Clinical trial NCT03673943
Conditions: Neuroendocrine Tumors
Sponsor: Radiomedix, Inc.
Start date: 2018-08-23; Completion date: 2019-08-07
Enrollment: 63 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, single-dose, single-arm, single-center imaging study using DOTATATE peptide, labelled with the 64Cu tracer.

Detailed description:
In total, 59 subjects will be recruited in the study. The study will recruit both healthy volunteers as well as patients with confirmed or suspicious NET disease by histology or conventional anatomical and functional imaging modalities including but not limited to magnetic resonance imaging (MRI), and/or computed tomography (CT), and/or, F-18 FDG fluorodeoxyglucose PET (positron emission tomography)/CT and /or F-18 NaF sodium fluoride bone PET/CT and/or bone scintigraphy, and/or Octreoscan.

Arms: arm 1: 64Cu-DOTATATE is an investigational radioactive drug that binds to somatostatin receptors on neuroendocrine cancer cells.
Interventions: intervention 1: 64Cu-DOTATATE
Intervention descriptions: intervention 1: Detection of somatostatin positive lesions in NET

Protocol documents:
Prot_000.pdf: 
 
 
 
Version 1.0, 06 March 2019 
 
1 TITLE PAGE 
STUDY TITLE: 
An Open-label, Single-dose, Single-arm, Single-center Clinical Trial of 
64Cu-DOTATATE (NETMedix™) PET-CT Scan for Imaging Patients 
with Known or Suspected Somatostatin Receptor-positive Neuroendocrine 
Tumors (NETs) 
PROTOCOL NUMBER: 
NCT number 
RMX-18-22 
NCT03673943 
STUDY PHASE: 
Phase 3 
IVESTIGATIONAL 
PRODUCT: 
NETMedix™ (64Cu-DOTATATE) injection, for intravenous use 
DRUG SUBSTANCE 
64Cu-DOTATATE 
STUDY DATES: 
January 22, 2018 to December 2, 2018 
INDICATION: 
Imaging of patients with known or suspected somatostatin receptor-
positive neuroendocrine tumors 
SPONSOR CONTACT 
INFORMATION: 
 
Ebrahim S. Delpassand, MD, FACNM 
RadioMedix, Inc. 
9701 Richmond Avenue, Suite 222 
Houston, TX 77042 
+1 (713) 358-6570 
REPORT DATE: 
March 6, 2019 
LEAD INVESTIGATOR: 
Rodolfo Nunez, M.D. 
GCP COMPLIANCE: 
The investigators agreed to conduct the study in compliance with the study 
protocol, the International Conference on Harmonisation (ICH) of 
Technical Requirements for Registration of Pharmaceuticals for Human 
Use guidance for industry entitled “E6 Good Clinical Practice (GCP): 
Consolidated Guidance”, the “Declaration of Helsinki: Ethical Principles 
for Research Involving Human Subjects” (World Medical Association), 
and applicable law and regulatory requirements. 
 


 
 
 
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2 SYNOPSIS 
NAME OF SPONSOR/COMPANY: 
RadioMedix, Inc. 
 
NAME OF TEST PRODUCT: 
NETMedixTM (64Cu-DOTATATE) 
injection, for intravenous use 
NAME OF ACTIVE INGREDIENT: 
64Cu-DOTATATE 
INDIVIDUAL STUDY TABLE 
REFERRING TO PART OF  
THE DOSSIER 
 
Volume: 
 
Page: 
(FOR NATIONAL 
AUTHORITY USE ONLY) 
 
 
Title of Study: An Open-label, Single-dose, Single-arm, Single-center Clinical Trial of 64Cu-DOTATATE 
(NETMedix™) PET-CT Scan for Imaging Patients with Known or Suspected Somatostatin Receptor-positive 
Neuroendocrine Tumors (NETs) 
Principal Investigator: Rodolfo Nunez, M.D. 
Publication (ref.):   
Study Period: 
Date First Subject Enrolled:  January 22, 2018 
 
Date Last Subject Completed:  December 2, 2018 
Phase of Development:  
Phase 3 
 
Objectives: 
Primary Objective: 
• 
To assess the performance (sensitivity and specificity) of 64Cu-DOTATATE PET-CT imaging in subjects 
with known or suspected NETs, when comparing individual reader results to a standard of truth (SOT) for 
each subject. 
Secondary Objectives: 
• 
To characterize the predictive value of 64Cu-DOTATATE PET-CT imaging when comparing an imaging 
reader-majority rule determination to the SOT for each subject and also when the comparison was 
performed on an individual reader basis. 
• 
To evaluate the imaging performance (sensitivity and specificity) of 64Cu-DOTATATE when comparing 
an imaging reader-majority rule determination to the SOT for each subject. 
• 
To evaluate the imaging performance of 64Cu-DOTATATE to determine if subjects had metastatic or 
localized disease as compared to the SOT. 
Tertiary Objective: 
• 
To evaluate the intra-reader reliability and inter-reader agreement. 
Exploratory Objective: 
• 
To evaluate pharmacokinetics and identify any major 64Cu moieties other than intact parent drug (64Cu-
DOTATATE), free 64Cu and known radiolysis byproducts of parent drug. 


 
 
 
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NAME OF SPONSOR/COMPANY: 
RadioMedix, Inc. 
 
NAME OF TEST PRODUCT: 
NETMedixTM (64Cu-DOTATATE) 
injection, for intravenous use 
NAME OF ACTIVE INGREDIENT: 
64Cu-DOTATATE 
INDIVIDUAL STUDY TABLE 
REFERRING TO PART OF  
THE DOSSIER 
 
Volume: 
 
Page: 
(FOR NATIONAL 
AUTHORITY USE ONLY) 
 
 
Methodology: 
This was an open-label, single-dose, single-arm, single-center imaging study using DOTATATE peptide, labelled 
with the 64Cu tracer. In total, 59 subjects were expected to be recruited in the study. The study recruited both healthy 
volunteers as well as patients with confirmed or suspicion of NET disease by histology or conventional anatomical 
and functional imaging modalities including but not limited to magnetic resonance imaging (MRI), and/or computed 
tomography (CT), and/or, F-18 FDG PET/CT and /or F-18 NaF bone PET/CT and/or bone scintigraphy, and/or 
Octreoscan®.   
For safety assessment, vital signs were measured within 30 minutes before and up to 1 hour after administration of 
64Cu-DOTATATE. A blood sample was collected within 30 minutes before the injection and within 2 hours post 
64Cu-DOTATATE administration to assess clinical chemistries and haematology. 
Any adverse events observed or reported were recorded for up to 48 hours following study drug administration. In 
addition, observed or patient reported immediate adverse events including but not limited to pain, injection site 
reaction, headache, nausea, vomiting, flushing or other as reported, were assessed within 1 hour before and within 
2 hours after the study drug administration.   
All subjects underwent a continuous ECG recording at least 15 minutes prior to administration of the study drug 
and continuing for at least 30 minutes after administration. In addition, a 12-lead static ECG was performed within 
60 minutes before and within 60 minutes following study drug administration. All the ECG data were collected in 
digital format, analysed and reviewed (with manual over-read) by an independent physician to determine normal or 
abnormal and if abnormal, whether clinically significant or not significant. 
To assess pharmacokinetics, blood and urine samples were collected after the administration of 64Cu-DOTATATE 
on 6 subjects. Five 10 mL blood samples were collected at 1, 10, 30, 60, and 120 minutes after the administration 
of 64Cu-DOTATATE. Urine samples were collected in three intervals after the administration of 64Cu-DOTATATE; 
0-60 minutes, 60-120 minutes, and 120-360 minutes. The pharmacokinetic (PK) analysis was focused only on 
radiometric detection using a bioanalytical high performance liquid chromatography (HPLC) method. 
Number of Subjects (planned and analyzed): 
Planned: It was anticipated that a total of 59 subjects would be recruited. The study population comprised of both 
healthy volunteers and patients with lesions confirmed or suspicious for NETs. The efficacy analysis sample size 
was planned to be 63 evaluable subjects, 59 subjects from this phase 3 study and 4 subjects from the selected 4.0 
mCi dose cohort of the phase 1 study. This sample size was appropriate to achieve statistical power for the primary 
endpoints of this clinical trial. It was anticipated that the PK assessment would be performed on 6 subjects. 
Analyzed: The study enrolled 66 subjects including 4 subjects from the Phase 1 study. In total, 63 subjects (59 from 
the Phase 3 study and 4 from the Phase 1 study) were injected with study drug at an intended dose of 4.0 mCi and 
met the criteria to be analyzed for safety and efficacy.  
Diagnosis and Main Criteria for Eligibility: 
Inclusion Criteria: 
Patients 
1. Subjects of either sex, aged ≥18 years.  
2. Met at least one of the following criteria: 
a. 
Confirmed or suspicion of NET based on histology/ biopsy report.   
b. Confirmed or suspicion of NET based on conventional imaging scans of affected area such as 
MRI and/or contrast enhanced CT and/or an FDG PET-CT scan and/or NaF PET-CT scan and/or 
OctreoScan® performed within 8 weeks prior to study date. 
 


 
 
 
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NAME OF SPONSOR/COMPANY: 
RadioMedix, Inc. 
 
NAME OF TEST PRODUCT: 
NETMedixTM (64Cu-DOTATATE) 
injection, for intravenous use 
NAME OF ACTIVE INGREDIENT: 
64Cu-DOTATATE 
INDIVIDUAL STUDY TABLE 
REFERRING TO PART OF  
THE DOSSIER 
 
Volume: 
 
Page: 
(FOR NATIONAL 
AUTHORITY USE ONLY) 
 
 
Healthy volunteers  
Healthy male or female subjects age ≥18 years of age and in good health as determined by absence of clinically 
relevant abnormalities determined by a full medical history, physical examination, vital signs and clinical laboratory 
tests. 
 
Patients and Healthy volunteers  
1. Willing to sign informed consent form. 
2. Able to understand and comply with the procedures and requirements of the study. 
3. Negative pregnancy test in women of child-bearing potential, performed on the day of the study, using 
urine or blood-based testing. 
4. For women of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) 
or use non-hormonal contraceptive methods for at least 2 weeks following administration of study drug. 
5. For men, agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures 
for at least 2 weeks following administration of study drug;  
6. Recent blood test results (within 4 weeks pre-dose) as follows: 
a. 
WBC: >2×109/L 
b. Haemoglobin: >8.0g/dL 
c. 
Platelets: >50×109/L 
d. ALT, AST, AP: ≤5 times ULN 
e. 
Bilirubin: ≤3 times ULN 
f. 
Serum creatinine: <170 μmol/L 
 
Exclusion Criteria: 
Subjects must not have had any of the following conditions to be enrolled in this study: 
1. Pregnant or planning to become pregnant within the next two weeks. 
2. Inability to provide written consent. 
3. Therapeutic use of any somatostatin analogue, including Sandostatin® LAR (within 28 days) and 
Sandostatin® (within 2 days) prior to study imaging. If a subject is on Sandostatin® LAR, a wash-out 
period of 28 days was required before the injection of the study drug. 
4. History or presence of significant hematological abnormalities or immunodeficiency or any condition that 
might compromise the immune system (infection, vaccination), or any etiology as indicated by clinically 
significant abnormal values of any of the following hematologic parameters: platelets, hemoglobin, WBC 
count and ANC. 
5. Lactating and breast-feeding women. 
6. Acute or chronic clinically significant conditions such as uncontrolled congestive heart failure, liver or 
kidney dysfunction, uncontrolled hypertension 
7. History of hypersensitivity to drugs with a similar chemical structure to the investigational product or any 
of its excipients 
8. History of significant drug abuse within 1 year prior to screening or use of soft drugs (such as marijuana) 
within 3 months prior to the screening visit or hard drugs (such as cocaine, phencyclidine, and crack) within 
1 year prior to screening 


 
 
 
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NAME OF SPONSOR/COMPANY: 
RadioMedix, Inc. 
 
