Clinical trial NCT03054870
Conditions: Lung Structure Determination
Keywords: pulmonary ventilation ventilation scintigraphy
Sponsor: Cyclomedica Australia PTY Limited
Start date: 2017-09-01; Completion date: 2020-11-23
Enrollment: 226 participants; Allocation: NA; Intervention model: CROSSOVER

Brief summary:
Phase 3 within-subject non-inferiority trial of Technegas ventilation imaging compared to Xenon-133 (Xe-133) ventilation imaging to demonstrate the non-inferiority of Technegas compared to Xe-133 ventilation studies with respect to subject pulmonary ventilatory distribution. Subjects will undergo site-specific standard of care (SOC) Xe-133 imaging per medical needs followed by Technegas ventilation imaging per study protocol.

Detailed description:
This is a Phase 3 within-subject non-inferiority trial of Technegas ventilation imaging compared to Xenon-133 (Xe-133) ventilation imaging to demonstrate the non-inferiority of Technegas compared to Xe-133 ventilation studies with respect to subject pulmonary ventilatory distribution. Subjects will undergo site-specific standard of care (SOC) Xe-133 imaging per medical needs followed by Technegas ventilation imaging per study protocol. Primary assessments of efficacy will be based on three blinded readers' assessments of the Technegas and Xe-133 ventilation images in independent reading sessions.

Arms: arm 1: Subjects first inhaled active comparator Xe-133, approximately 10 to 30 millicuries (mCi), and ventilation planar scintigraphy was performed per site standard of care procedures for subject medical need. On the same day, following completion of Xe-133 imaging, subjects inhaled experimental Technegas (Technetium-99m labeled carbon particles), approximately 1.1 mCi, and ventilation planar scintigraphy was performed.
Interventions: intervention 1: Xe-133 intervention 2: Technegas
Intervention descriptions: intervention 1: Xe-133 ventilation scintigraphy intervention 2: Technegas ventilation scintigraphy

Protocol documents:
Prot_SAP_001.pdf: 
5.3.5.1 Efficacy and Safety 
Page 1 
Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
 
CONFIDENTIAL 
 
 
NCT03054870 
 
Clinical Study Protocol 
 
 
A Comparison of Technegas® and Xenon 133 Planar Lung Imaging in Subjects 
Referred for Ventilation Scintigraphy 
 
Protocol Number:  CYC-009 
 
 
Phase 3 Study 
 
 
 
 
Sponsor:  
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
Phone Number:  +61 2 9541 0411 
Fax Number:  +61 2 9543 0960 
Gary Somerville 
E-mail:  gsomerville@Cyclomedica.com.au  
 
 
 
Original Protocol (Version 1.1) 
Date: 4 October 2016 
 
Protocol Amendment 1 
 
Date: 2 November 2018 
 
 
The information contained in this document is confidential and, except to the extent 
necessary to obtain approval by your Institutional Review Board/Independent Ethics 
Committee and informed consent, cannot be disclosed unless required by federal law or 
governmental regulation.  Persons to whom any portion of the contents of this document is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 
 


5.3.5.1 Efficacy and Safety 
Page 2 
Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
Sponsor Approval  
 
 
 
 
 
 
 
 
 
 
Name and Title 
 (Signature and title of Sponsor’s Responsible Party) 
 
Date 
 
 
 
 
 


5.3.5.1 Efficacy and Safety 
Page 3 
Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
Sponsor Approval (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name and Title 
 (Signature and title of Sponsor’s Study Statistician or other 
responsible party) 
 
Date 
 


5.3.5.1 Efficacy and Safety 
Page 4 
Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
Investigator’s Signature  
 
 
 
 
Investigator’s Printed Name 
 
 
 
 
 
Investigator’s Signature 
 
Date 
 


5.3.5.1 Efficacy and Safety 
Page 5 
Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
1 
Study Synopsis 
Name of Sponsor: 
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
 
(For National Authority Use 
Only) 
Name of Finished Product: 
Technegas 
Name of Active Ingredient: 
Tc-99m labeled carbon 
Title of Study: 
A Comparison of Technegas® and Xenon 133 Planar Lung Imaging in Subjects Referred 
for Ventilation Scintigraphy 
Protocol Number:   
CYC-009 
Investigators and Study Center(s):   
To be determined 
Phase of Development:  
Phase 3 
Primary Objectives: 
1. To demonstrate the non-inferiority of Technegas compared to Xenon 133 (Xe-133) 
ventilation studies, using planar scintigraphic imaging, with respect to their 
pulmonary ventilatory distribution in subjects that are candidates for ventilation 
imaging. 
2. To assess the safety profile of Technegas by monitoring adverse events (AEs), pulse 
oximetry, and vital signs pre- and post-Technegas administration. 
Methodology:  
The design of this study is a Phase 3 within-subject non-inferiority trial of Technegas 
ventilation imaging compared to Xe-133 ventilation imaging.  Subjects referred for 
ventilation scintigraphy will have undergone a chest X-ray, and will undergo planar Xe-
133 imaging followed by planar Technegas imaging.  Xe-133 images will include site-
specific standard of care wash-in and wash-out views.  Site-specific standard of care Xe-
133 images are most commonly either posterior and posterior oblique image views or 
alternatively posterior and anterior image views.  Technegas images will include a six 
view image set: anterior, posterior, left posterior oblique, right posterior oblique, left 
anterior oblique, and right anterior oblique views. 


5.3.5.1 Efficacy and Safety 
Page 6 
Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
Name of Sponsor: 
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
 
(For National Authority Use 
Only) 
Name of Finished Product: 
Technegas 
Name of Active Ingredient: 
Tc-99m labeled carbon 
The non-inferiority margin to be used in this study was principally determined from a 
study conducted under Protocol CYC-010.  Using the same efficacy assessments as 
planned for this study; the CYC-010 study compared a first read and second re-read of 75 
Xe-133 lung images, spaced at least 4 weeks apart, to establish a non-inferiority margin 
for two successive reads of Xe-133 images.  Since Xe-133 is an approved agent for 
ventilation imaging, it by default is considered non-inferior to itself, and hence provides a 
suitable limit for establishing the non-inferiority of Technegas compared to Xe-133.   
Primary assessments of efficacy will be based on three blinded readers’ assessments of 
the Technegas and Xe-133 ventilation images in independent reading sessions.  In each 
reading session, readers will visually divide each lung into three regions of approximately 
equal size arranged craniocaudally and designated as the right and left apical, mid and 
basal regions.  Based on the image set presented, readers will provide a ventilation score 
for each lung region: 0 = absent ventilation, 1 = decreased ventilation, or 2 = normal 
ventilation.  For the blinded reads of the Xe-133 images, readers will be presented with all 
acquired ventilation image views for a subject and will assign a single ventilation score to 
each region.  For the reads of the Technegas images, readers will first be presented with 
the subset of ventilation image views that match the views acquired with Xe-133 and will 
assign ventilation scores to each lung region based on those views.  They will then be 
presented with the additional Technegas image views and will assign a second score 
based on the complete set of Technegas images.  The ventilation scores will be used to 
derive a binary agreement score for the paired Technegas and Xe-133 images by subject 
and lung region.  For the primary endpoint analysis, agreement scores will be determined 
from matching Technegas and  
Xe-133 image views only. Agreement scores based on all Technegas image views 
compared to the Xe-133 images will provide a secondary efficacy endpoint. 
After approximately 40 subjects have completed the study, an interim pilot blind read of 
the Xe-133 and Technegas ventilation images will be conducted to assess the viability of 
the planned efficacy measurements for comparing the Technegas and Xe-133 image sets 
for demonstrating non-inferiority.  If it is determined that the initial study design and 
efficacy parameters are not viable due to the differences in the image sets being acquired, 


5.3.5.1 Efficacy and Safety 
Page 7 
Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
Name of Sponsor: 
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
 
(For National Authority Use 
Only) 
Name of Finished Product: 
Technegas 
Name of Active Ingredient: 
Tc-99m labeled carbon 
the protocol will either be amended in accordance with Agency input, or the study may be 
terminated. The readers performing the interim blind read will not be used for the final 
blind read of images, and unless imaging parameters change, the images from these first 
40 subjects will be included in the final read of images.   
Number of Subjects Planned:  
Two hundred and forty (240) subjects who complete the study are planned. The subject 
must have completed all Xe-133 and Technegas planar ventilation imaging as required by 
the protocol, and the images must be of interpretable image quality according to site 
investigators’ assessments.   
Diagnosis and Main Criteria for Inclusion:  
• Male or female subject at least 18 years of age. 
• Subject is a candidate for ventilation imaging. 
• Subject must be willing and able to provide informed consent. 
• Subject must be stable and able to undergo Xe-133 planar imaging and Technegas 
planar imaging. 
• Subject must be willing and agree to complete study procedures. 
• Subject is using adequate birth control, if female and fertile. Adequate birth control is 
defined as surgical sterilization, hormone contraceptive use or intrauterine device 
(IUD). 
• Female subject has a negative urine or serum pregnancy test. 
• Subject has had or is scheduled to have a chest X-ray within 24 hours prior to the 
investigational imaging study. 


5.3.5.1 Efficacy and Safety 
Page 8 
Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
Name of Sponsor: 
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
 
(For National Authority Use 
Only) 
Name of Finished Product: 
Technegas 
Name of Active Ingredient: 
Tc-99m labeled carbon 
Investigational Drug, Dose and Mode of Administration: 
The investigational drug is Technegas. Technegas consists of aerosolized particles of 
carbon labeled with Tc-99m that are dispersed in high purity argon gas. It is manufactured 
at point of use before administration using a computer controlled and operated automated 
synthesis module (TechnegasPlus Generator System). 
Subjects will inhale Technegas aerosol until an adequate amount of radioactivity has 
localized in the lungs.  The amount required for imaging should produce 1.5-2.5 kilo-
counts per second (kcps) in the posterior projection as measured on a gamma camera.  
This equates to approximately 1.1 millicurie (mCi) (40 Megabecquerel [MBq]). 
Reference Therapy, Dose and Mode of Administration:  
Xenon 133 (Xe-133) gas, an approved imaging agent for assessment of pulmonary 
function and for imaging of the lungs, will be used as the comparator. 
Subjects will be administered between 10-30 mCi (370-1110 MBq) of Xe-133 for planar 
ventilation imaging. 
Study Duration:   
Study duration is approximately one to two days.  Subjects will undergo screening 
procedures.  Immediately thereafter, qualified subjects will be enrolled in the study.  The 
subject will first undergo a Xe-133 planar imaging study.  As soon as practical, but no 
longer than 24 hours after completing the Xe-133 imaging study, subjects will undergo a 
Technegas planar imaging study.  
Criteria for Evaluation: 
Efficacy: 
The primary endpoint is the percent agreement between Technegas and Xe-133 obtained 
from the blinded readers’ ventilation assessments of matching image views.  It will be 
derived as follows.  Comparing a reader’s Technegas and Xe-133 ventilation scores for 
each subject, a binary agreement score will be obtained for each lung region: if the 
Technegas and Xe-133 ventilation scores are the same for the region, it is assigned an 
agreement score of 1, otherwise it is assigned a score of 0 for no agreement.  Each blinded 


5.3.5.1 Efficacy and Safety 
Page 9 
Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
Name of Sponsor: 
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
 
(For National Authority Use 
Only) 
Name of Finished Product: 
Technegas 
Name of Active Ingredient: 
Tc-99m labeled carbon 
reader’s agreement scores for the subjects’ lung regions will be analyzed to determine an 
overall estimate of percent agreement and its confidence interval. 
Secondary endpoints are: percent agreement between Technegas and Xe-133 based 
upon blinded readers’ ventilation assessments of all image views (not just matched image 
views); percent agreement between Technegas and Xe-133 for the subgroups of subjects 
with and without pleural effusion (as observed in subjects’ chest X-rays); percent 
agreement measuring inter-observer agreement between pairs of blinded readers for their 
Technegas ventilation scores, and for their Xe-133 ventilation scores; and by lung-region 
kappa statistics measuring inter-observer agreement between pairs of blinded readers for 
their Technegas ventilation scores and for their Xe-133 ventilation scores.  
Safety: 
All subjects will be evaluated for safety throughout the study.  Vital signs (systolic blood 
pressure, diastolic blood pressure, pulse, and respiratory rate) and pulse oximetry will be 
collected prior to Xe-133 administration (baseline safety) and at various times during the 
study up to 15 minutes post-Technegas administration.  AEs will be monitored throughout 
the study until subject discharge.  
Statistical Methods: 
Tabulation of summary statistics, graphical presentations, and statistical analyses will be 
performed using SAS® software.  All testing and confidence intervals will use a two-sided 
significance level of 5%, unless otherwise stated. 
Efficacy: 
Each blinded readers’ binary agreement scores will be analyzed using a generalized linear 
model with SAS® PROC GENMOD.  The logit function (log odds ratio) will be specified 
as the link function, and subject will be specified as a repeated measure to allow for 
correlations between lung regions within a subject.  The estimate of the intercept of the 
model using generalized estimating equation (GEE) methodology will provide an overall 
estimate of the agreement and its 95% confidence interval in terms of the log odds ratio; 
simple algebra will be used to obtain the corresponding estimates and confidence intervals 


5.3.5.1 Efficacy and Safety 
Page 10 
Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
Name of Sponsor: 
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
 
(For National Authority Use 
Only) 
Name of Finished Product: 
Technegas 
Name of Active Ingredient: 
Tc-99m labeled carbon 
in terms of percent agreement (PA). 
The non-inferiority hypothesis to be tested is: 
 
H0: PA   60%  versus  HA: PA > 60% 
If the lower boundary from the 95% confidence interval for the PA difference is greater 
than 60%, Technegas will be considered non-inferior to Xe-133 with respect to the 
measurement of pulmonary ventilatory distribution. 
Study Success Criteria:  For the study to be deemed a success, the null hypothesis must be 
rejected for PA for at least two of the blinded readers for the primary efficacy endpoint. 
Inter-observer agreement between pairs of readers of Technegas images, and between 
pairs of readers of Xe-133 images will be evaluated using the GEE methodology that 
takes into account correlations between lung regions within a subject.  Ninety-five percent 
(95%) confidence intervals will be obtained for the agreement.  In addition, by lung-
region kappas will be obtained for pairs of readers of Technegas images and pairs of 
readers of Xe-133 images.  
 
Safety: 
Frequency distributions will be used to summarize the qualitative safety data, including 
adverse events, clinically significant changes in vital signs, and clinically significant 
oxygen saturation measurements that fall below 90%.   
Summary statistics will be provided for all continuous safety data including change in 
vital signs and oxygen saturations.  Paired t-tests or the signed rank test will be used to 
test for statistically significant changes over time.   
 


5.3.5.1 Efficacy and Safety 
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Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
2 
Table of Contents 
Sponsor Approval ..................................................................................................................... 2 
Investigator’s Signature ............................................................................................................ 4 
1 
Study Synopsis ........................................................................................................ 5 
2 
Table of Contents .................................................................................................. 11 
3 
Abbreviations ........................................................................................................ 15 
4 
Background Information ....................................................................................... 17 
4.1 
Description of Investigational Product ................................................................. 17 
4.2 
Summary of Nonclinical Studies .......................................................................... 19 
4.3 
Radiation Dosimetry ............................................................................................. 20 
4.4 
Summary of Risks and Benefits ............................................................................ 20 
4.4.1 
Warnings, Precautions, and Contraindications ................................................. 20 
4.5 
Route of Administration, Dosage, Dosage Regimen and Treatment Period ........ 20 
4.6 
Treatment Compliance .......................................................................................... 21 
5 
Study Objectives and Purpose .............................................................................. 22 
6 
Trial Design .......................................................................................................... 23 
6.1 
Primary and Secondary Efficacy Endpoints ......................................................... 24 
6.1.1 
Primary Efficacy Endpoint ............................................................................... 24 
6.1.2 
Secondary Efficacy Endpoints .......................................................................... 24 
6.1.3 
Safety Endpoints ............................................................................................... 24 
6.2 
Randomization and Blinding ................................................................................ 25 
6.3 
Treatment, Dosage, and Dosage Regimen ............................................................ 25 
6.3.1 
Investigational Drug Dose and Mode of Administration:................................. 25 
6.3.2 
Reference Therapy, Dose and Mode of Administration: .................................. 26 
6.4 
Study Period .......................................................................................................... 26 
6.5 
Discontinuation Criteria ........................................................................................ 26 
6.5.1 
Subject Discontinuation or Termination ........................................................... 26 
6.5.2 
Study or Site Termination ................................................................................. 27 
6.6 
Accountability of Investigational Drug ................................................................ 27 
6.6.1 
Receipt of Investigational Drug ........................................................................ 27 
6.6.1.1 
TechnegasPlus Generator .......................................................................... 27 
6.6.1.2 
Technegas Crucibles .................................................................................. 27 
6.6.1.3 
Technegas Patient Administration Set (PAS) ............................................ 28 
6.6.1.4 
Argon Gas Source ...................................................................................... 28 
6.6.1.5 
Source of Tc-99m Sodium Pertechnetate Injection ................................... 28 
6.6.2 
Disposition of Unused Investigational Drug..................................................... 28 
7 
Selection and Withdrawal of Subjects .................................................................. 29 
7.1 
Inclusion Criteria .................................................................................................. 29 
7.2 
Exclusion Criteria ................................................................................................. 29 
7.3 
Withdrawal or Termination of Participation ......................................................... 29 
8 
Treatment of Subjects ........................................................................................... 31 


5.3.5.1 Efficacy and Safety 
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Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
8.1 
Treatment Administered ....................................................................................... 31 
8.1.1 
Technegas ......................................................................................................... 31 
8.1.1.1 
TechnegasPlus Generator .......................................................................... 31 
8.1.1.2 
Investigational Agent Preparation ............................................................. 32 
8.1.1.3 
Argon Gas Source ...................................................................................... 32 
8.1.1.4 
Source of Tc-99m Sodium Pertechnetate .................................................. 32 
8.1.2 
Xe-133 Preparation ........................................................................................... 33 
8.2 
Concomitant Medication ....................................................................................... 33 
8.3 
Subject Compliance .............................................................................................. 33 
8.4 
Protocol Deviations ............................................................................................... 33 
9 
Imaging ................................................................................................................. 34 
9.1 
Xe-133 Ventilation and Imaging .......................................................................... 34 
9.2 
Technegas Ventilation and Imaging ..................................................................... 34 
10 
Assessment of Efficacy ......................................................................................... 36 
10.1 
Blinded Read of Xe-133 Images ........................................................................... 36 
10.2 
Blinded Read of Technegas Images ...................................................................... 36 
11 
Assessment of Safety ............................................................................................ 38 
11.1 
Screening/Baseline Assessments .......................................................................... 38 
11.2 
Safety Indicators ................................................................................................... 38 
11.2.1 Clinical Laboratory Measurements ................................................................... 39 
11.2.2 Physical Examinations ...................................................................................... 39 
11.2.3 Vital Signs ......................................................................................................... 39 
11.2.4 Oxygen Saturation of the Blood using Pulse Oximetry .................................... 40 
11.3 
Adverse Events ..................................................................................................... 40 
11.3.1 Suspected Adverse Reaction ............................................................................. 41 
11.3.2 Adverse Reaction .............................................................................................. 41 
11.3.3 Unexpected Adverse Events ............................................................................. 41 
11.3.4 Serious Adverse Events .................................................................................... 41 
11.3.5 Severity of Adverse Events ............................................................................... 42 
11.3.6 Relationship to Study Drug ............................................................................... 43 
11.4 
Procedures for Reporting AEs, SAEs and Suspected Unexpected Serious Adverse 
Reactions (SUSARs) ............................................................................................. 43 
11.4.1 Suspected Unexpected Serious Adverse Reaction (SUSAR) ........................... 45 
12 
Schedule of Efficacy and Safety Assessments...................................................... 46 
12.1 
Visit 1 .................................................................................................................... 46 
12.2 
Schedule of Efficacy and Safety Assessments...................................................... 47 
13 
Statistical Analysis ................................................................................................ 48 
13.1 
General Considerations ......................................................................................... 48 
13.2 
Analysis Populations ............................................................................................. 48 
13.2.1 Disposition ........................................................................................................ 48 
13.2.2 Baseline Characteristics .................................................................................... 49 
13.3 
Efficacy Evaluations ............................................................................................. 49 


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IND 62660; Technegas® 
CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
13.3.1 Primary Efficacy Endpoint ............................................................................... 49 
13.3.2 Secondary Efficacy Endpoints .......................................................................... 49 
13.4 
Efficacy Analyses ................................................................................................. 50 
13.4.1 Primary Efficacy Analyses ............................................................................... 50 
13.4.2 Secondary Efficacy Analyses ........................................................................... 50 
13.5 
Non-Inferiority Margin ......................................................................................... 51 
13.6 
Rationale for Sample Size ..................................................................................... 52 
13.7 
Interim Analysis .................................................................................................... 53 
13.8 
Safety Endpoints ................................................................................................... 53 
13.9 
Safety Analyses ..................................................................................................... 53 
14 
Data Handling and Record Keeping ..................................................................... 54 
14.1 
Case Report Forms ................................................................................................ 54 
14.2 
Completing, Signing and Archiving Case Report Forms ..................................... 54 
14.2.1 Archiving of Records ........................................................................................ 54 
14.3 
Direct Access to Source Data/Documents ............................................................ 55 
14.4 
Monitoring ............................................................................................................ 57 
14.4.1 Monitoring of Images and Imaging Data .......................................................... 58 
14.5 
Final Report .......................................................................................................... 58 
15 
Quality Control and Quality Assurance ................................................................ 59 
15.1 
Data Quality Assurance ........................................................................................ 59 
15.2 
Auditing ................................................................................................................ 59 
16 
Ethics..................................................................................................................... 60 
16.1 
Ethical Considerations .......................................................................................... 60 
16.2 
Institutional Review .............................................................................................. 60 
17 
Additional Requirements and Procedures ............................................................. 61 
17.1 
Regulatory Requirements–Sponsor/Investigator Obligations ............................... 61 
17.2 
Protocol Amendments ........................................................................................... 61 
17.3 
Protocol Deviations ............................................................................................... 61 
17.4 
Investigative Agreement ....................................................................................... 61 
17.5 
Investigator’s Responsibilities .............................................................................. 61 
17.5.1 Informed Consent.............................................................................................. 62 
17.5.2 Curriculum Vitae .............................................................................................. 62 
17.5.3 Financial Disclosure.......................................................................................... 62 
17.5.4 Investigator Delegation of Responsibilities ...................................................... 62 
17.5.5 Investigator and Study Staff Training and Documentation .............................. 63 
17.6 
Conditions for Terminating the Study .................................................................. 63 
17.7 
Warnings, Precautions, Contraindications ............................................................ 63 
17.8 
Information ........................................................................................................... 64 
17.9 
Confidentiality ...................................................................................................... 64 
18 
Financing and Insurance ....................................................................................... 65 
18.1 
Financing............................................................................................................... 65 
19 
Publication Policy ................................................................................................. 66 


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CYC-009 
 
 
Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
19.1 
Use and Publication of Study Results ................................................................... 66 
19.2 
Disclosure of Data................................................................................................. 66 
20 
Appendices ............................................................................................................ 67 
20.1 
Investigator Agreement ......................................................................................... 67 
20.2 
Declaration of Helsinki ......................................................................................... 69 
21 
References ............................................................................................................. 73 
 
 
 


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Amendment 1: 02Nov2018 
 
3 
Abbreviations 
Abbreviation 
Definition  
AE(s) 
Adverse Event(s) 
AP 
Anteroposterior 
CFR 
Code of Federal Regulations 
CRA(s) 
Clinical Research Associate(s) 
CRF(s) 
Case Report Form(s) 
CV 
Curriculum Vitae 
DTPA 
Diethylenetriamine Pentaacetic Acid 
DVT 
Deep Vein Thrombosis 
ECRF(s) 
Electronic Case Report Form(s) 
EDC 
Electronic Data Capture 
EPA 
Environmental Protection Agency 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GEE 
Generalized Estimating Equation 
GCP(s) 
Good Clinical Practice(s) 
I-131 
Iodine-131 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IEC(s) 
Independent Ethics Committee(s) 
In-111 
Indium-111 
IND 
Investigational New Drug 
IRB(s) 
Institutional Review Board(s) 
IUD 
Intrauterine Device 
kcps 
Kilo-counts per Second 
LAO 
Left Anterior Oblique 
LPO 
Left Posterior Oblique 
MBq 
Megabecquerel 
mCi 
Millicurie 
µg 
Microgram 
mm Hg 
Millimeters of Mercury 
MITT 
Modified Intent-to-Treat 
Mo-99 
Molybdenum-99 
Na99mTcO4 
Sodium Pertechnetate 
ng/L 
Nanograms per Liter 
nm 
Nanometer 


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Original Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Amendment 1: 02Nov2018 
Abbreviation 
Definition  
PA 
Percent agreement 
PAS 
Patient Administration Set 
PE 
Pulmonary Embolism 
PPS 
Per Protocol Set 
RAO 
Right Anterior Oblique 
RPO 
Right posterior Oblique 
SAE(s) 
Serious Adverse Event(s) 
SUSAR 
Serious and Unexpected Suspected Adverse Reaction 
SOP(s) 
Standard Operating Procedure(s) 
Tc-99m 
Technetium-99m 
WHO 
World Health Organization 
Xe-133 
Xenon-133 


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Original Protocol V1.1: 04Oct2016 
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Amendment 1: 02Nov2018 
4 
Background Information 
Xenon 133 (Xe-133) remains the only approved pulmonary ventilation imaging agent 
commercially available in the United States.  Xenon-133 gas has been shown to be valuable 
for diagnostic inhalation studies for the evaluation of pulmonary function and for imaging the 
lungs.1   
 
Technegas has been in clinical use for lung scintigraphy since its original approval in 
Australia in 1987. Technegas and/or the TechnegasPlus Generator and Technegas carbon 
crucibles (also known as “Pulmotec” in the European Union [EU]) are now marketed in 51 
countries world-wide. In some countries, the Technegas system is approved as a device. In 
the EU, the TechnegasPlus Generator is approved as a device while the crucible is controlled 
as a drug.  
 
According to the EANM  Guidelines for Ventilation/Perfusion Scintigraphy (2009), 
“Technegas has minimized the problem of hotspots in patients with obstructive lung disease 
and is according to clinical experience better than the best liquid aerosols” (p. 92) for 
ventilation imaging and “is preferred over DTPA in patients with COPD” (p. 97).2 
 
The development of Technegas as a ventilation imaging agent for approval in the United States 
has been ongoing for the past 15 years.  Current Technegas clinical development focuses on a 
structure delineation type of indication (ventilatory imaging) for use in general ventilatory 
scintigraphy.  The proposed indication is: Technegas is indicated for ventilatory scintigraphy in 
adult patients.  This indication is similar to the approved indication for Xe-133 inhalation 
imaging and will be supported by this structural imaging non-inferiority study. 
 
This Phase 3 study directly compares planar ventilation image views obtained using 
Technegas with those obtained using Xe-133, with a goal to establish the equivalence 
(acceptable agreement) of the two sets of images for assessing pulmonary ventilatory 
distribution.    
 
4.1 
Description of Investigational Product 
Technegas is a structured ultra-fine dispersion of Technetium-99m (Tc-99m) labeled carbon 
particles produced by a TechnegasPlus Generator.  Technetium-99m labeled carbon aerosol, 
delivered from the TechnegasPlus Generator system, distributes to normally ventilated 
regions of the lungs.  This distribution occurs as a result of its small and uniform particle 
size.  Initial deposition into the lungs is monitored by placing a gamma camera over the lungs 
and having the subject inspire Technegas until a desired count rate for pulmonary imaging is 
achieved.  Typically a subject may need to inhale Technegas for only a few breaths.  If 
needed, the subject can take a rest breath (breathe normal air or oxygen) between Technegas 
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The size distribution of Technegas delivered from the TechnegasPlus® Generator is well 
controlled such that the median particle diameter size is 177 nm and ranges from 
159-206 nm, and the ratio of the particle thickness to diameter is usually about 1:10.3   
 
It is well established that particles smaller than 500 nm behave like true gases, distributing to 
the most peripheral regions of the lungs.4  Following distribution, Technegas particles do not 
pass through the alveolar membrane to enter the systemic circulation.5,6  Once deposited in 
the periphery of the lungs (below the level of the bronchociliary elevator), Technegas 
particles do not undergo diffusion, or exhibit other means of re-distribution, but are gradually 
cleared by lung macrophages. 
   
Technegas particles initially deposited in the upper regions of the lung are removed by 
bronchociliary clearance and gastrointestinal elimination without absorption.3  Time-lapsed 
cinegraphic images of the chest region have documented that Technegas particles, initially 
deposited in the upper regions of the lung, are cleared by the bronchociliary elevator.  The 
web site of The John Curtain School of Medical Research, Australian National University, 
includes a cinegraphic illustration of this clearance mechanism.7  The cine image illustrates 
the upward movement of the radioactive particles followed by swallowing, transit through 
the esophagus and delivery into the stomach.   
 
Because Technegas does not undergo redistribution, it is possible to obtain as many different 
image projections as desired.  The ability to obtain multiple images is considered to be a 
definite advantage for assessing regional ventilation which displays focally decreased activity 
(“cold” regions) images.  In this study, Technegas planar image views will include a six view 
image set: anterior, posterior, left posterior oblique (LPO), right posterior oblique (RPO), left 
anterior oblique (LAO), and right anterior oblique (RAO) views.  Xenon 133 planar image 
views will be determined based on the site-specific standard of care which most commonly is 
posterior/posterior oblique or anterior/posterior image views collected during wash-in and 
wash-out. 
 
Technegas formation is achieved by using a high-purity carbon crucible loaded with sodium 
pertechnetate (Na99mTcO4).  The Tc-99m sodium pertechnetate is first evaporated to dryness 
using gentle heating in the presence of argon.  Technegas particles are formed by rapidly 
heating the crucible to approximately 2750°C ± 50ºC in an atmosphere of high-purity argon 
(99.99%).  Individual particles appear as hexagonal shaped single, flat technetium metal 
crystals encapsulated within a carbon sheath.  Data from an unpublished report (R. Browitt, 
R. Stephens, June 2005) showed the total particle output of one Technegas dose is in the 
range of 1.35106 particles per cm3.8   
 
These small, discrete individual particles begin agglomerating inside the chamber within 
minutes of formation, reaching an equilibrium particle size distribution with a median size of 
177 nm.2  Equilibrium is established as a net result of continuous agglomerate formation with 


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larger agglomerates depositing on the internal surface of the chamber.  While the 
agglomeration and deposition equilibrium results in a reproducible particle size distribution, 
the concentration of particles per unit volume decreases with time.  Inhalation of Technegas 
must occur within 10 minutes of manufacture.3   
 
The average concentration of carbon particles produced during a Technegas generation is 
approximately 370 nanograms per liter (ng/L).  Given no losses during the administration to 
the patient, the total extractable output would thus contain on average 2.2 microgram (µg) of 
carbon.  Because losses are expected, and patients do not inhale the complete contents of 
each Technegas generation, the actual carbon inhaled by the patient will be less than 2.2 µg 
of carbon.3  Inhalation of the amount of radioactivity recommended for multiple view 
imaging corresponds to about 1 μg of carbon inhaled per Technegas administration (Internal 
Report). 
 
4.2 
Summary of Nonclinical Studies  
The nonclinical testing strategy for Technegas was guided by the nature of the drug product’s 
ingredients, and considerations for a radiopharmaceutical administered by inhalation to 
assess pulmonary structures.   
 
