high purity N2 gas will be provided to the site from a commercial vendor.  
All cylinders will have normally required labeling upon site receipt.   
Labeling instructions for the hyperpolarized 129Xe in the Gas Delivery Bag are provided in the 
IMP Handling and Labeling Instruction Manual.   
5.10. Storage and Accountability 
The components of the device (Hyperpolarizer and Hyperpolarization Measurement Station) will 
be stored in an area located in a separate area (or room) close to the MRI suite.   
The Investigator (or delegate) will maintain accountability records for the receipt, dispensing, 
and return of all study products (including the gas cylinders used to make the study drug).  
Records will include (but not limited to):   
• The receipt of the gas cylinders to be used for study drug preparation;   
• Updated inventory of the gas cylinders, and 
• The return of empty or unused cylinders.  
5.11. Investigational Product Retention at Study Site 
During and at the end of the study, the number of gas cylinders will be reconciled against current 
inventory and dispensing records as part of routine monitoring visits.  After reconciliation, 
unused (full) gas cylinders will be returned to the Sponsor.    
Additionally, during and at the end of the study, the use of tedlar bags, tubing, and mouth pieces 
will be reconciled against current inventory and dispensing records as part of routine monitoring 
visits.  Items that have been used should be disposed of in a biohazard bag.  After reconciliation, 
all unused components will be returned to the Sponsor.    
6. STUDY PROCEDURES 
The Schedule of Assessments is provided in Appendix 1.  All assessments and treatments are to 
be performed either at a hospital or in a doctor’s office.   


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6.1. 
Informed Consent 
Written informed consent must be obtained from each subject or legal representative (if subject 
is unable to sign) after the nature of the study has been fully explained in accordance with 
International Conference on Harmonization (ICH) Good Clinical Practices (GCP).  Informed 
consent must be obtained prior to performing any study-specific procedures. 
6.2. 
Demographics, Medical History, and Concomitant Medications 
Demographic information (age, race, gender, weight, height, smoking history, etc.) will be 
collected during the Screening Period.  Medical history, including significant medical conditions, 
pulmonary function values, and surgical history, will also be collected during the Screening 
Period.  Additionally, any medications taken as well as baseline signs and symptoms occurring 
within 2 weeks of screening will be recorded.    
On the day(s) of the Imaging Period, any changes to the subject’s condition that affect 
inclusion/exclusion criteria will be documented, as well as any additional medications taken.  
Subject must meet all inclusion/exclusion criteria upon entering the Imaging Period. 
6.3. 
Vital Signs 
Vital signs will include blood pressure (BP, systolic and diastolic measurements), heart rate 
(HR), respiration rate, blood oxygen saturation (SpO2) and temperature.  Vital signs will be 
assessed during the Screening Period as well as before and after each scanning session (both 
129Xe and 133Xe) during the Imaging Period.  Subjects will have a 5-minute rest in a supine 
position before vital signs are assessed.   
The subject will be monitored for the duration of the MRI exam by qualified medical 
professionals.   
6.3.1. 
Heart Rate 
HR will be assessed during the Screening Period as well as before and after each scanning 
session (both 129Xe and 133Xe) during the Imaging Period.  Changes in HR of >20% are 
considered significant.  The next dose of any study treatment will not be administered until the 
HR is within 20% of the baseline value.  If the subject has received their last dose, they will be 
observed until the HR is within 20% of the baseline value.   
6.3.2. 
Blood Oxygen Saturation 
SpO2 will be assessed during the Screening Period as well as before (within 5 minutes) and after 
(within 1 minute) each scanning session (both 129Xe and 133Xe) during the Imaging Period.  An 
absolute decrease of SpO2 by >10% is considered significant.  The next dose of any study 
treatment will not be administered until the SpO2 is within 10% of the baseline value.  If the 


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subject has received their last dose, they will be observed until the SpO2 is within 10% of the 
baseline value.   
If the subject’s SpO2 value does not return to within 10% of the baseline value within a few 
minutes (2-5 minutes), supplemental oxygen should be provided until values are within range.  
Once the value is within range, the subject can proceed to the next dose.   
6.4. 
Baseline Physical Exam 
A standard physical exam will be performed during the Screening Period.  Baseline findings will 
be recorded on the eCRF. 
6.5. 
Clinical Laboratory Tests 
A negative serum pregnancy test must be confirmed at Screening for all females of childbearing 
potential.  A blood sample for serum pregnancy testing will be taken from all females of 
childbearing potential at Screening.  If the serum pregnancy test is positive, the patient must be 
discontinued from study treatment, unless subject is post-partum. 
6.6. 
MRI-suitable Screening 
As indicated in exclusion criteria #5 (Section 4.3), a subject who requires anesthesia or heavy 
sedation in order to undergo MRI testing cannot participate in this study.  However, mild 
sedation (i.e. a low dose oral acting anxiolytic medication such as alprazolam) could be 
acceptable if, in the investigator’s opinion, the subject is still able to comply with all study 
procedures.   
There are no additional protocol specific requirements or restrictions with respect to a subject 
being suitable for MRI testing.   
6.7. 
Spirometry Evaluation of FEV1  
Pulmonary function will be evaluated by measuring FEV1 using spirometry prior to imaging on 
Day 1 (Imaging Period).  For the sub-set of subjects undergoing surgery, FEV1 will also be 
measured during the Post-op Follow-up Period.     
6.8. 
Image Interpretation 
As indicated in Section 5.5, image interpretation will be performed by central readers.  Details 
for performing image evaluation are provided in the Imaging Manual.     




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dose has sufficient polarization, the polarization will be measured within 5 minutes prior to 
administration to ensure the value is >10%.   
Additional information for preparation and administration of hyperpolarized 129Xe gas are 
provided in Section 5.2.1 as well as the IMP Handling and Labeling Instuction Manual for this 
study.   
6.9.2. 
Anatomical Proton MRI (MRI Session Only) 
During the MRI session, one ore more conventional proton MRI scans will be collected to 
confirm lung anatomical features.  Subjects will be required to take a full inhalation breath of 
room air and hold their breath for a maximum of 15 seconds while the MRI is acquired.    
6.9.3. 
Active Comparator – 133Xe Administration 
The active comparator, 133Xe, will be administered in accordance with the Package Insert.  
Detailed information for preparation and administration of 133Xe gas are provided in the IMP 
Handling and Labeling Instruction Manual for this study.   
6.10. Adverse Events Assessments 
AEs will be reported using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA).   
The investigator (and any sub-investigators) is responsible for the appropriate medical care of 
subjects during the study.  The investigator remains responsible for following, through an 
appropriate health care option, serious adverse events (SAEs) or AEs that caused the subject to 
discontinue before completing the study.  The subject should be followed until the event is 
resolved or explained.  Frequency of follow-up evaluation is left to the discretion of the 
investigator. 
6.10.1. 
Adverse Events  
An AE is any untoward medical occurrence in a subject participating in a clinical 
investigation/study that has received treatment with a drug or biologic (medicinal) product.  The 
event does not necessarily have a causal relationship with the administration of the study drug.  
An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a study drug, whether or not considered related to the study drug.  This 
includes any side effect, injury, toxicity, or sensitivity reaction, and may include a single 
symptom or sign, a set of related symptoms or signs, or a disease.  An AE may also be any 
laboratory abnormality judged to be clinically significant by the Investigator (or sub-
investigator) that worsened when compared to baseline.   


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An abnormal laboratory value is not an AE unless it is considered to be clinically significant.  
AEs include the following: 
• All suspected adverse drug reactions. 
• All reactions from medication overdose, abuse, withdrawal, sensitivity, or toxicity. 
• Apparently unrelated illnesses, including the worsening of a pre-existing illness. 
• Injury or accidents.  Note that if a medical condition is known to have caused the injury 
or accident (e.g., a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) should be reported as 2 separate AEs.  
• Abnormalities in physiological testing or physical examination (findings that require 
clinical intervention or further investigation beyond ordering a repeat [confirmatory] 
test). 
• Laboratory abnormalities that are clinically significant and require clinical intervention or 
further investigation (beyond ordering a repeat [confirmatory] test) unless they are 
associated with an already reported clinical event.   
An AE does not include: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure is an AE. 
• Pre-existing diseases or conditions present or detected at screening/baseline that do not 
worsen in severity or frequency. 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions). 
• Overdose of either study drug or concomitant medication without any signs or symptoms. 
Throughout the course of the study, every effort should be made to remain alert to possible AEs.  
Subjects should be encouraged to report AEs spontaneously or in response to general, non-
directed questioning. 
With the occurrence of an AE, the primary concern is the safety of the subject.  If necessary, 
appropriate medical intervention should be provided, and the study drug discontinued.  Urgent 
safety issues may be discussed with physicians at the Contract Research Organization (CRO).  
6.10.1.1. 
Adverse Events of Special Interest  
Subjective sensation of residual anesthesia (e.g., lightheadedness, loss of sensation or awareness, 
loss of memory, or unconsciousness) is an AE of special interest for this study.  The next dose of 
any study treatment will not be administered until any sensation of residual analgesia has 
resolved.  If the subject has received their last dose, they will be observed until the sensation of 
residual analgesia has resolved.   


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6.10.1.2. 
Serious Adverse Events  
An SAE is defined by federal regulation as any AE occurring at any dose that results in any of 
the following outcomes:  
• Death. 
• A life-threatening AE (i.e., immediate risk of death)  
Note: The term “life-threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an event 
which, hypothetically, might have caused death if it were more severe. 
• Prolongation of existing hospitalization or re-hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, the 
AE may jeopardize the subject 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. 
6.10.1.3. 
Unexpected Adverse Event 
An unexpected AE is any AE that is not identified in nature, severity, or frequency in the current 
IB or product information.   
6.10.1.4. 
Unexpected Adverse Drug Reaction  
An adverse drug reaction (ADR) is an adverse reaction, the severity of which is not consistent 
with the applicable product information or IB.  All noxious and unintended responses to a 
medical product related to any dose should be considered an ADR.   
• The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility (meaning the relationship 
cannot be ruled out).   
• The expression “causal relationship” is meant to convey that, in general, there are facts, 
evidence, or arguments to suggest a reasonable causal relationship.  All serious and 
unexpected ADRs will have expedited reporting to regulatory agencies following ICH 
requirements.   