NAME OF TEST PRODUCT: 
NETMedixTM (64Cu-DOTATATE) 
injection, for intravenous use 
NAME OF ACTIVE INGREDIENT: 
64Cu-DOTATATE 
INDIVIDUAL STUDY TABLE 
REFERRING TO PART OF  
THE DOSSIER 
 
Volume: 
 
Page: 
(FOR NATIONAL 
AUTHORITY USE ONLY) 
 
 
9. Participation in other clinical research trials involving evaluation of other investigational treatments within 
30 days prior to enrollment and/or unwilling to allow at least one week before participation in another drug 
trial following the current study. 
Test Product, Dose and Mode of Administration: 
The drug product NETMedixTM Injection Solution contained 64Cu-DOTATATE filled in a glass vial, closed with 
butyl rubber stopper secured with an aluminum crimp seal. The drug product was delivered by RadioMedix Inc. to 
the clinical site. The study drug was administered as an intravenous bolus injection. 
Duration of Treatment: 
The duration of subject participation was from the time of signing the informed consent form through the 2-day 
post-injection visit. A subject was deemed enrolled in the study once the subject signed the informed consent form.  
Reference Therapy, Dose and Mode of Administration: 
This was a single-dose, single-arm study. There was no reference therapy. The study drug was administered as an 
intravenous bolus injection. The injection was given by hand into a 22 or 24-gauge catheter at a rate of 3-4 mL/min. 
The catheter was flushed with 3 mL of normal saline post-injection. The radioactivity/dose was measured before 
and after injection using a calibrated machine and recorded. The difference in radioactivity before the injection and 
after injection was considered as the total injected dose. 
CRITERIA FOR EVALUATION: 
Efficacy Endpoints: 
The co-primary effectiveness endpoints were the sensitivity and specificity of 64Cu-DOTATATE PET-CT imaging 
when each imaging reader’s subject-level result was compared to a SOT for the subject, with primary endpoint 
success defined as the same two out of three readers having sensitivity and specificity results exceeding the specified 
thresholds.   
The secondary effectiveness endpoints of the study were: 
• 
Majority of readers sensitivity; 
• 
Majority of readers specificity; 
• 
Majority of readers positive predictive value (PPV); 
• 
Majority of readers negative predictive value (NPV); 
• 
Majority of readers accuracy; 
• 
Individual reader sensitivity and specificity in distinguishing between localized and metastatic disease; 
• 
Majority reader sensitivity and specificity in distinguishing between localized and metastatic disease; 
• 
Individual reader accuracy, PPV, and NPV. 
The tertiary effectiveness endpoints of the study were: 
• 
Intra-reader agreement using Cohen’s Kappa 
• 
Inter-reader agreement using Cohen’s Kappa 
Safety Assessments: 
Safety was evaluated by review of the following: 
• 
Adverse events 
• 
Changes in vital signs 


 
 
 
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NAME OF SPONSOR/COMPANY: 
RadioMedix, Inc. 
 
NAME OF TEST PRODUCT: 
NETMedixTM (64Cu-DOTATATE) 
injection, for intravenous use 
NAME OF ACTIVE INGREDIENT: 
64Cu-DOTATATE 
INDIVIDUAL STUDY TABLE 
REFERRING TO PART OF  
THE DOSSIER 
 
Volume: 
 
Page: 
(FOR NATIONAL 
AUTHORITY USE ONLY) 
 
 
• 
Changes in clinical laboratory parameters 
• 
Changes in ECG recordings 
Pharmacokinetic Assessments: 
PK analysis was performed as recommended by FDA using a bioanalytical HPLC method focused only on 
radiometric detection that could separate intact parent drug (64Cu-DOTATATE), free 64Cu, and known radiolysis 
byproducts of 64Cu-DOTATATE. 
• 
Identifying any major 64Cu moieties other than intact parent drug (64Cu-DOTATATE), free 64Cu, and 
known radiolysis byproducts of 64Cu-DOTATATE in plasma and urine samples. 
 


 
 
 
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RESULTS: 
Treatment and Disposition:  
A total of 68 subjects were screened for this study. Of these, 66 were enrolled and 63 (95.5%) completed the study. 
Three subjects (4.5%) withdrew consent. A total of 63 subjects were injected with a mean dose of 4.11 mCi of 64Cu-
DOTATATE. 
Efficacy Results:  
• 
Based on the individual reader analysis, all three readers demonstrated success on the co-primary 
effectiveness endpoints with Sensitivity >70% and Specificity >60%. 
• 
The majority read analysis showed statistically significant sensitivity (0.9091, p=0.0042) and specificity 
(0.9655, p<0.0001) in detecting patients positive for disease and patients negative for disease, respectively. 
The probability of disease being present given a positive result with 64Cu-DOTATATE (PPV) was 0.9677. 
The probability of disease being absent given a negative result with 64Cu-DOTATATE (NPV) was 0.9032. 
In this study, the majority read analysis determined that imaging with 64Cu-DOTATATE had an accuracy 
of 0.9355. 
• 
The majority read analysis had a sensitivity of 1.000 and a specificity of 1.000 in distinguishing localized 
or metastatic disease among patients imaged with 64Cu-DOTATATE and having an image status of positive 
for disease. 
• 
All readers demonstrated a level of accuracy ranging from 0.8571 to 0.9355. Readers 1 and 3 were more 
accurate in determining the presence or absence of disease relative to the SOT than Reader 2. Reader 1 had 
a PPV of 0.9677, NPV of 0.9032, and accuracy of 0.9355; Reader 2 had a PPV of 0.8333, NPV of 0.8889, 
and accuracy of 0.8571; and Reader 3 had a PPV of 0.9091, NPV of 0.9000, and accuracy of 0.9048. 
• 
Overall, the 3 readers demonstrated a high degree of inter-reader agreement  (Kappa = 0.7664). 
• 
Relative to the 7 images that were re-read, Readers 1 and 3 demonstrated perfect intra-reader reliability 
upon image re-read (Kappa = 1.000). 
• 
It can be concluded that 64Cu-DOTATATE is an effective imaging agent in detecting the presence or 
absence of a NET. 
Safety Results: 
• 
Overall there were 9 adverse events experienced by 5 subjects. The most common adverse events by 
MedDRA system organ class were gastrointestinal disorders (4.8%), nervous system disorders (3.2%), 
vascular disorders (3.2%), and skin and subcutaneous disorders (1.6%). 
• 
All adverse events were either mild or moderate in severity. There were no adverse events that were severe, 
life-threatening or disabling, or that resulted in death. Adverse events that were mild in severity included 
nausea, vomiting, headache, melanoderma, and flushing. Adverse events that were moderate in severity 
included syncope and hypertension. 
• 
All adverse events were either probably not related or definitely not related to injection of a single dose of 
64Cu-DOTATATE. No adverse events were considered definitely related, probably related, or possibly 
related to 64Cu-DOTATATE injection. 
• 
There were no serious adverse events reported in subjects injected with 64Cu-DOTATATE. 
• 
There were no clinically significant changes from baseline in mean serum chemistry or hematology values 
that occurred post-injection with 64Cu-DOTATATE or at the Day 1-2 follow-up visit. 
• 
There were no clinically significant changes from baseline in mean vital signs occurring at 5-, 10-, 30-, or 
60- minutes post-injection or at discharge. 
• 
There were no shifts observed in ECG parameters from baseline to 1 hour post-injection of 64Cu-
DOTATATE. 
• 
Injection of a single dose of 64Cu-DOTATATE appears to be safe and well tolerated in this patient 
population. 
CONCLUSIONS: 
On the basis of these findings, the following overall conclusions can be drawn: 
• 
64Cu-DOTATATE has both a high sensitivity and specificity in detecting patients with and without NETs, 
respectively. 
• 
64Cu-DOTATATE has a high sensitivity and specificity in determining localized or metastatic disease. 
• 
64Cu-DOTATATE PET-CT image reads have a high level of inter-reader and intra-reader agreement. 
• 
Imaging with 64Cu-DOTATATE appears to be safe, effective, and well tolerated. 


 
 
 
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NAME OF SPONSOR/COMPANY: 
RadioMedix, Inc. 
 
NAME OF TEST PRODUCT: 
NETMedixTM (64Cu-DOTATATE) 
injection, for intravenous use 
NAME OF ACTIVE INGREDIENT: 
64Cu-DOTATATE 
INDIVIDUAL STUDY TABLE 
REFERRING TO PART OF  
THE DOSSIER 
 
Volume: 
 
Page: 
(FOR NATIONAL 
AUTHORITY USE ONLY) 
 
 
 
Date of the report: 06 March 2019  
 


 
 
 
Version 1.0, 06 March 2019 
 
3 TABLE OF CONTENTS 
1 TITLE PAGE ............................................................................................................................. 1 
2 SYNOPSIS .................................................................................................................................. 2 
3 TABLE OF CONTENTS .......................................................................................................... 9 
3.1 LIST OF IN-TEXT TABLES ............................................................................................... 13 
3.2 LIST OF APPENDICES ...................................................................................................... 13 
4 ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................................... 15 
5 ETHICS .................................................................................................................................... 17 
5.1 INSTITUTIONAL REVIEW BOARD ................................................................................ 17 
5.2 ETHICAL CONDUCT OF THE STUDY ............................................................................ 17 
5.3 SUBJECT INFORMATION AND CONSENT ................................................................... 17 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................... 19 
6.1 INVESTIGATORS .............................................................................................................. 19 
6.2 ADMINISTRATIVE STRUCTURE ................................................................................... 19 
7 INTRODUCTION.................................................................................................................... 20 
7.1 BACKGROUND ................................................................................................................. 20 
7.2 CHARACTERISTICS OF 64CU-DOTATATE .................................................................... 20 
7.3 BACKGROUND OF CLINICAL DEVELOPMENT ......................................................... 22 
8 STUDY OBJECTIVES ............................................................................................................ 22 
8.1 PRIMARY OBJECTIVE ..................................................................................................... 22 
8.2 SECONDARY OBJECTIVES ............................................................................................. 23 
8.3 TERTIARY OBJECTIVE ................................................................................................... 23 
8.4 EXPLORATORY OBJECTIVE .......................................................................................... 23 
9 INVESTIGATIONAL PLAN ................................................................................................. 24 
9.1 OVERALL STUDY DESIGN AND PLAN: DESCRIPTION ............................................. 24 
9.1.1 Screening Visit .............................................................................................................. 24 
9.1.1.1 Patients .................................................................................................................... 24 
9.1.1.2 Healthy Volunteers ................................................................................................. 25 
9.1.2 Injection Visit ................................................................................................................ 25 
9.1.2.1 Pre-dose and Dosing Procedures ............................................................................ 25 
9.1.2.2 Post-dose Procedures .............................................................................................. 25 
9.1.3 Follow-Up ..................................................................................................................... 26 
9.2 DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP ................. 26 
9.3 SELECTION OF STUDY POPULATION .......................................................................... 26 
9.3.1 Inclusion Criteria ........................................................................................................... 27 
9.3.1.1 Patients .................................................................................................................... 27 
9.3.1.2 Healthy Volunteers ................................................................................................. 27 
9.3.1.3 Patients and Healthy Volunteers ............................................................................. 27 
9.3.2 Exclusion Criteria .......................................................................................................... 28 
9.3.3 Removal of Subjects from Study Participation ............................................................. 28 