The biodistribution of radioactivity from Tc-99m after administration of Technegas was 
examined in nonclinical studies sponsored or conducted by Tetley Manufacturing, Ltd. 
(Sydney, New South Wales, Australia) during the mid-1990s, with supplementation by the 
European licensee, Medgenix Diagnostics, a division of MDS Nordion S.A. (Fleurus, 
Belgium).3  No additional pharmacokinetics studies of Technegas were undertaken by 
Cyclomedica.  The distribution of Technegas particles following intravenous administration 
is much the same as analogous medical tracers, such as Tc-99m sulfur colloid injection and 
Tc-99m albumin colloid injection with the exception that the radioactive tagging for 
Technegas is particularly stable (i.e., there is little leaching of pertechnetate) in keeping with 
its physical makeup. 
 
Coghe, Votion and Lekeux compared the biodistribution of radioactivity after inhalation of 
Technegas, krypton-Kr 81m gas or Tc-99m diethylenetriamine pentaacetic acid (DTPA) 
aerosol by healthy (free from respiratory disorder) calves.  Using external gamma-ray 
scintigraphy and region of interest analysis of scintigrams, these authors concluded that the 
Tc-99m DTPA liquid in air aerosol more poorly escaped impaction in the large conducting 
airways.  Technetium-99m radioactivity appeared in the forestomachs (the first three 
compartments of the ruminant stomach) after inhalation of either Tc-99m labeled DTPA 
aerosol or Technegas, which was attributed to swallowed saliva and respiratory secretions.  
The appearance was more frequent and intense with Tc-99m DTPA aerosol.9 
 
The nonclinical testing strategy regarding chemical toxicity of the drug was based upon the 


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nature of the carrier (elemental carbon) and route of administration.  There are two 
ingredients to the drug product, an elemental technetium core surrounded by a synthetic 
graphite shell.  Thus, exposure of the patient to Technegas is limited to pharmacologically 
inert, elemental carbon.  In consideration of this, no safety pharmacology studies were 
conducted of Technegas. 
 
No nonclinical laboratory studies of Technegas were undertaken to evaluate its chemical 
toxicity profile.  The literature establishes safe exposure limits to inhaled particulate graphite 
in the context of other sources of human exposure.  The level of exposure to inhaled 
particulate graphite from the anticipated clinical dose of Technegas is well within the limits 
for the material established in that body of regulatory literature.  The patient’s particulate 
exposure during a medical imaging session is approximately equivalent to one or two days’ 
exposure to particulates in ambient air that meets Environmental Protection Agency 
standards. 
 
4.3 
Radiation Dosimetry 
In data from an unpublished report (M. Stabin, May 2, 2008), serial whole body images were 
obtained following the inhalation administration of Technegas to human subjects in a 
completed phase 1 investigational trial.  The image data were processed by region of interest 
analysis to determine tissue residence time.  Radiation dosimetry estimates were calculated 
and shown to compare favorably to those from Tc-99m imaging procedures.10 
 
4.4 
Summary of Risks and Benefits 
4.4.1 Warnings, Precautions, and Contraindications 
For specific information concerning warnings, precautions and contraindications for the 
investigational drug, the investigator is asked to refer to the appropriate section of the 
Investigator’s Brochure.  Because of the possibility of AEs from both the procedure and the 
investigational drug, a fully equipped emergency cart, or equivalent supplies and equipment, 
and personnel competent in recognizing and treating adverse reactions of all types should be 
immediately available. 
 
4.5 
Route of Administration, Dosage, Dosage Regimen and Treatment Period 
The recommended activity of Tc-99m sodium pertechnetate to be added to the crucible 
ranges between 6.8 and 19 mCi (250-700 MBq).  For adults, adequate images are obtained 
after approximately 1.1 mCi (40 MBq) of Technegas deposits in the lungs.9 The radioactive 
dose allows for sufficient count rates to obtain high quality images across a range of body 
habitus in a reasonable imaging time. 
 


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Technegas consists of aerosolized particles of carbon labeled with Tc-99m that is dispersed 
in high-purity argon gas.  It is manufactured at the point of use minutes before administration 
using a computer-controlled and operated automated synthesis module (TechnegasPlus 
Generator).  It may only be necessary for a subject to inhale Technegas over a few breaths.  If 
needed, the subject can take a rest breath (breathe normal air or oxygen) between Technegas 
inhalations.3 
 
4.6 
Treatment Compliance 
Trained clinical staff will be responsible for initiating and completing Technegas 
administration and ventilation imaging.  The trial will be conducted in compliance with this 
protocol, Good Clinical Practice (GCP) guidelines and applicable regulatory requirements. 
 


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5 
Study Objectives and Purpose  
The primary objectives and purpose of this study are: 
 
1. To demonstrate the non-inferiority of Technegas compared to Xenon 133 (Xe-133) 
ventilation studies, using planar scintigraphic imaging, with respect to their 
pulmonary ventilatory distribution in subjects that are candidates for ventilation 
imaging.  
2. To assess the safety profile of Technegas by monitoring AEs, pulse oximetry, and 
vital signs pre- and post-Technegas administration. 


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6 
 Trial Design 
This is a Phase 3 within-subject non-inferiority trial of Technegas ventilation planar imaging 
compared to Xe-133 ventilation planar imaging.  Subjects will be males and females at least 
18 years of age who have been referred for ventilation scintigraphy for any medical reason. 
Subjects will have undergone a chest X-ray, and during the study will undergo planar Xe-133 
imaging followed by planar Technegas imaging.  
 
Xe-133 images will be obtained per site-specific standard of care at each investigational site, 
which most commonly is posterior/posterior oblique image views or anterior/posterior image 
views collected during wash-in and wash-out.  Technegas images will include a six view 
image set: anterior, posterior, LPO, RPO, LAO, and RAO views. 
 
Enrollment will continue until 240 subjects have completed the study.  This number of 
subjects is expected to provide 90% power for demonstrating the non-inferiority of 
Technegas compared to Xe-133 in the assessment of ventilation imaging.  The 
non-inferiority margin to be used in this study was primarily determined from a separate 
study conducted under Protocol CYC-010. 
 
Primary assessments of efficacy will be based on three blinded readers’ assessments of the 
Technegas and Xe-133 ventilation images in independent reading sessions.  The primary 
efficacy endpoint will use only the subset of Technegas image views that match the site 
specific-standard views obtained for Xe-133.  Specifically, if only anterior/posterior images 
are collected with the Xe-133 ventilation study for a subject, then initially anterior/posterior 
image sets will be assessed for the subject’s Technegas ventilation study.  Likewise, if 
posterior/posterior oblique images are collected with the Xe-133 ventilation study, the 
posterior/posterior oblique images from the Technegas study will be assessed.  Following the 
initial primary assessment of the subset of matched Technegas image views, readers will 
assess the complete set of Technegas images for a secondary efficacy endpoint.  Ventilation 
will be scored in each of three regions of approximately equal size for each lung arranged 
craniocaudally and designated as the right and left apical, mid and basal regions, 
respectively.  Ventilation in each region will be assigned a ventilation score: 0 = absent 
ventilation, 1 = decreased ventilation, 2 = normal ventilation.  These scores will be used to 
derive a binary agreement score for the paired Technegas and Xe-133 images.  The 
agreement scores will be analyzed to provide an estimate of overall percent agreement 
between the Technegas and Xe-133 images.  
 
After approximately 40 subjects have completed the Xe-133 and Technegas image sessions, 
an interim blinded read of the images will be conducted.  Agreement between Xe-133 and 
Technegas will then be analyzed to assess the viability of the planned efficacy measurements.  
If it is determined that changes need to be made, either the CYC-009 clinical protocol will be 
amended with the Agency’s input and agreement or the study will be terminated.  The 


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readers performing the pilot blind read will not be used for the final blind read of images. 
However, the images from these first 40 subjects will be included in the final read of images 
unless the imaging parameters change. 
 
6.1 
Primary and Secondary Efficacy Endpoints 
6.1.1 Primary Efficacy Endpoint 
The primary endpoint is the percent agreement between the Technegas and Xe-133 obtained 
from blinded readers’ ventilation assessments of matching image views.  It will be derived as 
follows.  Binary agreement scores for each subject’s six lung regions will be obtained: if the 
Technegas and Xe-133 ventilation scores are the same for a lung region, the region is 
assigned an agreement score of 1, otherwise it is assigned a score of 0 for no agreement.  
Each blinded reader’s agreement scores for the subjects’ lung regions will be analyzed to 
determine an overall estimate of percent agreement and its confidence interval. 
 
6.1.2 Secondary Efficacy Endpoints 
The secondary endpoints include:  
1. Percent agreement between Technegas and Xe-133 obtained from blinded readers’ 
ventilation assessments of all image views acquired with Technegas (i.e. not limited 
to the matched image views). 
2. Percent agreement between Technegas and Xe-133 for the subgroups of subjects with 
and without pleural effusion as noted in subjects’ chest X-rays, from blinded readers 
ventilation assessments.  
3. Percent agreement measuring inter-observer agreement between pairs of blinded 
readers for their Technegas ventilation scores, and for their Xe-133 ventilation scores. 
4. By lung-region kappa statistics measuring inter-observer agreement between pairs of 
blinded readers for their Technegas ventilation scores and for their Xe-133 ventilation 
scores. 
 
6.1.3 Safety Endpoints 
All subjects will be evaluated for safety throughout the study.  Vital signs (systolic blood 
pressure, diastolic blood pressure, pulse, and respiratory rate) and pulse oximetry will be 
collected prior to Xe-133 administration (baseline safety) and at various times during the 
study up to 15 minutes post-Technegas administration.  Adverse events will be monitored 
throughout the imaging study until subject is discharged. 
 


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6.2 
Randomization and Blinding 
This is an open-label, non-randomized clinical trial.  All subjects will undergo Xe-133 planar 
imaging and Technegas planar imaging.  Subjects will undergo Xe-133 inhalation and 
imaging first, followed by Technegas inhalation and imaging as soon as practical and no 
longer than 24 hours after completing the Xe-133 imaging.  Because of the rapid clearance of 
Xe-133 from the lungs and the low, non-interfering energy of Xe-133 photons, a wash-out 
period is not required.   
 
While the Xe-133 will not interfere with the Technegas images, it is recognized that there 
will be potentially confounding effects of Xe-133 and Technegas on safety parameters. 
 
The primary efficacy data will be from a blinded read managed by Certus International, a 
contract research company and imaging core lab located in Bedford, NH and St. Louis, 
Missouri.  Three experienced nuclear medicine physicians will be selected to perform 
independent blinded reads.  The readers will have experience reading Xe-133 ventilation 
images, as well as experience reading DTPA ventilation scans.  Like Technegas, DTPA is a 
particulate based ventilation imaging agent.  Training in reading Technegas scans will also be 
provided.  Each reader will independently assess both the Xe-133 images and the Technegas 
images in separate sessions.  Each image set will be assigned a unique random code number, 
which will govern the order in which the subjects’ images are read. The readers will be 
shown a recent anteroposterior or posteroanterior chest X-ray of the lungs but will be blinded 
to subject identity, reason for the ventilation scan, results of procedures and to any other 
subject information. 
 
Additional details on the blinded read are provided in the Imaging Charter. 
 
6.3 
Treatment, Dosage, and Dosage Regimen 
6.3.1 Investigational Drug Dose and Mode of Administration: 
The investigational drug is Technegas.  Technegas consists of aerosolized particles of carbon 
labeled with Tc-99m that are dispersed in high purity argon gas.  It is manufactured at point 
of use before administration using a computer controlled and operated automated synthesis 
module (TechnegasPlus Generator System). 
 
The recommended activity of Tc-99m sodium pertechnetate to be added to the Technegas 
crucible ranges between 6.8 and 19 mCi (250-700 MBq).  For adults, adequate images are 
obtained after approximately 1.1 mCi (40 MBq) of Technegas deposits in the lungs.9   
 
Subjects will inhale Technegas aerosol until radiation monitors positioned over the lungs 
indicate that an adequate amount of radioactivity has localized in the lungs. The amount 
required for imaging is 1.5-2.5 kcps in the posterior projection as measured on a gamma 


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camera.  This equates to approximately 1.1 mCi (40 MBq). 
6.3.2 Reference Therapy, Dose and Mode of Administration: 
Xenon 133 gas, an approved imaging agent for assessment of pulmonary function and for 
imaging of the lungs, will be used as the comparator.  Subjects will be administered between 
10-30 mCi (370-1110 MBq) of Xe-133 for planar ventilation imaging. 
 
6.4 
Study Period 
The period from enrollment to pre-Xe-133 inhalation will serve as the baseline period for 
safety assessments.  The treatment period begins at the time of Technegas inhalation and 
extends through the post-Technegas imaging safety assessment.   
 
During Visit 1, screening procedures and enrollment occur.  The subject will then undergo 
Xe-133 inhalation and planar imaging.  Subjects will then undergo Technegas inhalation and 
planar imaging as soon as practical and no longer than 24 hours after completing the Xe-133 
imaging. 
 
6.5 
Discontinuation Criteria 
6.5.1 Subject Discontinuation or Termination 
Every subject has the right to terminate his or her participation in the study at any time 
without providing reasons.  A subject’s participation will terminate immediately upon his/her 
request.  However, every attempt should be made by the investigator to complete the safety 
assessments to ensure the subject experiences no AEs. 
 
If a subject chooses to withdraw from the study, the investigator should attempt to obtain the 
reason for withdrawal and document this on the case report form (CRF). 
 
The termination of a subject’s participation in the study should be considered by the 
investigator or sponsor and/or designee in the case of a serious adverse event (SAE). 
 
The subject may be withdrawn from the study at any time at the discretion of the investigator 
or sponsor.  The reason for such withdrawal should be fully documented on the CRF.  
Potential reasons for withdrawal of the subject include, but are not limited to, withdrawal of 
informed consent, death, subject lost to follow-up, enrollment of a subject subsequently 
found to have not met inclusion and/or exclusion criteria or study or site termination by the 
sponsor. 
 


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6.5.2 Study or Site Termination 
The sponsor retains the right to terminate or suspend an investigator or site from participation 
in the study and/or to terminate or suspend the entire study at its sole discretion.  Potential 
reasons for site or study termination include, but are not limited to, serious safety concerns, 
the inability of a site or sites to carry out the study as agreed to in the protocol, repeated 
enrollment of subjects that do not meet inclusion or exclusion criteria or repeated protocol 
deviations. 
 
In the event of premature investigator, site or study termination, investigators will be 
promptly informed of the termination or suspension, as will the institutions, regulatory 
authorities, and Institutional Review Boards (IRBs) or Independent Ethics Committees 
(IECs). 
 
6.6 
Accountability of Investigational Drug 
6.6.1 Receipt of Investigational Drug 
Shipment of investigational TechnegasPlus generator and Technegas crucibles and the 
Patient Administration Set (PAS) from the sponsor to the investigator or other designated 
persons cooperating with the investigator will be accompanied by a receipt form, which will 
describe the batch and/or lot number(s) and the amount of investigational drug or supplies 
provided for the study.  The form(s) will be signed, dated, returned to the sponsor and a copy 
will be maintained in the site file. 
 
6.6.1.1 TechnegasPlus Generator 
All sites will have the use of a dedicated TechnegasPlus Generator for study purposes.   
 
6.6.1.2 Technegas Crucibles 
Crucibles will be supplied to the sites with documentation regarding lot/batch number and 
shipment amounts.  The groups of 10 crucibles are packaged in a molded polyvinyl chloride 
pack with a printed cardboard sliding cover and labeled “for Investigational Use only”.  
Crucibles must be stored at a controlled room temperature of 8° to 30°C (46° to 86°F) in a 
secure area.  Accountability will be performed on those crucibles used for the trial.  The 
crucible is broken automatically following Technegas generation to prevent accidental re-use 
which would result in erratic yields.  The debris is collected in a tray beneath the contacts, 
and will contain a residue of radioactivity.  It should be treated as low level radioactive 
waste.  Residual radioactivity in used crucibles will be allowed to decay and they will be 
disposed of according to the study site’s standard operating procedures (SOPs).  
 


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6.6.1.3 Technegas Patient Administration Set (PAS) 
A single-use-only Technegas PAS will be supplied for each subject.  Batch and/or lot 
numbers will be tracked and accountability will be performed for all PAS used for the trial.  
Unused PAS will be stored in a secure location.  Residual radioactivity in used PAS will be 
allowed to decay and they will be disposed of according to the study site’s SOPs. 
 
6.6.1.4 Argon Gas Source 
Investigational sites will obtain their own high-purity (≥ 99.99%) medical-grade argon gas 
supplied by a qualified vendor in stand-alone cylinders. It will be handled according to the 
investigational site’s SOPs and the instructions provided in the TechnegasPlus Technegas 
Generator User Manual (TechnegasPlus Generator User Manual)11.  Documentation of the 
Argon supplier’s name, the batch number if applicable and cylinder tracking information will 
be maintained at the investigational site. 
  
6.6.1.5 Source of Tc-99m Sodium Pertechnetate Injection 
All Tc-99m will be obtained from the investigational site’s molybdenum-99  
(Mo-99)/Tc-99m generator or a local radiopharmacy, which must be approved by the state or 
national regulatory authority in its respective location.  Documentation of the generator 
manufacturer name, lot number and date of manufacture must be maintained at the 
investigational site in their study records.  
 
The Tc-99m will be in the form of sodium pertechnetate (Na99mTcO4), which must meet USP 
requirements for Tc-99m sodium pertechnetate injection.  The amount of radioactivity 
dispensed, date and time dispensed, time injected and amount of radioactivity injected must 
be tracked and recorded on the CRFs.  
 
6.6.2 Disposition of Unused Investigational Drug 
Upon completion of the study, the investigator will return all unused investigational drug to 
the sponsor or will dispose of it according to pre-arranged methods and procedures agreed 
upon by the sponsor. 
 


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7 
Selection and Withdrawal of Subjects 
A minimum of 240 subjects are required to complete this study.  The study is open to all 
subjects satisfying inclusion and exclusion criteria.   
 
All subjects enrolled into the study will receive a subject number that will consist of a two-
digit site number, followed by a three-digit consecutive number of enrollment.  An example 
of a subject number would be 02001, representing the first subject enrolled from Site 2. 
 
7.1 
Inclusion Criteria 
Subjects may be enrolled if they meet the following requirements: 
 
1. Male or female subject at least 18 years of age. 
2. Subject is a candidate for ventilation imaging. 
3. Subject must be willing and able to provide informed consent. 
4. Subject must be stable and able to undergo Xe-133 planar imaging and Technegas 
planar imaging. 
5. Subject must be willing and agree to complete study procedures. 
6. Subject is using adequate birth control, if female and fertile. Adequate birth control is 
defined as surgical sterilization, hormone contraceptive use or intrauterine device 
(IUD). 
7. Female subject of child-bearing potential has a negative urine or serum pregnancy 
test. 
8. Subject has had or is scheduled to have a chest X-ray within 24 hours prior to the 
investigational imaging study. 
 
7.2 
Exclusion Criteria 
1. Subject has been administered any other radiopharmaceutical within a timeframe that 
might cause interference with study imaging.   
2. Subject is a pregnant or lactating female. 
3. Subject has received Technegas in the past. 
4. Subject has received an investigational drug within 30 days prior to dosing. 
5. Subject is hemodynamically unstable. 
 
7.3 
Withdrawal or Termination of Participation 
Every subject has the right to terminate his or her participation in the study at any time 


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without providing reasons.  A subject’s participation will terminate immediately upon his/her 
request.   
 
A subject who signs the informed consent form, but discontinues study participation 
without inhaling Technegas is termed a withdrawn subject.  Subjects may withdraw 
themselves or may be withdrawn by the investigator.  Data collection for withdrawn subjects 
will cease at the time of their withdrawal. 
 
Subjects may withdraw or be withdrawn for any of the reasons listed below: 
• Did not meet inclusion/exclusion criteria 
• Withdrew consent 
• Lack of compliance with study procedures 
• Investigator decided it is in the subject’s best interest to be withdrawn 
 
A subject who signs the informed consent form and then undergoes Technegas inhalation, 
but does not complete all of the imaging procedures and/or all of the safety assessments is 
termed an incomplete subject. 
 
Whatever the reason for lack of study completion, the investigator should attempt to collect 
and report the required Technegas safety data. 
 
A subject who meets all inclusion criteria and no exclusion criteria, undergoes Technegas 
inhalation and completes all study procedures is termed a complete subject. 


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8 
Treatment of Subjects 
Subjects will undergo Xe-133 and Technegas inhalation and imaging.  Safety will be 
monitored pre- and post-inhalation of Technegas by assessing changes in vital signs and, 
blood oxygen saturation by pulse oximetry, and physical examination. 
 
 
8.1 
Treatment Administered 
8.1.1 Technegas 
Technegas will be manufactured at point of use immediately before administration using the 
TechnegasPlus Generator. 
 
Subjects will inhale approximately 1.1 mCi (40 MBq) of Technegas for image acquisition. 
 
8.1.1.1 TechnegasPlus Generator  
The TechnegasPlus Generator is a microprocessor-controlled device consisting of a 6-liter 
shielded, sealed generation chamber.  The chamber is housed above two (2) electrodes 
between which a carbon crucible is inserted.  A drawer in the front of the generator provides 
access to the electrodes.  
 
Technegas is produced by vaporization in the generation chamber.  The TechnegasPlus 
Generator includes several automatic security features that allow safe and efficient 
generation and delivery of the Technegas. 
 
The 6-minute purge phase with argon gas before each generation assures the elimination of 
air from the sealed chamber.  In addition, for each Technegas generation, an automatic leak 
test is performed during this purge stage. 
 
To assure an accurately reproducible yield and quality of Technegas, a phototransistor is used 
to monitor and maintain crucible burn temperature of around 2750ºC ± 50ºC over a  
15-second interval.  If the acceptable temperature cannot be maintained over a prescribed 
period, then the TechnegasPlus Generator prohibits the delivery of Technegas to the subject.  
If the acceptable temperature is maintained over a shorter defined burn period, then the user 
is notified that the yield could be low.  The user then has the option to administer the product 
to the subject.  For the purposes of this protocol, burns that produce a low yield will not be 
given to study subjects.   
 
Technegas is intended to be administered to the subject within 10 minutes after its 
generation.  After this time, the generator stops delivery to the subject in order to prevent 
accidental use of expired Technegas. 


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See the TechnegasPlus Generator User Manual (supplied separately) for complete details and 
instructions.10 
 
8.1.1.2 Investigational Agent Preparation 
A carbon crucible, pre-moistened with ethanol to assist in the complete loading of the 
crucible’s reservoir, is fitted between electrodes and loaded with the required activity of 
Tc-99m sodium pertechnetate in approximately 0.14 mL saline (standard Mo-99/Tc-99m 
generator eluate).  The volume and loading time should be recorded on the CRF.  Any 
additional Tc-99m sodium pertechnetate added to the crucible should be recorded as well.  
The chamber is closed for the evaporation cycle during which a small electric current is used 
to heat the crucible to approximately 70ºC.  High-purity argon gas is also passed over the 
crucible and purges the generation chamber of air and moisture.   
 
The eluate must evaporate to dryness and leave a white crust of salt (sodium chloride and  
Tc-99m sodium pertechnetate) on the carbon crucible.  Technegas is then generated in a short 
heating cycle where a large electric current is used to rapidly heat the carbon crucible to a 
temperature of 2750ºC ± 50ºC for 15 seconds, in an atmosphere of high-purity argon.  
 
The resulting vapor and argon mixture is inhaled by the subject through a disposable PAS, 
which is a mouthpiece valve-filter transfer tubing assembly.  Residual, unused Technegas is 
purged from the generation chamber with high-purity argon into an exhaust-trapping filter 
before the chamber can be opened and reloaded for the next cycle.   
 
As the carbon crucibles are intended for single-use, the machine automatically breaks the 
crucible to prevent accidental re-use.  The debris is collected in a tray beneath the electrodes. 
 
8.1.1.3 Argon Gas Source 
Argon gas will be supplied by a qualified vendor in stand-alone cylinders and will be 
medical-grade high-purity 99.99% argon.  Documentation of the batch and cylinder tracking 
information will be maintained at all sites. 
 
8.1.1.4 Source of Tc-99m Sodium Pertechnetate 
All Tc-99m sodium pertechnetate will be obtained from Mo-99/Tc-99m generators approved 
by state or national regulatory authorities in their respective regions or from local 
radiopharmacies.  Documentation for Technetium received from a local radiopharmacy, such 
as prescription, radiopharmacy log, delivery receipt, etc, as applicable for a site, will be kept 
at the site. 
 


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8.1.2 Xe-133 Preparation 
Xenon Xe-133 gas will be prepared and administered according to the investigational site’s 
standard practice for subjects presenting for ventilation imaging.  The radioactivity at time of 
loading and the start and stop times of inhalation will be captured in the CRF. 
 
8.2 
Concomitant Medication 
Concomitant medications are any medications, including over-the-counter preparations, 
which the subject receives within 24 hours prior to signing informed consent through  
completion of the study.  If a Tc-99m MAA perfusion study occurs following Technegas 
imaging but within this time period, the MAA and radioactive dose associated with the study 
should be considered a concomitant medication.  
 
All medications given prior to and during the study will be recorded on the CRF.  
Documentation will include information concerning generic or trade names, indication, total 
daily dose (including units), route of administration, date of administration, and date of 
termination.  All medications and therapies will be coded using WHODRUG®. 
 
8.3 
Subject Compliance 
Subjects will be monitored by clinical personnel during each visit of this study.  Subjects 
who are not compliant with the procedures outlined in this protocol should be withdrawn 
from the study at the discretion of the investigator or the Sponsor. 
 
8.4 
Protocol Deviations 
An investigator may not deviate from the protocol, except when necessary to eliminate an 
immediate hazard (risk) to the rights, safety or welfare of a subject. The investigator must 
notify the sponsor immediately and not enroll any additional subjects or administer the 
investigational drug to any subsequent subjects until the immediate hazard is eliminated from 
the study protocol or otherwise resolved.  The investigator must notify the sponsor of all 
protocol deviations and must notify the IRB/IEC of any protocol deviations following the 
IRB/IEC standard procedures. 
 


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9 
Imaging 
The same camera should be used to obtain planar Xe-133 and planar Technegas images.  
Planar scintigraphy with a nuclear medicine gamma camera will be used to image the 
distribution of both Xe-133 and Technegas.  Imaging will first be performed with Xe-133 
followed by Technegas.  Because of the rapid clearance of Xe-133 from the lungs and the 
low, non-interfering energy of Xe-133 photons, a washout period is not required.  
 
9.1 
Xe-133 Ventilation and Imaging 
Xe-133 ventilation and imaging should be performed in accordance with the standard of care 
for Xe-133 administration and imaging at the investigational site, which will be documented 
at the Site Qualification visit.  Images should be labeled to indicate when each phase of the 
study begins (first breath, wash-in, wash-out).  The wash-in/wash-out protocol for Xe-133 
ventilation imaging used at each investigational site will be documented in the study files. 
 
9.2 
Technegas Ventilation and Imaging  
Technegas inhalation will be performed after the Xe-133 portion of this study.  Because of 
the rapid clearance of Xe-133 from the lungs and the low, non-interfering energy of Xe-133 
photons, a washout period is not required.  Technegas is administered by inhalation through 
the PAS within 10 minutes after preparation.  This consists of a plastic tube connected to the 
TechnegasPlus Generator, fitted with a mouthpiece, one-way flow values and expiration 
filter. 
 
The subject will be instructed to breathe through the mouthpiece in one of the methods 
described below: 
▪ Slow, deep breathing from the residual functional capacity (end of calm expiration) 
followed by a 5-second breath-hold (recommended method) 
▪ Normal breathing with deep inhalations without breath-holding 
▪ Rapid and deep inspirations from the residual functional capacity followed by a 
breath-hold of about 5 seconds at the end of the inspiration 
 
The count rate should be monitored until a rate of 1.5-2.5 kcps is achieved.  This typically 
requires 1 to 5 breaths, but additional breaths may be necessary to achieve this target.  The 
number of inhalations required to achieve the target counting rate should be recorded on the 
CRF, along with the time of the first inhalation and time of the final inhalation.  To yield 
uniform apex-to-base deposition, it is recommended that the subject is ventilated in the 
supine position on the scanning bed with a detector positioned under the bed to monitor the 
lung count rate. 


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The same dual-headed camera used for Xe-133 imaging will be used to collect Technegas 
images in multiple projections.   
 
Technegas images will include a six view image set:  
• anterior view 
• posterior view 
• left posterior oblique view 
• right posterior oblique view 
• left anterior oblique view 
• right anterior oblique view 
 
Additional details and specifications related to the Technegas ventilation and imaging are 
provided in the Imaging Manual. 
 
 
 
 


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10 Assessment of Efficacy 
Primary assessments of efficacy will be based on three blinded readers’ independent 
assessments of the Technegas and Xe-133 ventilation images in independent, randomized 
reading sessions.  Readers will be selected as having experience reading both Xe-133 and 
DTPA ventilation scans.  Readers will also receive training on reading Technegas ventilation 
images.   
 
In each reading session readers will be blinded to all clinical information except the chest X-
rays required for this study.  At the start of each case read, with the aid of the subject’s chest 
X-ray,  a reader will visually divide each lung into three regions of approximately equal size 
arranged craniocaudally and designated as the right apical, left apical, right mid, left mid, 
right basal and left basal regions.  The readers will then assess each lung region for 
ventilation, assigning the region a ventilation score on a three-point scale:   
0 = absent ventilation  
1 = decreased ventilation  
2 = normal ventilation. 
If a lung region is completely obscured (as a result of pleural effusion for example), or if a 
lung region is completely absent as a result of lung resection, the region will be designated a 
score of 99 to indicate that ventilation cannot be assessed. 
  
10.1 Blinded Read of Xe-133 Images 
The Xe-133 planar ventilation images will be read by three (3) expert readers, blinded to all 
clinical information except the chest X-rays required for this study.  Each reader will 
independently assess the images identified only by a random code number, which will dictate 
the order of presentation of images to the readers.  Together with a subject’s chest X-ray, a 
reader will be presented with all acquired ventilation image views for a subject.  The reader 
will visually divide each lung into three regions of approximately equal size as described 
above and will assign a single ventilation score to each lung region.   
 
Additional details on the blinded read are provided in the CYC-009 Imaging Charter. 
 
10.2 Blinded Read of Technegas Images 
In separate reading sessions, the same three readers who assessed the Xe-133 ventilation 
images will also assess the Technegas planar ventilation images.  Again, the readers will be 
blinded to all clinical information except chest X-rays and the Technegas images will be 
identified by a random code number, distinct from the Xe-133 assigned code number.  Each 
reader will independently assess the images presented in the order of their assigned code 


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numbers.   
 
Two sequential reads will be conducted of Technegas ventilation images.  In the first read of 
a case, a reader will be presented with the subject’s chest X-ray and the subset of ventilation 
image views that match the views acquired with Xe-133 for that subject.  The reader will 
visually divide each lung into three regions of approximately equal size as described above 
and then will assign ventilation scores to each lung region based on those views.  He/she will 
then be presented with the additional Technegas image views and will assign a second score 
based on the complete set of Technegas images for the subject.  If the second ventilation 
score for a region differs from the first, the reader will be asked to document the basis for the 
changed score.   
 
The ventilation scores obtained from the first Technegas read of the subset of image views 
that match the Xe-133 image views will be used to determine agreement with Xe-133 for the 
primary efficacy endpoint.  The ventilation scores obtained from the read of all Technegas 
image views will provide a secondary efficacy endpoint of agreement with Xe-133. 
 