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6.10.2. 
Adverse Event Reporting Period 
The AE reporting period for this study begins upon receiving the first dose of study treatment 
during the Imaging Period and ends during the Imaging Follow-up Period.  If a subject 
experiences an AE after signing the informed consent, but prior to receiving study drug, the 
event will NOT be collected unless the investigator feels the event may have been caused by a 
protocol procedure.  Likewise, if a subject experiences an AE during the Post-Op Follow-up 
Period, the event will NOT be collected unless the investigator feels the event may have been 
caused by a protocol procedure.   
All AEs (both serious and non-serious) must be assessed through the Imaging Follow-up Period.  
All measures required for AE management and the ultimate outcome of the AE must be recorded 
in the eCRF and reported to the Sponsor.  All study-drug related AEs must be followed until 
resolution, the return to baseline, or until the event is deemed stable or irreversible.   
In addition, any known untoward event that occurs subsequent to the AE-reporting period that 
the investigator assesses as related to the study drug should also be reported as an AE and must 
be recorded in the eCRF.   
6.10.3. 
Recording Adverse Events 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g. hospital progress notes, laboratory, and diagnostic reports) relative to the event.  The 
Investigator will then record all relevant information regarding an AE/SAE in the eCRF.  All 
details of any treatments initiated due to the AE should also be recorded in the subjects’ notes 
and the eCRF. 
All AEs will be documented in the appropriate section of the eCRF.  Among these AEs, all SAEs 
(refer to Section 6.10.1.2) will be additionally documented in an SAE Report.  The following 
will be recorded for each event on the eCRF: 
• A description of the AE in medical terms, not as reported by the subject.  Whenever 
possible, a diagnosis should be given when signs and symptoms are due to common 
etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as “upper respiratory infection”). 
• The date of onset (start date). 
• The date of resolution (stop date). 
• The severity as assessed by the investigator according to the definitions in Section 6.10.4. 
• The causal relationship to study drug as assessed by the investigator; the decisive factor 
in the documentation is the temporal relation between the AE and the study drug (refer to 
Section 6.10.5).  


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• Action taken for study drug (none, study drug discontinued, study drug dose reduction, 
study drug delayed). 
• Other action(s) taken (none, concomitant medication given, new or prolonged 
hospitalization, procedural surgery). 
• The outcome according to the following definitions: 
o Recovered with sequelae; 
o Recovered without sequelae; 
o Ongoing, no therapy; 
o Ongoing, therapy; 
o Died, or 
o Change in toxicity grade/severity. 
• Serious Adverse Event (as defined in Section 6.10.1.2):  yes or no. 
If, in any subject, the same AE occurs on several occasions (unless the AE is continuous and of 
stable grade), then the AE in question will be documented and assessed each time.  For an SAE, 
the information listed above to be recorded in the eCRF will also be recorded in the SAE Report.  
Only AEs that fulfill the criteria for SAEs (refer to Section 6.10.1.2) should be recorded in the 
SAE Report. 
6.10.4. 
Assessing Adverse Event Severity 
To ensure there is no confusion or misunderstanding of the difference between the terms 
“serious” and “severe”, which are not synonymous, the following note of clarification is 
provided: 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache).   
This is not the same as “serious”, which is based on subject/event outcome or action criteria 
usually associated with events that pose a threat to a subject’s life or functioning.  
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
All AEs are to be evaluated with respect to severity using: 
• Mild; 
• Moderate, or 
• Severe. 
6.10.5. 
Assessing Adverse Event Relationship to Study Drug 
The investigator (or sub-investigator) must record his/her opinion concerning the relationship of 
the AE to study treatment on the eCRF.  Investigators will determine relatedness of an event to 


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study drug based on a temporal relationship as well as if the event is unanticipated or 
unexplained given the subject’s clinical course, previous medical conditions, and concomitant 
medications.  An event should be recorded as “drug related” if the investigator believes it to be 
reasonably related to study drug. 
6.10.6. 
Reporting Adverse Events 
Each AE is to be classified by the investigator as serious or non-serious.  This classification 
determines the reporting procedures to be followed (Table 1).   
Table 1 
Reporting Requirements for Adverse Events 
Gravity 
Reporting Time 
Type of Report 
Serious 
Within 24 hours 
Complete AE eCRF 
Non-serious 
Per eCRF submission procedure 
Appropriate AE eCRF 
 
6.10.7. 
Reporting Serious or Unexpected Adverse Events 
Any SAE, irrespective of the relationship to Study Drug, that occurs during the course of the 
study (from the first dose of study treatment during the Imaging Period up to and including the 
Imaging Follow-up Period) will be reported on the eCRF as soon as possible (within 24 hours 
after the site becomes aware of the event).   
The investigator is encouraged to discuss with the Pharmacovigilance group any AE for which 
the issue of reportability is unclear or questioned.   
An SAE Report should be prepared, containing as much available information concerning the 
event as possible, so that a written report can be filed with the appropriate regulatory authorities.  
If causality cannot be definitively assessed at the time of the SAE, it is important to notify the 
Sponsor, or its designee, within the timelines stated in Table 1.  When new significant 
information is obtained, and the outcome and attribution of the event is known, the investigator 
will communicate this on the eCRF.  The relevant information will be provided in a timely 
manner to allow reporting to regulatory authorities within the required reporting period.   
For a follow-up report to the regulatory authorities, the Sponsor may be required to collect 
further information for a detailed description and a final evaluation of the case, including copies 
of hospital reports, autopsy reports, or other relevant documents.  Any SAE follow-up 
information requested by the Sponsor (or its designee) should be provided in a timely manner to 
ensure that the SAE report is made to regulatory authorities within the requested timeframe.   
The Investigator, or Sponsor where applicable, will notify the relevant Institutional Review 
Borad (IRB) of any SAEs and safety reports according to local regulation requirements. 


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6.10.8. 
Follow-Up of Adverse Events 
All AEs (both serious and non-serious) should be followed through the end of the observation 
period or until resolution, whichever is longer.  All measures required for AE management, as 
well as the ultimate outcome of the AE, must be recorded in the source document and reported to 
the Sponsor. 
6.11. Removal of Subjects from the Study or Study Drug 
The investigator may withdraw a subject from study participation for any of the following 
reasons: 
• A significant protocol violation occurs; 
• A serious or intolerable AE occurs; 
• The sponsor or investigator terminates the study, or 
• The subject requests to be discontinued from the study. 
6.12. Discontinuation of Study Sites 
Study site participation may be discontinued if the Sponsor, investigator, or the IRB of the study 
site judges it necessary for any reason. 
6.13. Discontinuation of the Study 
The study will be discontinued if the Sponsor judges it necessary for any reason. 
6.14. Appropriateness of Measurements 
All procedures and assessments used to evaluate the safety and efficacy of hyperpolarized 129Xe 
are widely used and generally regarded as reliable, accurate, and relevant.  Pulmonary function 
tests are used to evaluate potential post-operative risks and complications in patients considering 
lung surgery (Wang, 2004).  The specific tests used in this protocol to assess pulmonary 
function, FEV1, and ventilation assessments, are both commonly used assessments in this patient 
population.   
7. QUALITY CONTROL AND ASSURANCE 
A study start-up/investigator training will be held for all sites prior to first subject enrollment.  
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will: 
• Provide instructional material to the study sites, as appropriate. 


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• Conduct a start-up training session to instruct the investigators and study coordinators.  
This session will give instruction on the protocol, the completion of the eCRF, and study 
procedures. 
• Make periodic visits to the study site. 
• Be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax. 
• Review and evaluate eCRF data and use standard computer edits to detect errors in data 
collection. 
• Conduct a quality review of the database. 
In addition, the Sponsor or its representatives may periodically check a sample of subject data 
recorded against source documents at the study site.  The study may be audited by the Sponsor or 
its representatives, and/or regulatory agencies at any time.  Investigators will be given notice 
before an audit occurs. 
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and medical records in 
the subject’s files as original source documents for the study.  If requested, the Investigator will 
provide the sponsor, applicable regulatory agencies, and applicable ethical review boards with 
direct access to original source documents. 
8. PLANNED STATISTICAL METHODS 
8.1. 
Determination of Sample Size 
The sample size required to demonstrate equivalence is driven by 2 factors: 1) the intra-subject 
variability of the difference between the predicted post-operative FEV1 from the 2 methods, and 
2) the pre-specified equivalence margin.  From prior literature, the intra-subject variability for 
133Xe scintigraphy leads to an estimated variability in predicted post-operative FEV1 of 
0.21 L/sec.  Similarly, prior studies have suggested that the equivalence margin between the 
2 imaging techniques currently used for resection planning is 0.3 L/sec.  Using these 
assumptions, and based on the use of a two-sided test at the alpha=0.05 level of significance, a 
sample size of 15 subjects is required for 90% power.  However, given limited literature on 133Xe 
variability, we have accounted for the possibility that it could be higher.  If true variability is 
0.32 L/sec, then a sample size of 32 subjects will provide 90% power to establish equivalence.   


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8.2. 
Analysis Populations  
This study will evaluate 2 different subject populations:   
• Efficacy Population:  The efficacy analysis set will consist of all subjects that have both a 
129Xe MRI scan and a 133Xe scintigraphy scan.  Primary and the 6-zone analysis 
secondary efficacy endpoints will be analyzed using the efficacy analysis set.   
• Post-operative Population:  This analysis set will consist of all subjects that have both a 
129Xe MRI scan and a 133Xe scintigraphy scan, and have a post-operative FEV1 
(spirometry) value.   
• Safety:  The safety analysis set will consist of all subjects who received at least 1 dose of 
either hyperpolarized 129Xe or 133Xe.  Secondary safety endpoints will be analyzed using 
the Safety analysis set.   
8.3. 
Demographics and Baseline Characteristics 
Patients’ age, height, weight, and baseline characteristics (including smoking history) will be 
summarized using descriptive statistics, while gender, race, and other categorical variables will 
be provided using frequency tabulations.  Medical history will be summarized using frequency 
tabulations by system organ class (SOC) and preferred term. 
8.4. 
Study Endpoints 
8.4.1. 
Primary Efficacy Endpoint 
The primary endpoint is the scan predicted post-operative FEV1.  The scans will be quantified 
using commercially available software to report the fraction of activity arising from 6 zones.  
This will be used to predict post-operative FEV1 by multiplying the percentage of function 
remaining in the non-operated zones by pre-operative FEV1. 
8.4.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include the post-operative FEV1 value (spirometry) and the 
percentage function contributed by each of the individual 6 lung zones.   
8.4.3. 
Secondary Safety Endpoints 
Safety and tolerability will be assessed based on the incidence and severity of treatment 
emergent AEs and SAEs.  Additionally, subjects will be monitored before, during, and after each 
dose to monitor for changes in vital signs. 