 
 
 
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9.4 TREATMENTS ................................................................................................................... 28 
9.4.1 Study Drug Administered ............................................................................................. 28 
9.4.1.1 Study Drug Dosing and Schedule ........................................................................... 30 
9.4.2 Identity of Investigational Product(s) ............................................................................ 30 
9.4.3 Method of Assigning Subjects to Treatment Groups .................................................... 30 
9.4.4 Selection of Doses in the Study..................................................................................... 31 
9.4.5 Selection and Timing of Dose for Each Subject ........................................................... 31 
9.4.6 Prior and Concomitant Therapy .................................................................................... 31 
9.4.7 Treatment Compliance .................................................................................................. 31 
9.5 EFFICACY AND SAFETY VARIABLES ......................................................................... 31 
9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart ..................................... 31 
9.5.1.1 Efficacy Assessments.............................................................................................. 34 
9.5.1.2 Safety Assessments ................................................................................................. 34 
9.5.1.3 Pharmacokinetic Assessments ................................................................................ 34 
9.5.2 Appropriateness of Measurements ................................................................................ 34 
9.5.3 Primary Efficacy Variables ........................................................................................... 34 
9.5.4 Secondary Efficacy Variables ....................................................................................... 35 
9.5.5 Tertiary Efficacy Variables ........................................................................................... 35 
9.5.6 Safety Variables ............................................................................................................ 35 
9.5.7 Drug Concentration Measurements ............................................................................... 35 
9.6 DATA QUALITY ASSURANCE ....................................................................................... 35 
9.7 STATISTICAL METHODS PLANNED IN THE PROTOCOL AND DETERMINATION 
OF SAMPLE SIZE .................................................................................................................... 36 
9.7.1 Statistical and Analytical Plans ..................................................................................... 36 
9.7.1.1 Analysis Populations ............................................................................................... 36 
9.7.1.2 General Statistical Methodology............................................................................. 36 
9.7.1.2.1 Disposition and Demographics ......................................................................... 37 
9.7.1.2.2 Protocol Deviations .......................................................................................... 37 
9.7.1.2.3 Medical History ................................................................................................ 37 
9.7.1.2.4 Extent of Exposure and Treatment Compliance ............................................... 37 
9.7.1.2.5 Safety Analysis ................................................................................................. 37 
9.7.1.2.6 Analysis of Efficacy Data ................................................................................. 38 
9.7.1.2.6.1 Analysis of Primary Efficacy Endpoints .................................................... 38 
9.7.1.2.6.2 Analysis of Secondary Efficacy Endpoints ................................................ 39 
9.7.1.2.6.3 Analysis of Tertiary Efficacy Endpoints .................................................... 39 
9.7.1.2.7 Pharmacokinetic Analysis ................................................................................ 39 
9.7.2 Determination of Sample Size ...................................................................................... 39 
9.8 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ............. 40 
10 STUDY SUBJECTS ............................................................................................................... 41 
10.1 DISPOSITION OF SUBJECTS ......................................................................................... 41 
10.2 PROTOCOL DEVIATIONS ............................................................................................. 41 
11 EFFICACY EVALUATION ................................................................................................. 42 
11.1 DATA SETS ANALYZED ................................................................................................ 42 
11.2 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................. 42 
11.3 MEASUREMENTS OF TREATMENT COMPLIANCE ................................................. 43 


 
 
 
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11.4 EFFICACY RESULTS AND TABULATIONS OF INDIVIDUAL SUBJECT DATA .... 44 
11.4.1 Analysis of Efficacy .................................................................................................... 44 
11.4.1.1 Primary Endpoint Analysis ................................................................................... 44 
11.4.1.2 Secondary Endpoint Analysis ............................................................................... 45 
11.4.1.3 Tertiary Endpoint Analysis ................................................................................... 46 
11.4.1.4 Pharmacokinetic Analysis ..................................................................................... 47 
11.4.2 Statistical and Analytical Summary ............................................................................ 47 
11.4.2.1 Adjustments for Covariates................................................................................... 47 
11.4.2.2 Handling of Dropouts or Missing Data ................................................................. 48 
11.4.2.3 Interim Analysis and Data Monitoring ................................................................. 48 
11.4.2.4 Use of an “Efficacy Subject” of Subjects ............................................................. 48 
11.4.2.5 Examination of Subgroups .................................................................................... 48 
11.4.3 Drug Dose, Drug Concentration, and Relationship to Response ................................ 48 
11.4.4 Drug-Drug and Drug-Disease Interactions ................................................................. 48 
11.4.5 By-Subject Displays .................................................................................................... 48 
11.4.6 Efficacy Conclusions................................................................................................... 48 
12 SAFETY EVALUATION ...................................................................................................... 50 
12.1 EXTENT OF EXPOSURE ................................................................................................ 50 
12.2 ADVERSE EVENTS ......................................................................................................... 50 
12.2.1 Display of Adverse Events .......................................................................................... 50 
12.2.2 Analysis of Adverse Events ........................................................................................ 51 
12.2.2.1 Adverse Events by Severity .................................................................................. 51 
12.2.2.2 Adverse Events by Relationship ........................................................................... 51 
12.2.3 Listing of Adverse Events by Subject ......................................................................... 51 
12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT 
ADVERSE EVENTS ................................................................................................................. 51 
12.4 CLINICAL LABORATORY EVALUATIONS ................................................................ 52 
12.5 VITAL SIGNS, PHYSICAL EXAMINATIONS, AND OTHER OBSERVATIONS 
RELATED TO SAFETY ........................................................................................................... 52 
12.5.1 Vital Signs ................................................................................................................... 52 
12.5.2 Physical Examinations ................................................................................................ 52 
12.5.3 ECG Parameters .......................................................................................................... 52 
12.5.4 Concomitant Medications ........................................................................................... 52 
12.6 SAFETY CONCLUSIONS ............................................................................................... 52 
13 DISCUSSION AND OVERALL CONCLUSIONS ............................................................ 54 
13.1 DISCUSSION .................................................................................................................... 54 
13.2 CONCLUSIONS ............................................................................................................... 55 
14 TABLES AND FIGURES NOT INCLUDED IN THE TEXT (SOME REFERRED AS 
SOURCE)..................................................................................................................................... 56 
15 REFERENCE LIST ............................................................................................................... 58 
16 APPENDICES ........................................................................................................................ 60 
16.1 STUDY INFORMATION ................................................................................................. 60 
16.1.1 Protocol ....................................................................................................................... 60 


 
 
 
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16.1.2 Sample Case Report Forms (CRFs) ............................................................................ 61 
16.1.3 Institutional Review Board and Subject Consent and Information ............................. 62 
16.1.3.1 Name and Address of Institutional Review Board ............................................... 62 
16.1.3.2 Sample Informed Consent Form (ICF) ................................................................. 62 
16.1.4 Description of Investigators, Investigator CVs, and FDA 1572 ................................. 63 
16.1.4.1 Investigators and Locations .................................................................................. 63 
16.1.4.2 Curriculum Vitae of Principal Investigators and FDA 1572 ................................ 63 
16.1.5 Signature of Sponsor’s Responsible Officer or Medical Representative .................... 64 
16.1.6 Listing of Patients Receiving Test Drug(s)/Investigational Product(s) from Specific 
Batches, Where More Than One Batch Was Used ................................................................ 65 
16.1.7 Subject Randomization Scheme and Codes ................................................................ 66 
16.1.8 Audit Certificates (if available) ................................................................................... 67 
16.1.9 Documentation of Statistical Methods ........................................................................ 68 
16.1.10 Documentation of Inter laboratory Standardization Methods and Quality Assurance 
Procedures, if Used ................................................................................................................ 69 
16.1.11 Pharmacokinetic Assessment Report ........................................................................ 70 
16.1.12 Oncologist Note to File ............................................................................................. 71 
16.1.13 Clinical Laboratory and PET Imaging Deviations .................................................... 72 
16.1.14 Publications Based on the Study ............................................................................... 73 
16.1.15 Important Publications Referenced in the Report ..................................................... 74 
16.2 SUBJECT DATA LISTINGS ............................................................................................ 75 
16.3 CASE REPORT FORMS ................................................................................................... 76 
16.4 INDIVIDUAL SUBJECT DATA LISTINGS ................................................................... 77 


 
 
 
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3.1 LIST OF IN-TEXT TABLES 
Table 9.5.1-1: 
Study Schedule and Flow Chart ......................................................................... 32 
Table 10.1-1: Subject Disposition (All Screened Subjects).......................................................... 41 
Table 11.2-1: Demographics and Baseline Characteristics (Safety Population) .......................... 43 
Table 11.4.1.1-1: Summary of Individual Reader Results for 64Cu-DOTATATE PET 
Imaging Versus SOT – EE Population (N=63) ...................................................................... 44 
Table 11.4.1.2-1: 64Cu-DOTATATE PET Majority Read Imaging Versus Standard of Truth 
Two-Way Table – EE Population (N=63) ............................................................................. 45 
Table 11.4.1.2-2: Summary Statistics for 64Cu-DOTATATE Majority Read Imaging Versus 
Standard of Truth – EE Population (N=63) ........................................................................... 45 
Table 11.4.1.2-3: Individual Reader Summary Statistics for 64Cu-DOTATATE PET Imaging 
Versus SOT – EE Population (N=63) .................................................................................... 46 
Table 11.4.1.2-4: Majority Read Classification of Localized and Metastatic Disease – EE 
Population (N=63) .................................................................................................................. 46 
Table 11.4.1.3-1: Summary of Inter-Reader Agreement for Assessment of 64Cu-
DOTATATE Imaging – EE Population (N=63). ................................................................... 47 
Table 11.4.1.3-2: Summary of Intra-Reader Agreement of 64Cu-DOTATATE PET Imaging 
– EE Population (N=63) ......................................................................................................... 47 
Table 12.1-1: Summary of 64Cu-DOTATATE Dose Administration ........................................... 50 
Table 12.2.1-1: Number and Percentage of Subjects with Adverse Events (Safety 
Population) ............................................................................................................................. 51 
3.2 LIST OF APPENDICES 
16.1 
STUDY INFORMATION 
16.1.1 
Protocol  
16.1.2 
Sample Case Report Forms (CRFs)  
16.1.3 
Institutional Review Board and Subject Consent and Information 
16.1.4 
Description of Investigators, Investigator CVs, and FDA 1572 
16.1.5 
Signature of Sponsor’s Responsible Officer or Medical Representative 
16.1.6 
Listing of Patients Receiving Test Drug(s)/Investigational Product(s) from Specific 
Batches, Where More Than One Batch Was Used  
16.1.7 
Subject Randomization Scheme and Codes 
16.1.8 
Audit Certificates (if available) 
16.1.9 
Documentation of Statistical Methods 
16.1.10 Documentation of Inter-laboratory Standardization Methods and Quality Assurance 
Procedures, if Used 
16.1.11 Pharmacokinetic Assessment Report 
16.1.12 Oncologist Note to File 
16.1.13 Clinical Laboratory and PET Imaging Deviations 
16.1.14 Publications Based on the Study 