Additional details on the blinded read are provided in the Imaging Charter. 
 
 
 


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11 Assessment of Safety 
Subjects will be screened prior to enrollment in the clinical trial to ensure that they meet all 
eligibility criteria, which are designed to exclude subjects for whom participation may not be 
safe.  Women who are of childbearing potential must have a negative pregnancy test as part 
of the eligibility assessments.   
 
11.1 Screening/Baseline Assessments 
1. Subject is evaluated against the inclusion/exclusion criteria. 
2. If subject meets inclusion/exclusion criteria informed consent will be obtained and a 
subject number will be assigned. 
3. Demographic data is obtained (date of birth, gender, and ethnicity). 
4. Allergies (including known food, environmental, and drug allergies) are documented. 
5. Medical and surgical history is obtained including concomitant medications, smoking 
history and reason for Xe-133 ventilation imaging. 
 
The following clinical and laboratory studies will be obtained at screening and must be 
performed within 24 hours prior to the first imaging study: 
1. Physical examination including auscultation of the lungs and heart, and height and 
weight 
2. Chest X-ray in either anteroposterior view or posteroanterior view.  A chest X-ray 
obtained within 24 hours of signing the Informed Consent may be used in subjects with 
no significant clinical change. 
3. Clinical chemistry and hematology 
4. Serum or urine pregnancy test (for females of childbearing potential) 
 
11.2 Safety Indicators 
Safety will be monitored by the following parameters: vital signs (systolic and diastolic 
blood pressure, respiratory rate and pulse rate), oxygen saturation of the blood using pulse 
oximetry, and adverse event assessments during and post-administration of Xe-133 and 
Technegas inhalation.   
 
If a clinically significant change from baseline is observed, and it represents a worsening of a 
clinical condition for any safety parameter, the change will be considered an AE, it will be 
documented on the AE page of the CRF, and the investigator will continue to monitor the 
subject until the parameter returns to baseline levels or until the investigator judges that 


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follow-up is no longer necessary. 
 
11.2.1 Clinical Laboratory Measurements 
Subjects will have blood drawn during screening to obtain clinical laboratory measurements.  
Blood samples will be sent for analysis by a central laboratory.   
 
The following clinical chemistry measurements will be obtained:  albumin, alkaline 
phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea 
nitrogen (BUN), calcium, chloride, carbon dioxide (CO2), serum creatinine, direct bilirubin, 
gamma-glutamyl transpeptidase (GGT), glucose, lactate dehydrogenase (LDH), serum 
phosphorus, potassium (K+), sodium (Na+), total bilirubin, total cholesterol, total protein, uric 
acid. 
 
The following hematology measurements will be obtained:  hemoglobin (Hgb), hematocrit 
(Hct), red blood cell count (RBC), mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell 
distribution width (RDW), mean platelet volume (MPV), white blood cell count (WBC), 
white blood cell differential, including lymphocytes, neutrophils, monocytes, eosinophils, 
and basophils. 
 
11.2.2 Physical Examinations 
A physical examination will be performed by a physician during screening and the findings 
recorded on the CRF.  
 
11.2.3 Vital Signs 
Vital signs must be obtained and recorded, including: 
 
• Systolic and diastolic blood pressure millimeters of mercury (mm Hg) 
• Pulse rate (beats/minute) 
• Respiratory rate (breaths/minute) 
 
The same position and arm should be used each time vital signs are measured for a given 
subject.   
 
Vital signs will be collected within 30 minutes prior to the Xe-133 imaging study.  These will 
be considered baseline measurements.  Additional vital signs will also be taken following 
completion of the Xe-133 imaging, but prior to Technegas imaging. 
 
Vital signs will be taken at approximately 10 minutes (± 5 minutes) prior to Technegas 


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inhalation and within 15 minutes following completion of the Technegas imaging.   
 
The following changes (increases or decreases) in vital signs from pre-study baseline values are 
considered to be clinically significant and require commentary: 
 
• systolic blood pressure > 45 mm Hg 
• diastolic blood pressure > 30 mm Hg 
 
Any clinically significant worsening changes will be documented on the AE page of the CRF.  
 
11.2.4 Oxygen Saturation of the Blood using Pulse Oximetry 
Oxygen saturation of the blood using pulse oximetry will be collected within 30 minutes  
prior to the Xe-133 study.  This will be considered the baseline measurement.  Oxygen 
saturation will also be taken following completion of the Xe-133 imaging, but prior to 
Technegas imaging.   
 
Oxygen saturation will be taken at approximately 10 minutes (± 5 minutes) prior to 
Technegas inhalation and within 15 minutes following completion of the Technegas imaging.   
 
The investigator will assess and comment if oxygen saturation falls below 90%.  
Attributability of any changes below 90% will be assessed as follows: 
 
 
1 = Attributable to disease; no follow-up required 
 
2 = Attributable to Xe-133 procedure; no follow-up required 
 
3 = Possibly attributable to Technegas, FOLLOW-UP REQUIRED 
 
Any oxygen saturation measurements with clinically significant changes below 90% and 
possibly attributable to Technegas will be repeated at appropriate intervals following the 
procedure until the values return to baseline or until the investigator and the Medical Monitor 
agree that further follow-up is no longer clinically relevant. 
Any changes considered clinically significant and assessed as “3 = Possibly attributable to 
Technegas, FOLLOW-UP REQUIRED” will be documented on the AE page of the CRF.  
 
11.3 Adverse Events 
An AE is any untoward medical occurrence in a subject administered an investigational drug, 
which does not necessarily have a causal relationship with the treatment.  An AE can be any 
unfavorable or unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 


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temporally associated with the use of the study drug, whether or not it is considered to be 
study drug related.  This includes any newly occurring event or previous condition that has 
increased in severity or frequency since the administration of the drug. 
 
All AEs, ascertained through subject interview, physical examination or other means will be 
recorded on the AE page of the CRF.  Adverse events will be recorded beginning at the time 
the subject signs the informed consent.  Any AEs recorded before Technegas inhalation will 
be considered a pre-treatment AE.  
 
Any AE that is on-going at the completion of the imaging study will be followed by the 
investigator until resolution or until the principal investigator and the Medical Monitor agree 
that further follow-up is no longer clinically relevant. 
 
11.3.1 Suspected Adverse Reaction 
Suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reactions are the subset of all adverse events for 
which there is reasonable possibility that the drug caused the event.  Reasonable possibility 
means there is evidence to suggest a causal relationship between the drug and the adverse 
event. 
 
11.3.2 Adverse Reaction 
An adverse reaction means any adverse event caused by a drug.  Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event. 
 
11.3.3 Unexpected Adverse Events 
An unexpected AE is any AE for which the specificity or severity is not consistent with the 
current Investigator’s Brochure, the general investigational plan, or other product labeling. 
 
11.3.4 Serious Adverse Events 
A SAE is any AE, regardless of causality that: 
• Results in death. 
• Is life-threatening.  Life-threatening means that the subject was at immediate risk of 
death from the reaction as it occurred, (i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form). 
• Requires subject hospitalization or prolongation of existing hospitalization.  
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period, but planned prior to study entry are not considered AEs if the illness or 


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disease existed before the subject was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier 
than planned). 
• Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a persons’ ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event.  An important medical event is an event that may not 
result in death, be life-threatening, or require hospitalization but may be considered 
an SAE when, based upon appropriate medical judgment, it may jeopardize the 
subject, or may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition for SAEs.  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 subject hospitalization, or 
the development of drug dependency or drug abuse. 
 
In this subject population, hospitalization for lung disease, lung surgery, to treat pulmonary 
embolism (PE) or an underlying deep vein thrombosis (DVT) that may have caused PE is an 
expected event and actual admission may occur before or after a subject is enrolled in the 
study; therefore, hospitalization for lung disease, lung surgery or to treat DVT and/or PE 
which was the triggering factor for study enrollment will not be considered an SAE.  
 
Planned hospital admissions or surgical procedures for an illness or disease which existed 
before the subject was enrolled in the trial or before study drug was given, are not to be 
considered AEs unless they occur at a time other than the planned date. 
 
11.3.5 Severity of Adverse Events 
Severity is defined according to the following criteria: 
 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort enough to cause interference with normal daily 
activities 
Severe 
Inability to perform normal daily activities 
 
The terms “serious” and “severe” ARE NOT synonymous.  The term “severe” is often used 
to describe the 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 a severe headache).  This is NOT the same as “serious,” which is based on subject/event 
outcome or action criteria described above and are usually associated with events that pose a 
threat to a subject’s life or functioning.   


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A severe AE does not necessarily need to be considered serious.  For example, persistent 
nausea of several hours duration may be considered severe nausea but not an SAE.  On the 
other hand, a stroke resulting in only a minor degree of disability may be considered mild, 
but would be defined as an SAE based on the above noted criteria. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations.  
 
11.3.6 Relationship to Study Drug 
Relationship to study drug administration will be determined as follows:  
 
None 
No relationship between the experience and the drug; related 
to other etiologies such as concomitant medications or 
subject’s clinical state. 
Unlikely 
The current state of knowledge indicates that a relationship is 
unlikely. 
Possible 
A reaction that follows a plausible temporal sequence from 
use of the drug and follows a known response pattern to the 
suspected drug.  The reaction might have been produced by 
the subject’s clinical state or other modes of therapy 
administered to the subject. 
Probable 
A reaction that follows a plausible temporal sequence from 
the use of the drug and follows a known response pattern to 
the suspected drug.  The reaction cannot be reasonably 
explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the 
subject. 
Definite 
A reaction that follows a plausible temporal sequence from 
use of a drug and follows a known response pattern to the 
suspected drug. 
 
 
11.4 Procedures for Reporting AEs, SAEs and Suspected Unexpected Serious Adverse 
Reactions (SUSARs) 
All AEs spontaneously reported by the subject and/or in response to an open question from 
study personnel or revealed by observation, physical examination or other diagnostic 
procedures will be recorded on the AE section of the CRF.  Any clinically relevant 
deterioration in any safety assessment is considered an AE and must be recorded on the AE 
section of the CRF.   
 
All AEs will be noted and evaluated on the CRF with a full description of the nature, onset, 


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duration, severity, attribution, and outcome of the event.  All AEs will be coded using 
MedDRA.  Any treatment used to alleviate the AE(s) will also be recorded. 
 
Adverse event recording and reporting will conform to International Conference on 
Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for 
Human Use Guidelines for Clinical Safety Data Management. 
 
When possible, signs and symptoms indicating a common underlying pathology should be 
noted as one comprehensive event.  All AEs should be recorded using standard medical 
terminology.   
 
All SAEs that occur during the course of the study, as defined by the protocol, must be 
reported immediately by the investigator to the Medical Monitor by telephone or fax within 
24 hours of the time the investigator first becomes aware of the SAE.  Such preliminary 
reports should be followed with a detailed written description (within 5 days) which will 
include copies of hospital records and other documents when applicable.   
 
All SAEs must be reported whether or not considered causally related to the study product.  
An SAE form will be provided to each clinical study site.   
 
The investigator is required to document in full the course of the SAE, including any therapy 
given to the subject.  The information collected will include, at a minimum, the following: 
subject number, description of the event and an assessment by the investigator as to the 
severity of the event and relatedness to study product.  Follow-up information on the SAE 
may be requested by Cyclomedica.  The SAE must also be recorded on the AE section of the 
CRF. 
 
The investigator will also inform the sponsor of any relevant follow up information and the 
outcome of the SAE as soon as possible in a follow-up report. 
 
Medical Monitor Contact Information: 
 
Edward Aten, MD 
President and CEO 
Certus International, Inc. 
9 Cedarwood Drive, Suite 8 
Bedford, NH 03110 
Phone: (603) 627-1212 
Cell: (603) 867-0359 
E-mail: eaten@certusintl.com  
 


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11.4.1 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
The Sponsor must submit an Investigational New Drug (IND) Safety Report to the United 
States Food and Drug Administration (FDA) for any suspected adverse reaction that is both 
serious and unexpected.  Before submitting the report, the sponsor will need to ensure that 
the event meets the following criteria: 
 
• Suspected adverse reaction 
• Serious 
• Unexpected 
 
If the AE does not meet all three of the definitions, it should not be submitted to the FDA in 
an IND Safety Report.  The Sponsor, with input from the Medical Monitor, will evaluate the 
information and decide if there is a reasonable possibility that the drug caused the AE and 
therefore meets the definition of suspected adverse reaction.  Reasonable possibility means 
there is evidence to suggest a causal relationship between the drug and the AE. 
 
A written IND Safety Report must be submitted to FDA within 15 calendar days since the 
determination that the suspected adverse reaction or any other information qualifies for 
reporting. 
 
Unexpected fatal or life-threatening suspected adverse reactions must be reported to FDA in 
an expedited report no later than 7 calendar days after the Sponsor’s initial receipt of 
information.   
 


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12 Schedule of Efficacy and Safety Assessments 
12.1 Visit 1 
During Visit 1, screening procedures are performed, informed consent is obtained and 
documented with signature and date, and eligible subjects are enrolled.  The investigators 
will be asked to record the purpose for a subject’s Xe-133 ventilation imaging, and based on 
their recent chest X-ray indicate whether pleural effusion is present for the subject. 
 
Subjects will undergo Xe-133 ventilation imaging.  This will be followed as soon as practical 
by the Technegas imaging procedure.  Because of the rapid clearance of Xe-133 from the 
lungs and the low, non-interfering energy of Xe-133 photons, a washout period is not 
required.   
 
The Sponsor must be notified if Xe-133 and Technegas imaging sessions are to be performed 
in separate visits.  The Sponsor will grant approvals only on a case-by-case basis.  If the 
second imaging procedure must be done during a separate visit occurring within 24 hours of 
the first visit, this will result in an additional visit for the subject. 
 
If a Tc-99m MAA perfusion study is planned for the subject as part of their standard of care 
at this visit, it must occur after Technegas imaging is complete, and after the post-Technegas 
imaging safety assessments, within 15 minutes post-imaging, have been captured. 
 
 
 


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12.2 Schedule of Efficacy and Safety Assessments 
 
 
Visit 1 
 
Xe-133 
Technegas 
Prior to  
Inhalation  
(≤ 30  min.) 
Ventilation 
and 
Imaging 
Post- 
Imaging 
Prior to  
Inhalation  
(10 ± 5 min.) 
Ventilation 
and 
Imaging 
 Post- Imaging 
(≤ 15 min.) 
Screening 
Baseline 
 
 
 
 
 
Inclusion/Exclusion 
x 
 
 
 
 
 
 
Informed Consent 
x 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
Pregnancy Test 
x 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
Physical Exam 
x 
 
 
 
 
 
 
Chest X-ray 
x 
 
 
 
 
 
 
Clinical Labs 
x 
 
 
 
 
 
 
Vital Signs 
 
x 
 
x 
x 
 
x 
Oxygen Saturation 
 
x 
 
x 
x 
 
x 
Ventilation  Imaging 
 
 
x 
 
 
x 
 
Adverse Events 
x 
Monitored throughout the study 
Concomitant Medication 
x 
Monitored throughout the study 
 


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13 Statistical Analysis 
13.1 General Considerations 
The primary presentations and analyses will be based on data pooled across study centers.  
Relevant summaries for individual centers, or combinations of centers, also may be presented 
for primary data.  Standard descriptive statistics will be used to summarize data, including 
one- and multi-way frequency tables for discrete or categorical variables, and mean, median, 
standard deviation, minimum, maximum for continuous variables. 
 
All data collected and entered into the study database will be provided in data listings by 
variable type presenting individual subject values.  All testing and confidence intervals will 
use a two-sided significance level of 5%, unless otherwise specified. 
 
Additional details concerning the planned statistical methodologies are provided in the 
Statistical Analysis Plan. 
 
13.2 Analysis Populations 
Three analysis data sets will be defined for the study: 
• Modified Intent-to-Treat (MITT) Set will consist of all subjects who are enrolled in 
this study and receive any dose of Technegas treatment; it will be the analysis set for 
the safety analyses. 
• Full Analysis Set (FAS) will consist of subjects who completed all of the ventilation 
imaging on the study, and both sets of Xe-133 planar scans and the Technegas planar 
scans are of interpretable image quality according to site investigators’ assessment. 
• Per Protocol Set (PPS) will consist of those subjects in the FAS who are compliant 
with regard to the Technegas and Xe-133 procedures (dosing and imaging), and have 
no other major protocol violations.   
 
13.2.1 Disposition 
Subject disposition will be summarized and will include: 
• Number of subjects screened 
• Number of subjects enrolled in the study 
• Number of subjects included in the MITT set 
• Number of subjects withdrawn from the study and the reason for withdrawal 
• Number of subjects in the FAS 


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• Number of subjects in the PPS 
 
The screening data for all subjects who were screened but not enrolled into the study will be 
provided in a separate data listing.  These subjects will not be included in any other listings, 
tabulations, or analyses. 
 
13.2.2 Baseline Characteristics 
Demographic data, including age, gender, race, ethnic group, and reason for ventilation 
imaging will be summarized using descriptive statistics. 
  
Abnormal medical histories and prior/concurrent medications will be summarized using 
counts and percents.  Prior/concurrent medications will be coded using the World Health 
Organization (WHO) classification system.  Prior and concurrent medication use overall and 
by WHO medication classification will be summarized using counts and percentages. 
 
13.3 Efficacy Evaluations 
13.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is percent agreement between Technegas and Xe-133 obtained 
from each blinded reader’s ventilation scores of matching image views. 
The agreement statistic will be derived from the ventilation scores as follows.  Binary 
agreement scores will be obtained for each subject’s six lung regions: if the Technegas and 
Xe-133 ventilation scores are the same for a lung region, the region is assigned an agreement 
score of 1, otherwise the region is assigned a score of 0 for no agreement.  The subjects’ 
binary agreement scores will provide the basis for an overall estimate of percent agreement 
and confidence interval for each of the three readers. 
 
In the case of a missing ventilation score (score = 99) as a result of a reader assessing a 
region as obscured or absent, the binary agreement score will be determined as follows.  If 
both Technegas and Xe-133 scores are missing for the region, the binary agreement score 
will be missing for the region.  If the score is missing for one of the imaging modalities and 
not the other, then the region will be assigned a score of 0 for no agreement. 
 
13.3.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
1. Percent agreement between Technegas and Xe-133 obtained from blinded readers’ 
ventilation scores based on all image views collected for Technegas and Xe-133. 
2. Percent agreement between Technegas and Xe-133 for the subgroups of subjects with 


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and without pleural effusion as noted in subjects’ chest X-rays, from blinded readers 
ventilation scores.  
3. Percent agreement measuring inter-observer agreement between pairs of blinded 
readers for their Technegas ventilation scores, and for their Xe-133 ventilation scores. 
4. By lung-region kappa statistics measuring inter-observer agreement between pairs of 
blinded readers for their Technegas ventilation scores, and for their Xe-133 
ventilation scores.  
 
13.4 Efficacy Analyses 
13.4.1 Primary Efficacy Analyses 
The primary analysis will be conducted on the FAS for Technegas and Xe-133 matched 
image views.  Each blinded readers’ binary agreement scores will be analyzed using a 
generalized linear model with SAS® PROC GENMOD.  The logit function (log odds ratio) 
will be specified as the link function, and subject will be specified as a repeated measure to 
allow for correlations between lung regions within a subject.  The estimate of the intercept of 
the model using generalized estimating equation (GEE) methodology will provide an overall 
estimate of the agreement and its 95% confidence interval in terms of the log odds ratio; 
simple algebra will be used to obtain the corresponding estimates and confidence intervals in 
terms of percent agreement (PA). 
The non-inferiority hypothesis to be tested is: 
 
H0: PA   60%  versus  HA: PA > 60% 
If the lower boundary from the 95% confidence interval for PA is greater than 60%, 
Technegas will be considered non-inferior to Xe-133 with respect to the measurement of 
pulmonary ventilatory distribution. 
Study Success Criteria 
For the study to be deemed a success, the null hypothesis must be rejected for at least two of 
the blinded readers. 
 
13.4.2 Secondary Efficacy Analyses 
The same methodology as described for primary efficacy analyses in the previous section 
will be applied to the binary agreement scores between Technegas and Xe-133 obtained from 
blinded readers’ ventilation scores based on all image views, both for the FAS and PPS 
analysis datasets.  The methodology will also be applied to the agreement scores between 
Technegas and Xe-133 for the subgroups of subjects with and without pleural effusion.  
 
Inter-reader percent agreement between pairs of blinded readers Technegas ventilation 


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scores and their 95% confidence intervals will be obtained using the same methodology 
described for the primary efficacy endpoint.  Analyses will be performed for both FAS and 
PPS.  For comparison, the inter-reader percent agreement will be obtained in the same 
manner for Xe-133 ventilation scores.  
 
By lung region, inter-reader kappa statistics and their 95% confidence intervals will be 
calculated for pairs of blinded readers using the three by three tables of the frequencies of 
ventilation scores for Technegas as displayed: 
 
 
Ventilation Score 
Reader I 
Ventilation Score Reader J 
0 
1 
2 
0 
N00 
N01 
N02 
1 
N10 
N11 
N12 
2 
N20 
N21 
N22 
 
where Nij represents the agreement frequency for a cell.  For comparison, the by-region inter-
reader kappas based on the blinded readers’ ventilation scores for Xe-133 scans will also be 
obtained. 
 
13.5 Non-Inferiority Margin 
The non-inferiority margin used in the analysis of the primary endpoint of this study was 
principally determined from a separate study conducted under Protocol CYC-010.  In Study 
CYC-010, six blinded readers read 75 Xe-133 planar ventilation imaging studies in two read 
sessions separated by a minimum of 4 weeks.  The readers scored the six regions of the lung 
using the same ventilation scoring metric to be used in this protocol.  The two sets of 
assessments from the read and re-read of the Xe-133 images were used to determine a 
measure of agreement between successive reads of Xe-133 lungs scans for each of the 
readers, and the compilation of the six readers’ estimates were then used to establish a 95% 
tolerance interval for the population of readers.  The lower bound of the tolerance interval 
was 62%.  Since Xe-133 is an approved agent for ventilation imaging, it by default is 
considered non-inferior to itself, and hence the read/re-read results provide a suitable limit 
for establishing the non-inferiority of Technegas compared to Xe-133. 
 
When comparing Xe-133 and Technegas imaging, it is recognized that there are inherent 
differences between the imaging performed with Xe-133 and Technegas: Xe-133 imaging 
includes both wash-in and wash-out views, while Technegas imaging has no equivalent to the 
wash-in/wash-out views but collects additional views.  This has the potential to result in 
differences in ventilation scoring which are not clinically relevant.  For example, in subjects 
that have regions of pleural effusion, on Xe-133 the region would likely be scored as 


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1=decreased ventilation based on retention visible in wash-out views, whereas on Technegas 
it would be scored as 0=absent ventilation.  Only a small percentage of subjects are expected 
to exhibit such discrepancies and to account for this, a small adjustment was made to the 
non-inferiority margin obtained from the CYC-010 study from 62% to 60%.  The anticipated 
agreement between Technegas and Xe-133 imaging is 70%.  The standard error of the 
agreement for the Xe-133 to Xe-133 image comparison among the six readers from study 
CYC-010 was 4.6% and thus a lower confidence interval bound of 2 standard errors also 
supports a non-inferiority margin of about 60%.  Thus the non-inferiority margin planned for 
this study is 60%. 
 
13.6 Rationale for Sample Size 
Using the normal approximation to the binomial distribution for calculation of the sample 
size, and the proportion associated with the non-inferiority margin (P0) to estimate the 
standard deviation, the following table provides sample size requirements for testing the 
hypotheses: 
 
H0: PA   P0  versus  HA: PA > P0 
where PA (percent agreement) has expected true values of 70% to 75%, and the non-
inferiority margin (P0) is 60%. 
 
Table 
Sample Size for 90% Power and 0.025 One-sided Type 1 Error 
Non-inferiority Margin 
P0 (%) 
Expected True Value 
PA (%) 
Required  
Sample Size (N) 
60 
70 
240 
71 
197 
72 
164 
73 
139 
74 
119 
75 
103 
Calculations performed with PASS 1412 
 
The planned sample size for the study is 240 subjects who have completed Xe-133 and 
Technegas ventilation imaging, and the images are of interpretable quality (FAS).  This 
sample size will provide 90% power to establish that agreement between the blinded read 
assessments of Xe-133 and Technegas is better than 60%, assuming an expected true level of 
agreement between Xe-133 and Technegas of 70%.   
 


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13.7 Interim Analysis 
After approximately 40 subjects have completed the study, an interim pilot blind read of the 
Xe-133 and Technegas ventilation images will be conducted to assess the viability of the 
planned efficacy measurements for comparing the two sets of images.  If it is determined that 
the initial study design and efficacy parameters are not viable due to the differences in the 
image sets being acquired, the protocol will either be amended in accordance with Agency 
input, or the study may be terminated.  The readers performing the pilot blind read will not 
be used for the final blind read of images, and unless imaging parameters change, the images 
from these first 40 subjects will be included in the final read of images. 
 
13.8 Safety Endpoints 
Safety endpoints include: 
1. Incidence of treatment emergent AEs. 
2. Change (post minus baseline) in vital signs at each time-point post Xe-133 and 
Technegas administration.  The measurements within 30 minutes prior to Xe-133 
inhalation will serve as the baseline. 
3. Incidence of clinically significant changes in blood pressure (defined Section 11.2.3). 
4. Change (post minus baseline) in oxygen saturation at each time-point post Xe-133 
and Technegas administration. The measurements within 30 minutes prior to Xe-133 
inhalation will serve as the baseline. 
 
13.9 Safety Analyses 
The summary and analysis of safety data will be conducted on the modified ITT dataset.  
 
Frequency distributions including counts and percentages will be used to summarize the 
qualitative safety data, including AEs, clinically significant changes in vital signs and 
clinically significant oxygen saturation measurements that fall below 90%.  The summary of 
AEs will include summaries by MedDRA system organ class, relationship to study treatment, 
and event severity.  Serious adverse events also will be summarized separately.   
 
Summary statistics will be provided for all continuous safety data including change in vital 
signs and oxygen saturations.  Paired t-tests will be used to test for statistically significant 
changes over time. 


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14 Data Handling and Record Keeping 
14.1 Case Report Forms 
Electronic CRFs (eCRFs) will be used and clinical trial data will be entered into directly into 
the electronic data capture (EDC) system.  The EDC system will be a 21 Code of Federal 
Regulations (CFR) Part 11 compliant data capture system.  The data system will include 
password protection, logs to identify individual entering or correcting data and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate.  Any changes, corrections or deletions made in the eCRFs will 
identify the responsible investigator or other authorized person modifying the data.   The 
investigator will review the completed eCRFs and electronically sign and date them to 
indicate his/her review, agreement with the data included, and the completeness and accuracy 
of the data. 
 
Case report forms (CRFs) must be completed for all enrolled subjects, even if the subject 
fails to complete the study.  No section of the CRF is to be left blank without an appropriate 
explanation by the investigator, since the lack of such explanation may necessitate discarding 
an otherwise usable observation. 
 
14.2 Completing, Signing and Archiving Case Report Forms 
Data collection is the responsibility of the investigator at the investigative site or clinical trial 
staff under the supervision of the respective site investigator.  The investigator is responsible 
for ensuring the accuracy, completeness, legibility, timeliness and attributability of the data 
reported.  
 
Clinical data may be entered directly into the eCRF at the time of data collection or from the 
source documents.  Data reported in the eCRF derived from source documents should be 
consistent with the source documents or the discrepancies should be explained and captured 
in a study note and maintained in the participant’s electronic study record.  
 
To comply with the requirement to maintain accurate case histories investigator(s) should 
review and electronically sign the completed eCRF for each subject before the data are 
archived or submitted to FDA.  If changes are made to the eCRF after the investigator(s) has 
already signed, the changes should be reviewed and electronically signed by the clinical 
investigator(s).  
 
14.2.1 Archiving of Records 
The following information must be retained at the investigational site for at least 2 years after 
the last approval of a marketing application and until there are no pending or contemplated 


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marketing applications in an ICH region; or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational drug; or for the 
maximum period of time as required by the study center, whichever is greater: 
 
• Source data (including digital images) 
• Source documents 
• Copies of protocols  
• Protocol amendments 
• Correspondence 
• Subject identification codes and lists 
• Signed informed consent forms 
• Any other essential documents pertaining to the conduct of the study 
 
No study document or image should be destroyed without prior written agreement between 
the sponsor and the investigator(s).  Should the investigator(s) wish to assign the study 
records to another party or move them to another location, advance written notice should be 
given to the sponsor. 
 
It is the responsibility of the sponsor to inform the investigator(s)/institution(s) when these 
documents need no longer be retained. 
 
The sponsor will ensure all other study documents (e.g.: protocol, report, all data 
management documentation) are filed and archived in a secure area in the Trial Master File 
for at least 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications in an ICH region; or until at least 2 years 
have elapsed since the formal discontinuation of clinical development of the investigational 
product; or for the lifetime of the product, as required by regulation.  In addition, the final 
trial report must be retained by the sponsor, or the subsequent owner, for five years beyond 
the lifetime of the study agent. 
 
14.3 Direct Access to Source Data/Documents 
All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction 
and evaluation of the trial will be made directly available for clinical monitoring activities. 
Source data are contained in source documents (original records or certified copies).  Source 
documents are original documents, data, and records (e.g. hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 


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dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 
negative, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
trial).13 
 
All source documents must be accurate, clear, unambiguous, legible, contemporaneous, 
original, permanent and available for inspection and audit.  Paper-based source documents 
should be made using a permanent form of recording (ink, typing, printing, optical disc, etc.) 
and they should not be obscured by correcting fluid or have temporary attachments (such as 
“post-it” notes). 
 
If electronic medical records are used as source data to support trial data, the investigator will 
authorize the monitor to compare the data stored in the electronic medical records to the CRF 
data to ensure all data are complete, consistent, and accurate and ensure prior to enrolling a 
subject that a GCP-compliant method of doing this is available for the monitor.   
 
If electronic medical records are used to support trial data and the monitor is not allowed 
direct access to the electronic medical records for monitoring and data verification purposes, 
the source documents that are computer-generated and stored on magnetic support media 
must be printed and must be certified by the investigator as being an exact duplicate of the 
original electronic record.  The investigator or designee will identify each printed page as a 
certified copy and will sign and date the printed pages to so indicate.   
 
The minimum requirements for source documents used in clinical trials are that they should 
contain: the identity of the subject (or trial-related identifiers such as trial enrollment number, 
treatment number), the subject’s participation in the trial (protocol/study title or number), 
subject’s demographic data, the date and time the subject provided informed consent, the 
subject’s medical history, the treatment that the subject received, AEs, SAEs and the dates of 
the trial visits.  The end of the subject’s trial participation must be documented.  Information 
recorded in the CRF must be consistent with entries in the source documents. 
 
The following data may be recorded directly in the CRF.  If it is, it will be considered as 
source data: 
 
• Imaging parameters 
• Assessment of images for technical adequacy 
 
If other data are recorded directly into the CRF at the time the data are obtained, it will be 
considered as source data, too. The investigator must document in the study file the use of the 
CRF as its own source document for any such data. 
 


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Source documents in connection with the study, including but not limited to, subject charts, 
radiology reports and laboratory data, will be made available to the sponsor upon request 
with due precaution towards protecting the privacy of the subject.  
14.4 Monitoring 
For this trial, a combination of automated data checks/verification, central (remote, off-site) 
monitoring of data recording in the eCRFs and data-driven on-site monitoring with targeted 
source data verification of key data will be used. Automated data checks/verification and 
centralized monitoring will make most efficient use of limited monitor on-site time and it 
may allow risks or problems to be identified faster, since some eCRF data will be reviewed 
centrally prior to an on-site visit. Therefore; it may allow problems to be addressed pro-
actively and mitigated instead of being identified and addressed at an on-site visit. 
 