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8.5. 
Study Disposition 
The number of enrolled, completed, and discontinued subjects, with the reason for 
discontinuation, will be summarized descriptively. 
8.6. 
Primary Efficacy Analysis 
The primary analysis for this study will be to test the mean difference in predicted post-operative 
FEV1 (measured in L/sec) values as measured using hyperpolarized 129Xe gas MRI relative to 
133Xe scintigraphy (reference standard).  The primary analysis will be conducted by estimating 
the 95% confidence interval (CI) for the mean difference in predicted FEV1 from the 2 methods.  
The scans will be quantified using commercially available software to report the fraction of 
activity arising from 6 zones.  This will be used to predict post-operative FEV1 by multiplying 
the percentage of function remaining in the non-operated zones by pre-operative FEV1.  The CI 
will be constructed assuming that the within-subject difference between methods is normally 
distributed.  If the 95% CI for the mean difference is contained within the interval (-0.30, +0.30 
L/sec), equivalence will have been demonstrated. 
8.7. 
Secondary Efficacy Analysis 
The post-operative secondary analysis for this study will be to test the mean difference in 
predicted post-operative FEV1 (measured in L/sec) values as measured using hyperpolarized 
129Xe gas MRI and 133Xe scintigraphy (reference standard) relative to the final post-operative 
FEV1 value (spirometry).  The secondary equivalence analysis will be conducted using the same 
methodology and same equivalence margin as specified for the primary analysis. 
The 6-zone secondary analysis for this study will be to evaluate the individual percentage 
function assessments from each of the 6 zone analyses from both the 129Xe and the 133Xe 
ventilation images. The equivalence margin will be 5 percentage points.  Thus, for each of the 
six zones, equivalence will have been demonstrated if the 95% CI for the mean difference is 
contained within the interval (-5%, +5%). 
8.8. 
Safety Analysis 
All safety analyses will be performed on the Safety population, unless otherwise stated.  
AEs will be coded using MedDRA terminology.  Events are defined as AEs if they start or 
worsen after a subject's administration of study drug.  All AEs will be summarized by SOC, 
preferred term, severity and relationship to study drug.  AEs leading to death or to 
discontinuation from study drug and SAEs will also be tabulated.  In the by-subject summary, a 
subject having the same event more than once will be counted only once and by greatest severity. 
Vital signs, including change from baseline, will be summarized.    


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Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug dictionary.  Concomitant medications will be summarized descriptively.  The summary 
tables will show the number and percentage of subjects by preferred term.  Subjects who take the 
same medication (in terms of the preferred term) more than once will only be counted once for 
that medication.  Prior and concomitant medications will be listed separately. 
8.9. 
Interim Analysis 
No formal interim analyses are planned for this study.   
9. ADMINISTRATIVE CONSIDERATIONS 
9.1. 
Institutional Review Board Approval 
The study protocol and ICF, as well as any amendments, will be approved by the appropriate 
ethical review board (IRB) prior to initiation of the study at a particular site.  All subjects will 
sign an ICF prior to any study-specific procedures.  Site performance during the study will be 
routinely monitored by a study monitor (refer to Section 9.5).   
Documentation of ethical review board approval of the protocol and ICF must be provided to the 
Sponsor before the study may begin at the study sites.  The IRB will review the protocol and ICF 
as required in accordance with the ICH GCP guidelines.  Any member of the IRB who is directly 
affiliated with this study as an Investigator or as site personnel must abstain from the vote on the 
approval of the protocol. 
In the event of an SAE, the Investigator, or Sponsor where applicable, will notify the relevant 
IRB of any SAEs and safety reports according to local regulation requirements (refer to 
Section 6.10.7 for more information regarding reporting of SAEs). 
9.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with GCPs and the applicable laws and 
regulations.  The Investigator, head of the medical institution, or designee will promptly submit 
the protocol to applicable ethical review boards. 
This investigational product is being studied in the US under an IND application.  Study sites 
will include approximately 2 sites in the US.   
All or some of the obligations of the Sponsor will be assigned to CROs. 
An identification code assigned for each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other study-related data. 


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9.3. 
Patient Information and Consent 
Written informed consent must be obtained from each subject or legal representative (if subject 
is unable to sign) after the nature of the study has been fully explained, in accordance with ICH 
GCPs.  Informed consent must be obtained during the Screening Period prior to performing any 
study-specific procedures.  The consent form that is used must be approved by both the 
reviewing IRB and by the Sponsor.  
The subject (or legal representative) and the individual explaining the study will sign the current 
IRB-approved version of the consent form.  A copy of the signed consent form will be given to 
the subject.  The date that consent was obtained will be recorded in the eCRF as well as the 
subject’s chart.   
A copy of the IRB approved version of the consent form will be provided to the Sponsor.  The 
original signed consent form must be maintained at the site and made available for inspection, as 
appropriate.   
9.4. 
Patient Confidentiality 
The anonymity of subjects participating in this study must be maintained.  Subjects will be 
identified by their assigned subject number in all written communications between the 
Investigator and Sponsor or its designees.  Site documents that are not submitted to the Sponsor 
or its designees and that identify the subject (e.g., signed informed consent; source 
documents/charts) will be made available to the Sponsor (or its designees) or regulatory 
authorities for inspections, but will be otherwise maintained in confidence. 
All study-related information provided by the Sponsor or its designees to the Investigator and not 
previously published (including but not limited to the active study agent identity, the IB, the 
study protocol, verbal and written communication, study data, assay methods and scientific data), 
will be considered confidential.  In addition, all information developed during the conduct of the 
clinical investigation of the study agent is also considered confidential.  Neither the Investigator 
nor any of his/her employees or agents shall disclose or use this information for any purpose 
other than the performance of the clinical study.  Such information shall remain the confidential 
and proprietary property of the Sponsor, and disclosure to others will be limited to other 
physicians who are conducting studies with the same active study agent, the IRB, and the 
applicable regulatory authorities except by prior written permission of the Sponsor or its agents.  
At such time, that information becomes widely and publicly available through no fault of the 
Investigator, the obligation of nondisclosure toward that particular information will cease. 


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9.5. 
Study Monitoring 
The Sponsor’s clinical research physician will monitor safety data throughout the course of the 
program.  All SAEs will be reviewed within time frames mandated by company procedures and 
local regulatory requirements.     
All deaths and SAE reports will be reviewed by the clinical team during the program.  These 
reports will be reviewed to assure completeness and accuracy. 
To ensure the safety of participants in the program, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the program.  If requested, the 
Investigator will provide the Sponsor, applicable regulatory agencies, and applicable ethical 
review boards with direct access to original source documents. 
The Sponsor or designee will assure the accuracy of data, the selection of qualified Investigators, 
appropriate program centers, and review protocol procedures with the Investigators and 
associated personnel prior to the program and during periodic monitoring visits.  The Sponsor or 
a designee will review CRFs for accuracy and completeness during on-site monitoring visits and 
after their return from the clinical site.  Discrepancies will be resolved with the Investigator as 
appropriate. 
The Sponsor or its designee will monitor the program using any of the following methods: 
• Telephone contacts; 
• Site visits, and 
• Review of original patient records, CRFs, drug accountability, storage, and general 
program documentation. 
So that the program may be adequately monitored, the Investigator will cooperate in providing 
the Sponsor’s designee with all program documents (e.g., subject charts and program files) and 
responding to inquiries that may arise as a result of the document review. 
Review of these documents will usually occur during a routine monitoring visit, but may also be 
required during a visit by a quality assurance auditor.  The Sponsor reserves the right to 
terminate the program if access to source documentation of work performed in this program is 
denied to the Sponsor or regulatory representatives. 
9.6. 
Case Report Forms and Study Records 
An eCRF will be provided for each study subject.  Data collected through the completion of 
study procedures required by this protocol will be recorded in the subject’s chart as source 
documentation.  This data will then be transcribed onto the eCRF.   


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All required study data will be entered onto the Sponsor-provided eCRF.  All information in the 
eCRFs must be supported by original data in the subject’s medical records.  All medical records, 
laboratory printouts, notes made by the physician, and other materials, such as x-rays, will be 
considered source data and must be available for inspection by the Sponsor, the Sponsor’s 
delegates, or government representatives.   
Appropriate training prior to study initiation at that site will be conducted to assist with making 
entries and corrections to data entered into an eCRF.  The Investigator remains responsible for 
the accuracy and adequacy of all data entered on the eCRF.   
Data will be monitored as described in Section 9.5.  Under direction of the clinical monitor, 
eCRFs will be verified, locked, and submitted for data entry and analysis.  A copy of each eCRF 
page must remain at the investigative site in the appropriate subject’s eCRF file.  Data entered 
into eCRFs will be monitored by monitors that are adequately trained on the system.   
Upon further data processing, queries may be generated and sent to the Investigator for 
clarification or correction.  The Investigator will address any queries and forward resolutions as 
directed by the site monitor.   
9.7. 
Data Disclosure  
The Investigator agrees by his/her participation that the results of this study may be used for 
submission to national and/or international registration and supervising authorities.  As required, 
authorities will be provided with the names of the Investigators, their addresses, qualifications, 
and extent of involvement.  The Investigator is required to provide the Sponsor, or its designee, 
with all study data, complete reports, and access to all study records. 
Data generated by this study must be available for inspection by the FDA and other regulatory 
authorities, the Sponsor or its designee, and the IRB, as appropriate.  At a subject’s request, 
medical information may be given to his or her personal physician or other appropriate medical 
personnel responsible for his or her welfare.  Subject medical information obtained during the 
course of this study is confidential and disclosure to third parties other than those noted above is 
prohibited. 
9.8. 
Retention of Data 
Source documents are the original documents, data, and records from which the subject’s eCRF 
data are obtained.  These include, but are not limited to, hospital records, clinical and office 
charts, laboratory and pharmacy records, radiographs, and correspondence.  eCRF entries may be 
considered source data if the eCRF is the site of the original data recording (i.e. no other written 
or electronic record of the data exists).  All source documents and study documentation will be 


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kept by the Investigator for the appropriate retention period as stipulated by the site IRB or FDA 
guidelines, whichever is longer.   
US IND regulations (21 CFR 312.62) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drugs including eCRFs, consent 
forms, laboratory test results, and medication inventory records be kept on file by the 
Investigator for 2 years after a marketing application is approved for the drug for the indication 
for which it is being studied.  If no application is filed or approved, these records must be kept 
for 2 years after the investigation has been discontinued and the FDA has been notified.  ICH 
guidelines indicate that documents should be retained until at least 2 years after the last approval 
of a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  If there is a country or 
institutional policy that specific records and documents be retained for a longer period than 
described above, the applicable sites must comply with those policies in addition to US and ICH 
policies.  No study records should be destroyed without prior authorization from Polarean. 
9.9. 
Financial Disclosure 
The FDA Financial Disclosure by Clinical Investigators (21 CFR 54) regulations require 
sponsors to obtain certain financial information from Investigators participating in covered 
clinical studies.  The Principal Investigator is required to provide the necessary financial 
information before participating in the study and to promptly update Polarean with any relevant 
changes to their financial information throughout the course of the clinical study and for up to 
1 year after its completion.  This rule applies to all principal investigators participating in 
covered clinical studies to be submitted to the FDA in support of an application for market 
approval. 
9.10. Publication and Disclosure Policy 
All data generated from this program are the property of the Sponsor and shall be held in strict 
confidence along with all information furnished by the Sponsor.  Independent analyses and/or 
publication of these data by the Investigator or any member of his/her staff are not permitted 
without prior written consent of the Sponsor.   
Any formal presentation or publication of data from this study will be considered as a joint 
publication by the Investigator(s) and appropriate Polarean personnel.  Authorship will be 
determined by mutual agreement.  For multicenter studies it is mandatory that the first 
publication is based on data from all centers, analyzed as stipulated in the protocol and not by 
individual Investigators.  Investigators participating in multicenter studies agree not to present 
data gathered from one center or a small group of centers before the full publication, unless 
formally agreed to in writing.  Written permission to Investigators to publish results will be 