 
 
 
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16.1.15 Important Publications Referenced in the Report 
16.2 
SUBJECT DATA LISTINGS 
16.3 
CASE REPORT FORMS 
16.4 
INDIVIDUAL SUBJECT DATA LISTINGS 
 


 
 
 
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4 ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation Term 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practice 
CI 
confidence interval 
CMC 
chemistry manufacturing and control 
(i)CRF 
(internet)case report form 
CRO 
contract research organization 
CT 
computed tomography 
Cu 
copper 
ECG 
electrocardiogram 
EE 
efficacy evaluable 
FDA 
United States Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FN 
false negative 
FP 
false positive 
GCP 
Good Clinical Practice 
GH 
growth hormone 
GI 
gastrointestinal 
HPLC 
high performance liquid chromatography 
hrs 
hours 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IGF 
insulin-like growth factor 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
L 
liter 
mCi 
millicurie 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
 
 
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Abbreviation Term 
MeV 
mega electron volt 
µg 
microgram 
min 
minute 
mL 
milliliter 
mm 
millimeter 
MRI 
magnetic resonance imaging 
NET 
neuroendocrine tumor 
NPV 
negative predictive value 
ns 
nanosecond 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PPV 
positive predictive value 
SAE(s) 
serious adverse event(s) 
SAP  
Statistical Analysis Plan  
SE 
standard error 
SOC 
system organ class 
SOT 
standard of truth 
SPECT 
single photon emission computed tomography 
SRIF 
somatotropin release inhibiting factor 
SRS 
somatostatin receptor scintigraphy 
SST 
somatostatin 
SSTR 
somatostatin receptor 
TEAE  
Treatment Emergent Adverse Event  
TN 
true negative 
TP 
true positive 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
VIP 
vasoactive intestinal peptide 
v/v 
volume/volume 
WBC 
white blood cell 
WHO 
World Health Organization 
w/v 
weight/volume 


 
 
 
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5 ETHICS 
5.1 INSTITUTIONAL REVIEW BOARD 
A properly constituted, valid Institutional Review Board (IRB) reviewed and approved the 
protocol, the investigator’s permission/informed consent form (ICF) documents, and related 
subject information and recruitment materials before the start of the study. 
It was the responsibility of the Investigator to obtain written informed consent from each 
individual participating in the study after adequate explanation of the aims, methods, objectives, 
and potential hazards of the study. The Investigator also explained to the subjects that they were 
free to refuse to enter the study or to withdraw from it at any time. All ICF documentation 
contained all the elements described in 21 CFR Part 50.  
Protocol amendments were reviewed and approved by the IRB. Written approval from the IRB 
or a designee was provided to RadioMedix before implementation. This written approval 
consisted of a completed IRB approval form or written documentation from the IRB containing 
the same information. 
The name of the IRB that approved the conduct of this study and a sample ICF are provided in 
the appendices. 
5.2 ETHICAL CONDUCT OF THE STUDY 
The study was conducted in accordance with Good Clinical Practice (GCP) requirements 
described in the current revision of Consolidated Guideline (International Conference on 
Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human 
Use, May 1996) and all applicable regulations, including the US Code of Federal Regulations 
dealing with clinical studies, and all national and local laws and regulations. Compliance with 
these regulations and guidelines also constituted compliance with the ethical principles described 
in the current revision of the Declaration of Helsinki (as modified by the 48th General Assembly, 
Somerset West, Republic of South Africa, October 1996. This study was carried out in 
accordance with local legal requirements. 
5.3 SUBJECT INFORMATION AND CONSENT 
Subjects were required to be registered with the site for verification of eligibility and the 
assignment of a study identification. The study site personnel registering the subject completed the 
appropriate baseline information, eligibility checklist, and required registration. Once eligibility 
was confirmed, the study site personnel conducted the consent discussion with the subject and 
once consent was obtained (signature of informed consent form as described in the next 
paragraph), the subject was considered enrolled in the study. The completed source documentation 
obtained for eligibility verification and registration was kept in the subject’s medical records for 
monitoring purposes. 
A signed informed consent form (ICF) was obtained from each research participant (referred to as 
‘subject’) or the subject’s legally acceptable representative(s) prior to the subject’s participation 
in the trial. The investigator or qualified designee was responsible for obtaining written informed 
consent from the subject after adequate explanation of the aims, methods, anticipated benefits, and 
potential hazards of the study and before any protocol specific procedures were performed (i.e., 
all procedures not considered standard of care). 


 
 
 
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The acquisition of informed consent was documented in the subject’s medical records and the ICF 
was signed and personally dated by the subject or the subject’s legally acceptable representative(s) 
and by the person who conducted the informed consent discussion (not necessarily an 
investigator). The original signed ICF was retained in accordance with institutional policy, and a 
copy of the signed consent form was provided to the subject prior to participation in the trial. 
 


 
 
 
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6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
6.1 INVESTIGATORS 
This was a single-center study. A list of investigators and study center location is provided below 
and in Appendix 16.1.4. 
6.2 ADMINISTRATIVE STRUCTURE 
The following is a list of individuals and organizations critical to the conduct of the study: 
STUDY SITE CENTER 
 
Excel Diagnostics and Nuclear Oncology Center 
9701 Richmond Ave. 
Houston, TX 77042   
The list of investigators is in Appendix 16.1.4. 
CLINICAL TRIAL MANAGER 
David Ranganathan, PhD 
RadioMedix 
CLINICAL MONITOR 
Simon Blackburn 
STATKING Clinical Services 
MEDICAL MONITOR 
 
Ebrahim S. Delpassand, MD, FACNM 
RadioMedix 
BIOSTATISTICIAN 
Dennis Clason, PhD 
STATKING Clinical Services 
CLINCAL STUDY REPORT AUTHOR Lindsay Cordes, PharmD 
STATKING Clinical Services 
 


 
 
 
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7 INTRODUCTION 
7.1 BACKGROUND 
Neuroendocrine tumors (NETs) are a heterogeneous group of rare neoplasms that originate from 
neuroendocrine cells. These neoplasms occur mostly in the gastrointestinal tract and pancreas (so 
called gastro-entero-pancreatic NET), but can also occur in other tissues including thymus, lung, 
and other uncommon sites such as ovaries, heart and prostate. Regardless of their primary site, 
NETs share histological, immunohistochemical and ultrastructural features (Raut, 2006). NETs 
retain multi-potent differentiation capacities including the ability to produce and secrete a variety 
of metabolically active substances including amines, peptides and prostaglandins. Symptoms of 
NETs are usually vague, nonspecific and vary by the affected organ (Horton, 2004). Thus; non-
functional NETs are not associated with any specific hormonal syndrome, instead, their clinical 
manifestations are similar to most solid tumors, i.e. causing mass-effect either inside the organ 
where the tumor is growing or pressuring adjacent organs and structures. Regardless of their 
functional capability, most differentiated NETs express somatostatin receptors on their cell 
surface. 
The endocrine-related characteristics of NETs arise from the enterochromaffin and 
enterochromaffin-like cells of the gut. Pancreatic, enteric and unknown origins account for most 
NETs (>85%). Glucagonomas, VIPomas, and somatostinomas (pancreatic) are the rarest (Fauci, 
1998; Robertson, 2006), the combined incidence accounting for only 2% of these neoplasms.  
64Cu-DOTATATE (the test product) is a radiolabeled receptor-targeted diagnostic product for the 
detection of somatostatin receptor expressing NETs. The product consists of a somatostatin 
receptor-targeting peptide complex that is radiolabeled with the isotope 64Copper which has a 
physical half-life of 12.7 hours.  
The use of somatostatin analogues for the diagnosis of neuroendocrine tumors was first established 
by 111In-pentetreotide (OctreoScan™, available since 1995) (Krenning, 1996). Since then, 
OctreoScan™ has provided good specificity in whole body SRS-SPECT. Somatostatin receptor 
(SSTR) has 5 subtypes. However, 111In-pentetreotide has no affinity for SSTR1 and SSTR4, low 
affinity to SSTR3 and SSTR5, and only high affinity to SSTR2 (Gorges, 2001). Thus, the primary 
tumor is not identified in 20-50% of NETs. There are three reasons for the relatively high detection 
failure. Firstly, gamma camera imaging sensitivity is lower than PET, so visualization of deep 
lesions can be impaired. Secondly, most somatostatin receptor-positive tumors express multiple 
SSTR subtypes simultaneously. Thirdly, even in the same subject the SSTR expression is 
heterogeneous. 
7.2 CHARACTERISTICS OF 64Cu-DOTATATE 
The somatostatin analog octreotate is similar to octreotide except the C-terminal threoninol is 
replaced with threonine. Octreotate has been conjugated to DOTA forming DOTA-Octreotate 
(DOTATATE). DOTATATE shows improved binding to SSTR-positive tumors in animal models 
(de Jong, 1998). Reubi et al. reported a 9-fold increase in the affinity for SST 2, the receptor with 
the highest expression in most NETs, for DOTATATE as compared to DOTATOC (Reubi, 2000). 
This finding has been confirmed in clinical studies, which demonstrated that while uptake in the 
kidneys, liver and spleen were comparable for DOTATOC and DOTATATE, tumor uptake of 
DOTATATE was 3 to 4 fold higher (Kwekkeboom, 2003). Therefore, 64Cu-DOTATATE PET-
CT potentially represents an improvement over the diagnostic agent Octreoscan because of the 
higher absorbed doses that can be achieved for most tumors. Encouraging clinical results have 
been reported for 64Cu-DOTATATE PET-CT (Pfeifer, 2012; Pfeifer, 2015). 