Targeted data verification, using pre-identified data points based on the type of data and its 
risk to trial integrity (for example informed consent to ensure a subject exists and provided 
prospective informed consent), or based on the critical nature of the data (for example AE 
details) or unusual or unexpected data are source data verified, with other data reviewed to 
the extent necessary to verify CRF completion may reduce the number of data points that are 
source data verified on-site by a monitor.  This will allow the site monitor to focus on the key 
data that are deemed most important to confirm protocol compliance, subject safety and data 
validity.  
 
The targeted data include: 
• Informed consent 
• Eligibility criteria 
• Dose administration 
• Clinical safety and AEs 
• Clinical laboratory assessment 
• Concomitant medications 
• Unusual or unexpected data 
 
Central monitoring of completed eCRFs will be performed primarily at Certus’ offices or 
other appropriate regional location. It will include a review of targeted data in the completed 
eCRFs.  
 
On-site monitoring visits will be performed at the investigational site per Certus SOP 403, 
Site Monitoring Visit, as modified by a project-specific Monitoring Plan. It will include a 
verification of informed consent and targeted data in the completed eCRFs using comparison 
to source records. 
 
A closeout visit will be performed at the conclusion of the Investigator’s involvement in the 


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study. 
 
14.4.1 Monitoring of Images and Imaging Data 
Images, including imaging parameters, image acquisition and other imaging-related data are 
verified by the investigator and/or medical physicist or other appropriate staff and they are 
verified by the imaging Core Lab following SOPs and project-specific methods after receipt 
of images and supporting data at the Core Lab.  
 
14.5 Final Report 
The final report of the trial will be written by the sponsor or its designee and will be 
submitted to the regulatory authority. 
 
 


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15 Quality Control and Quality Assurance 
15.1 Data Quality Assurance 
Data entry parameters and automated data checks will be used and implemented by the eCRF 
system to assist the site investigators and staff in CRF completion.  Completed CRFs will be 
reviewed by clinical research associates (CRAs) or a designee from the sponsor or a Clinical 
Research Organization representing the sponsor using centralized monitoring and/or on-site 
monitoring.  During monitoring activities, the CRA or designee will check for completion of 
the entries on the CRFs, site compliance with the study protocol and with GCP, will assess 
Technegas drug accountability and will evaluate if source data are accurately supports data 
recorded in the CRF.  In addition, the CRA will assess whether all AEs and SAEs have been 
appropriately reported within the time periods required. 
 
Data Management will also provide services to assure data quality.  To ensure the 
completeness, internal consistency and accuracy of the data in the study database, appropriate 
validation checks will either be incorporated into the EDC system and will execute at data 
entry, or they will be performed externally with SAS programs.  Details of the checks will be 
included in a Data Management Plan for the study. 
 
15.2 Auditing 
The sponsor or a representative of the sponsor may arrange to visit the investigator in order 
to audit the performance of the study at the study site and the study documents originating 
there at any time during the study or following completion of the study. The investigator and 
designated site staff will cooperate in the scheduling and performance of the investigator/site 
audit. The auditor(s) may be accompanied by the CRA and/or other the study staff.  The 
investigator will be informed of the results of the audit. 
 
In addition, inspections by the site IRB, by a local site research authority or by health 
authority representatives, including but not limited to the US FDA, the US Department of 
Health and Human Services, the US Office of Human Research Protections, the US Nuclear 
Regulatory Commission or the State regulatory authority are possible at any time.  The 
investigator will notify the sponsor immediately upon being contacted by any local, State or 
federal regulatory authority for any such inspection. 
 
The investigator will make all pertinent records available including source documentation for 
inspection by regulatory authorities and for auditing by the sponsor.  This information will be 
considered as confidential. 
 
 
 


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16 Ethics 
16.1 Ethical Considerations 
This study will be conducted in accordance with the Declaration of Helsinki and ICH E6 
GCP Guideline and in compliance with the protocol and all regulatory requirements 
including Title 21 CFR § 50, 54, 56 and 312.  To ensure compliance the investigator agrees, 
by written consent to this protocol, to fully cooperate with compliance checks by allowing 
access to all documentation by authorized individuals. 
 
A copy of the Declaration of Helsinki is provided in Appendix 20.2. 
 
16.2 Institutional Review 
This protocol and the informed consent form will be reviewed and approved by the research 
facility's IRB or IEC.  A copy of its letter or certificate of approval will be sent to the sponsor 
prior to the commencement of the study. 
 


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17 Additional Requirements and Procedures 
17.1 Regulatory Requirements–Sponsor/Investigator Obligations 
This study will be conducted in accordance with the Declaration of Helsinki and ICH E6 
GCP Guideline and compliance with the protocol and all regulatory requirements including 
Title 21 CFR § 50, 54, 56 and 312.  To ensure compliance the investigator agrees, by written 
consent to this protocol, to fully cooperate with compliance checks by allowing access to all 
documentation by authorized individuals. 
 
17.2 Protocol Amendments 
Any changes to the protocol will be made in the form of a protocol amendment.  No change 
to the protocol may be made without the joint agreement of both the investigator and the 
sponsor.  Any amendment to the protocol must be submitted to the FDA and to the IRB/IEC 
and approved before implementation. 
 
17.3 Protocol Deviations 
An investigator may not deviate from the protocol in any way, except when necessary to 
eliminate an immediate hazard (risk) to the rights, safety or welfare of a subject. The 
investigator must notify the sponsor immediately and NOT enroll any additional subjects or 
administer Technegas to any subsequent subjects until the hazard is eliminated from the 
study protocol or otherwise resolved. The investigator must notify the IRB/IEC of any 
protocol deviations.  The FDA will be notified of all protocol deviations in compliance with 
federal regulations and GCPs. 
 
17.4 Investigative Agreement 
Prior to initiation of the study, the principal investigator must agree to abide by the terms of 
the Investigative Agreement and sign, date and return the agreement to the sponsor.  A copy 
of this agreement is contained in Appendix 20.1. 
 
17.5 Investigator’s Responsibilities 
An investigator must comply with all obligations and responsibilities, described in 21 CFR 
50, 4, 56, 312, on the completed FDA Form 1571 and other local, state and federal 
regulations and in ICH GCPs, including but not limited to those responsibilities described in 
detail in this Section.  


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17.5.1 Informed Consent 
All subjects must sign and personally date an approved Informed Consent Form after 
receiving detailed written and verbal information about the reason, the nature and the 
possible risks associated with the administration of the investigational drug prior to 
enrollment in the study.  It is the responsibility of the investigator to obtain that consent.  The 
details of this requirement are explained in 21 CFR 50 Subpart B, the Declaration of Helsinki, 
and the ICH E6 Guideline for GCP.    
 
The subject must be made aware and agree that personal information may be scrutinized 
during audit by competent authorities and properly authorized persons.  However, personal 
information will be treated as strictly confidential and will not be publicly available.   
 
By signing the Investigative Agreement, the investigator assures the sponsor that Informed 
Consent will be obtained for each subject participating in the study.   
 
Prior to IRB/ IEC submission, the investigator must send a copy of the Informed Consent 
Form to be used at their institution to the sponsor for review to assure compliance with the 
ICH and CFR requirements. 
 
17.5.2 Curriculum Vitae 
The investigator and any sub-investigator(s) must provide the sponsor with a current copy of 
his/her own curriculum vitae (CV).  The CV must include a statement of the investigator's 
relevant experience.   
 
17.5.3 Financial Disclosure 
As required by 21 CFR § 54, all investigators, including sub-investigators and other study 
staff who perform significant clinical trial responsibilities must provide signed and dated 
financial disclosure before the study is initiated at the site and at the completion of the study.  
Any significant changes to the reported financial interests and arrangements must be 
disclosed for one year after completion of study participation. 
 
The investigator must obtain an original, completed, signed and dated Financial Disclosure 
Form for any sub-investigator who ends participation in the trial, whether it is due to leaving 
the research facility or any other reason. The investigator must notify the sponsor and 
provide the completed Form at the time the sub-investigators ends participation. 
 
17.5.4 Investigator Delegation of Responsibilities 
The investigator must complete prior to the start of the study and maintain on an on-going 
basis until close-out of the study, a Log or other detailed document that identifies all 


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individuals to who the investigator has delegated significant study-related responsibilities, 
describes the responsibilities, records personally-completed original signatures and initials of 
all of the individuals to whom responsibilities have been delegated and documents the 
individual’s acceptance of the delegated responsibilities.  
 
17.5.5 Investigator and Study Staff Training and Documentation 
The investigator must supervise and ensure that adequate training is provided for all 
sub-investigators and study staff to whom study-specific responsibilities and obligations are 
delegated. The investigator must ensure qualification documentation and training records are 
completed and available in the study file for the investigator, sub-investigators all pertinent 
study staff the start of the study and that they are maintained and updated as needed 
throughout the course of the trial. 
 
17.6 Conditions for Terminating the Study 
In the event that the investigator is unable to continue the study, another suitable person may 
be designated Investigator, and documentation testifying to this will be submitted to the 
sponsor immediately.  The new investigator must be approved by the sponsor and the 
IRB/IEC before the study can be continued. 
 
If the sponsor and/or the investigator should discover conditions arising during the study that 
indicate it should be terminated, an appropriate schedule for termination will be instituted.  If 
the investigator terminates the study, an explanatory letter will be provided to the sponsor. 
 
The sponsor also reserves the right to discontinue this study for administrative reasons at any 
time.  The investigator will be reimbursed for reasonable expenses incurred, if it is necessary 
to terminate the study or an individual subject's participation.  The sponsor will not reimburse 
the investigator for the evaluation of subjects if the evaluations are not conducted in 
compliance with the present protocol. 
 
The sponsor may terminate an investigator's participation in this study at any time for any 
reason, including the investigator's intentional or repeated noncompliance with the study 
protocol, GCPs, the Investigative Agreement, the FDA Form 1572 or regulatory 
requirements.  If the sponsor terminates an investigator's participation due to noncompliance, 
the FDA and site IRB or IEC must be notified by the sponsor, as required by 21 CFR 312. 
56. 
 
17.7 Warnings, Precautions, Contraindications 
For specific information concerning warnings, precautions and contraindications for the 
study device, the investigator is asked to refer to the appropriate section of the Technegas 


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Investigator’s Brochure and the TechnegasPlus Generator User Manual.  
 
17.8 Information  
Before the beginning of the study the investigator will have been given the last updated 
Investigator’s Brochure, TechnegasPlus Generator User Manual and other supporting 
documents to describe use, maintenance and other pertinent information related to the 
Technegas.  If this information is revised during the study, the investigator will receive a 
copy of the revised version.   
 
17.9 Confidentiality 
All information provided to the investigator dealing with the investigational drug, the 
protocol and this investigation will be regarded as confidential.  Acceptance constitutes the 
agreement by the recipient that no unpublished information herein contained will be 
published or disclosed without the sponsor's  prior written approval except that this document 
may be disclosed to appropriate IRB/IEC as long as they are required to keep it confidential.  
The members of the research team agree not to discuss such information in any way without 
prior written permission from the sponsor. 
 


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18 Financing and Insurance 
18.1 Financing 
A financial agreement (separate from the protocol) will be made with the investigator or 
designee.  Such agreement will be archived in the relevant file. 
 
Financial support to investigators/sub-investigators other than the cost of conducting the 
clinical study or other clinical studies will be disclosed in accordance with Title 21 CFR 54.2 
to 54.6. 
 
 


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19 Publication Policy 
19.1 Use and Publication of Study Results 
All unpublished documentation (including the protocol, CRF and Investigator's Brochure) 
given to the investigator is strictly confidential.  All recipients must agree not to disclose the 
information herein contained to any person without the prior written authorization of the 
sponsor.  The submission of these documents to the IRB/IEC is expressly permitted.  The 
investigator agrees that the sponsor maintains the right to use the results of this study in their 
original form and/or in a global report for submission to governmental and regulatory 
authorities of any country. 
 
The results of the study may be presented during scientific symposia or published in a 
scientific journal only after review by the sponsor in accordance with the guidelines set forth 
in the applicable publication or financial agreement. 
 
19.2 Disclosure of Data 
All information obtained during the conduct of this study will be regarded as confidential and 
written permission from the sponsor is required prior to disclosing any information relative to 
the study.  Manuscripts prepared for publication will be submitted to the sponsor for review 
and comment prior to submission to the publisher.  The sponsor will attempt to provide 
comments within 30 days.  This condition should not be construed as a means of restricting 
publication but is intended solely to assure mutual concurrence regarding data, evaluations 
and conclusions and to provide an opportunity to share with the investigator any new and/or 
unpublished information of which he/she may be unaware. 
 
 
 


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20 Appendices 
20.1 Investigator Agreement 
 
I have read and understand the information in the protocol and attached case report form, the 
Investigator’s Brochure, the TechnegasPlus Generator User Manual and other documents if 
applicable, understand the information contained and agree that it contains all necessary detail 
for carrying out this study.  I agree to conduct the study in accordance with the Investigator's 
Agreement, the current protocol, and applicable FDA regulations, and conditions of approval 
imposed by the reviewing IRB or FDA, and will only make changes in a protocol after 
notifying the sponsor, except when necessary to protect the safety, rights, or welfare of 
subjects. 
 
I have read and understood the provisions of Title 21 of the United States Code of Federal 
Regulations (CFR) Part 312, Subpart D regarding responsibilities of Sponsors and Investigators; 
Part 50 and Part 56 regarding the protection of human subjects and informed consent, and Part 
54 for financial disclosure.  I have read, understood and signed the Statement of Investigator 
Form FDA1572 which outlines my responsibilities as Principal Investigator.  
 
I agree to personally conduct or supervise the described investigation, including all testing of 
the investigational drug involving human subjects. I agree to report to the sponsor adverse 
experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312. 
 
I agree to inform any subjects that Technegas is being used for investigational purposes and I 
will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 
and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.  I will 
ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible 
for the initial and continuing review and approval of the clinical investigation.  I also agree to 
promptly report to the IRB all changes in the research activity and all unanticipated problems 
involving risks to human subjects or others.  Additionally, I will not make any changes in the 
research without IRB approval, except where necessary to eliminate apparent immediate 
hazards to human subjects. 
 
I agree to comply with all other requirements regarding the obligations of clinical 
investigators and all other pertinent requirements in 21 CFR Part 312. I agree to maintain 
adequate and accurate records in accordance with 21 CFR 312 and to make those records 
available for inspection.  
 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 


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Investigator Agreement (Continued) 
 
 
 
Additionally, I warrant and represent that neither I nor anyone else who will be involved in this 
study has been disqualified or debarred by a U.S. or Australian regulatory body for clinical 
investigations or any other purpose nor has been convicted of any felony for conduct relating 
to the development or approval, including the process for the development or approval, of any 
drug application, or otherwise relating to the regulation of any drug product. 
 
If at any time I or anyone involved in this study should become disqualified or become 
debarred or is convicted of violations for conduct relating to the development or approval, 
including the process for development or approval, of any drug application, or otherwise 
relating to the regulation of any drug product, I will give the sponsor prompt written notice of 
same. Additionally, I will notify the sponsor at any time in the future if such disqualification 
or debarment is based in whole or in part on participation in this study. 
 
 
 
 
____________________________________ 
Printed Name of Principal Investigator 
 
 
 
____________________________________, M.D. 
Signature of Principal Investigator 
 
 
 
Date: ______/______/______ 
 


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20.2 Declaration of Helsinki 
 
DECLARATION OF HELSINKI 
 
RECOMMENDATIONS guiding physicians in biomedical research involving human subjects 
(adopted by the Eighteenth World Medical Assembly, Helsinki, Finland, 1964; and amended by 
the Twenty-Ninth World Medical Assembly, Tokyo, Japan, 1975; by the Thirty-Fifth World 
Medical Assembly, Venice, Italy, 1983; and by the Forty-First World Medical Assembly, Hong 
Kong, 1989). 
 
INTRODUCTION 
 
It is the mission of the physician to safeguard the health of the people.  His or her knowledge 
and conscience are dedicated to the fulfillment of this mission. 
 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, “The health of my patient will be my first consideration,” and the International Code of 
Medical Ethics declares that, “A physician shall act only in the patient’s interest when providing 
medical care which might have the effect of weakening the physical and mental condition of the 
patient.” 
 
The purpose of biomedical research involving human subjects must be to improve diagnostic, 
therapeutic and prophylactic procedures and the understanding of the etiology and pathogenesis 
of disease. 
 
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve 
hazards.  This applies especially to biomedical research. 
 
Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
 
In the field of biomedical research a fundamental distinction must be recognized between 
medical research in which the aim is essentially diagnostic or therapeutic for a patient, and 
medical research, the essential object of which is purely scientific and without implying direct 
diagnostic or therapeutic value to the person subjected to the research. 
 
Special procedures must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
 
Because it is essential that the results of laboratory experiments be applied to human beings to 
further scientific knowledge and to help suffering humanity, the World Medical Association has 


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prepared the following recommendations as a guide to every physician in biomedical research 
involving human subjects.  They should be kept under review in the future.  It must be stressed 
that the standards as drafted are only a guide to physicians all over the world.  Physicians are not 
relieved from criminal, civil and ethical responsibilities under the laws of their own countries. 
 
I. 
BASIC PRINCIPLES 
 
1. 
Biomedical research involving human subjects must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and animal 
experimentation and on a thorough knowledge of the scientific literature. 
 
2. 
The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol which should be transmitted 
for consideration, comment and guidance to a specially appointed committee 
independent of the principal investigator and the sponsor provided that this independent 
committee is in conformity with the laws and regulations of the country in which the 
research experiment is performed. 
 
3. 
Biomedical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically competent 
medical person.  The responsibility for the human subject must always rest with a 
medically qualified person and never rest on the subject of the research, even though the 
subject has given his or her consent. 
 
4. 
Biomedical research involving human subjects cannot legitimately be carried out unless 
the importance of the objective is in proportion to the inherent risk to the subject. 
 
5. 
Every biomedical research project involving human subjects should be preceded by 
careful assessment of predictable risks in comparison with foreseeable benefits to the 
subject or to others.  Concern for the interests of the subject must always prevail over the 
interests of science and society. 
 
6. 
The right of the research subject to safeguard his or her integrity must always be 
respected.  Every precaution should be taken to respect the privacy of the subject and to 
minimize the impact of the study on the subject’s physical and mental integrity and on 
the personality of the subject. 
 
7. 
Physicians should abstain from engaging in research projects involving human subjects 
unless they are satisfied that the hazards involved are believed to be predictable.  
Physicians should cease any investigation if the hazards are found to outweigh the 
potential benefits. 
 


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8. 
In publication of the results of his or her research, the physician is obliged to preserve 
the accuracy of the results.  Reports of experimentation not in accordance with the 
principles laid down in this Declaration should not be accepted for publication. 
 
9. 
In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, anticipated benefits and potential hazards of the study and the 
discomfort it may entail.  He or she should be informed that he or she is at liberty to 
abstain from participation in the study and that he or she is free to withdraw his or her 
consent to participation at any time.  The physician should then obtain the subject’s 
freely given informed consent, preferably in writing. 
 
10. When obtaining informed consent for the research project, the physician should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress.  In that case, the informed consent should be obtained by a 
physician who is not engaged in the investigation and who is completely independent of 
this official relationship. 
 
11. In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation.  Where physical or mental incapacity 
makes it impossible to obtain informed consent or when the subject is a minor, 
permission from the responsible relative replaces that of the subject in accordance with 
national legislation.   
 
 
Whenever the minor child is in fact able to give a consent, the minor’s consent must be 
obtained additionally to the consent of the minor’s legal guardian. 
 
12. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration are 
complied with.  
 
II. 
MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE 
 
(CLINICAL RESEARCH) 
 
1. 
In the treatment of the sick person, the physician must be free to use a new diagnostic 
and therapeutic measure, if in his or her judgment it offers hope of saving life, re-
establishing health or alleviating suffering. 
 
2. 
The potential benefits, hazards and discomfort of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods. 
 
3. 
In any medical study, every patient - including those of a control group, if any - should 
be assured of the best proven diagnostic and therapeutic method. 


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4. 
The refusal of the patient to participate in a study must never interfere with the 
physician-patient relationship. 
 
5. 
If the physician considers it essential not to obtain informed consent, the specific reasons 
for this proposal should be stated in the experimental protocol for transmission to the 
independent committee (I, 2). 
 
6. 
The physician can combine medical research with professional care, the objective being 
the acquisition of new medical knowledge, only to the extent that medical research is 
justified by its potential diagnostic or therapeutic value for the patient. 
 
III. 
NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN 
 
SUBJECTS (NON-CLINICAL BIOMEDICAL RESEARCH) 
 
1. 
In the purely scientific application of medical research carried out on a human being, it 
is the duty of the physician to remain the protector of the life and health of that person 
on whom biomedical research is being carried out. 
 
2. 
The subjects should be volunteers - either healthy persons or patients for whom the 
experimental design is not related to the patient’s illness. 
 
3. 
The principal investigator or the investigating team should discontinue the research if in 
his/her or their judgment it may, if continued, be harmful to the individual. 
 
4. 
In research on man, the interest of science and society should never take precedence 
over considerations related to the well being of the subject. 
 
 
 
  


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21  References 
 
1 Xenon/Xe-133 [package insert].  St. Louis, MO:  Mallinckrodt Inc.; 2006. 
2    Bajc M, Neilly JB, Miniati M, Schuemichen C, Meignan M, Jonsson B.  EANM 
guidelines for ventilation/perfusion scintigraphy. 
3 Cyclomedica Australia Pty Ltd. Investigator’s Brochure TechnegasTM (Technetium  
(Tc-99m) carbon particles). Edition 4. 2011.  
4 Davis GS. Pathogenesis of silicosis: Current concepts and hypotheses. Lung. 
1986;164(3):139-54. 
5 Wiebert P, et al. Negligible clearance of ultrafine particles retained in healthy and affected 
human lungs. Eur Respir J. 2006;28:286-290. 
6 Weibert P, et al. No significant translocation of inhaled 35-nm carbon particles in the 
circulation in humans. Inhal Toxicol. 2006;18(10):741-747. 
7 Muco-ciliary escalator demonstration using a modified form of Technegas. John Curtin 
School of Medicine, The Australian National University. 
http://jcsmr.anu.edu.au/research/facilities/technegas/muco-ciliary-escalator-demonstration.  
8 Browitt R, Stephens R. Report on Vita Medical Technegas Mk II Generator Tests. 
Nanoparticle Laboratory, Research School of Physical Sciences and Engineering, Australian 
National University. June 2005;66-72. 
9 Coghe J, Votion D, Lekeux P. Comparison between radioactive aerosol, Technegas and 
krypton for ventilation imaging in healthy calves. Vet J. 2000 Jul;160(1):25-32. 
10 Stabin M. Radiation dose estimates for 99mTc-Labeled Technegas based on data gathered in 
patients by Certus Inc. Department of Radiology and Radiological Services, Vanderbilt 
University. May 2, 2008;1-10. 
11 TechnegasPlus Technegas Generator [User Manual]. Lucas Heights, New South Wales, 
Australia: Vita Medical Limited; 2005. 
12  PASS 14 Power Analysis and Sample Size Software (2015). NCSS, LLC. Kaysville, Utah, 
USA, ncss.com/software/pass. 
13 International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). Guideline for Good Clinical Practice. Geneva, 
Switzerland. 1997. 

SAP_002.pdf: 
1.8.1 Clinical Study 
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Statistical Analysis Plan Addendum, CYC-009 
 
 
 
SAP V2.0 Addendum 30Jul2020 
 
CONFIDENTIAL 
 
 
NCT03054870 
 
ADDENDUM TO STATISTICAL ANALYSIS PLAN  
FOR 
PROTOCOL CYC-009  
 
A Comparison of Technegas® and Xenon 133 Planar Lung Imaging in Subjects 
Referred for Ventilation Scintigraphy 
 
 
 
Study Drug: Technegas® 
 
 
Sponsor: 
Cyclomedica Australia Pty Ltd. 
Unit 4 
1 The Crescent 
Kingsgrove NSW 2208 Australia 
 
 
 
Prepared by: Certus International, Inc. 
 
 
Chesterfield, MO 
 
 
Original Protocol (Version 1.1) 
Date: 4 October 2016 
 
Protocol Amendment 1 
 
Date: 2 November 2018  
 
 
 
 
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


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Statistical Analysis Plan Addendum, CYC-009 
 
 
 
SAP V2.0 Addendum 30Jul2020 
 
CONFIDENTIAL 
 
 
APPROVAL SIGNATURE 
 
 
This analysis plan was reviewed and has the approval of: 
 
  Sponsor’s Study Statistician 
 
 
 
Kathleen S. Madsen PhD 
Date 
Vice President Biostatistics and Data Management, Certus International, Inc. 
 
 
 


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Statistical Analysis Plan Addendum, CYC-009 
 
 
 
SAP V2.0 Addendum 30Jul2020 
 
CONFIDENTIAL 
 
 
 
APPROVAL SIGNATURE 
 
 
This analysis plan was reviewed and has the approval of: 
 
  Sponsor’s Responsible Party 
 
 
 
James McBrayer 
Date 
Chief Executive Officer / Managing Director, Cyclopharm Ltd., Cyclomedica Australia Pty 
Ltd.  
 
 
 


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Statistical Analysis Plan Addendum, CYC-009 
 
 
 
SAP V2.0 Addendum 30Jul2020 
 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
 
1. 
REASON FOR SAP ADDENDUM .......................................................................... 5 
2. 
TRIAL INTEGRITY ................................................................................................. 5 
3. 
INTERIM ANALYSIS METHODOLOGY .............................................................. 6 
4. 
INTERIM ANALYSIS DECISION RULES ............................................................. 7 
5. 
INDEPENDENT THIRD PARTY STATISTICIAN ................................................ 8 
6. 
DATA EFFICACY MONITORING COMMITTEE................................................. 9 
7. 
FINAL ANALYSIS ................................................................................................... 9 
8. 
REFERENCES .......................................................................................................... 9 
 
 
 


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Statistical Analysis Plan Addendum, CYC-009 
 
 
 
SAP V2.0 Addendum 30Jul2020 
 
CONFIDENTIAL 
 
1. REASON FOR SAP ADDENDUM 
 
On March 26, 2020, Cyclomedica Australia Pty Ltd submitted an original 505(b)(2) New 
Drug Application (NDA), 022335, for the drug product, Technegas® (Technetium Tc-99m 
Carbon Aerosol), the TechnegasPlus Technegas® Generator and Pulmotec carbon crucible 
used in the TechnegasPlus Technegas® Generator to produce Technegas®. Technegas® and 
its generator, including the crucible, are regulated as diagnostic radiopharmaceutical drugs 
pursuant to 21. C.F.R. 315.2.  
 
Following the FDA filing review, it was determined by the Agency that the application was 
sufficiently complete to permit a substantive review. The CYC-009 study, whose protocol 
has been formally agreed upon by FDA under a Special Protocol Agreement, is not yet 
completed; an interim report of safety data was included in the NDA submission but no 
interim report of efficacy data was included.  Given that the trial is now approximately 80% 
complete and blinded reads of images of 200 subjects have been performed, the Agency 
requested that a formal interim efficacy analysis of the available blind read data be conducted 
by an independent third-party statistician. 
 
This addendum to the CYC-009 Statistical Analysis Plan (SAP), Version 2, describes how 
the sponsor intends to respond to this request. 
2. TRIAL INTEGRITY 
 
As of March 31, 2020, 225 subjects enrolled in the study, but as a result of the Coronavirus 
Disease 2019 (COVID-19) pandemic, enrollment in the study was suspended by the sites.  
Sixteen (16) of the 225 subjects withdrew prior to receiving Technegas, and data for the 
remaining 209 subjects are complete. The target number of enrolled subjects who receive 
both a Techegas and Xenon ventilation scan is 240.  Blinded reads of subjects’ ventilation 
scan images have been conducted in blocks of 40 subjects and to date, five blocks of 
subjects’ images (n = 200 subjects) have been read by the three blinded readers.  The 
independent read database is being hosted by an electronic data capture (EDC) vendor and is 
being securely maintained in a validated database system with an audit trail.  Once a reader 
commits a record to the independent read database, the record cannot be modified.  Refer to 
the Image Review Charter CYC-009 for more details.  To date, the independent read data 
have remained blinded. 
 
Analysis populations remain as described in SAP Section 5. The Full Analysis Set (FAS) will 
be the primary efficacy analysis data set. The Per Protocol Set (PPS) will be a secondary data 
set for analysis of efficacy data. 
 


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Statistical Analysis Plan Addendum, CYC-009 
 
 
 
SAP V2.0 Addendum 30Jul2020 
 
CONFIDENTIAL 
 
Efficacy endpoints are unchanged and are described in SAP Section 6.1. The primary 
efficacy endpoint is percent agreement between Technegas and Xe-133 obtained from 
blinded readers’ ventilation assessments of matching image views. 
 
The primary efficacy endpoint, percent agreement (PA) between Technegas and Xe-133, 
from analysis of each of the three blinded readers’ ventilation scores for the matched image 
views, will be subjected to the following test of null (H0) versus alternate hypotheses (HA), 
(SAP Section 7.1):  
 
H0: PA   60%  versus  HA: PA > 60% 
For the study to be deemed a success, the null primary efficacy hypothesis must be rejected 
for at least two of the blinded readers (SAP Section 7.2). 
Neither the primary efficacy endpoint or the secondary prespecified endpoints are modified 
in this addendum.  
3. INTERIM ANALYSIS METHODOLOGY 
 
Study CYC-009 is an ongoing study with planned enrollment of 240 subjects that have 
completed the Xe-133 and Technegas imaging.  To date, blinded reads have been performed 
by three independent readers of 200 subjects who have completed the study. A not previously 
planned interim analysis of these available blind read efficacy data will be performed at the 
request of FDA. Based on review of the various methodologies, the alpha spending function 
method of DeMets and Lan1,2 is determined to be appropriate for this situation, and the 
function which approximates the O'Brien-Fleming boundary will be used.3  Given that 200 of 
240 subjects have completed the blind-read and one-sided total alpha of 0.025 specified for 
the primary efficacy endpoint in the original SAP, this proposed method would test for 
significance at the one-sided alpha =0.0141 at the interim stage of the requested interim 
analysis (critical value is lower bound of 97.18% confidence interval), and at the one sided 
alpha=0.0210 at the final stage (critical value is lower bound of 95.80% confidence interval). 
 
In general, efficacy data will be analyzed in accordance with the methods described in SAP 
Section 10.5.  For each reader, binary agreement scores will be analyzed using a generalized 
linear model with SAS®4 PROC GENMOD.  The logit function (log odds ratio) will be 
specified as the link function, and subject will be specified as a repeated measure to allow for 
correlations between lung regions within a subject.  The estimate of the intercept of the 
model using generalized estimating equation (GEE) methodology will provide an overall 
estimate of the agreement and a confidence interval in terms of the log odds ratio; simple 
algebra will be used to obtain the corresponding estimates and confidence intervals in terms 
of percent agreement (PA).  
 


1.8.1 Clinical Study 
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NDA 022335; IND 62660; Technegas® 
 
 
Statistical Analysis Plan Addendum, CYC-009 
 
 
 
SAP V2.0 Addendum 30Jul2020 
 
CONFIDENTIAL 
 
Sample SAS code is provided below for the interim analysis that provides the test for 
significance at one-sided alpha=0.0141.  AGREEN represents the binary agreement score for 
each subject (PATNO) and lung-region. Setting ALPHA = 0.0282 (= 2 x 0.0141) obtains a 
97.18% confidence interval for the estimate of PA. The lower bound of that confidence 
interval represents the critical value associated with one-sided alpha = 0.0141. 
 