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contingent on review by Polarean of the methodology and statistical analyses and any 
publication or presentation will provide for nondisclosure of Polarean confidential or proprietary 
information.  In all cases, the parties agree to submit all manuscripts or abstracts to all other 
parties at least 60 days prior to submission.  This will enable all parties to protect proprietary 
information and to provide comments based on information that may not yet be available to other 
parties.   
Further details on the publication process are provided in individual contractual agreements 
signed by the Investigators and Polarean. 
10. REFERENCE LIST 
BMC website: http://www.bmc.org/thoraciconcology/treatments/lung-resection.htm accessed on 
28 March 2016. 
Burov NE, Arzamastev EV, Kornienko LI and Kudimova LA. Influence of xenon on 
reproductive function. Anaesteziol Reanimatol. 2002a Jul-Aug;(4):71-2.  
Burov NE, Arzamastev EV, Kornienko LI and Kudimova LA. Investigation of the teratogenic 
and embryotoxic action of xenon. Anaesteziol Reanimatol, 2002b Jul-Aug;(4):69-70.  
Burov NE, Arzamastev EV, Kornienko LI, Terekhova OA and Eliseeva, IL. Study of 
immunodepressive and allergic effects of xenon. Anaesteziol Reanimatol. 2002c May-
Jun;(3):71-2. 
Cleveland ZI, Cofer GP, Metx G, Beaver D, Nouls J, Kaushik SS, et al. Hyperpolarized Xe MR 
imaging of alveolar gas uptake in humans. PLoS One. 2010 Aug;5(8):e12192.  
de Rossi LW, Horn NA, Baumert JH, Gutensohn K, Hutschenreuter G, Rossaint R. Xenon does 
not affect human platelet function in vitro. Anesth Analg. 2001 Sept;93(3):635-40.  
de Rossi LW, Gott K, Horn N, Hecker K, Hutschenreuter G, Rossaint R. Xenon preserves 
neutrophil and monocyte function in human whole blood. Can J Anesth. 2002 Nov;49(9):942-
5.  
de Rossi LW, Horn NA, Stevanovic A, Buhre W, Hutschenreuter G, Rossaint R. Xenon 
modulates neutrophil adhesion molecule expression in vitro. Eur J Anesthesiol. 2004 
Feb;21(2):139-43. 
Driehuys, B, Martinez-Jimenez S, Cleveland ZI, Metz GM, Beaver DM, Nouls JC, et al. Chronic 
obstructive pulmonary disease: safety and tolerability of hyperpolarized 129Xe MR imaging in 
healthy volunteers and patients. Radiol. 2012 Jan;262(1):279-89. 


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Guyton AC, Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia: Elsevier; 2006, 
Chapter 37, Pullmonary Ventilation; p.471-90. 
Horn NA, Hecker KE, Bongers B, Baumert HJ, Reyle-Hahn SM, Rossaint R. Coagulation 
assessment in healthy pigs undergoing single xenon anaesthesia and combinations with isoflurane 
and sevoflurane. Acta Anaesthesiol Scand. 2001 May;45(5):634-8. 
He M, Heacock T, Kaushik SS, Robertson SH, Freeman MS, McAdams HP, et al.  
Hyperpolarized 129Xe MRI to quantify regional ventilation differences in older versus 
younger asthmatics.  Am J Respir Crit Care Med. 2014a May;189:A6370. 
He M, Kauskik SS, Robertson SH, Freeman MS, Virgincar RS McAdams HP, Driehuys B.  
Extending semiautomatic ventilation defect analysis for hyperpolarized 129Xe ventilation 
MRI.  Acad Radiol. 2014b Dec;21(12):1530–41. 
He M, Robertson SH, Kaushik SS, Freeman MS, Virgincar RS, Davies J, Stiles J, Foster WM, 
McAdams HP, Driehuys B. Dose and Pulse Sequence Considerations for Hyperpolarized 
129Xe Ventilation MRI. Magn Reson Imaging 2015;33(7):877-885. 
Kaushik SS, Cleveland ZI, Cofer GP, Metz G, Beaver D, Nouls J, et al. Diffusion-weighted 
hyperpolarized 129Xe MRI in healthy volunteers and subjects with chronic obstructive pulmonary 
disease. Magn. Reson. Med. 2011 Apr;65(4):1154-65. 
Kirby M, Coxson HO, Parraga G. Pulmonary functional magnetic resonance imaging for paediatric 
lung disease. Ped Respiratory reviews. 2013 Sept;14(3):180-9. 
Lane GA, Nahrwold ML, Tait AR, Taylor-Busch M, Cohen PJ, Beaudoin AR. Anesthetics as 
teratogens: nitrous oxide is fetotoxic, xenon is not. Science. 1980 Nov;210(4472);899-901. 
Reinelt H, Marx T, Kotzerke J, Topalidis P, Luederwald S, Armbruster S, et al. Hepatic function 
during xenon anesthesia in pigs. Acta Anaesthesiol Scand. 2002 Jul;46(6):713-6. 
Roughton FTW, Forster RE. Relative importance of diffusion and chemical reaction rates in 
determining rate of exchange of gases in the human lung, with special reference to true 
diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. J Appl 
Physiol 1957;11:290-302. 
Stewart NJ, Norquay G, Griffiths PD, Wild JM. Feasibility of human lung ventilation imaging using 
highly polarized naturally abundant xenon and optimized three-dimensional steady-state free 
precession. Magn Reson Med. 2015 Aug;74(2):346–52. 
Svenningsen A, Kirby M, Starr D, Leary D, Wheatley A, Maksym GN, et al. Hyperpolarized 3He 
and 129Xe MRI: differences in asthma before bronchodilation. JMRI. 2013 Feb;38:1521–30. 


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Virgincar RS, Cleveland ZI, Kaushik SS, Freeman MS, Nouls J, Cofer GP, et al. Quantitative 
analysis of hyperpolarized 129Xe ventilation imaging in healthy volunteers and subjects with 
chronic obstructive pulmonary disease. NMR Biomed. 2013 Apr;26(4):424-35. 
Wang JS.  Pulmonary function tests in preoperative pulmonary evaluation.  Respir Med.  2004 
July;98(7):598-605.  
 


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Appendix 1 
Schedule of Events 
 
Screening1 
Imaging1 
Imaging 
Follow-up2 
Post-Op Follow-up 
Evaluation 
Day -7 to Day 0 
Day 1 
Day 2 
1-2 Months Post-Op 
Informed Consent 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
Demographics and Medical History3 
X 
X 
 
 
Physical Exam 
X 
 
 
 
Concomitant Medications Review 
X 
X 
 
 
MRI-suitable Screening 
X 
 
 
 
Recording of potential resection 
location on eCRF 
X 
 
 
 
Spirometry (FEV1)4 
 
X 
 
X 
129Xe Administration1 
 
X 
 
 
Anatomical proton MRI (MRI session 
only) 
 
X 
 
 
133Xe Administration1 
 
X 
 
 
Vital Signs5,6 
X 
X 
 
 
SpO27 
X 
X 
 
 
Adverse Events (AE)8  
 
X 
X 
 
Local Laboratory Tests 
 
 
 
 
Serum Pregnancy Test9 
X 
 
 
 
Abbreviations:  Abbreviations:  AE = adverse event; eCRF = electronic case report form; FEV1 = forced expiratory 
volume; MRI = magnetic resonance imaging; SpO2 = arterial oxygen saturation.   
1  Screening and Imaging study periods can occur on the same day or on different days, however there should be ≤48 hours 
between administration of the study drug and reference standard scans.  
2  The Follow-Up period will occur on the day after (+3 days) the completion of all imaging and prior to resection surgery. 
3  Medical history will include any pulmonary function values (i.e. FEV1) from the subject files as well as smoking 
history.   
4 FEV1 measurement should occur prior to administration of the study drug and reference standard scans.   
5  Vital Signs (including heart rate, respiration rate, temperature, and blood pressure) will be assessed before and after each 
scanning session (both 129Xe and 133Xe).  Subjects will have a 5-minute rest in a supine position before vital signs are 
assessed. 
6 Changes in heart rate of greater than ±20% are considered significant.  If the subject is to receive another dose, the next 
dose will not be administered until the heart rate is within 20% of its baseline value.  If the subject has received their last 
dose, they will be observed until their heart rate is within 20% of its baseline value.  The subject will be monitored for the 
duration of the MRI exam by a qualified medical professional. 
7  SpO2 is measured at baseline as well as before and after each scanning session (both 129Xe and 133Xe).  An absolute 
decrease of SpO2 by greater than 10% is considered significant.  If the subject is to receive another dose, the next dose will 
not be administered until the SpO2 is within 10% of its baseline value.  If the subject has received their last dose, they will 
be observed until the SpO2 is within 10% of its baseline value.  The subject will be monitored for the duration of the MRI 
exam by a qualified medical professional. 
8 Subjects will be monitored for any subjective sensation of residual anesthesia (e.g., lightheadedness, loss of sensation or 
awareness, loss of memory, or unconsciousness).  If the subject is to receive another dose, the next dose will not be 
administered until the sensation has resolved.  If the subject has received their last dose, they will be observed until the 


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sensation has resolved.  The subject will be monitored for the duration of the MRI exam by a qualified medical 
professional. 
9 Eligibility assessment will include, if applicable, a negative pregnancy test.  
 


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Appendix 2 
Summary of Changes from Previous Version 
Summary and Justification of Changes 
The protocol Amendment 2, dated 29 January 2018, has been amended.  This amendment 
includes revisions to: 
• Refine the equivalence margin for the secondary efficacy endpoint comparing each 
individual zone within the 6-zone analysis between 133Xe and 129Xe. 
• Include potential resection location recording on the eCRF at the screening visit. 
• Provide correct location of 129Xe and 133Xe handling and labeling instructions. 
The individual changes are provided below for each impacted section.  For each section, the 
previously approved protocol verbiage is provided with all deleted text marked by using 
strikethrough.  The updated verbiage from the protocol amendment is also provided with all 
added test marked by using bold.  An ellipsis (…) is used to indicate the omission of unchanged 
text for concise representation of the changes made. 
 


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Individual Changes and Justification for Change 
Original Protocol Information 
Protocol Amendment 
Page 
No. 
Section No. 
Previous Text 
Amended Text 
Justification for 
Change 
2 - End 
Header 
Clinical Study Protocol:  POL-Xe-001 Amendment 2 
Clinical Study Protocol:  POL-Xe-001 Amendment 3 
Amended protocol.   
1 
Cover Page 
Amendment 2 
Date:  29 January 2018 
Replaces Amendment 2, released 07 November 
2017 
Original 
20 October 2017 
Amendment 1 
07 November 2017 
Amendment 2 
29 January 2018 
Amendment 3 
26 April 2018 
Amended protocol, 
revised cover page 
format.     
2 
Sponsor 
Signature Page 
Version:  Amendment 2 
Version Date: 29 January 2018 
Version: Amendment 3 
Version Date: 26 April 2018 
Amended protocol 
3 
Investigator 
Signature Page 
Version: Amendment 2 
Version Date:  29 January 2018 
Version: Amendment 3 
Version Date: 26 April 2018 
Amended protocol 
6 
Synopsis: 
Efficacy 
Assessments: 
Secondary Efficacy Endpoints:  The secondary efficacy 
endpoints include the post-operative FEV1 value 
(spirometry) and the percentage function contributed by 
each of the individual 6 lung zones.  For the post-
operative FEV1 endpoint we seek to demonstrate an 
equivalence margin of 0.3 L/sec.  For the 6-zone 
percentage function endpoint, we seek to demonstrate 
an equivalence margin of 4% for each of the zones.  
Secondary Efficacy Endpoints:  The secondary efficacy 
endpoints include the post-operative FEV1 value 
(spirometry) and the percentage function contributed by each 
of the individual 6 lung zones. 
Deletion of 
redundant text. 
6 
Synopsis: 
Statistical 
Methods 
Secondary Analysis:  … The equivalence margin will 
be 4 percentage points.  Thus, for each of the six zones, 
equivalence will have been demonstrated if the 95% CI 
for the mean difference is contained within the interval 
(-4%, +4%). 
Secondary Analysis:  … The equivalence margin will be 5 
percentage points.  Thus, for each of the six zones, 
equivalence will have been demonstrated if the 95% CI for 
the mean difference is contained within the interval (-5%, 
+5%). 
Adjustment of 
secondary efficacy 
endpoint equivalence 
margin. 