 
 
 
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64Cu-DOTATATE has 3 main components, namely the somatostatin analogue Octreotate, the 
chemical linker DOTA (tetraxetan) and the positron emitter 64Copper. These three components 
have been previously used in human subjects and in medical research.  
DOTA is a well-established bifunctional chelating agent first used in the 1970s (Stetter, 1976), 
with chemical formula 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, a 12 member 
tetraaza macrocycle, essentially a cyclen skeleton that has been modified with acetate side arms to 
form a polyamino carboxylic acid. At the time of its discovery DOTA was demonstrated to have 
the largest known formation constant for the complexation Ca2+ and Gd3+ ions. A modified version 
of DOTA C-functionalized to act as a bifunctional chelating agent was first reported in 1988. 
DOTA is the most frequently used moiety for elemental labeling, typically metal isotopes to 
proteins (antibodies and peptides). There are several derivatives of DOTA also used in 
investigational medicine, such as DOTATOC ((DOTA (0)-Phe (1)-Tyr (3)) octreotide) or 
edotreotide) and DOTATATE ((DOTA (0), Phe1, Tyr3)-octreotate). A gallium 68 radiolabeled 
DOTATATE imaging agent (NETSPOT) and a lutetium 177 radiolabeled DOTATATE analog 
(LUTETHERA) have been approved by the FDA for localization and treatment, respectively, of 
NETs in adult and pediatric patients. 
Copper (Cu) is a metallic element. Copper has two stable isotopes, 63Cu and 65Cu, along with 27 
radioisotopes. The most stable of these is 67Cu with a half-life of 61.83 hours. The least stable is 
54Cu with a half-life of approximately 75 ns. Most have half-lives under a minute. Unstable copper 
isotopes with atomic masses below 63 tend to undergo β+ decay, while isotopes with atomic 
masses above 65 tend to undergo β− decay. 64Cu decays by both β+ and β−. 64Cu (17% β+; 
maximum positron energy, 0.653 MeV; half-life [t1/2], 12.7 h) is a positron emitter making it a 
viable PET imaging radionuclide which can give real time images of the physiological processes 
in the system. 64Cu has been previously used in investigational pharmaceutical preparations such 
as 64Cu-ATSM, 64Cu-DOTATATE and 64Cu-TETATATE (Lewis, 1999). 64Cu-ATSM [diacetyl-
bis (N4-methylthiosemicarbazone)] is being studied as a possible cancer therapy (Lewis, 2001), 
64Cu-ATSM is preferentially taken up by hypoxic cells compared to normoxic cells; the extent of 
retention in tissue is inversely related to the state of tissue oxygenation allowing the quantitation 
of tissue hypoxia PET imaging. In addition, the radioactive copper moiety of this agent may deliver 
a selective cytotoxic dose of beta radiation to hypoxic tumor cells. 64Cu-DOTATATE or 
DOTATOC and 64Cu-TETATATE, are somatostatin analogues that have been researched for the 
diagnosis of neuroendocrine tumours. 
The natural peptide hormones somatostatin-14 and somatostatin-28 (also known as Somatotropin 
Release Inhibiting Factor; (SRIF) are widely expressed in the central nervous system, 
hypothalamus, gastrointestinal (GI) tract and the D-cells of the pancreas. On target tissues such as 
brain, pituitary, pancreas and the GI tract, SRIF peptides bind with high affinity to membrane 
receptors and through this binding exert a number of biological effects (Hoyer, 1994). 
Somatostatins are important inhibitory regulators of endocrine and exocrine secretion that reduce 
the release of a large number of hormones such as growth hormone (GH), glucagon, insulin, 
gastrin, secretin and thyroid-stimulating hormone (TSH). Furthermore, SRIF peptides in the brain 
were shown to act as neurotransmitters / neuromodulators that affect locomotor activity as well as 
cognitive and behavioral processes (Hoyer, 1994).  
The neuroendocrine activity of SRIF is well documented by its effective inhibition of GH release. 
GH is released from the pituitary gland in a pulsatile manner, which leads to IGF-1 synthesis in 
the liver as well as in other peripheral organs such as heart and kidney. Furthermore, a GH-
independent regulation of IGF-1 plasma levels by somatostatin has been documented previously 
(Serri, 1992).  


 
 
 
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In the pancreas somatostatin suppresses the release of glucagon from α cells as well as insulin 
release from pancreatic β cells, thus affecting glucose metabolism. Octreotide has been reported 
previously to be more selective than insulin in reducing glucagon secretion (Karashima, 1987).  
As noted above, the NET-selectivity of octreotide and octreotate is based upon their function as 
analogues of somatostatin. 
7.3 BACKGROUND OF CLINICAL DEVELOPMENT 
64Cu-DOTATATE is a radiolabeled receptor-targeted imaging product for the detection and 
monitoring of somatostatin receptor expressing NETs by Positron Emission Tomography (PET) 
imaging. The product consists of a somatostatin receptor-targeting peptide complex that is 
radiolabeled with the isotope, 64Copper (64Cu), which has a physical half-life of 12.7 hours.  
64Cu-DOTATATE offers several advantages over a recently approved imaging agent for 
neuroendocrine tumors (NETs), NETSPOTTM and overcomes shortcomings of Ga-68 based NET 
imaging agents. 
a. 64Cu is a cyclotron produced positron emitter. 
b. Longer half-life of 64Cu allows centralized production and unit dose dispensing and flexible 
patient scheduling. 
c. Robust, scaled up, well-controlled and centralized manufacturing of 64CuCl2 is possible. 
d. No need for a radioisotope generator, which makes this imaging test more accessible to 
patients across the country in any nuclear medicine facility with PET imaging capability.  
e. Reduces patient healthcare cost by eliminating the requirement for patient presence at a 
limited number of designated centers providing 68Ga based NET imaging agents. 
Two prior studies were conducted with 64Cu-DOTATATE. The first was a retrospective analysis 
of a study of the use of 64Cu-DOTATATE for the detection of somatostatin receptor-positive 
neuroendocrine tumors. The primary objective of the study was to investigate whether 64Cu-
DOTATATE PET scan findings had the ability to diagnose somatostatin receptor-positive NETs. 
The study results were previously published (Pfeifer, 2012: Pfeifer, 2015). The secondary 
objective of the study was to evaluate the PPV, NPV, and accuracy of 64Cu-DOTATATE PET 
scan findings relative to the SOT. The second study was an open-label, single-dose, dose-ranging 
study with a primary objective to identify the lowest amount of administered dose to obtain a 
diagnostic quality 64Cu-DOTATATE PET-CT scan for imaging patients with known somatostatin 
receptor-positive NETs, coincident with the as low as reasonably achievable (ALARA) principle. 
The secondary objective of this study was to assess the effect of 64Cu-DOTATATE dose on PET-
CT image quality. Reports for both of these studies are final and available upon request. The four 
subjects who received the selected dose in the dose ranging study are included in the analysis 
presented in this report. 
 
8 STUDY OBJECTIVES 
8.1 PRIMARY OBJECTIVE 
The primary objective of this study was to assess the performance (sensitivity and specificity) of 
64Cu-DOTATATE PET-CT imaging in subjects with known or suspected NETs, when 
comparing individual reader results to a standard of truth (SOT) for each subject. 


 
 
 
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8.2 SECONDARY OBJECTIVES 
The secondary objectives of this study were as follows: 
• To characterize the predictive value of 64Cu-DOTATATE PET-CT imaging when 
comparing an imaging reader-majority rule determination to the SOT for each subject and 
also when the comparison was performed on an individual reader basis.  
• To evaluate the imaging performance (sensitivity and specificity) of 64Cu-DOTATATE 
when comparing an imaging reader-majority rule determination to the SOT for each 
subject. 
• To evaluate the imaging performance of 64Cu-DOTATATE to determine if subjects had 
metastatic or local disease as compared to the SOT. 
8.3 TERTIARY OBJECTIVE 
The tertiary objective of this study was to evaluate the intra-reader and inter-reader agreement. 
8.4 EXPLORATORY OBJECTIVE 
The exploratory objective of this study was to evaluate pharmacokinetics and identify any major 
64Cu moieties other than intact parent drug (64Cu-DOTATATE), free 64Cu, and known radiolysis 
byproducts of the parent drug. 
 
 


 
 
 
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9 INVESTIGATIONAL PLAN 
9.1 OVERALL STUDY DESIGN AND PLAN: DESCRIPTION 
This was an open-label, single-dose, single-arm, single-center non-comparative study using 
DOTATATE peptide, labeled with the 64Cu tracer to assess imaging performance versus 
standard of truth (SOT).  
The imaging dose was identified in a phase 1 study. PET/CT imaging started 60 ± 15 minutes 
after injection for all subjects. The study recruited, enrolled, and investigated subjects 
comprising healthy volunteers as well as patients with confirmed or suspicious for NETs based 
on histopathology and/or by anatomical and/or functional imaging and/or blood tumor markers 
for NETs.     
For safety assessment, vital signs were measured within 30 minutes before and for up to 1 hour 
after administration of 64Cu-DOTATATE. A blood sample was collected within 30 minutes 
before the injection and within 2 hours post 64Cu-DOTATATE administration for assessing 
clinical chemistries and haematology. 
Any adverse events observed or reported were recorded for up to 48 hours following study drug 
administration. In addition, observed or patient reported immediate adverse events including but 
not limited to pain, injection site reaction, headache, nausea, vomiting, flushing or other as 
reported, were assessed within 1 hour before and within 2 hours after the study drug 
administration.   
All subjects underwent a continuous ECG recording at least 15 minutes prior to administration of 
the study drug and continuing for at least 30 minutes after administration. In addition, a 12-lead 
static ECG was performed within 60 minutes before and within 60 minutes following study drug 
administration. All the ECG data were collected in digital format, analysed and reviewed (with 
manual over-read) by an independent (i.e., not otherwise affiliated with the study) physician 
expert to assess the recordings as normal or abnormal and whether clinically significant or not 
significant. 
To assess pharmacokinetics, blood and urine samples were collected after the administration of 
64Cu-DOTATATE on 6 subjects. Five 10 mL blood samples were collected at 1, 10, 30, 60, and 
120 minutes after the administration of 64Cu-DOTATATE. Urine samples were collected in three 
intervals after the administration of 64Cu-DOTATATE; 0-60 minutes, 60-120 minutes, and 120-
360 minutes. The pharmacokinetic (PK) analysis was focused only on radiometric detection 
using a bioanalytical high performance liquid chromatography (HPLC) method. 
9.1.1 Screening Visit 
9.1.1.1 Patients 
• Written informed consent 
• Demographic information 
• Relevant medical history and concomitant medications 
• Vital signs 
• Histology and/or clinical information reports 
• Anatomical and functional imaging studies information 


 
 