PROC GENMOD DATA=FAS DESCENDING; 
  BY READER; 
  CLASS PATNO; 
  MODEL AGREEN = / DIST=BIN LINK=LOGIT ALPHA=0.0282; 
  REPEATED SUBJECT=PATNO / CORR=UNSTR PRINTMLE ; 
  ODS OUTPUT GEEEMPPEST=GEE;  
RUN; 
 
DATA GEE; 
  SET GEE; 
  IF PARM =: 'Inter'; 
  
*** anti-logit transform ***; 
  PA=100*(exp(ESTIMATE)/(1+exp(ESTIMATE))); 
  LOWER_CI = 100*(exp(LOWERCL)/(1+exp(LOWERCL))); 
  UPPER_CI = 100*(exp(UPPERCL)/(1+exp(UPPERCL))); 
 
  KEEP READER PA LOWER_CI UPPER_CI; 
RUN; 
 
The non-inferiority hypothesis to be tested is: 
 
H0: PA   60% versus  HA: PA > 60% 
where 60% is the non-inferiority margin.  If the null hypothesis is rejected based on the lower 
boundary from the 97.18% confidence interval for PA exceeding 60%, Technegas will be 
considered non-inferior to Xe-133 with respect to assessing pulmonary ventilatory 
distribution. 
4. INTERIM ANALYSIS DECISION RULES 
 
FDA has requested that one of the following four decisions be reached based on the interim 
efficacy analysis. The rules by which one of the four potential decisions will be selected are 
as follows: 
i. 
Successful outcome, trial terminates  
Two (2) or more of the 3 blinded readers reject the null hypothesis for PA, for 


1.8.1 Clinical Study 
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NDA 022335; IND 62660; Technegas® 
 
 
Statistical Analysis Plan Addendum, CYC-009 
 
 
 
SAP V2.0 Addendum 30Jul2020 
 
CONFIDENTIAL 
 
matched views PA.  
ii. 
Not yet successful outcome, trial continues 
Successful outcome criterion as described in (i) is not met, but 2 or more of the 3 
blinded readers demonstrate that PA > 50% for matched views PA. 
iii. 
Non-successful outcome, trial terminates (futility outcome) 
Outcome criteria described in either (i) or (ii) are not met; evidence does not support 
PA > 50%. 
iv. 
“Close Enough”  
The results of the analysis are not statistically significant to allow for a decision as in 
(i) but are ‘close enough’, in that at least two of the three readers have a PA greater 
than 0.60 and a p-value of less than 0.025 is realized, and it is clinically obvious that 
given the same results, a slightly larger sample size or not utilizing the adjustment 
due to the unplanned interim analysis, would have resulted in a statistically 
significant result. 
 
5. INDEPENDENT THIRD PARTY STATISTICIAN 
 
The interim analysis of the blinded read data will be performed by an independent third party 
statistician.  The EDC vendor will provide the statistician with a private and secure portal to 
access and download unblinded read data, which will be maintained in a secure location to 
which only the independent statistician has access. All data access will continue to be 
compliant with 21 C.F.R. Part 11.  
 
The independent statistician will analyze all primary and secondary efficacy endpoints for 
both FAS and PPS populations as described in the SAP Sections 10.5.1 and 10.5.2, except 
that any inferential testing of the non-inferiority hypothesis will be tested using one-sided 
alpha equal to 0.0141. 
 
In addition, descriptive statistics will be provided for subject disposition, demographic data, 
and clinical reason for imaging. 
 
A statistical report will be written by the statistician including subject data listings of data 
analyzed or summarized. The report will be provided only to the Data Efficacy Monitoring 
Committee (DEMC).  The sponsor and their contracted partners involved with any aspect of 
the study will remain blind to the efficacy results at this time. 
 
 
 


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Statistical Analysis Plan Addendum, CYC-009 
 
 
 
SAP V2.0 Addendum 30Jul2020 
 
CONFIDENTIAL 
 
6. DATA EFFICACY MONITORING COMMITTEE 
 
At the request of FDA, a DEMC will be formed by the sponsor to review the interim efficacy 
statistical report prepared by the independent third party statistician.  The DEMC will consist 
of three members each with expertise in clinical trials, including a statistician. The members 
will have no prior financial affiliation with the sponsor and have had no prior involvement in 
the CYC-009 trial. The DEMC will make a recommendation to the sponsor based on their 
review of the results of the interim analyses and the decision rules provided above. Details on 
DEMC membership and their role with respect to the study will be specified in the CYC-009 
DEMC Charter that will be provided to and agreed upon by each DEMC member prior to 
conduct of the DEMC.  
7. FINAL ANALYSIS 
 
If enrollment continues to completion, the final analysis will be conducted in accordance 
with the final SAP Version 2, except that inferential hypothesis testing of PA efficacy 
endpoints will be tested at one-sided alpha=0.0210. 
 
8. REFERENCES 
 
1  Lan KG and DeMets DL. Discrete sequential boundaries for clinical 
trials.  Biometrika 1983; 70: 659-663 
2   DeMets DL and Lan KG. Interim analysis: the alpha spending function 
approach. Statistics in Medicine 1994; 13: 1341-1352 
3  O'Brien PD and Fleming TR. A Multiple Testing Procedure for clinical 
trials. Biometrics 1979; 35:  549-556 
4  SAS Software Release 9.4 (TS1M2). Copyright© 2002-2012 by SAS Institute Inc., Cary, 
NC, USA  

Prot_SAP_000.pdf: 
1.8.1 Clinical Study  
Page 1 
Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
 
CONFIDENTIAL 
 
NCT 03054870 
 
Clinical Study Protocol 
 
 
A Comparison of Technegas® and Xenon 133 Planar Lung Imaging in Subjects 
Referred for Ventilation Scintigraphy 
 
Protocol Number:  CYC-009 
 
 
Phase 3 Study 
 
 
 
 
Sponsor:  
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
Phone Number:  +61 2 9541 0411 
Fax Number:  +61 2 9543 0960 
Gary Somerville 
E-mail:  gsomerville@Cyclomedica.com.au  
 
 
 
Protocol Version: 
1.1 
 
Protocol Date:  
4 October 2016 
 
 
 
 
 
The information contained in this document is confidential and, except to the extent 
necessary to obtain approval by your Institutional Review Board/Independent Ethics 
Committee and informed consent, cannot be disclosed unless required by federal law or 
governmental regulation.  Persons to whom any portion of the contents of this document is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them.  


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CYC-009 
 
 
Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Sponsor Approval  
 
 
 
 
 
 
 
 
 
Name and Title 
 (Signature and title of Sponsor’s Responsible Party) 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name and Title 
 (Signature and title of Sponsor’s Study Statistician or other 
responsible party) 
 
Date 
 
 
 


1.8.1 Clinical Study  
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IND 62660; Technegas® 
CYC-009 
 
 
Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Investigator’s Signature  
 
 
 
 
Investigator’s Printed Name 
 
 
 
 
 
Investigator’s Signature 
 
Date 
 


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CYC-009 
 
 
Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
1 
Study Synopsis 
Name of Sponsor: 
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
 
(For National Authority Use 
Only) 
Name of Finished Product: 
Technegas 
Name of Active Ingredient: 
Tc-99m labeled carbon 
Title of Study: 
A Comparison of Technegas® and Xenon 133 Planar Lung Imaging in Subjects Referred 
for Ventilation Scintigraphy 
Protocol Number:   
CYC-009 
Investigators and Study Center(s):   
To be determined 
Phase of Development:  
Phase 3 
Primary Objectives: 
1. To demonstrate the non-inferiority of Technegas compared to Xenon 133 (Xe-133) 
ventilation studies, using planar scintigraphic imaging, with respect to their 
pulmonary ventilatory distribution in subjects that are candidates for ventilation 
imaging. 
2. To assess the safety profile of Technegas by monitoring adverse events (AEs), 
clinical laboratory measurements (blood chemistry and hematology), pulse oximetry, 
and vital signs pre- and post-Technegas administration. 
Methodology:  
The design of this study is a Phase 3 within-subject non-inferiority trial of Technegas 
ventilation imaging compared to Xe-133 ventilation imaging.  Subjects referred for 
ventilation scintigraphy will have undergone a chest X-ray, and will undergo planar Xe-
133 imaging followed by planar Technegas imaging.  Xe-133 images will include site-
specific standard of care wash-in and wash-out views.  Site-specific standard of care Xe-
133 images are most commonly either posterior and posterior oblique image views or 
alternatively posterior and anterior image views.  Technegas images will include a six 
view image set: anterior, posterior, left posterior oblique, right posterior oblique, left 
anterior oblique, and right anterior oblique views. 


1.8.1 Clinical Study  
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Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Name of Sponsor: 
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
 
(For National Authority Use 
Only) 
Name of Finished Product: 
Technegas 
Name of Active Ingredient: 
Tc-99m labeled carbon 
The non-inferiority margin to be used in this study was principally determined from a 
study conducted under Protocol CYC-010.  Using the same efficacy assessments as 
planned for this study; the CYC-010 study compared a first read and second re-read of 75 
Xe-133 lung images, spaced at least 4 weeks apart, to establish a non-inferiority margin 
for two successive reads of Xe-133 images.  Since Xe-133 is an approved agent for 
ventilation imaging, it by default is considered non-inferior to itself, and hence provides a 
suitable limit for establishing the non-inferiority of Technegas compared to Xe-133.   
Primary assessments of efficacy will be based on three blinded readers’ assessments of 
the Technegas and Xe-133 ventilation images in independent reading sessions.  In each 
reading session, readers will visually divide each lung into three regions of approximately 
equal size arranged craniocaudally and designated as the right and left apical, mid and 
basal regions.  Based on the image set presented, readers will provide a ventilation score 
for each lung region: 0 = absent ventilation, 1 = decreased ventilation, or 2 = normal 
ventilation.  For the blinded reads of the Xe-133 images, readers will be presented with all 
acquired ventilation image views for a subject and will assign a single ventilation score to 
each region.  For the reads of the Technegas images, readers will first be presented with 
the subset of ventilation image views that match the views acquired with Xe-133 and will 
assign ventilation scores to each lung region based on those views.  They will then be 
presented with the additional Technegas image views and will assign a second score 
based on the complete set of Technegas images.  The ventilation scores will be used to 
derive a binary agreement score for the paired Technegas and Xe-133 images by subject 
and lung region.  For the primary endpoint analysis, agreement scores will be determined 
from matching Technegas and Xe-133 image views only. Agreement scores based on all 
Technegas image views compared to the Xe-133 images will provide a secondary efficacy 
endpoint. 
After approximately 40 subjects have completed the study, an interim pilot blind read of 
the Xe-133 and Technegas ventilation images will be conducted to assess the viability of 
the planned efficacy measurements for comparing the Technegas and Xe-133 image sets 
for demonstrating non-inferiority.  If it is determined that the initial study design and 
efficacy parameters are not viable due to the differences in the image sets being acquired, 
the protocol will either be amended in accordance with Agency input, or the study may be 


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CYC-009 
 
 
Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Name of Sponsor: 
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
 
(For National Authority Use 
Only) 
Name of Finished Product: 
Technegas 
Name of Active Ingredient: 
Tc-99m labeled carbon 
terminated. The readers performing the interim blind read will not be used for the final 
blind read of images, and unless imaging parameters change, the images from these first 
40 subjects will be included in the final read of images.   
Number of Subjects Planned:  
Two hundred and forty (240) subjects who complete the study are planned. The subject 
must have completed all Xe-133 and Technegas planar ventilation imaging as required by 
the protocol, and the images must be of interpretable image quality according to site 
investigators’ assessments.   
Diagnosis and Main Criteria for Inclusion:  
• Male or female subject at least 18 years of age. 
• Subject is a candidate for ventilation imaging. 
• Subject must be willing and able to provide informed consent. 
• Subject must be stable and able to undergo Xe-133 planar imaging and Technegas 
planar imaging. 
• Subject must be willing and agree to complete all study procedures, including 24-hour 
follow-up safety assessments, physical examination and clinical laboratory evaluations. 
• Subject is using adequate birth control, if female and fertile. Adequate birth control is 
defined as surgical sterilization, hormone contraceptive use or intrauterine device 
(IUD). 
• Female subject has a negative urine or serum pregnancy test. 
• Subject has had or is scheduled to have a chest X-ray within 24 hours prior to the 
investigational imaging study. 


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Cyclomedica Australia Pty Ltd 
IND 62660; Technegas® 
CYC-009 
 
 
Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Name of Sponsor: 
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
 
(For National Authority Use 
Only) 
Name of Finished Product: 
Technegas 
Name of Active Ingredient: 
Tc-99m labeled carbon 
Investigational Drug, Dose and Mode of Administration: 
The investigational drug is Technegas. Technegas consists of aerosolized particles of 
carbon labeled with Tc-99m that are dispersed in high purity argon gas. It is manufactured 
at point of use before administration using a computer controlled and operated automated 
synthesis module (TechnegasPlus Generator System). 
Subjects will inhale Technegas aerosol until an adequate amount of radioactivity has 
localized in the lungs.  The amount required for imaging should produce 1.5-2.5 kilo-
counts per second (kcps) in the posterior projection as measured on a gamma camera.  
This equates to approximately 1.1 millicurie (mCi) (40 Megabecquerel [MBq]). 
Reference Therapy, Dose and Mode of Administration:  
Xenon 133 (Xe-133) gas, an approved imaging agent for assessment of pulmonary 
function and for imaging of the lungs, will be used as the comparator. 
Subjects will be administered between 10-30 mCi (370-1110 MBq) of Xe-133 for planar 
ventilation imaging. 
Study Duration:   
Study duration is approximately one to two days.  Subjects will undergo screening 
procedures.  Immediately thereafter, qualified subjects will be enrolled in the study.  The 
subject will first undergo a Xe-133 planar imaging study.  As soon as practical, but no 
longer than 24 hours after completing the Xe-133 imaging study, subjects will undergo a 
Technegas planar imaging study.  
Subjects will complete a 24-hour follow-up safety assessment that will take place within 
20 to 36 hours after the Technegas procedure.   
Criteria for Evaluation: 
Efficacy: 
The primary endpoint is the percent agreement between Technegas and Xe-133 obtained 
from the blinded readers’ ventilation assessments of matching image views.  It will be 
derived as follows.  Comparing a reader’s Technegas and Xe-133 ventilation scores for 
each subject, a binary agreement score will be obtained for each lung region: if the 


1.8.1 Clinical Study  
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IND 62660; Technegas® 
CYC-009 
 
 
Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Name of Sponsor: 
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
 
(For National Authority Use 
Only) 
Name of Finished Product: 
Technegas 
Name of Active Ingredient: 
Tc-99m labeled carbon 
Technegas and Xe-133 ventilation scores are the same for the region, it is assigned an 
agreement score of 1, otherwise it is assigned a score of 0 for no agreement.  Each blinded 
reader’s agreement scores for the subjects’ lung regions will be analyzed to determine an 
overall estimate of percent agreement and its confidence interval. 
Secondary endpoints are: percent agreement between Technegas and Xe-133 based 
upon blinded readers’ ventilation assessments of all image views (not just matched image 
views); percent agreement between Technegas and Xe-133 for the subgroups of subjects 
with and without pleural effusion (as observed in subjects’ chest X-rays); percent 
agreement measuring inter-observer agreement between pairs of blinded readers for their 
Technegas ventilation scores, and for their Xe-133 ventilation scores; and by lung-region 
kappa statistics measuring inter-observer agreement between pairs of blinded readers for 
their Technegas ventilation scores and for theirXe-133 ventilation scores.  
Safety: 
All subjects will be evaluated for safety throughout the study.  Vital signs (systolic blood 
pressure, diastolic blood pressure, pulse, and respiratory rate), pulse oximetry, clinical 
laboratory measurements, and physical examination will be collected prior to Xe-133 
administration (baseline safety) and at various times during the study up to approximately 
24 hours post-Technegas administration.  AEs will be monitored throughout the study 
until completion of the 24-hour post-Technegas inhalation safety assessments.  
Statistical Methods: 
Tabulation of summary statistics, graphical presentations, and statistical analyses will be 
performed using SAS® software.  All testing and confidence intervals will use a two-sided 
significance level of 5%, unless otherwise stated. 
Efficacy: 
Each blinded readers’ binary agreement scores will be analyzed using a generalized linear 
model with SAS® PROC GENMOD.  The logit function (log odds ratio) will be specified 
as the link function, and subject will be specified as a repeated measure to allow for 
correlations between lung regions within a subject.  The estimate of the intercept of the 
model using generalized estimating equation (GEE) methodology will provide an overall 
estimate of the agreement and its 95% confidence interval in terms of the log odds ratio; 


1.8.1 Clinical Study  
Page 9 
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IND 62660; Technegas® 
CYC-009 
 
 
Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
Name of Sponsor: 
Cyclomedica Australia Pty Ltd 
Unit 4 
1 The Crescent 
Kingsgrove, 
NSW 2208 Australia 
 
(For National Authority Use 
Only) 
Name of Finished Product: 
Technegas 
Name of Active Ingredient: 
Tc-99m labeled carbon 
simple algebra will be used to obtain the corresponding estimates and confidence intervals 
in terms of percent agreement (PA). 
The non-inferiority hypothesis to be tested is: 
 
H0: PA   60%  versus  HA: PA > 60% 
If the lower boundary from the 95% confidence interval for the PA difference is greater 
than 60%, Technegas will be considered non-inferior to Xe-133 with respect to the 
measurement of pulmonary ventilatory distribution. 
Study Success Criteria:  For the study to be deemed a success, the null hypothesis must be 
rejected for PA for at least two of the blinded readers for the primary efficacy endpoint. 
Inter-observer agreement between pairs of readers of Technegas images, and between 
pairs of readers of Xe-133 images will be evaluated using the GEE methodology that 
takes into account correlations between lung regions within a subject.  Ninety-five percent 
(95%) confidence intervals will be obtained for the agreement.  In addition, by lung-
region kappas will be obtained for pairs of readers of Technegas images and pairs of 
readers of Xe-133 images.  
 
Safety: 
Frequency distributions will be used to summarize the qualitative safety data, including 
adverse events, clinically significant changes in laboratory measurements and vital signs, 
and treatment emergent abnormalities in physical examinations.   
Summary statistics will be provided for all continuous safety data including change in 
laboratory measurements, vital signs and oxygen saturations.  Paired t-tests or the signed 
rank test will be used to test for statistically significant changes over time.  The laboratory 
measurements at baseline and follow-up also will be categorized relative to their reference 
ranges as low, within range, or high, and shift tables comparing the distributions from 
baseline to follow-up will be provided for each test.  The Stuart Maxwell test will be used 
to test for statistically significant changes in pre- versus post-treatment distributions. 
 


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Protocol V1.1: 04Oct2016 
CONFIDENTIAL 
2 
Table of Contents 
Sponsor Approval ..................................................................................................................... 2 
Investigator’s Signature ............................................................................................................ 3 
1 
Study Synopsis ........................................................................................................ 4 
2 
Table of Contents .................................................................................................. 10 
3 
Abbreviations ........................................................................................................ 14 
4 
Background Information ....................................................................................... 16 
4.1 
Description of Investigational Product ................................................................. 16 
4.2 
Summary of Nonclinical Studies .......................................................................... 18 
4.3 
Radiation Dosimetry ............................................................................................. 19 
4.4 
Summary of Risks and Benefits ............................................................................ 19 
4.4.1 
Warnings, Precautions, and Contraindications ................................................. 19 
4.5 
Route of Administration, Dosage, Dosage Regimen and Treatment Period ........ 19 
4.6 
Treatment Compliance .......................................................................................... 20 
5 
Study Objectives and Purpose .............................................................................. 21 
6 
Trial Design .......................................................................................................... 22 
6.1 
Primary and Secondary Efficacy Endpoints ......................................................... 23 
6.1.1 
Primary Efficacy Endpoint ............................................................................... 23 
6.1.2 
Secondary Efficacy Endpoints .......................................................................... 23 
6.1.3 
Safety Endpoints ............................................................................................... 23 
6.2 
Randomization and Blinding ................................................................................ 24 
6.3 
Treatment, Dosage, and Dosage Regimen ............................................................ 24 
6.3.1 
Investigational Drug Dose and Mode of Administration:................................. 24 
6.3.2 
Reference Therapy, Dose and Mode of Administration: .................................. 25 
6.4 
Study Period .......................................................................................................... 25 
6.5 
Discontinuation Criteria ........................................................................................ 25 
6.5.1 
Subject Discontinuation or Termination ........................................................... 25 
6.5.2 
Study or Site Termination ................................................................................. 26 
6.6 
Accountability of Investigational Drug ................................................................ 26 
6.6.1 
Receipt of Investigational Drug ........................................................................ 26 
6.6.1.1 
TechnegasPlus Generator .......................................................................... 26 
6.6.1.2 
Technegas Crucibles .................................................................................. 26 
6.6.1.3 
Technegas Patient Administration Set (PAS) ............................................ 27 
6.6.1.4 
Argon Gas Source ...................................................................................... 27 
6.6.1.5 
Source of Tc-99m Sodium Pertechnetate Injection ................................... 27 
6.6.2 
Disposition of Unused Investigational Drug..................................................... 27 
7 
Selection and Withdrawal of Subjects .................................................................. 28 
7.1 
Inclusion Criteria .................................................................................................. 28 
7.2 
Exclusion Criteria ................................................................................................. 28 
7.3 
Withdrawal or Termination of Participation ......................................................... 29 
8 
Treatment of Subjects ........................................................................................... 30 
8.1 
Treatment Administered ....................................................................................... 30 


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Protocol V1.1: 04Oct2016 
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8.1.1 
Technegas ......................................................................................................... 30 
8.1.1.1 
TechnegasPlus Generator .......................................................................... 30 
8.1.1.2 
Investigational Agent Preparation ............................................................. 31 
8.1.1.3 
Argon Gas Source ...................................................................................... 31 
8.1.1.4 
Source of Tc-99m Sodium Pertechnetate .................................................. 32 
8.1.2 
Xe-133 Preparation ........................................................................................... 32 
8.2 
Concomitant Medication ....................................................................................... 32 
8.3 
Subject Compliance .............................................................................................. 32 
8.4 
Protocol Deviations ............................................................................................... 32 
9 
Imaging ................................................................................................................. 34 
9.1 
Xe-133 Ventilation and Imaging .......................................................................... 34 
9.2 
Technegas Ventilation and Imaging ..................................................................... 34 
10 
Assessment of Efficacy ......................................................................................... 36 
10.1 
Blinded Read of Xe-133 Images ........................................................................... 36 
10.2 
Blinded Read of Technegas Images ...................................................................... 36 
11 
Assessment of Safety ............................................................................................ 38 
11.1 
Screening/Baseline Assessments .......................................................................... 38 
11.2 
Safety Indicators ................................................................................................... 38 
11.2.1 Clinical Laboratory Measurements ................................................................... 39 
11.2.2 Physical Examinations ...................................................................................... 39 
11.2.3 Vital Signs ......................................................................................................... 40 
11.2.4 Oxygen Saturation of the Blood using Pulse Oximetry .................................... 40 
11.2.5 24-Hour Follow-Up Safety Assessment ........................................................... 41 
11.3 
Adverse Events ..................................................................................................... 42 
11.3.1 Suspected Adverse Reaction ............................................................................. 42 
11.3.2 Adverse Reaction .............................................................................................. 42 
11.3.3 Unexpected Adverse Events ............................................................................. 42 
11.3.4 Serious Adverse Events .................................................................................... 42 
11.3.5 Severity of Adverse Events ............................................................................... 43 
11.3.6 Relationship to Study Drug ............................................................................... 44 
11.4 
Follow-up of Adverse Events ............................................................................... 44 
11.5 
Procedures for Reporting AEs, SAEs and Suspected Unexpected Serious Adverse 
Reactions (SUSARs) ............................................................................................. 45 
11.5.1 Suspected Unexpected Serious Adverse Reaction (SUSAR) ........................... 46 
12 
Schedule of Efficacy and Safety Assessments...................................................... 47 
12.1 
Visit 1 .................................................................................................................... 47 
12.2 
Visit 2 .................................................................................................................... 47 
12.3 
Schedule of Efficacy and Safety Assessments...................................................... 48 
13 
Statistical Analysis ................................................................................................ 49 
13.1 
General Considerations ......................................................................................... 49 
13.2 
Analysis Populations ............................................................................................. 49 
13.2.1 Disposition ........................................................................................................ 49 
13.2.2 Baseline Characteristics .................................................................................... 50 


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Protocol V1.1: 04Oct2016 
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13.3 
Efficacy Evaluations ............................................................................................. 50 
13.3.1 Primary Efficacy Endpoint ............................................................................... 50 
13.3.2 Secondary Efficacy Endpoints .......................................................................... 50 
13.4 
Efficacy Analyses ................................................................................................. 51 
13.4.1 Primary Efficacy Analyses ............................................................................... 51 
13.4.2 Secondary Efficacy Analyses ........................................................................... 51 
13.5 
Non-Inferiority Margin ......................................................................................... 52 
13.6 
Rationale for Sample Size ..................................................................................... 53 
13.7 
Interim Analysis .................................................................................................... 53 
13.8 
Safety Endpoints ................................................................................................... 54 
13.9 
Safety Analyses ..................................................................................................... 54 
14 
Data Handling and Record Keeping ..................................................................... 55 
14.1 
Case Report Forms ................................................................................................ 55 
14.2 
Completing, Signing and Archiving Case Report Forms ..................................... 55 
14.2.1 Archiving of Records ........................................................................................ 55 
14.3 
Direct Access to Source Data/Documents ............................................................ 56 
14.4 
Monitoring ............................................................................................................ 58 
14.4.1 Monitoring of Images and Imaging Data .......................................................... 58 
14.5 
Final Report .......................................................................................................... 59 
15 
Quality Control and Quality Assurance ................................................................ 60 
15.1 
Data Quality Assurance ........................................................................................ 60 
15.2 
Auditing ................................................................................................................ 60 
16 
Ethics..................................................................................................................... 61 
16.1 
Ethical Considerations .......................................................................................... 61 
16.2 
Institutional Review .............................................................................................. 61 
17 
Additional Requirements and Procedures ............................................................. 62 
17.1 
Regulatory Requirements–Sponsor/Investigator Obligations ............................... 62 
17.2 
Protocol Amendments ........................................................................................... 62 
17.3 
Protocol Deviations ............................................................................................... 62 
17.4 
Investigative Agreement ....................................................................................... 62 
17.5 
Investigator’s Responsibilities .............................................................................. 62 
17.5.1 Informed Consent.............................................................................................. 62 
17.5.2 Curriculum Vitae .............................................................................................. 63 
17.5.3 Financial Disclosure.......................................................................................... 63 
17.5.4 Investigator Delegation of Responsibilities ...................................................... 63 
17.5.5 Investigator and Study Staff Training and Documentation .............................. 64 
17.6 
Conditions for Terminating the Study .................................................................. 64 
17.7 
Warnings, Precautions, Contraindications ............................................................ 64 
17.8 
Information ........................................................................................................... 65 
17.9 
Confidentiality ...................................................................................................... 65 
18 
Financing and Insurance ....................................................................................... 66 
18.1 
Financing............................................................................................................... 66 
19 
Publication Policy ................................................................................................. 67 


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19.1 
Use and Publication of Study Results ................................................................... 67 
19.2 
Disclosure of Data................................................................................................. 67 
20 
Appendices ............................................................................................................ 68 
20.1 
Investigator Agreement ......................................................................................... 68 
20.2 
Declaration of Helsinki ......................................................................................... 70 
21 
References ............................................................................................................. 74 
 
 
 


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3 
Abbreviations 
Abbreviation 
Definition  
AE(s) 
Adverse Event(s) 
AP 
Anteroposterior 
CFR 
Code of Federal Regulations 
CRA(s) 
Clinical Research Associate(s) 
CRF(s) 
Case Report Form(s) 
CV 
Curriculum Vitae 
DTPA 
Diethylenetriamine Pentaacetic Acid 
DVT 
Deep Vein Thrombosis 
ECRF(s) 
Electronic Case Report Form(s) 
EDC 
Electronic Data Capture 
EPA 
Environmental Protection Agency 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GEE 
Generalized Estimating Equation 
GCP(s) 
Good Clinical Practice(s) 
I-131 
Iodine-131 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IEC(s) 
Independent Ethics Committee(s) 
In-111 
Indium-111 
IND 
Investigational New Drug 
IRB(s) 
Institutional Review Board(s) 
IUD 
Intrauterine Device 
kcps 
Kilo-counts per Second 
LAO 
Left Anterior Oblique 
LPO 
Left Posterior Oblique 
MBq 
Megabecquerel 
mCi 
Millicurie 
µg 
Microgram 
mm Hg 
Millimeters of Mercury 
MITT 
Modified Intent-to-Treat 
Mo-99 
Molybdenum-99 
Na99mTcO4 
Sodium Pertechnetate 
ng/L 
Nanograms per Liter 
nm 
Nanometer 
PA 
Percent agreement 


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Abbreviation 
Definition  
PAS 
Patient Administration Set 
PE 
Pulmonary Embolism 
PPS 
Per Protocol Set 
RAO 
Right Anterior Oblique 
RPO 
Right posterior Oblique 
SAE(s) 
Serious Adverse Event(s) 
SUSAR 
Serious and Unexpected Suspected Adverse Reaction 
SOP(s) 
Standard Operating Procedure(s) 
Tc-99m 
Technetium-99m 
WHO 
World Health Organization 
Xe-133 
Xenon-133 


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4 
Background Information 
Xenon 133 (Xe-133) remains the only approved pulmonary ventilation imaging agent 
commercially available in the United States.  Xenon-133 gas has been shown to be valuable 
for diagnostic inhalation studies for the evaluation of pulmonary function and for imaging the 
lungs.1   
 
Technegas has been in clinical use for lung scintigraphy since its original approval in 
Australia in 1987. Technegas and/or the TechnegasPlus Generator and Technegas carbon 
crucibles (also known as “Pulmotec” in the European Union [EU]) are now marketed in 51 
countries world-wide. In some countries, the Technegas system is approved as a device. In 
the EU, the TechnegasPlus Generator is approved as a device while the crucible is controlled 
as a drug.  
 
According to the EANM  Guidelines for Ventilation/Perfusion Scintigraphy (2009), 
“Technegas has minimized the problem of hotspots in patients with obstructive lung disease 
and is according to clinical experience better than the best liquid aerosols” (p. 92) for 
ventilation imaging and “is preferred over DTPA in patients with COPD” (p. 97).2 
 
The development of Technegas as a ventilation imaging agent for approval in the United States 
has been ongoing for the past 15 years.  Current Technegas clinical development focuses on a 
structure delineation type of indication (ventilatory imaging) for use in general ventilatory 
scintigraphy.  The proposed indication is: Technegas is indicated for ventilatory scintigraphy in 
adult patients.  This indication is similar to the approved indication for Xe-133 inhalation 
imaging and will be supported by this structural imaging non-inferiority study. 
 
This Phase 3 study directly compares planar ventilation image views obtained using 
Technegas with those obtained using Xe-133, with a goal to establish the equivalence 
(acceptable agreement) of the two sets of images for assessing pulmonary ventilatory 
distribution.    
 