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Original Protocol Information 
Protocol Amendment 
Page 
No. 
Section No. 
Previous Text 
Amended Text 
Justification for 
Change 
15 
3.1  
… The 4 study periods are defined as:  
• Screening:  Subjects will be screened for study 
participation based on inclusion and exclusion 
criteria.  Informed consent will be obtained. 
… The 4 study periods are defined as:  
• Screening:  Subjects will be screened for study 
participation based on inclusion and exclusion 
criteria.Informed consent will be obtained and the 
investigator’s assessment of potential lcations of lung 
resection will be recorded on the electronic case report 
form (eCRF). 
Clarify instruction to 
investigators about 
recording of potential 
sections of lung to be 
resected. 
20, 26 
5.2.1, 5.2.2, 
and 6.9.3  
… Detailed information for preparation and 
administration of hyperpolarized 129Xe gas is provided 
in the Imaging Manual. 
… Detailed information for preparation and administration of 
hyperpolarized 129Xe gas is provided in the IMP Handling 
and Labeling Instruction Manual. 
Correction of 
location of 129Xe 
handling and labeling 
instructions. 
21 
5.3.3  
… 133Xe will be dosed according to the Pacage Insert.  
Please refer to the Imaging Manual for additional 
details. 
… 133Xe will be dosed according to the Pacage Insert.  Please 
refer to the the IMP Handling and Labeling Instruction 
Manual for additional details. 
Correction of 
location of 133Xe 
handling and labeling 
instructions. 
22 
5.9  
… Labeling instructions for the hyperpolarized 129Xe in 
the Gas Delivery Bag are provided in the Imaging 
Manual. 
… Labeling instructions for the hyperpolarized 129Xe in the 
Gas Delivery Bag are provided in the IMP Handling and 
Labeling Instruction Manual. 
Correction of 
location of 
instructions for 
labeling gas delivery 
bag. 
26 
6.9.1   
… Additional information for preparation and 
administration of hyperpolarized 129Xe gas are provided 
in Section 5.2.1 as well as the Imaging Manual for this 
study.   
… Additional information for preparation and administration 
of hyperpolarized 129Xe gas are provided in Section 5.2.1 as 
well as the IMP Handling and Labeling Instuction 
Manual for this study.   
Correction of 
location of 129Xe 
handling and labeling 
instructions. 
34 
8.4.2  
The secondary efficacy endpoints include the post-
operative FEV1 value (spirometry) and the percentage 
function contributed by each of the individual 6 lung 
zones.  For the post-operative FEV1 endpoint we seek 
to demonstrate an equivalence margin of 0.3 L/sec.  For 
the 6-zone percentage function endpoint, we seek to 
demonstrate an equivalence margin of 4% for each of 
the zones. 
The secondary efficacy endpoints include the post-operative 
FEV1 value (spirometry) and the percentage function 
contributed by each of the individual 6 lung zones.   
Deletion of 
redundant text. 


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Original Protocol Information 
Protocol Amendment 
Page 
No. 
Section No. 
Previous Text 
Amended Text 
Justification for 
Change 
35 
8.7  
… The equivalence margin will be 4 percentage points.  
Thus, for each of the six zones, equivalence will have 
been demonstrated if the 95% CI for the mean 
difference is contained within the interval (-4%, +4%). 
… The equivalence margin will be 5 percentage points.  
Thus, for each of the six zones, equivalence will have been 
demonstrated if the 95% CI for the mean difference is 
contained within the interval (-5%, +5%). 
Adjustment of 
secondary efficacy 
endpoint equivalence 
margin. 
44 
Appendix 1 
See previous Schedule of Events table below.   
See updated Schedule of Events table below.   
Provide instruction 
on timing of eCRF 
recording of potential 
resection locations. 
 


 Hyperpolarized Xenon (129Xe) gas in the BRANDNAME device 
Clinical Study Protocol:  POL-Xe-001 Amendment 3 
 
Confidential 
 
Previous Schedule of Events Table:   
 
Screening1 
Imaging1 
Imaging 
Follow-up2 
Post-Op Follow-up 
Evaluation 
Day -7 to Day 0 
Day 1 
Day 2 
1-2 Months Post-Op 
Informed Consent 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
Demographics and Medical History3 
X 
X 
 
 
Physical Exam 
X 
 
 
 
Concomitant Medications Review 
X 
X 
 
 
MRI-suitable Screening 
X 
 
 
 
Spirometry (FEV1)4 
 
X 
 
X 
129Xe Administration1 
 
X 
 
 
Anatomical proton MRI (MRI 
session only) 
 
X 
 
 
133Xe Administration1 
 
X 
 
 
Vital Signs5,6 
X 
X 
 
 
SpO27 
X 
X 
 
 
Adverse Events (AE)8  
 
X 
X 
 
Local Laboratory Tests 
 
 
 
 
Serum Pregnancy Test9 
X 
 
 
 
 


 Hyperpolarized Xenon (129Xe) gas in the BRANDNAME device 
Clinical Study Protocol:  POL-Xe-001 Amendment 3 
 
Confidential 
 
Updated Schedule of Events Table:   
 
Screening1 
Imaging1 
Imaging 
Follow-up2 
Post-Op Follow-up 
Evaluation 
Day -7 to Day 0 
Day 1 
Day 2 
1-2 Months Post-Op 
Informed Consent 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
Demographics and Medical History3 
X 
X 
 
 
Physical Exam 
X 
 
 
 
Concomitant Medications Review 
X 
X 
 
 
MRI-suitable Screening 
X 
 
 
 
Recording of potential resection 
location on eCRF 
X 
 
 
 
Spirometry (FEV1)4 
 
X 
 
X 
129Xe Administration1 
 
X 
 
 
Anatomical proton MRI (MRI 
session only) 
 
X 
 
 
133Xe Administration1 
 
X 
 
 
Vital Signs5,6 
X 
X 
 
 
SpO27 
X 
X 
 
 
Adverse Events (AE)8  
 
X 
X 
 
Local Laboratory Tests 
 
 
 
 
Serum Pregnancy Test9 
X 
 
 
 
 

SAP_001.pdf: 
Hyperpolarized Xenon (129Xe) Gas 
 
Statistical Analysis Plan:  POL-Xe-001 
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STATISTICAL ANALYSIS PLAN 
Polarean, Inc.  
 
POL-Xe-001 
 
 
 
Title: 
Evaluation of Hyperpolarized 129Xe MRI as Compared to 133Xe 
Scintigraphy for the Assessment of Pulmonary Function in Patients being 
Evaluated for Possible Lung Resection Surgery 
Date of Creation: 
02-Jun-2020 
Version: 
V3.0  
 
 
This Statistical Analysis Plan was prepared by the following personnel: 
 
Name         Carol Tseng, PhD 
 
 
Title 
Lead Statistician 
 
 
 
 
 
 
 
 
 


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Document Version Control 
Version 
Number 
Date 
Comments/Changes 
V1.0 
05-Sep-2019 
Original  
V2.0 
 
Revised following discussion with FDA 
• 
Addition of Section 3 Justification of Equivalence Margin 
• 
Revision of Primary Efficacy Endpoint (Section 4.1.1) 
• 
Addition of Section 4.1.3 Exploratory Endpoints 
• 
Clarification of efficacy analysis set definition (Section 4.2.1) 
• 
Clarification of post-surgical analysis set definition (Section 4.2.1) 
• 
Clarification of handling of missing data (Section 4.3.1) 
• 
Revision of Primary Efficacy Analyses (Section 4.4.1) 
• 
Revision of post-surgical secondary efficacy analysis (Section 
4.4.2.2) 
• 
Addition of Section 4.5 Exploratory Analyses 
• 
Revision of Section 6 Subgroup Analysis for Efficacy 
• 
Addition of Section 9 Changes from the Protocol 
Additional Revisions 
• 
Editorial revisions 
• 
Addition of Section 10 References 
  




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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 4 
LIST OF FIGURES ........................................................................................................................ 5 
LIST OF ABBREVIATIONS AND TERMS DEFINITIONS ....................................................... 6 
1. 
INTRODUCTION .................................................................................................................. 7 
1.1. 
Study Objectives ........................................................................................................... 7 
1.1.1. 
Primary Objectives ............................................................................................. 7 
1.1.2. 
Secondary Objective ........................................................................................... 7 
1.2. 
Overall Study Design and Plan ..................................................................................... 7 
1.3. 
Randomization and Blinding ........................................................................................ 8 
2. 
DETERMINATION OF SAMPLE SIZE ............................................................................... 8 
3. 
JUSTIFICATION OF EQUIVALENCE MARGIN ............................................................... 9 
4. 
STATISTICAL METHODS ................................................................................................... 9 
4.1. 
Study Endpoints .......................................................................................................... 10 
4.1.1. 
Primary Efficacy Endpoint ............................................................................... 10 
4.1.2. 
Secondary Efficacy Endpoints .......................................................................... 10 
4.1.3. 
Exploratory Endpoints ...................................................................................... 10 
4.1.4. 
Safety Endpoints ............................................................................................... 11 
4.2. 
Study Subjects ............................................................................................................. 11 
4.2.1. 
Definitions of Analysis Sets ............................................................................. 11 
4.2.2. 
Subject Disposition ........................................................................................... 11 
4.2.3. 
Protocol Deviations ........................................................................................... 11 
4.2.4. 
Demographic and Baseline Characteristics ...................................................... 12 
4.2.5. 
Medical History ................................................................................................ 12 
4.2.6. 
Vital Signs and Physical Examination at Screening ......................................... 12 
4.2.7. 
Prior and Concomitant Therapy ........................................................................ 12 
4.2.8. 
Exposure to Study Treatments .......................................................................... 13 
4.3. 
Data Analysis General Considerations ....................................................................... 13 
4.3.1. 
Handling of Missing Data ................................................................................. 13 
4.3.2. 
Visit Windows .................................................................................................. 13 
4.4. 
Efficacy Analyses ....................................................................................................... 13 
4.4.1. 
Primary Efficacy Analysis ................................................................................ 13 
4.4.2. 
Secondary Efficacy Analyses ........................................................................... 15 
4.5. 
Exploratory Analyses .................................................................................................. 16 
4.5.1. 
Difference in Predicted Proportion of Remaining Function Standardized to 
that Predicted by the Reference Standard (133Xe Scintigraphy) ....................... 16 
4.5.2. 
Patient-Level Equivalence between 129Xe MR-Predicted Remaining 
Function and 133Xe Scintigraphy-Predicted Remaining Function .................... 16 
4.6. 
Safety Analyses ........................................................................................................... 16 
4.6.1. 
Adverse Events ................................................................................................. 16 
4.6.2. 
Analysis of Vital Signs and Peripheral Capillary Oxygen Saturation .............. 18 