 
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• Urine or Blood Pregnancy test, if applicable 
9.1.1.2 Healthy Volunteers 
• Written informed consent 
• Demographic information 
• Relevant medical history 
• Vital signs 
• Physical Exam 
• ECG Exam  
• Anatomical imaging studies information 
• Urine or Blood Pregnancy test, if applicable 
• Illicit drug screening questionnaire 
• Concomitant medication information 
9.1.2 Injection Visit 
Once all screening/baseline procedures were performed, the following procedures were 
completed on the day of injection. In the event multiple tasks needed to be performed at the same 
time or within a short time frame, every effort was made to complete all tasks back to back in the 
most efficient way. 
9.1.2.1 Pre-dose and Dosing Procedures 
• Pre-dose vital signs – within 30 minutes before dose 
• Pre-dose observed or patient reported immediate adverse drug reactions – within 1 hour 
before dose 
• Pre-dose blood sample collection- within 30 minutes prior to study drug injection 
• Pre-dose static ECG recording - within 60 minutes prior to study drug injection 
• Pre-dose continuous ECG recording - within 15 minutes prior to study drug injection 
• Pre-dose Urine Pregnancy test, if applicable 
• Injection of study drug 64Cu-DOTATATE 
• Start recording adverse events 
9.1.2.2 Post-dose Procedures 
• Post-dose vital signs– 5, 10, 30, 60 minutes and discharge  
• Post-dose observed or patient reported immediate adverse drug reactions – up to 2 hours 
after dose 
• Post-dose blood sample collection- within 2 hours ± 30 minutes  
• Post-dose blood sample collection for PK analysis, for 6 subjects only – 1, 10, 30, 60, and 
120 minutes after study drug administration 


 
 
 
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• Post-dose urine sample collection for PK analysis, for 6 subjects only – collected over the 
following intervals: 0-60 minutes, 60-120 minutes, and 120-360 minutes after study drug 
administration 
• Post-dose static ECG recording - within 60 minutes after study drug administration 
• Post-dose continuous ECG recording - Continuous 30 minutes after study drug 
administration 
• Whole-body PET/CT from top of the skull to mid-thigh region.  
• Recording of adverse events up to 48 hours post injection 
9.1.3 Follow-Up 
24 ± 4 hours telephone follow-up 
• Adverse events 
• Patient reported symptoms 
48 ± 4 hours telephone follow-up 
• Adverse events 
• Patient reported symptoms 
Day 1-2 post-injection follow-up 
• Blood Sample for Clinical Laboratory tests 
9.2 DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP 
The study followed a standard imaging accuracy/efficiency evaluation design. The imaging 
sensitivity, specificity, accuracy and predictiveness of the study drug were assessed using a 
predefined standard of truth (SOT) parameter. A conventional scan, such as an anatomical 
imaging modalities CT, and MRI or functional imaging using OctreoScan®, 68Ga-DOTATATE 
18F-FDG and NaF PET/CT or bone scan along with clinical data composed a key part of the 
SOT, which were determined by an oncologist. 64Cu-DOTATATE images were independently 
interpreted by readers blinded to all clinical information for the subjects, including the results of 
any other imaging modalities. The primary endpoint required two out of three of the readers 
exceeding the pre-specified sensitivity and specificity thresholds. This design aligned with 
contemporary precedent for important imaging studies and provided a solid assessment of 64Cu-
DOTATATE performance. The study was a single-arm clinical trial and did not include a control 
group. 
9.3 SELECTION OF STUDY POPULATION 
The study population was comprised of both healthy volunteers, as required by the SAP and 
agreed upon by the FDA in the pre-IND meeting, and patients confirmed or suspicious for NETs. 
The EE population consisted of all subjects who were enrolled in the study and 4 subjects from 
the selected 4.0 mCi dose cohort of the Phase 1 study having the following characteristics: had 
an established SOT, were injected with 64Cu-DOTATATE, and had an image read result using 
64Cu-DOTATATE by three independent readers. This sample size was appropriate to achieve 


 
 
 
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statistical power for the primary endpoints of this clinical trial. The subjects were recruited at the 
clinical site, Excel Diagnostics and Nuclear Oncology Center located at 9701 Richmond Ave., 
Houston, TX 77042.  
9.3.1 Inclusion Criteria 
Subjects were eligible to participate in the study if they met all of the following inclusion 
criteria: 
9.3.1.1 Patients 
1. Subjects of either sex, aged ≥18 years. 
2. Met at least one of the following criteria: 
a. Confirmed or suspicion of NET based on histology/biopsy report. 
b. Confirmed or suspicion of NET based on conventional imaging scans of affected 
area such as MRI and/or contrast enhanced CT and/or FDG PET-CT scan and/or 
NaF PET-CT scan and/or OctreoScan® performed within 8 weeks prior to study 
date. 
9.3.1.2 Healthy Volunteers 
Healthy male or female subjects aged ≥18 years of age and in good health as determined by 
absence of clinically relevant abnormalities determined by a full medical history, physical 
examination, vital signs and clinical laboratory tests. 
9.3.1.3 Patients and Healthy Volunteers 
1. Willing to sign informed consent form. 
2. Able to understand and comply with the procedures and requirements of the study. 
3. Negative pregnancy test in women of child-bearing potential, performed within 48 hours 
prior to the study drug injection, using urine or blood-based testing. 
4. For women of childbearing potential, agreement to remain abstinent (refrain from 
heterosexual intercourse) or use non-hormonal contraceptive methods for at least 2 weeks 
following administration of study drug. 
5. For men, agreement to remain abstinent (refrain from heterosexual intercourse) for at 
least 2 weeks following administration of study drug or use contraceptive measures. 
6. Recent blood test results (within 4 weeks pre-dose) as follows: 
a. WBC: >2×109/L 
b. Haemoglobin: >8.0g/dL 
c. Platelets: >50×109/L 
d. ALT, AST, AP: ≤5 times ULN 
e. Bilirubin: ≤3 times ULN 
f. Serum creatinine: <170 μmol/L 


 
 
 
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9.3.2 Exclusion Criteria 
Subjects were excluded from study participation if they met any of the following exclusion 
criteria: 
1. Pregnant or planning to become pregnant within the next two weeks. 
2. Inability to provide written consent. 
3. Therapeutic use of any somatostatin analogue, including Sandostatin® LAR (within 28 
days) and Sandostatin® (within 2 days) prior to study imaging. If a subject was on 
Sandostatin® LAR, a wash-out period of 28 days was required before the injection of the 
study drug. 
4. History or presence of significant hematological abnormalities or immunodeficiency or 
any condition that might compromise the immune system (infection, vaccination), or any 
etiology as indicated by clinically significant abnormal values of any of the following 
hematologic parameters: platelets, hemoglobin, WBC count and ANC. 
5. Lactating and breast-feeding women. 
6. Acute or chronic clinically significant conditions such as uncontrolled congestive heart 
failure, liver or kidney dysfunction, uncontrolled hypertension. 
7. History of hypersensitivity to drugs with a similar chemical structure to the 
investigational product or any of its excipients. 
8. History of significant drug abuse within 1 year prior to screening or use of soft drugs 
(such as marijuana) within 3 months prior to the screening visit or hard drugs (such as 
cocaine, phencyclidine, and crack) within 1 year prior to screening. 
9. Participation in other clinical research trials involving evaluation of other investigational 
treatments within 30 days prior to enrollment and/or unwilling to allow at least one week 
before participation in another drug trial following the current study. 
9.3.3 Removal of Subjects from Study Participation 
The investigator could withdraw a subject from the trial for any of the following reasons: 
• Protocol violation, 
• Serious or intolerable adverse event (that in the opinion of the investigator, required the 
subject’s discontinuation; still, all adverse events were followed until resolution or 
stabilization to a non-clinically significant state), 
• Investigator withdrew the subject (at the investigator’s discretion for reasons other than 
an adverse event), 
• Sponsor terminated the study, or 
• Subject requested to be discontinued from the study, 
The investigator documented the reason(s) for any subject withdrawal in the CRF. 
9.4 TREATMENTS 
9.4.1 Study Drug Administered 


 
 
 
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Chemical name and structure: 
DOTATATE (Precursor) 
 
64Cu-DOTATATE (Drug Product) 
 
 
 
 
 
 
64Cu
Cl2 
→ 
 
 
The study drug is “Copper” 64Cu-DOTATATE, where 64Cu (the tracer) is a positron-emitter, 
Octreotate (the peptide) is a somatostatin analogue, and DOTA (chelator) is a chemical chelator 
used to link 64Cu to Octreotate.  
64Cu-DOTATATE: Copper(1-), [N-[[4,7,10-tris[(carboxy-κ O)methyl]-1,4,7,10-
tetraazacyclododec-1-yl-κ N1,κ N4,κ N7,κ N10]acetyl-κ O]-D-phenylalanyl-L-cysteinyl-L-
tyrosyl-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threonine cyclic (2→7)-disulfidato(4-)] 
Molecular weight: 1497.2 g/mol  
Route of administration: intravenous. 
Composition: A unit dose of 64Cu-DOTATATE contains the ingredients listed in Table 1: 
Table 1: Composition of 64Cu-DOTATATE Injection Solution 
Name of ingredient(s) 
Quantity per Unit dose 
Function 
64Cu-DOTATATE 
4.0 mCi ± 10% 
Active pharmaceutical 
ingredient  
DOTATATE  
< 100 µg  
Active pharmaceutical 
ingredient  
Sodium Ascorbate  
4.5% (w/v) 
Buffer and Stabilizer  
Gentisic Acid 
< 0.02% (w/v) 
Buffer and Stabilizer  
Ethanol 
5% (v/v) 
Stabilizer 


 
 
 
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Sterile Water for injection 
95% (v/v) 
Solvent  
 
64Copper is a positron-emitting isotope with an intermediate half-life (12.7 hours), produced in a 
cyclotron by bombarding proton beams to an enriched 64Ni target to produce a 64Ni(p,n) 64Cu 
nuclear reaction. The main advantage of Cu-64 is that it can be produced in large quantities in a 
centralized facility. Its intermediate half-life also allows shipment of radiolabeled unit doses to 
end-users. Furthermore, the non-halogenated and non-volatile chemical properties of 64Cu make 
this isotope ideal as a PET tracer. Other key radiochemical characteristics of 64Cu are summarized 
in Table 2. 
 
Table 2: Radiochemical characteristics of 64Cu isotope 
64Cu physical half-
life T½ 
Decay product 
Maximum positron 
energy 
Maximum linear 
range 
12.7 hrs 
64Ni (61%) 
64Zn (39%) 
0.66 MeV 
1.0 mm 
 
9.4.1.1 Study Drug Dosing and Schedule 
The study drug was administered as an intravenous bolus injection. Injection was given by hand 
directly into a 22 or 24-gauge catheter at a rate of 3-4 mL/min and the catheter was flushed with 
3 mL of normal saline post-injection. The radioactivity/dose was measured before and after 
injection using a calibrated machine and recorded. The difference in radioactivity before the 
injection and after injection was considered as the total injected dose. A 10 mL, sterile, single 
use syringe was used to administer the test drug and a 10 mL, sterile, single use syringe was used 
to flush the catheter port with normal saline. 
9.4.2 Identity of Investigational Product(s)  
The 64Cu-labeled radiopharmaceuticals were produced at a centralized production facility. The 
production of Cu-64 and radiolabeled 64Cu-DOTATATE drug product was manufactured at 
RadioMedix Inc. The radiolabeled drug product underwent radiopharmaceutical quality control 
tests, as specified in the chemistry manufacturing and control (CMC) document. A unit dose of 
64Cu-DOTATATE drug product calibrated to time of use was dispensed into a sterile vial and 
shipped to the study site.  
64Cu-DOTATATE drug product was prepared according to Current Good Manufacturing 
Practice (cGMP) per U.S. Food and Drug Administration (FDA) guidelines. Production was 
performed at RadioMedix Inc., located at 9701 Richmond Ave, Suite: 222 Houston, Texas 
77042.  
9.4.3 Method of Assigning Subjects to Treatment Groups 
This was a single-arm study. All subjects received the same treatment. 