4.1 
Description of Investigational Product 
Technegas is a structured ultra-fine dispersion of Technetium-99m (Tc-99m) labeled carbon 
particles produced by a TechnegasPlus Generator.  Technetium-99m labeled carbon aerosol, 
delivered from the TechnegasPlus Generator system, distributes to normally ventilated 
regions of the lungs.  This distribution occurs as a result of its small and uniform particle 
size.  Initial deposition into the lungs is monitored by placing a gamma camera over the lungs 
and having the subject inspire Technegas until a desired count rate for pulmonary imaging is 
achieved.  Typically a subject may need to inhale Technegas for only a few breaths.  If 
needed, the subject can take a rest breath (breathe normal air or oxygen) between Technegas 
inhalations. 
The size distribution of Technegas delivered from the TechnegasPlus® Generator is well 


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controlled such that the median particle diameter size is 177 nm and ranges from 
159-206 nm, and the ratio of the particle thickness to diameter is usually about 1:10.3   
 
It is well established that particles smaller than 500 nm behave like true gases, distributing to 
the most peripheral regions of the lungs.4  Following distribution, Technegas particles do not 
pass through the alveolar membrane to enter the systemic circulation.5,6  Once deposited in 
the periphery of the lungs (below the level of the bronchociliary elevator), Technegas 
particles do not undergo diffusion, or exhibit other means of re-distribution, but are gradually 
cleared by lung macrophages. 
   
Technegas particles initially deposited in the upper regions of the lung are removed by 
bronchociliary clearance and gastrointestinal elimination without absorption.3  Time-lapsed 
cinegraphic images of the chest region have documented that Technegas particles, initially 
deposited in the upper regions of the lung, are cleared by the bronchociliary elevator.  The 
web site of The John Curtain School of Medical Research, Australian National University, 
includes a cinegraphic illustration of this clearance mechanism.7  The cine image illustrates 
the upward movement of the radioactive particles followed by swallowing, transit through 
the esophagus and delivery into the stomach.   
 
Because Technegas does not undergo redistribution, it is possible to obtain as many different 
image projections as desired.  The ability to obtain multiple images is considered to be a 
definite advantage for assessing regional ventilation which displays focally decreased activity 
(“cold” regions) images.  In this study, Technegas planar image views will include a six view 
image set: anterior, posterior, left posterior oblique (LPO), right posterior oblique (RPO), left 
anterior oblique (LAO), and right anterior oblique (RAO) views.  Xenon 133 planar image 
views will be determined based on the site-specific standard of care which most commonly is 
posterior/posterior oblique or anterior/posterior image views collected during wash-in and 
wash-out. 
 
Technegas formation is achieved by using a high-purity carbon crucible loaded with sodium 
pertechnetate (Na99mTcO4).  The Tc-99m sodium pertechnetate is first evaporated to dryness 
using gentle heating in the presence of argon.  Technegas particles are formed by rapidly 
heating the crucible to approximately 2750°C ± 50ºC in an atmosphere of high-purity argon 
(99.99%).  Individual particles appear as hexagonal shaped single, flat technetium metal 
crystals encapsulated within a carbon sheath.  Data from an unpublished report (R. Browitt, 
R. Stephens, June 2005) showed the total particle output of one Technegas dose is in the 
range of 1.35106 particles per cm3.8   
 
These small, discrete individual particles begin agglomerating inside the chamber within 
minutes of formation, reaching an equilibrium particle size distribution with a median size of 
177 nm.2  Equilibrium is established as a net result of continuous agglomerate formation with 
larger agglomerates depositing on the internal surface of the chamber.  While the 
agglomeration and deposition equilibrium results in a reproducible particle size distribution, 


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the concentration of particles per unit volume decreases with time.  Inhalation of Technegas 
must occur within 10 minutes of manufacture.3   
 
The average concentration of carbon particles produced during a Technegas generation is 
approximately 370 nanograms per liter (ng/L).  Given no losses during the administration to 
the patient, the total extractable output would thus contain on average 2.2 microgram (µg) of 
carbon.  Because losses are expected, and patients do not inhale the complete contents of 
each Technegas generation, the actual carbon inhaled by the patient will be less than 2.2 µg 
of carbon.3  Inhalation of the amount of radioactivity recommended for multiple view 
imaging corresponds to about 1 μg of carbon inhaled per Technegas administration (Internal 
Report). 
 
4.2 
Summary of Nonclinical Studies  
The nonclinical testing strategy for Technegas was guided by the nature of the drug product’s 
ingredients, and considerations for a radiopharmaceutical administered by inhalation to 
assess pulmonary structures.   
 
The biodistribution of radioactivity from Tc-99m after administration of Technegas was 
examined in nonclinical studies sponsored or conducted by Tetley Manufacturing, Ltd. 
(Sydney, New South Wales, Australia) during the mid-1990s, with supplementation by the 
European licensee, Medgenix Diagnostics, a division of MDS Nordion S.A. (Fleurus, 
Belgium).3  No additional pharmacokinetics studies of Technegas were undertaken by 
Cyclomedica.  The distribution of Technegas particles following intravenous administration 
is much the same as analogous medical tracers, such as Tc-99m sulfur colloid injection and 
Tc-99m albumin colloid injection with the exception that the radioactive tagging for 
Technegas is particularly stable (i.e., there is little leaching of pertechnetate) in keeping with 
its physical makeup. 
 
Coghe, Votion and Lekeux compared the biodistribution of radioactivity after inhalation of 
Technegas, krypton-Kr 81m gas or Tc-99m diethylenetriamine pentaacetic acid (DTPA) 
aerosol by healthy (free from respiratory disorder) calves.  Using external gamma-ray 
scintigraphy and region of interest analysis of scintigrams, these authors concluded that the 
Tc-99m DTPA liquid in air aerosol more poorly escaped impaction in the large conducting 
airways.  Technetium-99m radioactivity appeared in the forestomachs (the first three 
compartments of the ruminant stomach) after inhalation of either Tc-99m labeled DTPA 
aerosol or Technegas, which was attributed to swallowed saliva and respiratory secretions.  
The appearance was more frequent and intense with Tc-99m DTPA aerosol.9 
 
The nonclinical testing strategy regarding chemical toxicity of the drug was based upon the 
nature of the carrier (elemental carbon) and route of administration.  There are two 
ingredients to the drug product, an elemental technetium core surrounded by a synthetic 
graphite shell.  Thus, exposure of the patient to Technegas is limited to pharmacologically 


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inert, elemental carbon.  In consideration of this, no safety pharmacology studies were 
conducted of Technegas. 
 
No nonclinical laboratory studies of Technegas were undertaken to evaluate its chemical 
toxicity profile.  The literature establishes safe exposure limits to inhaled particulate graphite 
in the context of other sources of human exposure.  The level of exposure to inhaled 
particulate graphite from the anticipated clinical dose of Technegas is well within the limits 
for the material established in that body of regulatory literature.  The patient’s particulate 
exposure during a medical imaging session is approximately equivalent to one or two days’ 
exposure to particulates in ambient air that meets Environmental Protection Agency 
standards. 
 
4.3 
Radiation Dosimetry 
In data from an unpublished report (M. Stabin, May 2, 2008), serial whole body images were 
obtained following the inhalation administration of Technegas to human subjects in a 
completed phase 1 investigational trial.  The image data were processed by region of interest 
analysis to determine tissue residence time.  Radiation dosimetry estimates were calculated 
and shown to compare favorably to those from Tc-99m imaging procedures.10 
 
4.4 
Summary of Risks and Benefits 
4.4.1 Warnings, Precautions, and Contraindications 
For specific information concerning warnings, precautions and contraindications for the 
investigational drug, the investigator is asked to refer to the appropriate section of the 
Investigator’s Brochure.  Because of the possibility of AEs from both the procedure and the 
investigational drug, a fully equipped emergency cart, or equivalent supplies and equipment, 
and personnel competent in recognizing and treating adverse reactions of all types should be 
immediately available. 
 
4.5 
Route of Administration, Dosage, Dosage Regimen and Treatment Period 
The recommended activity of Tc-99m sodium pertechnetate to be added to the crucible 
ranges between 6.8 and 19 mCi (250-700 MBq).  For adults, adequate images are obtained 
after approximately 1.1 mCi (40 MBq) of Technegas deposits in the lungs.9 The radioactive 
dose allows for sufficient count rates to obtain high quality images across a range of body 
habitus in a reasonable imaging time. 
 
Technegas consists of aerosolized particles of carbon labeled with Tc-99m that is dispersed 
in high-purity argon gas.  It is manufactured at the point of use minutes before administration 
using a computer-controlled and operated automated synthesis module (TechnegasPlus 
Generator).  It may only be necessary for a subject to inhale Technegas over a few breaths.  If 


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needed, the subject can take a rest breath (breathe normal air or oxygen) between Technegas 
inhalations.3 
 
 
4.6 
Treatment Compliance 
Trained clinical staff will be responsible for initiating and completing Technegas 
administration and ventilation imaging.  The trial will be conducted in compliance with this 
protocol, Good Clinical Practice (GCP) guidelines and applicable regulatory requirements. 
 


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5 
Study Objectives and Purpose  
The primary objectives and purpose of this study are: 
 
1. To demonstrate the non-inferiority of Technegas compared to Xenon 133 (Xe-133) 
ventilation studies, using planar scintigraphic imaging, with respect to their 
pulmonary ventilatory distribution in subjects that are candidates for ventilation 
imaging.  
2. To assess the safety profile of Technegas by monitoring AEs, clinical laboratory 
measurements (blood chemistry and hematology), pulse oximetry, and vital signs pre- 
and post-Technegas administration. 


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6 
 Trial Design 
This is a Phase 3 within-subject non-inferiority trial of Technegas ventilation planar imaging 
compared to Xe-133 ventilation planar imaging.  Subjects will be males and females at least 
18 years of age who have been referred for ventilation scintigraphy for any medical reason. 
Subjects will have undergone a chest X-ray, and during the study will undergo planar Xe-133 
imaging followed by planar Technegas imaging.  
 
Xe-133 images will be obtained per site-specific standard of care at each investigational site, 
which most commonly is posterior/posterior oblique image views or anterior/posterior image 
views collected during wash-in and wash-out.  Technegas images will include a six view 
image set: anterior, posterior, LPO, RPO, LAO, and RAO views. 
 
Enrollment will continue until 240 subjects have completed the study.  This number of 
subjects is expected to provide 90% power for demonstrating the non-inferiority of 
Technegas compared to Xe-133 in the assessment of ventilation imaging.  The 
non-inferiority margin to be used in this study was primarily determined from a separate 
study conducted under Protocol CYC-010. 
 
Primary assessments of efficacy will be based on three blinded readers’ assessments of the 
Technegas and Xe-133 ventilation images in independent reading sessions.  The primary 
efficacy endpoint will use only the subset of Technegas image views that match the site 
specific-standard views obtained for Xe-133.  Specifically, if only anterior/posterior images 
are collected with the Xe-133 ventilation study for a subject, then initially anterior/posterior 
image sets will be assessed for the subject’s Technegas ventilation study.  Likewise, if 
posterior/posterior oblique images are collected with the Xe-133 ventilation study, the 
posterior/posterior oblique images from the Technegas study will be assessed.  Following the 
initial primary assessment of the subset of matched Technegas image views, readers will 
assess the complete set of Technegas images for a secondary efficacy endpoint.  Ventilation 
will be scored in each of three regions of approximately equal size for each lung arranged 
craniocaudally and designated as the right and left apical, mid and basal regions, 
respectively.  Ventilation in each region will be assigned a ventilation score: 0 = absent 
ventilation, 1 = decreased ventilation, 2 = normal ventilation.  These scores will be used to 
derive a binary agreement score for the paired Technegas and Xe-133 images.  The 
agreement scores will be analyzed to provide an estimate of overall percent agreement 
between the Technegas and Xe-133 images.  
 
After approximately 40 subjects have completed the Xe-133 and Technegas image sessions, 
an interim blinded read of the images will be conducted.  Agreement between Xe-133 and 
Technegas will then be analyzed to assess the viability of the planned efficacy measurements.  
If it is determined that changes need to be made, either the CYC-009 clinical protocol will be 
amended with the Agency’s input and agreement or the study will be terminated.  The 
readers performing the pilot blind read will not be used for the final blind read of images. 


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However, the images from these first 40 subjects will be included in the final read of images 
unless the imaging parameters change. 
 
6.1 
Primary and Secondary Efficacy Endpoints 
6.1.1 Primary Efficacy Endpoint 
The primary endpoint is the percent agreement between the Technegas and Xe-133 obtained 
from blinded readers’ ventilation assessments of matching image views.  It will be derived as 
follows.  Binary agreement scores for each subject’s six lung regions will be obtained: if the 
Technegas and Xe-133 ventilation scores are the same for a lung region, the region is 
assigned an agreement score of 1, otherwise it is assigned a score of 0 for no agreement.  
Each blinded reader’s agreement scores for the subjects’ lung regions will be analyzed to 
determine an overall estimate of percent agreement and its confidence interval. 
 
6.1.2 Secondary Efficacy Endpoints 
The secondary endpoints include:  
1. Percent agreement between Technegas and Xe-133 obtained from blinded readers’ 
ventilation assessments of all image views acquired with Technegas (i.e. not limited 
to the matched image views). 
2. Percent agreement between Technegas and Xe-133 for the subgroups of subjects with 
and without pleural effusion as noted in subjects’ chest X-rays, from blinded readers 
ventilation assessments.  
3. Percent agreement measuring inter-observer agreement between pairs of blinded 
readers for their Technegas ventilation scores, and for their Xe-133 ventilation scores. 
4. By lung-region kappa statistics measuring inter-observer agreement between pairs of 
blinded readers for their Technegas ventilation scores and for their Xe-133 ventilation 
scores. 
 
6.1.3 Safety Endpoints 
All subjects will be evaluated for safety throughout the study.  Vital signs (systolic blood 
pressure, diastolic blood pressure, pulse, and respiratory rate), pulse oximetry, clinical 
laboratory measurements,), will be collected prior to Xe-133 administration (baseline safety) 
and at various times during the study up to approximately 24 hours post-Technegas 
administration (20 to 36 hours post-Technegas permitted).  Adverse events will be monitored 
throughout the study until completion of the 24-hour follow-up. 
 


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6.2 
Randomization and Blinding 
This is an open-label, non-randomized clinical trial.  All subjects will undergo Xe-133 planar 
imaging and Technegas planar imaging.  Subjects will undergo Xe-133 inhalation and 
imaging first, followed by Technegas inhalation and imaging as soon as practical and no 
longer than 24 hours after completing the Xe-133 imaging.  Because of the rapid clearance of 
Xe-133 from the lungs and the low, non-interfering energy of Xe-133 photons, a wash-out 
period is not required.   
 
While the Xe-133 will not interfere with the Technegas images, it is recognized that there 
will be potentially confounding effects of Xe-133 and Technegas on safety parameters. 
 
The primary efficacy data will be from a blinded read managed by Certus International, a 
contract research company and imaging core lab located in Bedford, NH and St. Louis, 
Missouri.  Three experienced nuclear medicine physicians will be selected to perform 
independent blinded reads.  The readers will have experience reading Xe-133 ventilation 
images, as well as experience reading DTPA ventilation scans.  Like Technegas, DTPA is a 
particulate based ventilation imaging agent.  Training in reading Technegas scans will also be 
provided.  Each reader will independently assess both the Xe-133 images and the Technegas 
images in separate sessions.  Each image set will be assigned a unique random code number, 
which will govern the order in which the subjects’ images are read. The readers will be 
shown a recent anteroposterior or posteroanterior chest X-ray of the lungs but will be blinded 
to subject identity, reason for the ventilation scan, results of procedures and to any other 
subject information. 
 
Additional details on the blinded read are provided in the Imaging Charter. 
 
6.3 
Treatment, Dosage, and Dosage Regimen 
6.3.1 Investigational Drug Dose and Mode of Administration: 
The investigational drug is Technegas.  Technegas consists of aerosolized particles of carbon 
labeled with Tc-99m that are dispersed in high purity argon gas.  It is manufactured at point 
of use before administration using a computer controlled and operated automated synthesis 
module (TechnegasPlus Generator System). 
 
The recommended activity of Tc-99m sodium pertechnetate to be added to the Technegas 
crucible ranges between 6.8 and 19 mCi (250-700 MBq).  For adults, adequate images are 
obtained after approximately 1.1 mCi (40 MBq) of Technegas deposits in the lungs.9   
 
Subjects will inhale Technegas aerosol until radiation monitors positioned over the lungs 
indicate that an adequate amount of radioactivity has localized in the lungs. The amount 
required for imaging is 1.5-2.5 kcps in the posterior projection as measured on a gamma 
camera.  This equates to approximately 1.1 mCi (40 MBq). 


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6.3.2 Reference Therapy, Dose and Mode of Administration: 
Xenon 133 gas, an approved imaging agent for assessment of pulmonary function and for 
imaging of the lungs, will be used as the comparator.  Subjects will be administered between 
10-30 mCi (370-1110 MBq) of Xe-133 for planar ventilation imaging. 
 
6.4 
Study Period 
The period from enrollment to pre-Xe-133 inhalation will serve as the baseline period for 
safety assessments.  The treatment period begins at the time of Technegas inhalation and 
extends through the 24-hour follow-up safety assessment.   
 
During Visit 1, screening procedures and enrollment occur.  The subject will then undergo 
Xe-133 inhalation and planar imaging.  Subjects will then undergo Technegas inhalation and 
planar imaging as soon as practical and no longer than 24 hours after completing the Xe-133 
imaging. 
 
Subjects will complete a 24-hour follow-up safety assessment, including physical 
examination and clinical laboratory assessment that will take place within 20 to 36 hours 
after the Technegas procedure.   
 
6.5 
Discontinuation Criteria 
6.5.1 Subject Discontinuation or Termination 
Every subject has the right to terminate his or her participation in the study at any time 
without providing reasons.  A subject’s participation will terminate immediately upon his/her 
request.  However, every attempt should be made by the investigator to complete the safety 
assessments to ensure the subject experiences no AEs. 
 
If a subject chooses to withdraw from the study, the investigator should attempt to obtain the 
reason for withdrawal and document this on the case report form (CRF). 
 
The termination of a subject’s participation in the study should be considered by the 
investigator or sponsor and/or designee in the case of a serious adverse event (SAE). 
 
The subject may be withdrawn from the study at any time at the discretion of the investigator 
or sponsor.  The reason for such withdrawal should be fully documented on the CRF.  
Potential reasons for withdrawal of the subject include, but are not limited to, withdrawal of 
informed consent, death, subject lost to follow-up, enrollment of a subject subsequently 
found to have not met inclusion and/or exclusion criteria or study or site termination by the 
sponsor. 
 


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6.5.2 Study or Site Termination 
The sponsor retains the right to terminate or suspend an investigator or site from participation 
in the study and/or to terminate or suspend the entire study at its sole discretion.  Potential 
reasons for site or study termination include, but are not limited to, serious safety concerns, 
the inability of a site or sites to carry out the study as agreed to in the protocol, repeated 
enrollment of subjects that do not meet inclusion or exclusion criteria or repeated protocol 
deviations. 
 
In the event of premature investigator, site or study termination, investigators will be 
promptly informed of the termination or suspension, as will the institutions, regulatory 
authorities, and Institutional Review Boards (IRBs) or Independent Ethics Committees 
(IECs). 
 
6.6 
Accountability of Investigational Drug 
6.6.1 Receipt of Investigational Drug 
Shipment of investigational TechnegasPlus generator and Technegas crucibles and the 
Patient Administration Set (PAS) from the sponsor to the investigator or other designated 
persons cooperating with the investigator will be accompanied by a receipt form, which will 
describe the batch and/or lot number(s) and the amount of investigational drug or supplies 
provided for the study.  The form(s) will be signed, dated, returned to the sponsor and a copy 
will be maintained in the site file. 
 
6.6.1.1 TechnegasPlus Generator 
All sites will have the use of a dedicated TechnegasPlus Generator for study purposes.   
 
6.6.1.2 Technegas Crucibles 
Crucibles will be supplied to the sites with documentation regarding lot/batch number and 
shipment amounts.  The groups of 10 crucibles are packaged in a molded polyvinyl chloride 
pack with a printed cardboard sliding cover and labeled “for Investigational Use only”.  
Crucibles must be stored at a controlled room temperature of 8° to 30°C (46° to 86°F) in a 
secure area.  Accountability will be performed on those crucibles used for the trial.  The 
crucible is broken automatically following Technegas generation to prevent accidental re-use 
which would result in erratic yields.  The debris is collected in a tray beneath the contacts, 
and will contain a residue of radioactivity.  It should be treated as low level radioactive 
waste.  Residual radioactivity in used crucibles will be allowed to decay and they will be 
disposed of according to the study site’s standard operating procedures (SOPs).  
 


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6.6.1.3 Technegas Patient Administration Set (PAS) 
A single-use-only Technegas PAS will be supplied for each subject.  Batch and/or lot 
numbers will be tracked and accountability will be performed for all PAS used for the trial.  
Unused PAS will be stored in a secure location.  Residual radioactivity in used PAS will be 
allowed to decay and they will be disposed of according to the study site’s SOPs. 
 
6.6.1.4 Argon Gas Source 
Investigational sites will obtain their own high-purity (≥ 99.99%) medical-grade argon gas 
supplied by a qualified vendor in stand-alone cylinders. It will be handled according to the 
investigational site’s SOPs and the instructions provided in the TechnegasPlus Technegas 
Generator User Manual (TechnegasPlus Generator User Manual)11.  Documentation of the 
Argon supplier’s name, the batch number if applicable and cylinder tracking information will 
be maintained at the investigational site. 
  
6.6.1.5 Source of Tc-99m Sodium Pertechnetate Injection 
All Tc-99m will be obtained from the investigational site’s molybdenum-99  
(Mo-99)/Tc-99m generator or a local radiopharmacy, which must be approved by the state or 
national regulatory authority in its respective location.  Documentation of the generator 
manufacturer name, lot number and date of manufacture must be maintained at the 
investigational site in their study records.  
 
The Tc-99m will be in the form of sodium pertechnetate (Na99mTcO4), which must meet USP 
requirements for Tc-99m sodium pertechnetate injection.  The amount of radioactivity 
dispensed, date and time dispensed, time injected and amount of radioactivity injected must 
be tracked and recorded on the CRFs.  
 
6.6.2 Disposition of Unused Investigational Drug 
Upon completion of the study, the investigator will return all unused investigational drug to 
the sponsor or will dispose of it according to pre-arranged methods and procedures agreed 
upon by the sponsor. 
 


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7 
Selection and Withdrawal of Subjects 
A minimum of 240 subjects are required to complete this study.  The study is open to all 
subjects satisfying inclusion and exclusion criteria.   
 
All subjects enrolled into the study will receive a subject number that will consist of a two-
digit site number, followed by a three-digit consecutive number of enrollment.  An example 
of a subject number would be 02001, representing the first subject enrolled from Site 2. 
 
7.1 
Inclusion Criteria 
Subjects may be enrolled if they meet the following requirements: 
 
1. Male or female subject at least 18 years of age. 
2. Subject is a candidate for ventilation imaging. 
3. Subject must be willing and able to provide informed consent. 
4. Subject must be stable and able to undergo Xe-133 planar imaging and Technegas 
planar imaging. 
5. Subject must be willing and agree to complete study procedures, including returning 
for all 24-hour follow-up safety assessments, such as physical examination and 
clinical laboratory evaluation. 
6. Subject is using adequate birth control, if female and fertile. Adequate birth control is 
defined as surgical sterilization, hormone contraceptive use or intrauterine device 
(IUD). 
7. Female subject of child-bearing potential has a negative urine or serum pregnancy 
test. 
8. Subject has had or is scheduled to have a chest X-ray within 24 hours prior to the 
investigational imaging study. 
 
7.2 
Exclusion Criteria 
1. Subject has been administered any other radiopharmaceutical within a timeframe that 
might cause interference with study imaging.   
2. Subject is a pregnant or lactating female. 
3. Subject has received Technegas in the past. 
4. Subject has received an investigational drug within 30 days prior to dosing. 
5. Subject is hemodynamically unstable. 
 


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7.3 
Withdrawal or Termination of Participation 
Every subject has the right to terminate his or her participation in the study at any time 
without providing reasons.  A subject’s participation will terminate immediately upon his/her 
request.   
 
A subject who signs the informed consent form, but discontinues study participation 
without inhaling Technegas is termed a withdrawn subject.  Subjects may withdraw 
themselves or may be withdrawn by the investigator. Data collection for withdrawn subjects 
will cease at the time of their withdrawal. 
 
Subjects may withdraw or be withdrawn for any of the reasons listed below: 
• Did not meet inclusion/exclusion criteria 
• Withdrew consent 
• Lack of compliance with study procedures 
• Investigator decided it is in the subject’s best interest to be withdrawn 
 
A subject who signs the informed consent form and then undergoes Technegas inhalation, 
but does not complete all of the imaging procedures and/or all of the safety assessments 
including clinical laboratory evaluation, is termed an incomplete subject. 
 
Whatever the reason for lack of study completion, the investigator should attempt to collect 
and report the required Technegas safety data. 
 
A subject who meets all inclusion criteria and no exclusion criteria, undergoes Technegas 
inhalation and completes all study procedures is termed a complete subject. 


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8 
Treatment of Subjects 
Subjects will undergo Xe-133 and Technegas inhalation and imaging.  Safety will be 
monitored pre- and post-inhalation of Technegas by assessing changes in clinical laboratory 
measurements, vital signs, blood oxygen saturation by pulse oximetry, and physical 
examination. 
 
Subjects must agree to return for an in-person 24-hour follow-up after Technegas inhalation 
to obtain safety assessments.  Prior to enrolling the subject, the required 24-hour follow-up 
safety assessment will be discussed with the patient and documented.  Subjects that agree to 
return for the 24-hour follow-up and sign the informed consent form will be entered into the 
study.   
 
If a subject withdraws consent for participation by not returning for the 24-hour follow-up 
safety assessment, the subject will be considered to be an incomplete subject. However, the 
subject must be contacted by telephone, interviewed for treatment emergent adverse events 
and the contact must be documented in the subject’s source records. All attempts to reach the 
subject by telephone, or by mail or email if telephone communication cannot be established, 
must be documented in the subject’s source records.  
 
8.1 
Treatment Administered 
8.1.1 Technegas 
Technegas will be manufactured at point of use immediately before administration using the 
TechnegasPlus Generator. 
 
Subjects will inhale approximately 1.1 mCi (40 MBq) of Technegas for image acquisition. 
 
8.1.1.1 TechnegasPlus Generator  
The TechnegasPlus Generator is a microprocessor-controlled device consisting of a 6-liter 
shielded, sealed generation chamber.  The chamber is housed above two (2) electrodes 
between which a carbon crucible is inserted.  A drawer in the front of the generator provides 
access to the electrodes.  
 
Technegas is produced by vaporization in the generation chamber.  The TechnegasPlus 
Generator includes several automatic security features that allow safe and efficient 
generation and delivery of the Technegas. 
 
The 6-minute purge phase with argon gas before each generation assures the elimination of 
air from the sealed chamber.  In addition, for each Technegas generation, an automatic leak 
test is performed during this purge stage. 
 


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To assure an accurately reproducible yield and quality of Technegas, a phototransistor is used 
to monitor and maintain crucible burn temperature of around 2750ºC ± 50ºC over a  
15-second interval.  If the acceptable temperature cannot be maintained over a prescribed 
period, then the TechnegasPlus Generator prohibits the delivery of Technegas to the subject.  
If the acceptable temperature is maintained over a shorter defined burn period, then the user 
is notified that the yield could be low.  The user then has the option to administer the product 
to the subject.  For the purposes of this protocol, burns that produce a low yield will not be 
given to study subjects.   
 
Technegas is intended to be administered to the subject within 10 minutes after its 
generation.  After this time, the generator stops delivery to the subject in order to prevent 
accidental use of expired Technegas. 
 
See the TechnegasPlus Generator User Manual (supplied separately) for complete details and 
instructions.10 
 
8.1.1.2 Investigational Agent Preparation 
A carbon crucible, pre-moistened with ethanol to assist in the complete loading of the 
crucible’s reservoir, is fitted between electrodes and loaded with the required activity of 
Tc-99m sodium pertechnetate in approximately 0.14 mL saline (standard Mo-99/Tc-99m 
generator eluate).  The volume and loading time should be recorded on the CRF.  Any 
additional Tc-99m sodium pertechnetate added to the crucible should be recorded as well.  
The chamber is closed for the evaporation cycle during which a small electric current is used 
to heat the crucible to approximately 70ºC.  High-purity argon gas is also passed over the 
crucible and purges the generation chamber of air and moisture.   
 
The eluate must evaporate to dryness and leave a white crust of salt (sodium chloride and  
Tc-99m sodium pertechnetate) on the carbon crucible.  Technegas is then generated in a short 
heating cycle where a large electric current is used to rapidly heat the carbon crucible to a 
temperature of 2750ºC ± 50ºC for 15 seconds, in an atmosphere of high-purity argon.  
 
The resulting vapor and argon mixture is inhaled by the subject through a disposable PAS, 
which is a mouthpiece valve-filter transfer tubing assembly.  Residual, unused Technegas is 
purged from the generation chamber with high-purity argon into an exhaust-trapping filter 
before the chamber can be opened and reloaded for the next cycle.   
 
As the carbon crucibles are intended for single-use, the machine automatically breaks the 
crucible to prevent accidental re-use.  The debris is collected in a tray beneath the electrodes. 
 
8.1.1.3 Argon Gas Source 
Argon gas will be supplied by a qualified vendor in stand-alone cylinders and will be 


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medical-grade high-purity 99.99% argon.  Documentation of the batch and cylinder tracking 
information will be maintained at all sites. 
 
8.1.1.4 Source of Tc-99m Sodium Pertechnetate 
All Tc-99m sodium pertechnetate will be obtained from Mo-99/Tc-99m generators approved 
by state or national regulatory authorities in their respective regions or from local 
radiopharmacies.  Documentation for Technetium received from a local radiopharmacy, such 
as prescription, radiopharmacy log, delivery receipt, etc, as applicable for a site, will be kept 
at the site. 
 
8.1.2 Xe-133 Preparation 
Xenon Xe-133 gas will be prepared and administered according to the investigational site’s 
standard practice for subjects presenting for ventilation imaging.  The radioactivity at time of 
loading and the start and stop times of inhalation will be captured in the CRF. 
 
8.2 
Concomitant Medication 
Concomitant medications are any medications, including over-the-counter preparations, 
which the subject receives within 24 hours prior to signing informed consent through  
24-hour follow-up, 20 to 36 hours after Technegas administration.  If a Tc-99m MAA 
perfusion study occurs following Technegas imaging but within this time period, the MAA 
and radioactive dose associated with the study should be considered a concomitant 
medication.  
 
All medications given until the 24-hour follow-up safety assessment will be recorded on the 
CRF.  Documentation will include information concerning generic or trade names, 
indication, total daily dose (including units), route of administration, date of administration, 
and date of termination.  All medications and therapies will be coded using WHODRUG®. 
 
8.3 
Subject Compliance 
Subjects will be monitored by clinical personnel during each visit of this study.  Subjects 
who are not compliant with the procedures outlined in this protocol should be withdrawn 
from the study at the discretion of the investigator or the Sponsor. 
 
8.4 
Protocol Deviations 
An investigator may not deviate from the protocol, except when necessary to eliminate an 
immediate hazard (risk) to the rights, safety or welfare of a subject. The investigator must 
notify the sponsor immediately and not enroll any additional subjects or administer the 


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investigational drug to any subsequent subjects until the immediate hazard is eliminated from 
the study protocol or otherwise resolved.  The investigator must notify the sponsor of all 
protocol deviations and must notify the IRB/IEC of any protocol deviations following the 
IRB/IEC standard procedures. 
 