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5. 
INTERIM ANALYSES ........................................................................................................ 18 
6. 
SUBGROUP ANALYSIS FOR EFFICACY ....................................................................... 18 
7. 
STATISTICAL SOFTWARE ............................................................................................... 18 
8. 
MOCK TABLES, LISTINGS AND FIGURES ................................................................... 18 
9. 
CHANGES FROM THE PROTOCOL ................................................................................ 19 
9.1. 
Analysis Populations ................................................................................................... 19 
9.1.1. 
Efficacy Analysis Set ........................................................................................ 19 
9.1.2. 
Post-operative Analysis Set .............................................................................. 19 
9.2. 
Primary Efficacy Endpoint ......................................................................................... 19 
9.3. 
Primary Efficacy Analysis .......................................................................................... 19 
9.4. 
Secondary Efficacy Analyses ..................................................................................... 19 
9.5. 
Exploratory Endpoints ................................................................................................ 20 
9.6. 
Exploratory Analyses .................................................................................................. 20 
10. REFERENCES ..................................................................................................................... 20 
11. APPENDIX ........................................................................................................................... 22 
11.1. Schedule of Events ...................................................................................................... 22 
 
LIST OF FIGURES 
Figure 1 
6 Lung Zones .............................................................................................................. 14 


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LIST OF ABBREVIATIONS AND TERMS DEFINITIONS  
Abbreviation Definition 
129Xe 
non-radioactive isotope of xenon (hyperpolarized 129Xe is the drug product)  
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
CI 
confidence interval 
eCRF 
electronic case report form 
FEV1 
forced expiratory volume in 1 second 
Lobectomy 
Refers to the removal of a lobe (or lobes). 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
magnetic resonance 
MRI 
magnetic resonance imaging 
Resection  
For this study, the definition of resection surgery includes segmentectomies, 
lobectomies, and pneumonectomies.   
n 
Number of observations 
PT 
preferred term 
SAP 
statistical analysis plan 
SOC 
system organ class 
SpO2 
peripheral capillary oxygen saturation 
SD 
standard deviation  
TEAE 
Treatment-emergent adverse event 
Xe 
xenon 
 


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1. INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for Polarean’s pivotal Phase 3 study 
POL-Xe-001.  
This document is prepared on the basis of the study protocol version Amendment 3 (dated 
26 April 2018).  The reader is referred to the study protocol, the electronic case report form 
(eCRF), general eCRF completion guidelines, and various data collection instruments employed 
in the study for details of study design, conduct and data collection.   
This SAP is to be reviewed, approved, and submitted to FDA prior to study database lock.  If any 
SAP updates are made upon blinded review of study data, or for any other reasons in the course 
of the study, such modifications and rationale are likewise to be documented and approved prior 
to unblinding of the study database.  
1.1. 
Study Objectives 
1.1.1. 
Primary Objectives 
The primary objective of this study is to demonstrate the equivalence of hyperpolarized 129Xe 
magnetic resonance imaging (MRI) as compared to 133Xe scintigraphy for the evaluation of 
pulmonary function. 
1.1.2. 
Secondary Objective  
The secondary objectives of this study are to:  
• Assess the safety and tolerability of hyperpolarized 129Xe gas; 
• Evaluate regional ventilation defects in each of the 6 zones, and 
• Demonstrate the equivalence of post-operative forced expiratory volume in 1 second 
(FEV1) values predicted using hyperpolarized 129Xe as compared to 133Xe scintigraphy. 
1.2. 
Overall Study Design and Plan 
This is a multicenter, randomized, open-label, cross-over Phase 3 study evaluating 
hyperpolarized 129Xe MRI as compared to 133Xe scintigraphy for the evaluation of pulmonary 
function.  This study will enroll male and female subjects being evaluated for possible lung 
resection surgery (i.e. segmentectomy, lobectomy, or pneumonectomy).  This study is comprised 
of 4 periods.  
• Screening: Subjects will be screened for study participation based on inclusion and 
exclusion criteria. Informed consent will be obtained.  


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• Imaging: Subjects will undergo both a hyperpolarized 129Xe MRI scan and 133Xe 
scintigraphy.  During the MRI session, one or more conventional proton MRI scans will 
also be collected to confirm lung anatomical features.  Both 133Xe scintigraphy and 
hyperpolarized 129Xe MRI will be quantified using commercially available software.  
Images will be interpreted by central readers who are blinded to the subject’s medical 
history and all study assessments.  Information related to any adverse events (AEs) will 
be collected during this period. 
• Follow-up: Subjects will be contacted by phone on the day after (+3 days) the completion 
of all imaging to collect information on any AEs.  
• Post-op Follow-up: If the subject has lung surgery, approximately 3 months after surgery 
the subject will come in for a post-operative FEV1 measurement (spirometry).  
Following completion of screening and baseline eligibility assessments, all subjects will receive 
both a hyperpolarized 129Xe MRI and 133Xe scintigraphy.  During the MRI session, one or more 
proton MRI scans will also be collected to confirm lung anatomical features.  If a subject 
undergoes resection surgery, an additional study visit to record post-operative FEV1 levels 
(spirometry) will be required approximately 3 months after surgery. 
Safety will be monitored after the administration of both hyperpolarized 129Xe and 133Xe (Day 1) 
and again on Day 2 during the Imaging Follow-up period. 
1.3. 
Randomization and Blinding 
All randomized subjects will be divided between 2 treatment sequences in a 1:1 ratio.  Subjects 
will be randomized to receive either 129Xe followed by 133Xe, or 133Xe followed by 129Xe.  All 
subjects will receive at least 1 dose of hyperpolarized 129Xe and 1 dose of 133Xe during study 
participation.  
This is an open-label study.  Images generated from this study will be interpreted by a trained 
central reader, blinded to the subject’s medical history and all study assessments.  The images 
will be uploaded in a blinded manner to a computer for review.  Both 133Xe scintigraphy and 
hyperpolarized 129Xe MRI will be quantified using commercially available software. 
2. DETERMINATION OF SAMPLE SIZE 
The sample size required to demonstrate equivalence is driven by 2 factors: 1) the intra-subject 
variability of the difference between the predicted post-operative FEV1 from the 2 methods, and 
2) the pre-specified equivalence margin.  From prior literature, the intra-subject variability for 
133Xe scintigraphy leads to an estimated variability in predicted post-operative FEV1 of 0.21 L.  
Similarly, prior studies have suggested that the equivalence margin between the 2 imaging 
techniques currently used for resection planning is 0.3 L. Using these assumptions, and based on 


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the use of a two-sided test at the alpha = 0.05 level of significance, a sample size of 15 subjects is 
required for 90% power.  However, given limited literature on 133Xe variability, we have 
accounted for the possibility that it could be higher.  If true variability is 0.32 L, then a sample 
size of 32 subjects will provide 90% power to establish equivalence. 
3. JUSTIFICATION OF EQUIVALENCE MARGIN 
The acceptable equivalence margin between the predicted proportion of remaining function from 
129Xe MRI and 133Xe scintigraphy is justified based on literature describing both variability and 
equivalence margin for the currently available pulmonary function imaging techniques, the 
ventilation-perfusion scan in the field of lung resection and pneumonectomy (Tulchinsky et al., 
2017, Wernly et al., 1980, Win et al., 2006).  This literature permits both variability and 
equivalence margin to be determined by converting the typical predicted post-operative FEV1 
values back to their underlying zonal function percentages.  From prior literature, the 
equivalence margin between the 2 imaging techniques currently used for resection planning is 
0.3 L (Mariano-Goulart et al., 2006).  In this work, the cohort that underwent pneumonectomy, 
had a mean pre-operative FEV1 of 2.02 L.  Assuming the removed lung contributed 50% of total 
function, the equivalence margin of 0.3 L converts in percentage terms to ±14.7%.  This same 
work, showed that in the pneumonectomy population the intra-subject variability for 133Xe 
scintigraphy leads to an estimated variability in predicted post-operative FEV1 of 0.17 L.  Thus, 
using similar calculations suggests the intra-subject standard deviation for 133Xe can be estimated 
in percentage terms to be ±8.3%.  We thus seek to demonstrate an equivalence margin of 14.7% 
between the imaging tests. 
4. STATISTICAL METHODS 
All final statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released.   
All descriptive statistics for continuous variables will be reported using the number of 
observations (n), mean (arithmetic unless otherwise specified), standard deviation (SD), median, 
minimum and maximum.  Categorical variables will be summarized as the number and 
percentage of subjects.  
All inferential statistics will be based on the 5% level of significance (two-sided).   
All data from this study will be presented in listings.  All listings will be sorted by treatment 
sequence, subject number, and visit date, as applicable. 


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4.1. 
Study Endpoints 
4.1.1. 
Primary Efficacy Endpoint 
The primary endpoint is the scan-predicted proportion of pulmonary function that will remain 
after resection of a pre-specified lung area (predicted proportion of remaining function).  The 
scans will be quantified using commercially available software to report the fraction of activity 
arising from 6 lung zones.  This will be used to predict post-operative percentage of function 
remaining in the non-operated zones.  
4.1.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include the post-operative FEV1 value (spirometry) and the 
percentage function assessments (fraction of ventilation) contributed by each of the individual 
6 lung zones. 
4.1.3. 
Exploratory Endpoints 
Exploratory endpoints include: 
• The difference in scan-predicted proportion of remaining function from the 2 methods 
standardized to the 133Xe scintigraphy-predicted remaining function.  This endpoint is 
calculated by the following: 
Δ𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓= 𝑓𝑓𝑟𝑟𝑟𝑟𝑟𝑟129 − 𝑓𝑓𝑟𝑟𝑟𝑟𝑟𝑟133
𝑓𝑓𝑟𝑟𝑟𝑟𝑟𝑟133
 
Where: 
Δ𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓= standardized difference in predicted proportion of remaining function between 
the 2 methods; 
𝑓𝑓𝑟𝑟𝑟𝑟𝑟𝑟129 = 129Xe MRI predicted proportion of remaining function, and 
𝑓𝑓𝑟𝑟𝑟𝑟𝑟𝑟133 = 133Xe scintigraphy predicted proportion of remaining function. 
• Proportion of patients with differences between the 129Xe magnetic resonance (MR)-
predicted proportion of remaining function and the 133Xe scintigraphy-predicted 
proportion of remaining function that exceeds the equivalence margin (-14.7%, +14.7%), 
and 
• Proportion of patients with differences between the 129Xe MR-predicted proportion of 
remaining function and the 133Xe scintigraphy-predicted proportion of remaining function 
that exceeds each of the following ranges:  (-2.5%, +2.5%), (-5%, +5%), (-7.5%, +7.5%), 
(-10%, +10%), (-12.5%, +12.5%). 