 
 
 
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9.4.4 Selection of Doses in the Study 
The optimal dose of 64Cu-DOTATATE was determined by the dose ranging study to be 4 mCi 
administered as an intravenous bolus injection. 
9.4.5 Selection and Timing of Dose for Each Subject 
The duration of subject participation was from the time of signing the informed consent form 
through the 2-day post-injection visit. A subject was deemed enrolled in the study once the 
subject signed the informed consent form. 
Each subject received a one-time dose of radiolabeled 64Cu-DOTATATE drug product. Subjects 
followed their normal diet before and after the administration of the study drug. Subjects were 
encouraged to increase fluid intake at baseline and after image acquisition to maintain proper 
hydration throughout the study period and decrease radiation exposure to the urinary bladder. To 
enhance imaging, subjects were encouraged to void prior to study imaging, post-injection. There 
were no dietary, food, or activity restrictions for this study. 
9.4.6 Prior and Concomitant Therapy 
All prior and concomitant medications taken by or administered to a subject in the safety 
population were collected from the 30 days prior to informed consent until 
completion/withdrawal from the study. Concomitant medications were coded using the WHO 
Drug Dictionary. A data listing for concomitant medications for all safety subjects was provided.   
9.4.7 Treatment Compliance 
All study drug administration was done under the supervision of the principal investigator. 
Details of study drug injection were captured in each subject’s source documents. 
9.5 EFFICACY AND SAFETY VARIABLES 
9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart 
The following sections define the efficacy and safety assessments that were performed during the 
study. The schedule of events is summarized in Table 9.5.1-1. 


 
 
 
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Table 9.5.1-1: Study Schedule and Flow Chart 
 
 
Study Day 
Follow up 
 
Evaluation/ Procedure 
Screening 
Within 14 days 
of injection 
Day 1 
Day 2 
(24 ± 4 hr) 
 
Day 3 
(48 ± 4 hr) 
Day 1- 
2 
 
Pre-study drug 
administration (within) 
Study drug 
injection 
Post-study drug administration (within) 
 
 
 
60 
min 
30 
min 
0 
min 
30 
min 
60 min 
120 min / 
Discharge 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Physical exam (healthy volunteers 
only) 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
 
 
 
 
 
 
 
 
 
Urine or blood  Pregnancy Test 
(females only) if applicable [j] 
X 
 
 
 
 
 
 
 
 
 
SOT imaging report[a] 
X 
 
 
 
 
 
 
 
 
 
Screening Lab Tests [b] 
X 
 
 
 
 
 
 
 
 
 
Illicit drug screening questionnaire 
X 
 
 
 
 
 
 
 
 
 
Vital Signs [c] 
X 
 
X [c] 
 
X [c] 
X [c] 
X [c] 
 
 
 
12-lead static ECG [i] 
X 
X 
 
 
 
X 
 
 
 
 
Study drug administration 
 
 
 
X 
 
 
 
 
 
 
Observed or patient reported 
immediate drug reactions [d] 
 
X [c] 
 
 
 
 
X [c] 
 
 
 
Clinical Laboratory Tests [e] 
 
 
X 
 
 
 
X 
 
 
X 
12-Lead continuous 
Electrocardiogram 
 
 
X [f] 
start 
 
X [f] 
stop 
 
 
 
 
 


 
 
 
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Study Day 
Follow up 
 
Evaluation/ Procedure 
Screening 
Within 14 days 
of injection 
Day 1 
Day 2 
(24 ± 4 hr) 
 
Day 3 
(48 ± 4 hr) 
Day 1- 
2 
 
Pre-study drug 
administration (within) 
Study drug 
injection 
Post-study drug administration (within) 
 
 
 
60 
min 
30 
min 
0 
min 
30 
min 
60 min 
120 min / 
Discharge 
Adverse Events [g] 
 
X 
start 
 
 
 
 
 
 
X 
stop 
 
Post -study drug imaging [h] 
 
 
 
 
 
X 
 
 
 
 
Blood sample collection for PK 
analysis 
 
 
 
 
X [k] 
X [k] 
X [k] 
 
 
 
Urine sample collection for PK 
analysis  
 
 
 
 
 
X [l] 
X [l] 
 
 
 
Schedule of Events Footnotes 
a) 
SOT images/report within 8 weeks. 
b) 
Screening lab and other relevant clinical information within 4 weeks. 
c) 
Vital signs (blood pressure, body temperature, respiratory rate, and pulse rate) were collected pre-dose (within 30 minutes) and 5, 10, 30, 60, and at the time of discharge post 64Cu-DOTATATE 
injection. 
d) 
Observed or patient reported immediate adverse drug reactions (pain, injection site reaction, headache, nausea, vomiting, flushing, or other) were collected pre-dose (within 1 hour) and post 
64Cu-DOTATATE injection (within 2 hours). 
e) 
Blood sample collection for clinical laboratory assessments (including hematology and clinical chemistry) within 30 minutes pre-dose, within 2 hours and within 1-2 days post-dose. 
f) 
Continuous ECG monitoring was performed for at least 15 minutes pre-dose and 30 minutes after study drug administration. 
g) 
Adverse events were collected pre-dose (within 1 hour) and post 64Cu-DOTATATE injection (within 2 hours), and a follow-up by phone at 48 hours. 
h) 
Post study drug imaging times were ± 15 minutes. 
i) 
For healthy volunteers only. 
j) 
Urine dip stick on the day of injection or blood based pregnancy test within 48 hours 
k) 
Blood sample collection for PK analysis, on 6 subjects only – 1, 10, 30, 60, and 120 minutes after study drug administration. 
l) 
Urine sample collection for PK analysis, on 6 subjects only – 0-60 minutes, 60-120 minutes, and 120-360 minutes after study drug administration. 
*In the event multiple tasks needed to be performed at the same time or within a short time frame, every effort was made to complete all tasks back to back in the most efficient way.


 
 
 
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9.5.1.1 Efficacy Assessments 
The co-primary effectiveness endpoints of the study were assessed by the sensitivity and 
specificity of 64Cu-DOTATATE when comparing individual reader results relative to the SOT.   
9.5.1.2 Safety Assessments 
Safety was primarily assessed through treatment emergent adverse events (TEAEs). An AE was 
considered treatment emergent if the start date and time were on or after the start date and time 
of the injection of study drug. If the AE had a missing start date or time, or if the injection start 
time was unknown, then the event was considered treatment emergent. 
Adverse events (AEs) were monitored for each subject from the time of enrollment to exit from 
the study. AEs that were collected from the time of informed consent to immediately before 
injection were recorded in the medical history. Vital signs were recorded on each subject at 30 
minutes pre-injection (baseline) and within 1-hour post-injection. Clinical laboratory parameters 
were obtained from blood samples taken at 30 minutes prior to injection and at the Day 1-4 
Follow-up visit. A 12-lead ECG reading was taken 30 minutes prior to injection and within 2 
hours post-injection. 
9.5.1.3 Pharmacokinetic Assessments 
To assess pharmacokinetics, blood and urine samples were collected after the administration of 
64Cu-DOTATATE on 6 subjects. The PK analysis was focused only on radiometric detection 
using a bioanalytical HPLC method. 
The PK assessment was performed as recommended by the FDA during the October 4th, 2016 
PIND meeting. Blood samples were analyzed at 1, 10, 30, 60, and 120 minutes. Urine samples 
were analyzed in three intervals post-injection of the study drug (64Cu-DOTATATE); 0-60 
minutes, 60-120 minutes, and 120-360 minutes. The rationale for selecting these timepoints to 
assess PK characteristics was based on the PK reports of 177Lu-DOTATATE (Esser, 2006). 
Radioactivity is rapidly cleared from the plasma leaving <10% of the injected dose in the blood 
at 3 hours after administration and half of the injected dose is recoverable in the urine within six 
hours post-injection. 
The PK assessment was exploratory in nature. Results of the PK assessment are presented in 
Section 16.1.11. 
9.5.2 Appropriateness of Measurements 
The efficacy and safety assessments are widely used and generally recognized as reliable, 
accurate, and relevant. 
9.5.3 Primary Efficacy Variables 
The co-primary effectiveness endpoints were the sensitivity and specificity of 64Cu-DOTATATE 
PET-CT imaging when each imaging reader’s subject-level result was compared to a SOT for the 
subject, with primary endpoint success defined as the same two out of three readers having 
sensitivity and specificity results exceeding the specified thresholds. 


 
 
 
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9.5.4 Secondary Efficacy Variables 
The secondary effectiveness endpoints of the study were: 
• majority of readers sensitivity  
• majority of readers specificity 
• majority of readers positive predictive value (PPV) 
• majority of readers negative predictive value (NPV) 
• majority of readers accuracy 
• individual reader sensitivity and specificity in distinguishing between localized and 
metastatic disease 
• majority reader sensitivity and specificity in distinguishing between localized and 
metastatic disease 
• individual reader accuracy, PPV, and NPV 
9.5.5 Tertiary Efficacy Variables 
The following tertiary effectiveness endpoints of the study evaluated the variability between 
readers as well as the variability within readers using repeat reads of selected images: 
• intra-reader agreement using Cohen’s Kappa 
• inter-reader agreement using Cohen’s Kappa 
Agreement was assessed across the categories of “Localized Disease”, “Metastatic Disease”, and 
“No Disease”. Agreement among the 3 readers was assessed using Fleiss’s generalized Kappa. 
9.5.6 Safety Variables 
The following safety variables were measured in this trial: 
• Adverse events 
• Vital signs 
• Clinical laboratory parameters 
• ECG Recordings 
9.5.7 Drug Concentration Measurements 
The radioactivity/dose was measured before and after injection using a calibrated machine and 
recorded. The difference in radioactivity before the injection and after the injection was 
considered as the total injected dose. 
9.6 DATA QUALITY ASSURANCE 
The study site was chosen with regard to the capability and expertise of the principal 
investigators and the site staff. Prior to initiation of the study, the investigator and the sponsor’s 
representative met to discuss the study design and conduct of the study. The investigator signed 


 
 
 
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the protocol acknowledging that he understood the design and all procedures and intended to 
conduct the study and all procedures according to protocol. 
During the study, a representative of the sponsor made periodic visits to the investigational site 
while the study was in progress to check the accuracy and completeness of the data being 
entered. Site visits were conducted to inspect study data, subjects’ medical records, and eCRFs in 
accordance with ICH guidelines, GCPs, and the respective local and national government 
regulations and guidelines. The investigator permitted authorized representatives and the 
respective local and national health authorities to inspect facilities and records relevant to this 
study, if needed. 
Subject data was collected on source documents and entered in the eCRF. Data was reviewed 
and validated. The investigator signed and dated a declaration on the eCRF attesting to his/her 
responsibility for the quality of all data recorded and that the data represents a complete and 
accurate record of each subject in the study. 
Records of subjects, source documents, monitoring visit logs, inventory of study product, 
regulatory documents (e.g., protocol and amendments, IRB/IEC correspondence and approvals, 
approved and signed informed consent forms, Investigator’s Agreement, clinical supplies 
receipts, and distribution and return records), and other sponsor correspondence pertaining to the 
study were kept in the appropriate study files at the site. Source documents included all 
recordings and observations or notations of clinical activities and all reports and records 
necessary for the evaluation and reconstruction of the clinical study. At the end of the study, 
eCRF data was provided to the investigator. 
9.7 STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE 
9.7.1 Statistical and Analytical Plans 
9.7.1.1 Analysis Populations 
The following analysis populations were defined: 
 
Efficacy Evaluable (EE) Population – The EE population consisted of all subjects who were 
enrolled in the phase 3 study and 4 subjects from the selected 4.0 mCi dose cohort of the Phase 1 
study having the following characteristics:  
• had an established SOT; 
• were injected with 64Cu-DOTATATE; and  
• had an image read result using 64Cu-DOTATATE by three independent readers.  
 