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9 
Imaging 
The same camera should be used to obtain planar Xe-133 and planar Technegas images.  
Planar scintigraphy with a nuclear medicine gamma camera will be used to image the 
distribution of both Xe-133 and Technegas.  Imaging will first be performed with Xe-133 
followed by Technegas.  Because of the rapid clearance of Xe-133 from the lungs and the 
low, non-interfering energy of Xe-133 photons, a washout period is not required.  
 
9.1 
Xe-133 Ventilation and Imaging 
Xe-133 ventilation and imaging should be performed in accordance with the standard of care 
for Xe-133 administration and imaging at the investigational site, which will be documented 
at the Site Qualification visit.  Images should be labeled to indicate when each phase of the 
study begins (first breath, wash-in, wash-out).  The wash-in/wash-out protocol for Xe-133 
ventilation imaging used at each investigational site will be documented in the study files. 
 
9.2 
Technegas Ventilation and Imaging  
Technegas inhalation will be performed after the Xe-133 portion of this study.  Because of 
the rapid clearance of Xe-133 from the lungs and the low, non-interfering energy of Xe-133 
photons, a washout period is not required.  Technegas is administered by inhalation through 
the PAS within 10 minutes after preparation.  This consists of a plastic tube connected to the 
TechnegasPlus Generator, fitted with a mouthpiece, one-way flow values and expiration 
filter. 
 
The subject will be instructed to breathe through the mouthpiece in one of the methods 
described below: 
▪ Slow, deep breathing from the residual functional capacity (end of calm expiration) 
followed by a 5-second breath-hold (recommended method) 
▪ Normal breathing with deep inhalations without breath-holding 
▪ Rapid and deep inspirations from the residual functional capacity followed by a 
breath-hold of about 5 seconds at the end of the inspiration 
 
The count rate should be monitored until a rate of 1.5-2.5 kcps is achieved.  This typically 
requires 1 to 5 breaths, but additional breaths may be necessary to achieve this target.  The 
number of inhalations required to achieve the target counting rate should be recorded on the 
CRF, along with the time of the first inhalation and time of the final inhalation.  To yield 
uniform apex-to-base deposition, it is recommended that the subject is ventilated in the 
supine position on the scanning bed with a detector positioned under the bed to monitor the 
lung count rate. 
 


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The same dual-headed camera used for Xe-133 imaging will be used to collect Technegas 
images in multiple projections.   
 
Technegas images will include a six view image set:  
• anterior view 
• posterior view 
• left posterior oblique view 
• right posterior oblique view 
• left anterior oblique view 
• right anterior oblique view 
 
Additional details and specifications related to the Technegas ventilation and imaging are 
provided in the Imaging Manual. 
 
 
 
 


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10 Assessment of Efficacy 
Primary assessments of efficacy will be based on three blinded readers’ independent 
assessments of the Technegas and Xe-133 ventilation images in independent, randomized 
reading sessions.  Readers will be selected as having experience reading both Xe-133 and 
DTPA ventilation scans.  Readers will also receive training on reading Technegas ventilation 
images.   
 
In each reading session readers will be blinded to all clinical information except the chest X-
rays required for this study.  At the start of each case read, with the aid of the subject’s chest 
X-ray,  a reader will visually divide each lung into three regions of approximately equal size 
arranged craniocaudally and designated as the right apical, left apical, right mid, left mid, 
right basal and left basal regions.  The readers will then assess each lung region for 
ventilation, assigning the region a ventilation score on a three-point scale:   
0 = absent ventilation  
1 = decreased ventilation  
2 = normal ventilation. 
If a lung region is completely obscured (as a result of pleural effusion for example), or if a 
lung region is completely absent as a result of lung resection, the region will be designated a 
score of 99 to indicate that ventilation cannot be assessed. 
  
10.1 Blinded Read of Xe-133 Images 
The Xe-133 planar ventilation images will be read by three (3) expert readers, blinded to all 
clinical information except the chest X-rays required for this study.  Each reader will 
independently assess the images identified only by a random code number, which will dictate 
the order of presentation of images to the readers.  Together with a subject’s chest X-ray, a 
reader will be presented with all acquired ventilation image views for a subject.  The reader 
will visually divide each lung into three regions of approximately equal size as described 
above and will assign a single ventilation score to each lung region.   
 
Additional details on the blinded read are provided in the CYC-009 Imaging Charter. 
 
10.2 Blinded Read of Technegas Images 
In separate reading sessions, the same three readers who assessed the Xe-133 ventilation 
images will also assess the Technegas planar ventilation images.  Again, the readers will be 
blinded to all clinical information except chest X-rays and the Technegas images will be 
identified by a random code number, distinct from the Xe-133 assigned code number.  Each 
reader will independently assess the images presented in the order of their assigned code 
numbers.   


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Two sequential reads will be conducted of Technegas ventilation images.  In the first read of 
a case, a reader will be presented with the subject’s chest X-ray and the subset of ventilation 
image views that match the views acquired with Xe-133 for that subject.  The reader will 
visually divide each lung into three regions of approximately equal size as described above 
and then will assign ventilation scores to each lung region based on those views.  He/she will 
then be presented with the additional Technegas image views and will assign a second score 
based on the complete set of Technegas images for the subject.  If the second ventilation 
score for a region differs from the first, the reader will be asked to document the basis for the 
changed score.   
 
The ventilation scores obtained from the first Technegas read of the subset of image views 
that match the Xe-133 image views will be used to determine agreement with Xe-133 for the 
primary efficacy endpoint.  The ventilation scores obtained from the read of all Technegas 
image views will provide a secondary efficacy endpoint of agreement with Xe-133. 
 
Additional details on the blinded read are provided in the Imaging Charter. 
 
 
 


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11 Assessment of Safety 
Subjects will be screened prior to enrollment in the clinical trial to ensure that they meet all 
eligibility criteria, which are designed to exclude subjects for whom participation may not be 
safe.  Women who are of childbearing potential must have a negative pregnancy test as part 
of the eligibility assessments.   
 
11.1 Screening/Baseline Assessments 
1. Subject is evaluated against the inclusion/exclusion criteria. 
2. If subject meets inclusion/exclusion criteria and agrees to return for 24-hour follow-up, 
informed consent will be obtained and a subject number will be assigned. 
3. Demographic data is obtained (date of birth, gender, and ethnicity). 
4. Allergies (including known food, environmental, and drug allergies) are documented. 
5. Medical and surgical history is obtained including concomitant medications, smoking 
history and reason for Xe-133 ventilation imaging. 
 
The following clinical and laboratory studies will be obtained at screening and must be 
performed within 24 hours prior to the first imaging study: 
1. Physical examination including auscultation of the lungs and heart, and height and 
weight 
2. Chest X-ray in either anteroposterior view or posteroanterior view.  A chest X-ray 
obtained within 24 hours of signing the Informed Consent may be used in subjects with 
no significant clinical change. 
3. Clinical chemistry and hematology 
4. Serum or urine pregnancy test (for females of childbearing potential) 
 
11.2 Safety Indicators 
Safety will be monitored by the following parameters: vital signs (systolic and diastolic 
blood pressure, respiratory rate and pulse rate), oxygen saturation of the blood using pulse 
oximetry, clinical laboratory parameters, and adverse event assessments for approximately 24 
hours (20 to 36 hours) after Technegas inhalation.  A physical examination will be obtained 
during screening and at the 24-hour follow-up safety assessment. 
 
If a clinically significant change from baseline is observed, and it represents a worsening of a 
clinical condition for any safety parameter, the change will be considered an AE, it will be 
documented on the AE page of the CRF, and the investigator will continue to monitor the 
subject until the parameter returns to baseline levels or until the investigator judges that 


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follow-up is no longer necessary. 
 
11.2.1 Clinical Laboratory Measurements 
Subjects will have blood drawn during screening and at the 24-hour follow-up safety 
assessment to obtain clinical laboratory measurements.  Blood samples will be sent for 
analysis by a central laboratory.   
 
The following clinical chemistry measurements will be obtained:  albumin, alkaline 
phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea 
nitrogen (BUN), calcium, chloride, carbon dioxide (CO2), serum creatinine, direct bilirubin, 
gamma-glutamyl transpeptidase (GGT), glucose, lactate dehydrogenase (LDH), serum 
phosphorus, potassium (K+), sodium (Na+), total bilirubin, total cholesterol, total protein, uric 
acid. 
 
The following hematology measurements will be obtained:  hemoglobin (Hgb), hematocrit 
(Hct), red blood cell count (RBC), mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell 
distribution width (RDW), mean platelet volume (MPV), white blood cell count (WBC), 
white blood cell differential, including lymphocytes, neutrophils, monocytes, eosinophils, 
and basophils. 
 
The investigator will compare 24-hour post-Technegas measurements to baseline 
measurements and comment on any changes that are considered clinically significant.  
Attributability of any changes considered clinically significant will be assessed as follows: 
 
 
1 = Attributable to disease; no follow-up required 
 
2 = Possibly attributable to Technegas, FOLLOW-UP REQUIRED 
 
3 = Apparent laboratory error 
 
4 = Unevaluable; includes instances where baseline values not reported and instances 
where sample was hemolyzed 
Any changes considered clinically significant and assessed as “2 = Possibly attributable to 
Technegas, FOLLOW-UP REQUIRED” will be documented on the AE page of the CRF.  
 
All laboratory tests with clinically significant changes will be repeated at appropriate 
intervals following the procedure until the values return to baseline or until the investigator 
and the Medical Monitor agree that further follow-up is no longer clinically relevant. 
 
11.2.2 Physical Examinations 
A physical examination will be performed by a physician during screening and during the 


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24-hour follow-up safety assessment to assess possible changes in the subject’s clinical 
condition.   
 
The findings of each examination will be recorded on the appropriate CRF.  Any physical 
examination finding that is classified by the investigator as a clinically significant worsening 
(i.e., that resulted in a change in subject management) compared to previous examination will 
be considered an AE, documented on the AE page of the CRF, and followed until resolution.  
 
11.2.3 Vital Signs 
Vital signs must be obtained and recorded, including: 
 
• Systolic and diastolic blood pressure millimeters of mercury (mm Hg) 
• Pulse rate (beats/minute) 
• Respiratory rate (breaths/minute) 
 
The same position and arm should be used each time vital signs are measured for a given 
subject.   
 
Vital signs will be collected within 30 minutes prior to the Xe-133 imaging study.  These will 
be considered baseline measurements.  Additional vital signs will also be taken following 
completion of the Xe-133 imaging, but prior to Technegas imaging. 
 
Vital signs will be taken at approximately 10 minutes (± 5 minutes) prior to Technegas 
inhalation and within 15 minutes following completion of the Technegas imaging.  
Additional vital signs will be taken during the 24-hour follow-up safety assessment. 
 
The following changes (increases or decreases) in vital signs from pre-study baseline values are 
considered to be clinically significant and require commentary: 
 
• systolic blood pressure > 45 mm Hg 
• diastolic blood pressure > 30 mm Hg 
 
Any clinically significant worsening changes will be documented on the AE page of the CRF.  
 
11.2.4 Oxygen Saturation of the Blood using Pulse Oximetry 
Oxygen saturation of the blood using pulse oximetry will be collected within 30 minutes  
prior to the Xe-133 study.  This will be considered the baseline measurement.  Oxygen 
saturation will also be taken following completion of the Xe-133 imaging, but prior to 
Technegas imaging.   
 


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Oxygen saturation will be taken at approximately 10 minutes (± 5 minutes) prior to 
Technegas inhalation and within 15 minutes following completion of the Technegas imaging.  
Additional oxygen saturation will be taken during the 24-hour follow-up safety assessment. 
 
The investigator will assess and comment if oxygen saturation falls below 90%.  
Attributability of any changes below 90% will be assessed as follows: 
 
 
1 = Attributable to disease; no follow-up required 
 
2 = Attributable to Xe-133 procedure; no follow-up required 
 
3 = Possibly attributable to Technegas, FOLLOW-UP REQUIRED 
 
Any oxygen saturation measurements with clinically significant changes below 90% and 
possibly attributable to Technegas will be repeated at appropriate intervals following the 
procedure until the values return to baseline or until the investigator and the Medical Monitor 
agree that further follow-up is no longer clinically relevant. 
Any changes considered clinically significant and assessed as “3 = Possibly attributable to 
Technegas, FOLLOW-UP REQUIRED” will be documented on the AE page of the CRF.  
 
11.2.5 24-Hour Follow-Up Safety Assessment 
Subjects will return to the clinical site for a 24-hour follow-up safety assessment, to occur 
within 20 to 36 hours following the Technegas procedure.  Subjects will undergo a physical 
examination, a blood draw for clinical chemistry and hematology laboratory measurements, 
vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate), pulse oximetry, 
and adverse event and concomitant medication assessments.  Adverse event follow-up safety 
assessment will conclude at this visit if none are noted.  
 
Any changes that the investigator feels are clinically significant should be noted and the 
investigator will comment on whether the change can be attributed to Technegas.  If 
clinically significant changes are noted, appropriate follow-up will be conducted by the 
investigator as long as deemed necessary. 
 
Investigators will make every effort to obtain the 24-hour assessment, as agreed to by the 
subject prior to enrollment. 
 
However, if the subject is unable to return for the 24-hour safety assessment, the subject must 
be contacted by the Principal Investigator at 20 to 36 hours by telephone and interviewed for 
emergent adverse events.  The telephone contact and results will be documented on the CRF 
and in subject records, including date, time and summary of conversation.  If the subject 
cannot be reached by telephone, the Principal Investigator will attempt to contact the subject 
by mail or email to obtain information for emergent adverse events.  All attempts to reach the 


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subject by telephone, or by mail or email if telephone communication cannot be established, 
must be documented in the subject’s source records.  
 
11.3 Adverse Events 
An AE is any untoward medical occurrence in a subject administered an investigational drug, 
which does not necessarily have a causal relationship with the treatment.  An AE can be any 
unfavorable or unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of the study drug, whether or not it is considered to be 
study drug related.  This includes any newly occurring event or previous condition that has 
increased in severity or frequency since the administration of the drug. 
 
All AEs, ascertained through subject interview, physical examination or other means will be 
recorded on the AE page of the CRF.  Adverse events will be recorded beginning at the time 
the subject signs the informed consent.  Any AEs recorded before Technegas inhalation will 
be considered a pre-treatment AE.  
 
11.3.1 Suspected Adverse Reaction 
Suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reactions are the subset of all adverse events for 
which there is reasonable possibility that the drug caused the event.  Reasonable possibility 
means there is evidence to suggest a causal relationship between the drug and the adverse 
event. 
 
11.3.2 Adverse Reaction 
An adverse reaction means any adverse event caused by a drug.  Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event. 
 
11.3.3 Unexpected Adverse Events 
An unexpected AE is any AE for which the specificity or severity is not consistent with the 
current Investigator’s Brochure, the general investigational plan, or other product labeling. 
 
11.3.4 Serious Adverse Events 
A SAE is any AE, regardless of causality that: 
• Results in death. 
• Is life-threatening.  Life-threatening means that the subject was at immediate risk of 
death from the reaction as it occurred, (i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form). 


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• Requires subject hospitalization or prolongation of existing hospitalization.  
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period, but planned prior to study entry are not considered AEs if the illness or 
disease existed before the subject was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier 
than planned). 
• Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a persons’ ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event.  An important medical event is an event that may not 
result in death, be life-threatening, or require hospitalization but may be considered 
an SAE when, based upon appropriate medical judgment, it may jeopardize the 
subject, or may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition for SAEs.  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 subject hospitalization, or 
the development of drug dependency or drug abuse. 
 
In this subject population, hospitalization for lung disease, lung surgery, to treat pulmonary 
embolism (PE) or an underlying deep vein thrombosis (DVT) that may have caused PE is an 
expected event and actual admission may occur before or after a subject is enrolled in the 
study; therefore, hospitalization for lung disease, lung surgery or to treat DVT and/or PE 
which was the triggering factor for study enrollment will not be considered an SAE.  
 
Planned hospital admissions or surgical procedures for an illness or disease which existed 
before the subject was enrolled in the trial or before study drug was given, are not to be 
considered AEs unless they occur at a time other than the planned date. 
 
11.3.5 Severity of Adverse Events 
Severity is defined according to the following criteria: 
 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort enough to cause interference with normal daily 
activities 
Severe 
Inability to perform normal daily activities 
 
The terms “serious” and “severe” ARE NOT synonymous.  The term “severe” is often used 
to describe the 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 a severe headache).  This is NOT the same as “serious,” which is based on subject/event 


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outcome or action criteria described above and are usually associated with events that pose a 
threat to a subject’s life or functioning.   
 
A severe AE does not necessarily need to be considered serious.  For example, persistent 
nausea of several hours duration may be considered severe nausea but not an SAE.  On the 
other hand, a stroke resulting in only a minor degree of disability may be considered mild, 
but would be defined as an SAE based on the above noted criteria. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations.  
 
11.3.6 Relationship to Study Drug 
Relationship to study drug administration will be determined as follows:  
 
None 
No relationship between the experience and the drug; related 
to other etiologies such as concomitant medications or 
subject’s clinical state. 
Unlikely 
The current state of knowledge indicates that a relationship is 
unlikely. 
Possible 
A reaction that follows a plausible temporal sequence from 
use of the drug and follows a known response pattern to the 
suspected drug.  The reaction might have been produced by 
the subject’s clinical state or other modes of therapy 
administered to the subject. 
Probable 
A reaction that follows a plausible temporal sequence from 
the use of the drug and follows a known response pattern to 
the suspected drug.  The reaction cannot be reasonably 
explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the 
subject. 
Definite 
A reaction that follows a plausible temporal sequence from 
use of a drug and follows a known response pattern to the 
suspected drug. 
 
11.4 Follow-up of Adverse Events 
Subjects will return to the clinical site for a 24-hour follow-up safety assessment which will 
include an assessment of AEs.  Any AE that is on-going at the time of the 24-hour follow-up 
assessment will be followed by the investigator until resolution or until the principal 
investigator and the Medical Monitor agree that further follow-up is no longer clinically 
relevant. 
 
If subjects do not return for the 24 hour safety assessment, a follow-up telephone contact for 
AE resolution assessment must be documented on the CRF and in subject records, including 


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date, time and summary of conversation.  
11.5 Procedures for Reporting AEs, SAEs and Suspected Unexpected Serious Adverse 
Reactions (SUSARs) 
All AEs spontaneously reported by the subject and/or in response to an open question from 
study personnel or revealed by observation, physical examination or other diagnostic 
procedures will be recorded on the AE section of the CRF.  Any clinically relevant 
deterioration in laboratory assessments or other clinical findings is considered an AE must be 
recorded on the AE section of the CRF.   
 
All AEs will be noted and evaluated on the CRF with a full description of the nature, onset, 
duration, severity, attribution, and outcome of the event.  All AEs will be coded using 
MedDRA.  Any treatment used to alleviate the AE(s) will also be recorded. 
 
Adverse event recording and reporting will conform to International Conference on 
Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for 
Human Use Guidelines for Clinical Safety Data Management. 
 
When possible, signs and symptoms indicating a common underlying pathology should be 
noted as one comprehensive event.  All AEs should be recorded using standard medical 
terminology.   
 
All SAEs that occur during the course of the study, as defined by the protocol, must be 
reported immediately by the investigator to the Medical Monitor by telephone or fax within 
24 hours of the time the investigator first becomes aware of the SAE.  Such preliminary 
reports should be followed with a detailed written description (within 5 days) which will 
include copies of hospital records and other documents when applicable.   
 
All SAEs must be reported whether or not considered causally related to the study product.  
An SAE form will be provided to each clinical study site.   
 
The investigator is required to document in full the course of the SAE, including any therapy 
given to the subject.  The information collected will include, at a minimum, the following: 
subject number, description of the event and an assessment by the investigator as to the 
severity of the event and relatedness to study product.  Follow-up information on the SAE 
may be requested by Cyclomedica.  The SAE must also be recorded on the AE section of the 
CRF. 
 
The investigator will also inform the sponsor of any relevant follow up information and the 
outcome of the SAE as soon as possible in a follow-up report. 
 
 
 


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Medical Monitor Contact Information: 
 
Edward Aten, MD 
President and CEO 
Certus International, Inc. 
9 Cedarwood Drive, Suite 8 
Bedford, NH 03110 
Phone: (603) 627-1212 
Cell: (603) 867-0359 
E-mail: eaten@certusintl.com  
 
11.5.1 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
The Sponsor must submit an Investigational New Drug (IND) Safety Report to the United 
States Food and Drug Administration (FDA) for any suspected adverse reaction that is both 
serious and unexpected.  Before submitting the report, the sponsor will need to ensure that 
the event meets the following criteria: 
 
• Suspected adverse reaction 
• Serious 
• Unexpected 
 
If the AE does not meet all three of the definitions, it should not be submitted to the FDA in 
an IND Safety Report.  The Sponsor, with input from the Medical Monitor, will evaluate the 
information and decide if there is a reasonable possibility that the drug caused the AE and 
therefore meets the definition of suspected adverse reaction.  Reasonable possibility means 
there is evidence to suggest a causal relationship between the drug and the AE. 
 
A written IND Safety Report must be submitted to FDA within 15 calendar days since the 
determination that the suspected adverse reaction or any other information qualifies for 
reporting. 
 
Unexpected fatal or life-threatening suspected adverse reactions must be reported to FDA in 
an expedited report no later than 7 calendar days after the Sponsor’s initial receipt of 
information.   
 


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12 Schedule of Efficacy and Safety Assessments 
12.1 Visit 1 
During Visit 1, screening procedures are performed, informed consent is obtained and 
documented with signature and date, and eligible subjects are enrolled.  The investigators 
will be asked to record the purpose for a subject’s Xe-133 ventilation imaging, and based on 
their recent chest X-ray indicate whether pleural effusion is present for the subject. 
 
Subjects will undergo Xe-133 ventilation imaging.  This will be followed as soon as practical 
by the Technegas imaging procedure.  Because of the rapid clearance of Xe-133 from the 
lungs and the low, non-interfering energy of Xe-133 photons, a washout period is not 
required.   
 
The Sponsor must be notified if Xe-133 and Technegas imaging sessions are to be performed 
in separate visits.  The Sponsor will grant approvals only on a case-by-case basis.  If the 
second imaging procedure must be done during a separate visit occurring within 24 hours of 
the first visit, this will result in an additional visit for the subject. 
 
If a Tc-99m MAA perfusion study is planned for the subject as part of their standard of care 
at this visit, it must occur after Technegas imaging is complete, and after the post-Technegas 
imaging safety assessments, within 15 minutes post-imaging, have been captured. 
 
12.2 Visit 2  
Subjects will be asked to return to the clinical site 24 (20-36) hours after completing 
Technegas planar ventilation imaging for a complete safety assessment, including clinical 
laboratory evaluation.  
 
If the subject does not return for the 24-hour safety assessment, the subject must be contacted 
by the Principal Investigator at approximately 24 hours by telephone and interviewed for 
emergent AEs.  The telephone contact and results will be documented on the CRF and in 
subject records, including date, time and summary of conversation.  In addition, it should be 
documented as a protocol deviation, and the subject will be considered incomplete with 
respect to safety assessments.   
 
 


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12.3 Schedule of Efficacy and Safety Assessments 
 
 
Visit 1 
Visit 2 
 
Xe-133 
Technegas 
 
Prior to  
Inhalation  
(≤ 30  min.) 
Ventilation 
and 
Imaging 
Post- Imaging 
Prior to  
Inhalation  
(10 ± 5 min.) 
Ventilation 
and 
Imaging 
 Post- Imaging 
(≤ 15 min.) 
24-hour (20-36)  
Follow-up 
Screening 
Baseline 
 
 
 
 
 
 
Inclusion/Exclusion 
x 
 
 
 
 
 
 
 
Informed Consent 
x 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
Pregnancy Test 
x 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
Physical Exam 
x 
 
 
 
 
 
 
x 
Chest X-ray 
x 
 
 
 
 
 
 
 
Clinical Labs 
x 
 
 
 
 
 
 
x 
Vital Signs 
 
x 
 
x 
x 
 
x 
x 
Oxygen Saturation 
 
x 
 
x 
x 
 
x 
x 
Ventilation  Imaging 
 
 
x 
 
 
x 
 
 
Adverse Events 
x 
Monitored throughout the study 
x 
Concomitant Medication 
x 
Monitored throughout the study 
x 
 


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13 Statistical Analysis 
13.1 General Considerations 
The primary presentations and analyses will be based on data pooled across study centers.  
Relevant summaries for individual centers, or combinations of centers, also may be presented 
for primary data.  Standard descriptive statistics will be used to summarize data, including 
one- and multi-way frequency tables for discrete or categorical variables, and mean, median, 
standard deviation, minimum, maximum for continuous variables. 
 
All data collected and entered into the study database will be provided in data listings by 
variable type presenting individual subject values.  All testing and confidence intervals will 
use a two-sided significance level of 5%, unless otherwise specified. 
 
Additional details concerning the planned statistical methodologies are provided in the 
Statistical Analysis Plan. 
 
13.2 Analysis Populations 
Three analysis data sets will be defined for the study: 
• Modified Intent-to-Treat (MITT) Set will consist of all subjects who are enrolled in 
this study and receive any dose of Technegas treatment; it will be the analysis set for 
the safety analyses. 
• Full Analysis Set (FAS) will consist of subjects who completed all of the ventilation 
imaging on the study, and both sets of Xe-133 planar scans and the Technegas planar 
scans are of interpretable image quality according to site investigators’ assessment. 
• Per Protocol Set (PPS) will consist of those subjects in the FAS who are compliant 
with regard to the Technegas and Xe-133 procedures (dosing and imaging), and have 
no other major protocol violations.   
 
13.2.1 Disposition 
Subject disposition will be summarized and will include: 
• Number of subjects screened 
• Number of subjects enrolled in the study 
• Number of subjects included in the MITT set 
• Number of subjects withdrawn from the study and the reason for withdrawal 
• Number of subjects in the FAS 
• Number of subjects in the PPS 


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The screening data for all subjects who were screened but not enrolled into the study will be 
provided in a separate data listing.  These subjects will not be included in any other listings, 
tabulations, or analyses. 
 
13.2.2 Baseline Characteristics 
Demographic data, including age, gender, race, ethnic group, and reason for ventilation 
imaging will be summarized using descriptive statistics. 
  
Abnormal medical histories and prior/concurrent medications will be summarized using 
counts and percents.  Prior/concurrent medications will be coded using the World Health 
Organization (WHO) classification system.  Prior and concurrent medication use overall and 
by WHO medication classification will be summarized using counts and percentages. 
 
13.3 Efficacy Evaluations 
13.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is percent agreement between Technegas and Xe-133 obtained 
from each blinded reader’s ventilation scores of matching image views. 
The agreement statistic will be derived from the ventilation scores as follows.  Binary 
agreement scores will be obtained for each subject’s six lung regions: if the Technegas and 
Xe-133 ventilation scores are the same for a lung region, the region is assigned an agreement 
score of 1, otherwise the region is assigned a score of 0 for no agreement.  The subjects’ 
binary agreement scores will provide the basis for an overall estimate of percent agreement 
and confidence interval for each of the three readers. 
 
In the case of a missing ventilation score (score = 99) as a result of a reader assessing a 
region as obscured or absent, the binary agreement score will be determined as follows.  If 
both Technegas and Xe-133 scores are missing for the region, the binary agreement score 
will be missing for the region.  If the score is missing for one of the imaging modalities and 
not the other, then the region will be assigned a score of 0 for no agreement. 
 
13.3.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
1. Percent agreement between Technegas and Xe-133 obtained from blinded readers’ 
ventilation scores based on all image views collected for Technegas and Xe-133. 
2. Percent agreement between Technegas and Xe-133 for the subgroups of subjects with 
and without pleural effusion as noted in subjects’ chest X-rays, from blinded readers 
ventilation scores.  


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3. Percent agreement measuring inter-observer agreement between pairs of blinded 
readers for their Technegas ventilation scores, and for their Xe-133 ventilation scores. 
4. By lung-region kappa statistics measuring inter-observer agreement between pairs of 
blinded readers for their Technegas ventilation scores, and for their Xe-133 
ventilation scores.  
 
13.4 Efficacy Analyses 
13.4.1 Primary Efficacy Analyses 
The primary analysis will be conducted on the FAS for Technegas and Xe-133 matched 
image views.  Each blinded readers’ binary agreement scores will be analyzed using a 
generalized linear model with SAS® PROC GENMOD.  The logit function (log odds ratio) 
will be specified as the link function, and subject will be specified as a repeated measure to 
allow for correlations between lung regions within a subject.  The estimate of the intercept of 
the model using generalized estimating equation (GEE) methodology will provide an overall 
estimate of the agreement and its 95% confidence interval in terms of the log odds ratio; 
simple algebra will be used to obtain the corresponding estimates and confidence intervals in 
terms of percent agreement (PA). 
The non-inferiority hypothesis to be tested is: 
 
H0: PA   60%  versus  HA: PA > 60% 
If the lower boundary from the 95% confidence interval for PA is greater than 60%, 
Technegas will be considered non-inferior to Xe-133 with respect to the measurement of 
pulmonary ventilatory distribution. 
Study Success Criteria 
For the study to be deemed a success, the null hypothesis must be rejected for at least two of 
the blinded readers. 
 
13.4.2 Secondary Efficacy Analyses 
The same methodology as described for primary efficacy analyses in the previous section 
will be applied to the binary agreement scores between Technegas and Xe-133 obtained from 
blinded readers’ ventilation scores based on all image views, both for the FAS and PPS 
analysis datasets.  The methodology will also be applied to the agreement scores between 
Technegas and Xe-133 for the subgroups of subjects with and without pleural effusion.  
 
Inter-reader percent agreement between pairs of blinded readers Technegas ventilation 
scores and their 95% confidence intervals will be obtained using the same methodology 
described for the primary efficacy endpoint.  Analyses will be performed for both FAS and 
PPS.  For comparison, the inter-reader percent agreement will be obtained in the same 
manner for Xe-133 ventilation scores.  


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By lung region, inter-reader kappa statistics and their 95% confidence intervals will be 
calculated for pairs of blinded readers using the three by three tables of the frequencies of 
ventilation scores for Technegas as displayed: 
 
 
Ventilation Score 
Reader I 
Ventilation Score Reader J 
0 
1 
2 
0 
N00 
N01 
N02 
1 
N10 
N11 
N12 
2 
N20 
N21 
N22 
 
where Nij represents the agreement frequency for a cell.  For comparison, the by-region inter-
reader kappas based on the blinded readers’ ventilation scores for Xe-133 scans will also be 
obtained. 
 
13.5 Non-Inferiority Margin 
The non-inferiority margin used in the analysis of the primary endpoint of this study was 
principally determined from a separate study conducted under Protocol CYC-010.  In Study 
CYC-010, six blinded readers read 75 Xe-133 planar ventilation imaging studies in two read 
sessions separated by a minimum of 4 weeks.  The readers scored the six regions of the lung 
using the same ventilation scoring metric to be used in this protocol.  The two sets of 
assessments from the read and re-read of the Xe-133 images were used to determine a 
measure of agreement between successive reads of Xe-133 lungs scans for each of the 
readers, and the compilation of the six readers’ estimates were then used to establish a 95% 
tolerance interval for the population of readers.  The lower bound of the tolerance interval 
was 62%.  Since Xe-133 is an approved agent for ventilation imaging, it by default is 
considered non-inferior to itself, and hence the read/re-read results provide a suitable limit 
for establishing the non-inferiority of Technegas compared to Xe-133. 
 