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4.1.4. 
Safety Endpoints 
Safety and tolerability will be assessed based on the incidence and severity of AEs and serious 
adverse events.  Additionally, subjects will be monitored before, during, and after each dose to 
monitor for changes in vital signs. 
4.2. 
Study Subjects 
4.2.1. 
Definitions of Analysis Sets  
Efficacy Analysis Set: The Efficacy Analysis Set is the group of subjects who had both a 129Xe 
MRI scan and a 133Xe scintigraphy scan, and for whom both scans met quality control criteria for 
analysis.  The primary and the 6-zone analysis secondary efficacy endpoints will be analyzed 
using the Efficacy Analysis Set. 
Post-operative Analysis Set: The Post-operative Analysis Set is the group of subjects that met the 
criteria for inclusion in the efficacy analysis set, and had a post-operative FEV1 (spirometry) 
value.  The post-operative secondary endpoint will be analyzed using the Post-operative Analysis 
Set. 
Safety Analysis Set: The Safety Analysis Set is the group of subjects who received at least 
1 dose of either hyperpolarized 129Xe or 133Xe. Safety endpoints will be analyzed using the 
Safety Analysis Set.  
Unless otherwise specified, the number and percentage of subjects in each analysis set will be 
summarized by treatment sequence using descriptive statistics.  This and similar summaries will 
be presented by treatment sequence because the washout period between scans is generally short.    
4.2.2. 
Subject Disposition 
Subject disposition will be summarized by treatment sequence for all randomized subjects.  The 
number and percentage of subjects who completed or discontinued prematurely from the study 
and their reason for discontinuation will be summarized by treatment sequence.   
In addition, the number of subjects screened, the number and percentage of screen failures, and 
their primary reason for screen failure will be summarized.  
4.2.3. 
Protocol Deviations 
Protocol deviations will be identified, reviewed and documented by the clinical team prior to 
database lock.  Protocol deviations will be summarized by deviation categories and treatment 
sequence for all subjects.  The listing for protocol deviations, in addition to containing treatment 
sequence, subject number, visit, and deviations (by categories), will also contain several 
categories of demographic information.  


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4.2.4. 
Demographic and Baseline Characteristics 
Demographic and other baseline characteristics for the Efficacy, Post-operative, and Safety 
Analysis Sets will be summarized for each treatment sequence using descriptive statistics, 
separately.  Continuous demographic and baseline variables include age, height, weight, body 
mass index, peripheral capillary oxygen saturation (SpO2) at screening, current cigarettes/day, 
and pack-years of smoking; categorical variables include sex, race, ethnicity, current smoking 
status, and Hypothetical Assessment of Resection Location.    
4.2.5. 
Medical History 
All medical histories as documented by the Medical and Surgical History eCRF will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) Version 20.1. 
The number and percentage of subjects with any medical history will be summarized by System 
Organ Class (SOC) and preferred term (PT) for each treatment sequence based on the Safety 
Analysis Set.    
4.2.6. 
Vital Signs and Physical Examination at Screening 
Results of vital signs and physical examinations at screening will be summarized for each 
treatment sequence using descriptive statistics. 
4.2.7. 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the eCRF will be coded using the World 
Health Organization Drug Dictionary Version 01 September 2017. 
Prior medications are defined as medications that stopped before the first dose of study product.  
Concomitant medications are defined as medications that (1) started before the first dose of study 
product and are continuing at the time of the first dose of study product, or (2) started on or after 
the date of the first dose of study product.  
The number and percentage of subjects who take concomitant medications will be summarized 
using the Safety Analysis Set by treatment sequence, Anatomical Therapeutic Chemical (ATC) 
class, and PT.  If a subject takes the same medication for the same ATC class or PT, the subject 
will be counted only once for that ATC class or PT. Prior and concomitant medications will be 
listed separately. 
Oxygen flow rate for subjects who used supplemental oxygen will be summarized using 
descriptive statistics.   
Patients who used an inhaler will be summarized using descriptive statistics.   


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4.2.8. 
Exposure to Study Treatments  
The polarization (%) of 129Xe and the dose amount of 133Xe will be summarized using descriptive 
statistics.  One summary will include data for only those subjects who received only 1 full dose 
of 129Xe in addition to their dose of 133Xe.  A second summary will include data for only those 
subjects who took 2 full doses of 129Xe in addition to their dose of 133Xe.    
The duration between the time of dosing with 129Xe and the time of polarization will be 
summarized using descriptive statistics.  As in the paragraph above, there will be separate 
summaries for subjects with only 1 full dose of 129Xe and subjects with 2 full doses of 129Xe.   
4.3. 
Data Analysis General Considerations 
4.3.1. 
Handling of Missing Data  
Except for the AE causal relationship to the study drug and AE severity (see Section 4.6.1), 
missing values will not be substituted by estimated values, but treated as missing in the statistical 
evaluation.  Missing efficacy values are not anticipated as all subjects included in the efficacy 
analysis set must provide acceptable images for both 129Xe MRI and 133Xe scintigraphy.  All data 
from all subjects dosed in the study will be included in all listings, plots, summary tables, and 
statistical analyses when appropriate. 
4.3.2. 
Visit Windows 
There are no visit windows for this study, while time windows are allowable for study 
assessments as shown in Appendix 11.1.  For the statistical analyses, data will be analyzed by 
their time point of collection. 
4.4. 
Efficacy Analyses 
Unless specified otherwise, the efficacy endpoints will be summarized and analyzed using the 
Efficacy Analysis Set. 
4.4.1. 
Primary Efficacy Analysis 
The primary analysis for this study will be to test the mean difference in the predicted proportion 
of remaining function as measured using hyperpolarized 129Xe MRI relative to the value as 
measured by 133Xe scintigraphy (reference standard).  The primary analysis will be conducted by 
estimating the two-sided 95% confidence interval (CI) for the mean difference in predicted 
proportion of remaining function from the 2 methods.  
The calculation of the predicted proportion of remaining function will be based on pre-operative 
imaging and the extent of planned lung resection.  The scans will be quantified using 
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H0: |Δ|>14.7% 
HA:|Δ|<14.7% 
The listing for the efficacy data will present data for all 6 zones for both imaging methods and 
indicate the zones expected to be resected.   
4.4.2. 
Secondary Efficacy Analyses  
4.4.2.1. 
By-Zone Analysis 
The by-zone secondary analysis for this study will be evaluated by comparing the individual 
percentage function assessments (fraction of ventilation) from each of the 6 zones as derived 
from the 129Xe and the 133Xe ventilation images.  The equivalence analysis will be conducted 
using similar methodology to that in the primary efficacy analysis, and the equivalence margin 
will be ±5 percentage points.  Thus, for each of the 6 zones, equivalence will have been 
demonstrated if the 95% CI for mean difference between the 2 methods is contained within the 
interval (-5%, +5%). 
4.4.2.2. 
Post-Operative Analysis 
The post-operative secondary analyses for this study will be to compare the final measured post-
operative FEV1 value (spirometry) to those predicted by both hyperpolarized 129Xe MRI and 
133Xe scintigraphy.  
The calculation of predicted post-operative FEV1 will be based on pre-operative imaging and the 
extent of planned lung resection.  The scans will be quantified using commercially available 
software to report the fraction of activity arising from each of 6 lung zones, 3 in each lung.  On 
the eCRF, the surgeon will check the zones that are planned for resection.  The predicted post-
operative FEV1 will be calculated by multiplying the percentage of function remaining in the 
non-operated zones by the pre-operative FEV1.  For example, assume that the quantified 
fractions of activity for zone 1 to zone 6 are 15%, 20%, 25%, 10%, 15% and 15%, respectively 
and the surgeon notes that zone 4 and zone 5 are planned for complete resection.  Then, the 
predicted post-operative FEV1 = pre-operative FEV1 * {(15%+20%+25%) + (15%)}. 
For each of these two comparisons, the null hypothesis that the mean difference is equal to zero, 
will be tested using the one-sample t test.  The two-sided 95% CI for the mean difference will 
also be reported.  A third comparison will be to test the null hypothesis that the mean difference 
between predicted post-operative FEV1 (measured in L) predicted by hyperpolarized 129Xe MRI 
and 133Xe scintigraphy is equal to zero.  This analysis will also be conducted using the one-
sample t test and the two-sided 95% CI for the mean difference will be reported. 


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This analysis will use the Post-operative Analysis Set.  Because the final post-operative FEV1 
value will be obtained approximately 3 months after surgery, this post-operative secondary 
analysis will be performed about 3 months after the other planned statistical analyses.   
4.5. 
Exploratory Analyses 
As a result of comments and discussion on Version 1.0 of this SAP from the FDA prior to 
database lock, the following analyses will be included as exploratory analyses. 
4.5.1. 
Difference in Predicted Proportion of Remaining Function Standardized to that 
Predicted by the Reference Standard (133Xe Scintigraphy) 
To standardize each patient’s results, predicted remaining function will be expressed as the 
difference between 129Xe MR and 133Xe scintigraphy predicted proportion of remaining function 
divided by the 133Xe-predicted proportion of remaining function.  The two-sided 95% CI for the 
mean difference will be estimated and presented as described for the primary endpoint. 
4.5.2. 
Patient-Level Equivalence between 129Xe MR-Predicted Remaining Function and 
133Xe Scintigraphy-Predicted Remaining Function 
To evaluate the equivalence of the scan methods on a patient level, the proportion of patients will 
be reported whose difference in scan-predicted proportion of remaining function from 129Xe MRI 
vs 133Xe scintigraphy exceeds the equivalence margin (-14.7%, +14.7%).  These results will also 
be presented using each of the ranges specified in Section 4.1.3. 
4.6. 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  Safety data, where presented 
by treatment, will be summarized on an “as treated” basis using descriptive statistics (e.g., n, 
mean, SD, median, minimum, and maximum for continuous variables; n [%] for categorical 
variables).  Safety variables include AEs and change from baseline in vital signs and SpO2. 
4.6.1. 
Adverse Events 
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the MedDRA.  AEs will be coded to the MedDRA 
(Version 20.1) lower level term closest to the verbatim term. The linked MedDRA PT and 
primary SOC are also captured in the database.  
Per CRF design, all reported AEs are treatment-emergent adverse events (TEAEs) and will be 
included in summary tables.  An overview of the TEAEs will be summarized by treatment 
sequence and overall, including the number and percentage of subjects who experience TEAEs, 
serious TEAEs, study drug-related TEAEs, TEAEs by maximum severity, and TEAEs leading to 


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death or to discontinuation from study treatment.  This and similar summaries will be provided 
by treatment sequence because the washout period between scans is generally short, and the 
hypothetical lag period between a scan and an AE potentially associated with drug product is of 
unknown duration.   
The number and percentage of subjects with TEAEs will be summarized by SOC and PT for 
each treatment sequence and overall.  A subject will be counted only once within a SOC and PT, 
even if the subject experienced more than one TEAE within that specific SOC and PT.  
The number and percentage of subjects with TEAEs will be summarized by maximum severity 
(mild, moderate, or severe). If severity is missing, the TEAE will be regarded as severe.  
The number and percentage of subjects with TEAEs will be summarized by causality to study 
drug (related/unrelated).  AEs recorded as being related to study drug includes all AEs marked as 
having a reasonable possibility of being related to the study drug.  AEs recorded as being 
unrelated to study drug includes all AEs marked as having no reasonable possibility of being 
related to study drug.  If causality is missing, the TEAE will be regarded as related to study drug. 
In addition to the TEAE summaries by relationship to study drug, the number and percentage of 
subjects with TEAEs will be summarized by the relationship to scan procedure (129Xe or 133Xe), 
as judged by investigator.  
The number and percentage of subjects with TEAEs leading to death will be summarized by 
SOC and PT for each treatment sequence and overall.  A subject data listing of all TEAEs 
leading to death will also be provided.  
The number and percentage of subjects with serious TEAEs will be summarized by SOC and PT 
for each treatment sequence and overall.  A subject data listing of all serious TEAEs will also be 
provided. 
The number and percentage of subjects with TEAEs leading to discontinuation from study 
treatment will be summarized by SOC and PT for each treatment sequence and overall.  A 
subject data listing of all TEAEs leading to discontinuation from study treatment will also be 
provided. 
The number and percentage of subjects with a subjective sensation of residual anesthesia (e.g., 
lightheadedness, loss of sensation or awareness, loss of memory, or unconsciousness) will be 
summarized by PT for each treatment sequence and overall.  Any such AEs related to subjective 
sensation of residual anesthesia will be identified by the sponsor and medical monitor prior to 
unblinding. 


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4.6.2. 
Analysis of Vital Signs and Peripheral Capillary Oxygen Saturation  
Descriptive statistics for vital sign parameters (i.e., diastolic and systolic blood pressure, heart 
rate, respiration rate, and temperature) and SpO2, and their changes from before each study drug 
scan to after that study drug scan will be summarized by each treatment (129Xe and 133Xe).  Also, 
if a subject takes a 2nd full dose of 129Xe with accompanying vital sign and SpO2 assessments, the 
changes from before the scan with the 2nd dose of 129Xe to after that scan will be summarized 
separately.  In addition, the shifts (normal to abnormal and vice versa) from before study drug 
scan to after study drug scan of blood pressure and heart rate evaluation will be summarized by 
each treatment. 
5. INTERIM ANALYSES 
No interim analyses are planned for this study.  
6. SUBGROUP ANALYSIS FOR EFFICACY  
Subgroup summaries for the primary efficacy endpoint will be provided separately by the 
following subgroups using the same methods as described in Section 4.4.1. 
• Age group (<65 and ≥65 years old);  
• Gender (male and female); 
• Race (white and other); 
• Current smoking status (current smoker and non-current smoker); 
• Inhaler use (Yes and No), and  
• Oxygen use (Yes and No). 
7. STATISTICAL SOFTWARE 
Analysis will be performed using SAS for Windows (release 9.4). 
8. MOCK TABLES, LISTINGS AND FIGURES 
The study tables, listings and figure shells will be provided in a separate document, which will 
show the content and format of all tables, listings, and figures in detail. 


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9. CHANGES FROM THE PROTOCOL 
9.1. 
Analysis Populations 
9.1.1. 
Efficacy Analysis Set 
The inclusion criteria for the efficacy analysis set was revised to clarify that both the 129Xe MRI 
and 133Xe scintigraphy scan images must meet quality control criteria for inclusion in the 
efficacy analysis set (refer to Section 4.2.1). 
9.1.2. 
Post-operative Analysis Set 
The definition of the post-operative population was revised to clarify that that both the 129Xe 
MRI and 133Xe scintigraphy scan images must meet quality control criteria for inclusion in the 
efficacy analysis set (refer to Section 4.2.1). 
9.2. 
Primary Efficacy Endpoint 
Following discussion of Version 1.0 of the SAP with the FDA, the primary efficacy endpoint 
was revised.  The protocol states that the primary efficacy endpoint is the scan predicted post-
operative FEV1.  The scan-predicted FEV1 is calculated by multiplying the subject’s baseline 
FEV1 by the proportion of remaining function predicted by each scan.  However, inclusion of 
the baseline FEV1 as part of the endpoint potentially introduces unnecessary variability in the 
comparison of 129Xe MRI and 133Xe scintigraphy.  Thus, the primary efficacy endpoint was 
revised to directly compare 129Xe MRI to 133Xe scintigraphy without inclusion of the baseline 
FEV1 (refer to Section 4.1.1).   
The primary endpoint is the scan-predicted proportion of pulmonary function that will remain 
after resection of a pre-specified lung area (predicted proportion of remaining function).   
9.3. 
Primary Efficacy Analysis 
The primary efficacy analysis (Section 4.4.1) was revised to account for the comparison of the 
scan-predicted remaining function from 129Xe MRI and 133Xe scintigraphy without inclusion of 
the baseline FEV1 in the primary efficacy endpoint.  The equivalence margin is expressed in 
terms of percent remaining function instead of FEV1, measured in L.  The revised equivalence 
margin is (-14.7%, +14.7%).   
9.4. 
Secondary Efficacy Analyses 
The post-operative secondary analysis was revised to provide a comparison between the 
measured post-operative FEV1 and each scan-predicted post-operative FEV1.  An additional 


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analysis was added to compare the difference between predicted post-operative FEV1 from each 
scan. 
9.5. 
Exploratory Endpoints 
As a result of discussion of Version 1.0 of the SAP with the FDA, 2 exploratory endpoints were 
added. 
• The difference in scan-predicted proportion of remaining function from the 2 methods 
standardized to the 133Xe scintigraphy-predicted remaining function. 
• Proportion of patients with differences between the 129Xe MR-predicted proportion of 
remaining function and the 133Xe scintigraphy-predicted proportion of remaining function 
that exceeds the equivalence margin (-14.7%, +14.7%). 
An additional exploratory endpoint was added by the Sponsor. 
• Proportion of patients with differences between the 129Xe MR-predicted proportion of 
remaining function and the 133Xe scintigraphy-predicted proportion of remaining function 
that exceeds each of the following ranges:  (-2.5%, +2.5%), (-5%, +5%), (-7.5%, +7.5%), 
(-10%, +10%), (-12.5%, +12.5%). 
9.6. 
Exploratory Analyses 
Section 4.5 was added to the SAP to describe the analysis of the added exploratory endpoints.   
10. REFERENCES 
Mariano-Goulart D, Barbotte E, Basurko C, Comte F, Rossi M.  Accuracy and precision of 
perfusion lung scintigraphy versus Xe-133-radiospirometry for preoperative pulmonary 
functional assessment of patients with lung cancer.  Eur J Nucl Med Mol Imaging.  
2006;33(9):1048-54. 
Tulchinsky M, Fotos JS, Wechalekar K, Dadparvar S.  Applications of ventilation-perfusion 
scintigraphy in surgical management of chronic obstructive lung disease and cancer.  Semin 
Nucl Med.  2017;47(6):671-9. 
Wernly JA, Demeester TR, Kirchner PT, Myerowitz PD, Oxford DE, Golomb HM.  Clinical 
value of quantitative ventilation-perfusion lung scans in the surgical management of 
bronchogenic carcinoma.  J Thorac Cardiovasc Surg.  1980 Oct;80(4):535-43. 


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Win T, Tasker AD, Groves AM, White C, Ritchie AJ, Wells FC, Laroche CM.  Ventilation-
perfusion scintigraphy to predict postoperative pulmonary function in lung cancer patients 
undergoing pneumonectomy.  AJR Am J Roentgenol.  2006 Nov;187(5):1260-5. 
 


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11. APPENDIX 
11.1. Schedule of Events   
 
Screening1 
Imaging1 
Imaging Follow-up2 
Post-Op Follow-up 
Evaluation 
Day -7 to Day 0 
Day 1 
Day 2 
1-2 Months Post-Op 
Informed Consent 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
Demographics and Medical History3 
X 
X 
 
 
Physical Exam 
X 
 
 
 
Concomitant Medications Review 
X 
X 
 
 
MRI-suitable Screening 
X 
 
 
 
Recording of potential resection 
location on eCRF 
X 
 
 
 
Spirometry (FEV1)4 
 
X 
 
X 
129Xe Administration1 
 
X 
 
 
Anatomical proton MRI (MRI 
session only) 
 
X 
 
 
133Xe Administration1 
 
X 
 
 
Vital Signs5,6 
X 
X 
 
 
SpO27 
X 
X 
 
 
Adverse Events8  
 
X 
X 
 
Local Laboratory Tests 
 
 
 
 
Serum Pregnancy Test9 
X 
 
 
 
Abbreviations: eCRF = electronic case report form; FEV1 = forced expiratory volume; MRI = magnetic resonance imaging; 
Op = operative; SpO2 = arterial oxygen saturation.   
1 Screening and Imaging study periods can occur on the same day or on different days, however there should be ≤48 hours 
between administration of the study drug and reference standard scans.  
2 The Follow-Up period will occur on the day after (+3 days) the completion of all imaging and prior to resection surgery. 
3 Medical history will include any pulmonary function values (i.e. FEV1) from the subject files as well as smoking history.   
4 FEV1 measurement should occur prior to administration of the study drug and reference standard scans.   
5 Vital Signs (including heart rate, respiration rate, temperature, and blood pressure) will be assessed before and after each 
scanning session (both 129Xe and 133Xe). Subjects will have a 5-minute rest in a supine position before vital signs are assessed. 
6 Changes in heart rate of greater than ±20% are considered significant. If the subject is to receive another dose, the next dose 
will not be administered until the heart rate is within 20% of its baseline value. If the subject has received their last dose, they 
will be observed until their heart rate is within 20% of its baseline value. The subject will be monitored for the duration of the 
MRI exam by a qualified medical professional. 
7 SpO2 is measured at baseline as well as before and after each scanning session (both 129Xe and 133Xe). An absolute decrease of 
SpO2 by greater than 10% is considered significant. If the subject is to receive another dose, the next dose will not be 
administered until the SpO2 is within 10% of its baseline value. If the subject has received their last dose, they will be observed 
until the SpO2 is within 10% of its baseline value. The subject will be monitored for the duration of the MRI exam by a qualified 
medical professional. 
8 Subjects will be monitored for any subjective sensation of residual anesthesia (e.g., lightheadedness, loss of sensation or 
awareness, loss of memory, or unconsciousness). If the subject is to receive another dose, the next dose will not be administered 
until the sensation has resolved. If the subject has received their last dose, they will be observed until the sensation has resolved. 
The subject will be monitored for the duration of the MRI exam by a qualified medical professional. 
9 Eligibility assessment will include, if applicable, a negative pregnancy test.