When comparing Xe-133 and Technegas imaging, it is recognized that there are inherent 
differences between the imaging performed with Xe-133 and Technegas: Xe-133 imaging 
includes both wash-in and wash-out views, while Technegas imaging has no equivalent to the 
wash-in/wash-out views but collects additional views.  This has the potential to result in 
differences in ventilation scoring which are not clinically relevant.  For example, in subjects 
that have regions of pleural effusion, on Xe-133 the region would likely be scored as 
1=decreased ventilation based on retention visible in wash-out views, whereas on Technegas 
it would be scored as 0=absent ventilation.  Only a small percentage of subjects are expected 
to exhibit such discrepancies and to account for this, a small adjustment was made to the 
non-inferiority margin obtained from the CYC-010 study from 62% to 60%.  The anticipated 


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agreement between Technegas and Xe-133 imaging is 70%.  The standard error of the 
agreement for the Xe-133 to Xe-133 image comparison among the six readers from study 
CYC-010 was 4.6% and thus a lower confidence interval bound of 2 standard errors also 
supports a non-inferiority margin of about 60%.  Thus the non-inferiority margin planned for 
this study is 60%. 
 
13.6 Rationale for Sample Size 
Using the normal approximation to the binomial distribution for calculation of the sample 
size, and the proportion associated with the non-inferiority margin (P0) to estimate the 
standard deviation, the following table provides sample size requirements for testing the 
hypotheses: 
 
H0: PA   P0  versus  HA: PA > P0 
where PA (percent agreement) has expected true values of 70% to 75%, and the non-
inferiority margin (P0) is 60%. 
 
Table 
Sample Size for 90% Power and 0.025 One-sided Type 1 Error 
Non-inferiority Margin 
P0 (%) 
Expected True Value 
PA (%) 
Required  
Sample Size (N) 
60 
70 
240 
71 
197 
72 
164 
73 
139 
74 
119 
75 
103 
Calculations performed with PASS 1412 
 
The planned sample size for the study is 240 subjects who have completed Xe-133 and 
Technegas ventilation imaging, and the images are of interpretable quality (FAS).  This 
sample size will provide 90% power to establish that agreement between the blinded read 
assessments of Xe-133 and Technegas is better than 60%, assuming an expected true level of 
agreement between Xe-133 and Technegas of 70%.   
 
13.7 Interim Analysis 
After approximately 40 subjects have completed the study, an interim pilot blind read of the 
Xe-133 and Technegas ventilation images will be conducted to assess the viability of the 
planned efficacy measurements for comparing the two sets of images.  If it is determined that 
the initial study design and efficacy parameters are not viable due to the differences in the 


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image sets being acquired, the protocol will either be amended in accordance with Agency 
input, or the study may be terminated.  The readers performing the pilot blind read will not 
be used for the final blind read of images, and unless imaging parameters change, the images 
from these first 40 subjects will be included in the final read of images. 
 
13.8 Safety Endpoints 
Safety endpoints include: 
1. Incidence of treatment emergent AEs. 
2. Changes (24 hours post-Technegas minus baseline) in laboratory measurements. The 
laboratory measurements at screening will serve as the baseline. 
3. Incidence of clinically significant changes in laboratory measurements. 
4. Change (post minus baseline) in vital signs at each time-point post Xe-133 and 
Technegas administration.  The measurements within 30 minutes prior to Xe-133 
inhalation will serve as the baseline. 
5. Incidence of clinically significant changes in blood pressure (defined Section 11.2.3). 
6. Change (post minus baseline) in oxygen saturation at each time-point post Xe-133 
and Technegas administration. The measurements within 30 minutes prior to Xe-133 
inhalation will serve as the baseline. 
7. Incidence of treatment emergent abnormalities in physical examinations. 
 
13.9 Safety Analyses 
The summary and analysis of safety data will be conducted on the modified ITT dataset.  
 
Frequency distributions including counts and percentages will be used to summarize the 
qualitative safety data, including AEs, clinically significant changes in laboratory 
measurements and vital signs, and treatment emergent abnormalities in physical 
examinations.  The summary of AEs will include summaries by MedDRA system organ 
class, relationship to study treatment, and event severity.  Serious adverse events also will be 
summarized separately.   
 
Summary statistics will be provided for all continuous safety data including change in 
laboratory measurements, vital signs and oxygen saturations.  Paired t-tests will be used to 
test for statistically significant changes over time.  The laboratory measurements at baseline 
and follow-up also will be categorized relative to their reference ranges as low, within range, 
or high, and shift tables comparing the distributions from baseline to follow-up will be 
provided for each test.  The Stuart Maxwell test will be used to test for statistically 
significant changes in pre- versus post-treatment distributions.  


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14 Data Handling and Record Keeping 
14.1 Case Report Forms 
Electronic CRFs (eCRFs) will be used and clinical trial data will be entered into directly into 
the electronic data capture (EDC) system.  The EDC system will be a 21 Code of Federal 
Regulations (CFR) Part 11 compliant data capture system.  The data system will include 
password protection, logs to identify individual entering or correcting data and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate.  Any changes, corrections or deletions made in the eCRFs will 
identify the responsible investigator or other authorized person modifying the data.   The 
investigator will review the completed eCRFs and electronically sign and date them to 
indicate his/her review, agreement with the data included, and the completeness and accuracy 
of the data. 
 
Case report forms (CRFs) must be completed for all enrolled subjects, even if the subject 
fails to complete the study.  No section of the CRF is to be left blank without an appropriate 
explanation by the investigator, since the lack of such explanation may necessitate discarding 
an otherwise usable observation. 
 
14.2 Completing, Signing and Archiving Case Report Forms 
Data collection is the responsibility of the investigator at the investigative site or clinical trial 
staff under the supervision of the respective site investigator.  The investigator is responsible 
for ensuring the accuracy, completeness, legibility, timeliness and attributability of the data 
reported.  
 
Clinical data may be entered directly into the eCRF at the time of data collection or from the 
source documents.  Data reported in the eCRF derived from source documents should be 
consistent with the source documents or the discrepancies should be explained and captured 
in a study note and maintained in the participant’s electronic study record.  
 
To comply with the requirement to maintain accurate case histories investigator(s) should 
review and electronically sign the completed eCRF for each subject before the data are 
archived or submitted to FDA.  If changes are made to the eCRF after the investigator(s) has 
already signed, the changes should be reviewed and electronically signed by the clinical 
investigator(s).  
 
14.2.1 Archiving of Records 
The following information must be retained at the investigational site for at least 2 years after 
the last approval of a marketing application and until there are no pending or contemplated 
marketing applications in an ICH region; or until at least 2 years have elapsed since the 


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formal discontinuation of clinical development of the investigational drug; or for the 
maximum period of time as required by the study center, whichever is greater: 
 
• Source data (including digital images) 
• Source documents 
• Copies of protocols  
• Protocol amendments 
• Correspondence 
• Subject identification codes and lists 
• Signed informed consent forms 
• Any other essential documents pertaining to the conduct of the study 
 
No study document or image should be destroyed without prior written agreement between 
the sponsor and the investigator(s).  Should the investigator(s) wish to assign the study 
records to another party or move them to another location, advance written notice should be 
given to the sponsor. 
 
It is the responsibility of the sponsor to inform the investigator(s)/institution(s) when these 
documents need no longer be retained. 
 
The sponsor will ensure all other study documents (e.g.: protocol, report, all data 
management documentation) are filed and archived in a secure area in the Trial Master File 
for at least 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications in an ICH region; or until at least 2 years 
have elapsed since the formal discontinuation of clinical development of the investigational 
product; or for the lifetime of the product, as required by regulation.  In addition, the final 
trial report must be retained by the sponsor, or the subsequent owner, for five years beyond 
the lifetime of the study agent. 
 
14.3 Direct Access to Source Data/Documents 
All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction 
and evaluation of the trial will be made directly available for clinical monitoring activities. 
Source data are contained in source documents (original records or certified copies).  Source 
documents are original documents, data, and records (e.g. hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 


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negative, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
trial).13 
 
All source documents must be accurate, clear, unambiguous, legible, contemporaneous, 
original, permanent and available for inspection and audit.  Paper-based source documents 
should be made using a permanent form of recording (ink, typing, printing, optical disc, etc.) 
and they should not be obscured by correcting fluid or have temporary attachments (such as 
“post-it” notes). 
 
If electronic medical records are used as source data to support trial data, the investigator will 
authorize the monitor to compare the data stored in the electronic medical records to the CRF 
data to ensure all data are complete, consistent, and accurate and ensure prior to enrolling a 
subject that a GCP-compliant method of doing this is available for the monitor.   
 
If electronic medical records are used to support trial data and the monitor is not allowed 
direct access to the electronic medical records for monitoring and data verification purposes, 
the source documents that are computer-generated and stored on magnetic support media 
must be printed and must be certified by the investigator as being an exact duplicate of the 
original electronic record.  The investigator or designee will identify each printed page as a 
certified copy and will sign and date the printed pages to so indicate.   
 
The minimum requirements for source documents used in clinical trials are that they should 
contain: the identity of the subject (or trial-related identifiers such as trial enrollment number, 
treatment number), the subject’s participation in the trial (protocol/study title or number), 
subject’s demographic data, the date and time the subject provided informed consent, the 
subject’s medical history, the treatment that the subject received, AEs, SAEs and the dates of 
the trial visits.  The end of the subject’s trial participation must be documented.  Information 
recorded in the CRF must be consistent with entries in the source documents. 
 
The following data may be recorded directly in the CRF.  If it is, it will be considered as 
source data: 
 
• Imaging parameters 
• Assessment of images for technical adequacy 
 
If other data are recorded directly into the CRF at the time the data are obtained, it will be 
considered as source data, too. The investigator must document in the study file the use of the 
CRF as its own source document for any such data. 
 
Source documents in connection with the study, including but not limited to, subject charts, 
radiology reports and laboratory data, will be made available to the sponsor upon request 
with due precaution towards protecting the privacy of the subject.  


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14.4 Monitoring 
For this trial, a combination of automated data checks/verification, central (remote, off-site) 
monitoring of data recording in the eCRFs and data-driven on-site monitoring with targeted 
source data verification of key data will be used. Automated data checks/verification and 
centralized monitoring will make most efficient use of limited monitor on-site time and it 
may allow risks or problems to be identified faster, since some eCRF data will be reviewed 
centrally prior to an on-site visit. Therefore; it may allow problems to be addressed pro-
actively and mitigated instead of being identified and addressed at an on-site visit. 
 
Targeted data verification, using pre-identified data points based on the type of data and its 
risk to trial integrity (for example informed consent to ensure a subject exists and provided 
prospective informed consent), or based on the critical nature of the data (for example AE 
details) or unusual or unexpected data are source data verified, with other data reviewed to 
the extent necessary to verify CRF completion may reduce the number of data points that are 
source data verified on-site by a monitor.  This will allow the site monitor to focus on the key 
data that are deemed most important to confirm protocol compliance, subject safety and data 
validity.  
 
The targeted data include: 
• Informed consent 
• Eligibility criteria 
• Dose administration 
• Clinical safety and AEs 
• Clinical laboratory assessment 
• Concomitant medications 
• Unusual or unexpected data 
 
Central monitoring of completed eCRFs will be performed primarily at Certus’ offices or 
other appropriate regional location. It will include a review of targeted data in the completed 
eCRFs.  
 
On-site monitoring visits will be performed at the investigational site per Certus SOP 403, 
Site Monitoring Visit, as modified by a project-specific Monitoring Plan. It will include a 
verification of informed consent and targeted data in the completed eCRFs using comparison 
to source records. 
 
A closeout visit will be performed at the conclusion of the Investigator’s involvement in the 
study. 
 
14.4.1 Monitoring of Images and Imaging Data 
Images, including imaging parameters, image acquisition and other imaging-related data are 


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verified by the investigator and/or medical physicist or other appropriate staff and they are 
verified by the imaging Core Lab following SOPs and project-specific methods after receipt 
of images and supporting data at the Core Lab.  
 
14.5 Final Report 
The final report of the trial will be written by the sponsor or its designee and will be 
submitted to the regulatory authority. 
 
 


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15 Quality Control and Quality Assurance 
15.1 Data Quality Assurance 
Data entry parameters and automated data checks will be used and implemented by the eCRF 
system to assist the site investigators and staff in CRF completion.  Completed CRFs will be 
reviewed by clinical research associates (CRAs) or a designee from the sponsor or a Clinical 
Research Organization representing the sponsor using centralized monitoring and/or on-site 
monitoring.  During monitoring activities, the CRA or designee will check for completion of 
the entries on the CRFs, site compliance with the study protocol and with GCP, will assess 
Technegas drug accountability and will evaluate if source data are accurately supports data 
recorded in the CRF.  In addition, the CRA will assess whether all AEs and SAEs have been 
appropriately reported within the time periods required. 
 
Data Management will also provide services to assure data quality.  To ensure the 
completeness, internal consistency and accuracy of the data in the study database, appropriate 
validation checks will either be incorporated into the EDC system and will execute at data 
entry, or they will be performed externally with SAS programs.  Details of the checks will be 
included in a Data Management Plan for the study. 
 
15.2 Auditing 
The sponsor or a representative of the sponsor may arrange to visit the investigator in order 
to audit the performance of the study at the study site and the study documents originating 
there at any time during the study or following completion of the study. The investigator and 
designated site staff will cooperate in the scheduling and performance of the investigator/site 
audit. The auditor(s) may be accompanied by the CRA and/or other the study staff.  The 
investigator will be informed of the results of the audit. 
 
In addition, inspections by the site IRB, by a local site research authority or by health 
authority representatives, including but not limited to the US FDA, the US Department of 
Health and Human Services, the US Office of Human Research Protections, the US Nuclear 
Regulatory Commission or the State regulatory authority are possible at any time.  The 
investigator will notify the sponsor immediately upon being contacted by any local, State or 
federal regulatory authority for any such inspection. 
 
The investigator will make all pertinent records available including source documentation for 
inspection by regulatory authorities and for auditing by the sponsor.  This information will be 
considered as confidential. 
 
 
 


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16 Ethics 
16.1 Ethical Considerations 
This study will be conducted in accordance with the Declaration of Helsinki and ICH E6 
GCP Guideline and in compliance with the protocol and all regulatory requirements 
including Title 21 CFR § 50, 54, 56 and 312.  To ensure compliance the investigator agrees, 
by written consent to this protocol, to fully cooperate with compliance checks by allowing 
access to all documentation by authorized individuals. 
 
A copy of the Declaration of Helsinki is provided in Appendix 20.2. 
 
16.2 Institutional Review 
This protocol and the informed consent form will be reviewed and approved by the research 
facility's IRB or IEC.  A copy of its letter or certificate of approval will be sent to the sponsor 
prior to the commencement of the study. 
 


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17 Additional Requirements and Procedures 
17.1 Regulatory Requirements–Sponsor/Investigator Obligations 
This study will be conducted in accordance with the Declaration of Helsinki and ICH E6 
GCP Guideline and compliance with the protocol and all regulatory requirements including 
Title 21 CFR § 50, 54, 56 and 312.  To ensure compliance the investigator agrees, by written 
consent to this protocol, to fully cooperate with compliance checks by allowing access to all 
documentation by authorized individuals. 
 
17.2 Protocol Amendments 
Any changes to the protocol will be made in the form of a protocol amendment.  No change 
to the protocol may be made without the joint agreement of both the investigator and the 
sponsor.  Any amendment to the protocol must be submitted to the FDA and to the IRB/IEC 
and approved before implementation. 
 
17.3 Protocol Deviations 
An investigator may not deviate from the protocol in any way, except when necessary to 
eliminate an immediate hazard (risk) to the rights, safety or welfare of a subject. The 
investigator must notify the sponsor immediately and NOT enroll any additional subjects or 
administer Technegas to any subsequent subjects until the hazard is eliminated from the 
study protocol or otherwise resolved. The investigator must notify the IRB/IEC of any 
protocol deviations.  The FDA will be notified of all protocol deviations in compliance with 
federal regulations and GCPs. 
 
17.4 Investigative Agreement 
Prior to initiation of the study, the principal investigator must agree to abide by the terms of 
the Investigative Agreement and sign, date and return the agreement to the sponsor.  A copy 
of this agreement is contained in Appendix 20.1. 
 
17.5 Investigator’s Responsibilities 
An investigator must comply with all obligations and responsibilities, described in 21 CFR 
50, 4, 56, 312, on the completed FDA Form 1571 and other local, state and federal 
regulations and in ICH GCPs, including but not limited to those responsibilities described in 
detail in this Section.  
17.5.1 Informed Consent 
All subjects must sign and personally date an approved Informed Consent Form after 


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receiving detailed written and verbal information about the reason, the nature and the 
possible risks associated with the administration of the investigational drug prior to 
enrollment in the study.  It is the responsibility of the investigator to obtain that consent.  The 
details of this requirement are explained in 21 CFR 50 Subpart B, the Declaration of Helsinki, 
and the ICH E6 Guideline for GCP.    
 
The subject must be made aware and agree that personal information may be scrutinized 
during audit by competent authorities and properly authorized persons.  However, personal 
information will be treated as strictly confidential and will not be publicly available.   
 
By signing the Investigative Agreement, the investigator assures the sponsor that Informed 
Consent will be obtained for each subject participating in the study.   
 
Prior to IRB/ IEC submission, the investigator must send a copy of the Informed Consent 
Form to be used at their institution to the sponsor for review to assure compliance with the 
ICH and CFR requirements. 
 
17.5.2 Curriculum Vitae 
The investigator and any sub-investigator(s) must provide the sponsor with a current copy of 
his/her own curriculum vitae (CV).  The CV must include a statement of the investigator's 
relevant experience.   
 
17.5.3 Financial Disclosure 
As required by 21 CFR § 54, all investigators, including sub-investigators and other study 
staff who perform significant clinical trial responsibilities must provide signed and dated 
financial disclosure before the study is initiated at the site and at the completion of the study.  
Any significant changes to the reported financial interests and arrangements must be 
disclosed for one year after completion of study participation. 
 
The investigator must obtain an original, completed, signed and dated Financial Disclosure 
Form for any sub-investigator who ends participation in the trial, whether it is due to leaving 
the research facility or any other reason. The investigator must notify the sponsor and 
provide the completed Form at the time the sub-investigators ends participation. 
 
17.5.4 Investigator Delegation of Responsibilities 
The investigator must complete prior to the start of the study and maintain on an on-going 
basis until close-out of the study, a Log or other detailed document that identifies all 
individuals to who the investigator has delegated significant study-related responsibilities, 
describes the responsibilities, records personally-completed original signatures and initials of 
all of the individuals to whom responsibilities have been delegated and documents the 


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individual’s acceptance of the delegated responsibilities.  
 
17.5.5 Investigator and Study Staff Training and Documentation 
The investigator must supervise and ensure that adequate training is provided for all 
sub-investigators and study staff to whom study-specific responsibilities and obligations are 
delegated. The investigator must ensure qualification documentation and training records are 
completed and available in the study file for the investigator, sub-investigators all pertinent 
study staff the start of the study and that they are maintained and updated as needed 
throughout the course of the trial. 
 
17.6 Conditions for Terminating the Study 
In the event that the investigator is unable to continue the study, another suitable person may 
be designated Investigator, and documentation testifying to this will be submitted to the 
sponsor immediately.  The new investigator must be approved by the sponsor and the 
IRB/IEC before the study can be continued. 
 
If the sponsor and/or the investigator should discover conditions arising during the study that 
indicate it should be terminated, an appropriate schedule for termination will be instituted.  If 
the investigator terminates the study, an explanatory letter will be provided to the sponsor. 
 
The sponsor also reserves the right to discontinue this study for administrative reasons at any 
time.  The investigator will be reimbursed for reasonable expenses incurred, if it is necessary 
to terminate the study or an individual subject's participation.  The sponsor will not reimburse 
the investigator for the evaluation of subjects if the evaluations are not conducted in 
compliance with the present protocol. 
 
The sponsor may terminate an investigator's participation in this study at any time for any 
reason, including the investigator's intentional or repeated noncompliance with the study 
protocol, GCPs, the Investigative Agreement, the FDA Form 1572 or regulatory 
requirements.  If the sponsor terminates an investigator's participation due to noncompliance, 
the FDA and site IRB or IEC must be notified by the sponsor, as required by 21 CFR 312. 
56. 
 
17.7 Warnings, Precautions, Contraindications 
For specific information concerning warnings, precautions and contraindications for the 
study device, the investigator is asked to refer to the appropriate section of the Technegas 
Investigator’s Brochure and the TechnegasPlus Generator User Manual.  
 


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17.8 Information  
Before the beginning of the study the investigator will have been given the last updated 
Investigator’s Brochure, TechnegasPlus Generator User Manual and other supporting 
documents to describe use, maintenance and other pertinent information related to the 
Technegas.  If this information is revised during the study, the investigator will receive a 
copy of the revised version.   
 
17.9 Confidentiality 
All information provided to the investigator dealing with the investigational drug, the 
protocol and this investigation will be regarded as confidential.  Acceptance constitutes the 
agreement by the recipient that no unpublished information herein contained will be 
published or disclosed without the sponsor's  prior written approval except that this document 
may be disclosed to appropriate IRB/IEC as long as they are required to keep it confidential.  
The members of the research team agree not to discuss such information in any way without 
prior written permission from the sponsor. 
 


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18 Financing and Insurance 
18.1 Financing 
A financial agreement (separate from the protocol) will be made with the investigator or 
designee.  Such agreement will be archived in the relevant file. 
 
Financial support to investigators/sub-investigators other than the cost of conducting the 
clinical study or other clinical studies will be disclosed in accordance with Title 21 CFR 54.2 
to 54.6. 
 
 


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19 Publication Policy 
19.1 Use and Publication of Study Results 
All unpublished documentation (including the protocol, CRF and Investigator's Brochure) 
given to the investigator is strictly confidential.  All recipients must agree not to disclose the 
information herein contained to any person without the prior written authorization of the 
sponsor.  The submission of these documents to the IRB/IEC is expressly permitted.  The 
investigator agrees that the sponsor maintains the right to use the results of this study in their 
original form and/or in a global report for submission to governmental and regulatory 
authorities of any country. 
 
The results of the study may be presented during scientific symposia or published in a 
scientific journal only after review by the sponsor in accordance with the guidelines set forth 
in the applicable publication or financial agreement. 
 
19.2 Disclosure of Data 
All information obtained during the conduct of this study will be regarded as confidential and 
written permission from the sponsor is required prior to disclosing any information relative to 
the study.  Manuscripts prepared for publication will be submitted to the sponsor for review 
and comment prior to submission to the publisher.  The sponsor will attempt to provide 
comments within 30 days.  This condition should not be construed as a means of restricting 
publication but is intended solely to assure mutual concurrence regarding data, evaluations 
and conclusions and to provide an opportunity to share with the investigator any new and/or 
unpublished information of which he/she may be unaware. 
 
 
 


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20 Appendices 
20.1 Investigator Agreement 
 
I have read and understand the information in the protocol and attached case report form, the 
Investigator’s Brochure, the TechnegasPlus Generator User Manual and other documents if 
applicable, understand the information contained and agree that it contains all necessary detail 
for carrying out this study.  I agree to conduct the study in accordance with the Investigator's 
Agreement, the current protocol, and applicable FDA regulations, and conditions of approval 
imposed by the reviewing IRB or FDA, and will only make changes in a protocol after 
notifying the sponsor, except when necessary to protect the safety, rights, or welfare of 
subjects. 
 
I have read and understood the provisions of Title 21 of the United States Code of Federal 
Regulations (CFR) Part 312, Subpart D regarding responsibilities of Sponsors and Investigators; 
Part 50 and Part 56 regarding the protection of human subjects and informed consent, and Part 
54 for financial disclosure.  I have read, understood and signed the Statement of Investigator 
Form FDA1572 which outlines my responsibilities as Principal Investigator.  
 
I agree to personally conduct or supervise the described investigation, including all testing of 
the investigational drug involving human subjects. I agree to report to the sponsor adverse 
experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312. 
 
I agree to inform any subjects that Technegas is being used for investigational purposes and I 
will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 
and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.  I will 
ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible 
for the initial and continuing review and approval of the clinical investigation.  I also agree to 
promptly report to the IRB all changes in the research activity and all unanticipated problems 
involving risks to human subjects or others.  Additionally, I will not make any changes in the 
research without IRB approval, except where necessary to eliminate apparent immediate 
hazards to human subjects. 
 
I agree to comply with all other requirements regarding the obligations of clinical 
investigators and all other pertinent requirements in 21 CFR Part 312. I agree to maintain 
adequate and accurate records in accordance with 21 CFR 312 and to make those records 
available for inspection.  
 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 


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Investigator Agreement (Continued) 
 
 
 
Additionally, I warrant and represent that neither I nor anyone else who will be involved in this 
study has been disqualified or debarred by a U.S. or Australian regulatory body for clinical 
investigations or any other purpose nor has been convicted of any felony for conduct relating 
to the development or approval, including the process for the development or approval, of any 
drug application, or otherwise relating to the regulation of any drug product. 
 
If at any time I or anyone involved in this study should become disqualified or become 
debarred or is convicted of violations for conduct relating to the development or approval, 
including the process for development or approval, of any drug application, or otherwise 
relating to the regulation of any drug product, I will give the sponsor prompt written notice of 
same. Additionally, I will notify the sponsor at any time in the future if such disqualification 
or debarment is based in whole or in part on participation in this study. 
 
 
 
 
____________________________________ 
Printed Name of Principal Investigator 
 
 
 
____________________________________, M.D. 
Signature of Principal Investigator 
 
 
 
Date: ______/______/______ 
 


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20.2 Declaration of Helsinki 
 
DECLARATION OF HELSINKI 
 
RECOMMENDATIONS guiding physicians in biomedical research involving human subjects 
(adopted by the Eighteenth World Medical Assembly, Helsinki, Finland, 1964; and amended by 
the Twenty-Ninth World Medical Assembly, Tokyo, Japan, 1975; by the Thirty-Fifth World 
Medical Assembly, Venice, Italy, 1983; and by the Forty-First World Medical Assembly, Hong 
Kong, 1989). 
 
INTRODUCTION 
 
It is the mission of the physician to safeguard the health of the people.  His or her knowledge 
and conscience are dedicated to the fulfillment of this mission. 
 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, “The health of my patient will be my first consideration,” and the International Code of 
Medical Ethics declares that, “A physician shall act only in the patient’s interest when providing 
medical care which might have the effect of weakening the physical and mental condition of the 
patient.” 
 
The purpose of biomedical research involving human subjects must be to improve diagnostic, 
therapeutic and prophylactic procedures and the understanding of the etiology and pathogenesis 
of disease. 
 
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve 
hazards.  This applies especially to biomedical research. 
 
Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
 
In the field of biomedical research a fundamental distinction must be recognized between 
medical research in which the aim is essentially diagnostic or therapeutic for a patient, and 
medical research, the essential object of which is purely scientific and without implying direct 
diagnostic or therapeutic value to the person subjected to the research. 
 
Special procedures must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
 
Because it is essential that the results of laboratory experiments be applied to human beings to 
further scientific knowledge and to help suffering humanity, the World Medical Association has 
prepared the following recommendations as a guide to every physician in biomedical research 


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involving human subjects.  They should be kept under review in the future.  It must be stressed 
that the standards as drafted are only a guide to physicians all over the world.  Physicians are not 
relieved from criminal, civil and ethical responsibilities under the laws of their own countries. 
 
I. 
BASIC PRINCIPLES 
 
1. 
Biomedical research involving human subjects must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and animal 
experimentation and on a thorough knowledge of the scientific literature. 
 
2. 
The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol which should be transmitted 
for consideration, comment and guidance to a specially appointed committee 
independent of the principal investigator and the sponsor provided that this independent 
committee is in conformity with the laws and regulations of the country in which the 
research experiment is performed. 
 
3. 
Biomedical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically competent 
medical person.  The responsibility for the human subject must always rest with a 
medically qualified person and never rest on the subject of the research, even though the 
subject has given his or her consent. 
 
4. 
Biomedical research involving human subjects cannot legitimately be carried out unless 
the importance of the objective is in proportion to the inherent risk to the subject. 
 
5. 
Every biomedical research project involving human subjects should be preceded by 
careful assessment of predictable risks in comparison with foreseeable benefits to the 
subject or to others.  Concern for the interests of the subject must always prevail over the 
interests of science and society. 
 
6. 
The right of the research subject to safeguard his or her integrity must always be 
respected.  Every precaution should be taken to respect the privacy of the subject and to 
minimize the impact of the study on the subject’s physical and mental integrity and on 
the personality of the subject. 
 
7. 
Physicians should abstain from engaging in research projects involving human subjects 
unless they are satisfied that the hazards involved are believed to be predictable.  
Physicians should cease any investigation if the hazards are found to outweigh the 
potential benefits. 
 
8. 
In publication of the results of his or her research, the physician is obliged to preserve 
the accuracy of the results.  Reports of experimentation not in accordance with the 


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principles laid down in this Declaration should not be accepted for publication. 
 
9. 
In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, anticipated benefits and potential hazards of the study and the 
discomfort it may entail.  He or she should be informed that he or she is at liberty to 
abstain from participation in the study and that he or she is free to withdraw his or her 
consent to participation at any time.  The physician should then obtain the subject’s 
freely given informed consent, preferably in writing. 
 
10. When obtaining informed consent for the research project, the physician should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress.  In that case, the informed consent should be obtained by a 
physician who is not engaged in the investigation and who is completely independent of 
this official relationship. 
 
11. In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation.  Where physical or mental incapacity 
makes it impossible to obtain informed consent or when the subject is a minor, 
permission from the responsible relative replaces that of the subject in accordance with 
national legislation.   
 
 
Whenever the minor child is in fact able to give a consent, the minor’s consent must be 
obtained additionally to the consent of the minor’s legal guardian. 
 
12. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration are 
complied with.  
 
II. 
MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE 
 
(CLINICAL RESEARCH) 
 
1. 
In the treatment of the sick person, the physician must be free to use a new diagnostic 
and therapeutic measure, if in his or her judgment it offers hope of saving life, re-
establishing health or alleviating suffering. 
 
2. 
The potential benefits, hazards and discomfort of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods. 
 
3. 
In any medical study, every patient - including those of a control group, if any - should 
be assured of the best proven diagnostic and therapeutic method. 
 
4. 
The refusal of the patient to participate in a study must never interfere with the 
physician-patient relationship. 


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5. 
If the physician considers it essential not to obtain informed consent, the specific reasons 
for this proposal should be stated in the experimental protocol for transmission to the 
independent committee (I, 2). 
 
6. 
The physician can combine medical research with professional care, the objective being 
the acquisition of new medical knowledge, only to the extent that medical research is 
justified by its potential diagnostic or therapeutic value for the patient. 
 
III. 
NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN 
 
SUBJECTS (NON-CLINICAL BIOMEDICAL RESEARCH) 
 
1. 
In the purely scientific application of medical research carried out on a human being, it 
is the duty of the physician to remain the protector of the life and health of that person 
on whom biomedical research is being carried out. 
 
2. 
The subjects should be volunteers - either healthy persons or patients for whom the 
experimental design is not related to the patient’s illness. 
 
3. 
The principal investigator or the investigating team should discontinue the research if in 
his/her or their judgment it may, if continued, be harmful to the individual. 
 
4. 
In research on man, the interest of science and society should never take precedence 
over considerations related to the well being of the subject. 
 
 
 
  


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21  References 
 
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