Safety Population – The safety population consisted of all subjects who were enrolled in the study 
and had been injected with 64Cu-DOTATATE. 
 
The EE population was used for the primary analysis of all effectiveness analyses. The safety 
population was used for the analysis of all safety variables and baseline characteristics. 
9.7.1.2 General Statistical Methodology 


 
 
 
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The data analyses were conducted using SAS© Software, Version 9.4 or higher. 
9.7.1.2.1 Disposition and Demographics 
The continuous demographic characteristics at screening (age, height, and weight) were 
summarized for all subjects in the safety population using descriptive statistics (mean, standard 
deviation, median, minimum, maximum, and number of non-missing observations). The 
categorical baseline characteristics (gender, race, ethnicity) were summarized for the safety 
population using frequency counts and percentages. Detailed listings of all baseline and 
demographic data for each subject are provided. 
9.7.1.2.2 Protocol Deviations 
Protocol violations/deviations were documented by the investigator and submitted to the 
IRB/IEC, as required by IRB/IEC requirements. 
9.7.1.2.3 Medical History 
A table was constructed with counts and percentages of the number of subjects who were 
normal/abnormal by body system. A data listing for medical history information for all safety 
subjects is provided. 
9.7.1.2.4 Extent of Exposure and Treatment Compliance 
A table was constructed to summarize 64Cu-DOTATATE dosing for the safety population in this 
study. Summary statistics (mean, standard deviation, n, minimum, maximum and median) were 
computed on the wand counts on the dosing unit both pre and post injection and on the dose 
volume. A data listing for dosing information for all safety subjects is provided. A summary of 
64Cu-DOTATATE dose administration is displayed in Section 12.1 of this report. 
9.7.1.2.5 Safety Analysis 
The following safety analyses were conducted on the safety population. 
Adverse Events 
All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA). Safety 
was primarily assessed through treatment emergent adverse events (TEAEs). An AE was 
considered treatment emergent if the start date and time was on or after the start date and time of 
the injection of study drug. If the AE had a missing start date or time, or if the injection start time 
was unknown, then the event was considered treatment emergent. 
TEAEs were summarized by the total number and by the number and proportion of subjects 
reporting at least one occurrence of the TEAE. Frequencies of each TEAE were summarized by 
MedDRA preferred term within system organ class (SOC) and by severity, relation to study 
drug, and time of onset (before or after the initiation of study drug). Frequencies of each SAE 
were summarized by total number, by the number and proportion of subjects reporting at least 
one occurrence of the SAE, and by MedDRA preferred term within system organ class (SOC).  
Vital Signs 


 
 
 
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For each vital sign parameter, summary statistics on the raw and change from baseline values at 
each time point were calculated. If multiple vital signs were recorded for a given time point, then 
the most recent results from each time point were used in the analysis. 
Clinical Laboratory Parameters 
For each quantitative clinical laboratory parameter, summary statistics on the raw and change 
from baseline values at each time point were calculated. If multiple pre-injection labs were 
recorded, then the results closest to imaging were used as baseline.  
ECG Parameters 
A shift table was constructed to show the shifts in ECG interpretations between the pre-dose 
recording and the post-dose recoding. The number and percentage of subjects with the following 
shifts were presented: normal/normal, normal/abnormal, abnormal/normal, and 
abnormal/abnormal.   
9.7.1.2.6 Analysis of Efficacy Data 
9.7.1.2.6.1 Analysis of Primary Efficacy Endpoints 
The following two-way table was utilized to compute sensitivity, specificity, NPV, PPV, and 
accuracy: 
 
 
SOT Reference Standard 
 
 
Disease 
No Disease 
64Cu-DOTATATE 
Scan Result 
Disease 
TP 
FP 
No Disease 
FN 
TN 
 
Based on the above, the co-primary effectiveness endpoints were computed as follows for each 
reader: 
• sensitivity = TP/(TP + FN) 
• specificity = TN/(TN + FP) 
The following two hypotheses were tested at the end of the study relative to the co-primary 
endpoints:  
Ha0: Sensitivity ≤ 70% vs Ha1: Sensitivity > 70% 
and 
Hb0: Specificity ≤ 60% vs Hb1: Specificity > 60% 
 
Each hypothesis test was conducted at the one-sided α = 0.025 level of significance. Point 
estimates of sensitivity and specificity were calculated along with two-sided 95% confidence 
intervals using the score method. The sensitivity and specificity were calculated on a by-reader 
basis. Success upon the primary endpoints was declared if two of the three independent readers 
achieved sensitivity and specificity results in excess of the thresholds designated above. That is, 
the same two out of three readers achieved success upon sensitivity and specificity.  


 
 
 
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9.7.1.2.6.2 Analysis of Secondary Efficacy Endpoints 
Based on the table presented above, the secondary effectiveness endpoints were computed as 
follows: 
• NPV = TN/(TN + FN) 
• PPV = TP/(TP + FP) 
• accuracy = (TP + TN)/(TP + TN + FP + FN) 
The above endpoints were computed using the majority read (i.e., majority 64Cu-DOTATATE 
diagnosis from the 3 readers) as well as by reader. Point estimates of the majority read and by 
reader NPV, PPV, and accuracy were calculated along with 95% confidence intervals using the 
score method. 
Readers who identified an image as positive were asked to further classify the disease as 
localized or metastatic. Sensitivity and specificity were determined relative to the SOT. 
In addition, majority sensitivity and specificity were computed as secondary effectiveness 
endpoints. Point estimates were calculated along with 95% confidence intervals using the score 
method.   
9.7.1.2.6.3 Analysis of Tertiary Efficacy Endpoints 
For each reader pair (Readers 1&2, Readers 1&3, and Readers 2&3), a Cohen’s Kappa along 
with a 95% confidence interval on Cohen’s Kappa was computed. A Generalized Fleiss Kappa 
and associated 95% confidence interval was computed to assess overall agreement among the 3 
readers.   
Intra-reader variability was assessed using the n=7 randomly chosen study images that were re-
read by the readers. Cohen’s Kappa was computed for each reader on the pairs of re-reads for 
each image. A 95% confidence interval on Cohen’s Kappa was computed. A generalized Kappa 
and 95% confidence interval was computed in order to assess overall intra-reader reliability. 
9.7.1.2.7 Pharmacokinetic Analysis 
Analysis of the PK data are provided in a separate PK report, included in Appendix 16.1.11 of 
this report. 
9.7.2 Determination of Sample Size 
The study was powered with respect to the co-primary endpoints of sensitivity and specificity.   
In order to have at least a 90% chance of showing that the sensitivity was at least 0.70 and the 
specificity was at least 0.60 a sample of 63 subjects was needed, divided among n1 = 42 SOT 
positive subjects and n2 = 21 SOT negative subjects. This sample size was derived under the 
assumptions that the readers were viewing the same images and that their reads were correlated 
at r = 0.70 and that the true Sensitivity and Specificity are each 0.90. The study was powered at 
90% for each subtest to give the overall study 80% power. 
This sample size was determined by Monte Carlo simulation with the parameter values given 
above. The simulation used 5000 replications: the standard error of the estimated power was no 


 
 
 
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more than 0.6%. To satisfy the sample size requirements for each endpoint a total of n=63 
subjects was needed, allocated in a 2:1 (Positive:Negative) ratio. 
These calculations assumed a one-sided α=0.025 level of significance and that the data came 
from a binomial distribution.   
PK Analysis Sample Size: 
The PK assessment was performed on 6 subjects as an exploratory study. 
9.8 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
Intra-reader variability was planned to be assessed using n=10 randomly chosen study images 
that were re-read by the readers. This was interpreted by World Care Clinical to mean n=10%, 
thus n=7 randomly chosen study images were ultimately re-read by the readers. 
The SAP and protocol planned for the creation of 20 clinical laboratory shift tables. Data in the 
clinical database allowed for the creation of 30 clinical laboratory shift tables. The additional, 
unplanned shift tables include albumin, calcium, carbon dioxide, chloride, glucose, potassium, 
protein, and sodium. Furthermore, the SAP planned a combined data table for shifts in mean 
corpuscular hemoglobin concentration, mean corpuscular hemoglobin, and mean corpuscular 
volume. The finalized tables include separate shift tables for these parameters. 
There was a discrepancy between the SAP and the protocol regarding the following items: 
injection of radioactivity, waiting time allowed for tracer distribution, and PET scan acquisition 
time. The SAP required an injection of 185-227 MBq (5.0-6.0 mCi) of 64Cu-DOTATATE 
followed by a 20 minute PET scan beginning 50 minutes post-injection. The protocol required an 
injection of 148 ± 10% MBq (4.0 ± 10% mCi) of 64Cu-DOTATATE followed by a 5 minute per 
bed position PET scan beginning 60 ± 15 minutes post-injection. The protocol was followed 
during the clinical study. 
68Ga-DOTATATE PET-CT reports were included in the clinical data package that was presented 
to the independent oncologist in order to establish the SOT as 68Ga-DOTATATE is the new gold 
standard for somatostatin receptor positive NET tumors. The revised SOT is therefore defined as 
follows: confirmed or suspicious NET disease by histology or conventional anatomical and/or 
functional imaging modalities including but not limited to magnetic resonance imaging (MRI), 
computed tomography (CT), F-18 FDG PET-CT, F-18 NaF bone PET-CT, bone scintigraphy, 
and/or Octreoscan®, and/or 68Ga-DOTATATE PET-CT. This SOT is the SOT used in the 
analysis. 
 
 


 
 
 
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10 STUDY SUBJECTS 
10.1 DISPOSITION OF SUBJECTS 
A total of 68 subjects were screened for this study. Of these, 66 were enrolled, including 4 
subjects from the 4.0 mCi dose cohort from the Phase 1 study. A total of 63 subjects (95.5%), 59 
from the Phase 3 study and 4 from the Phase 1 study cohort, completed the study. Three subjects 
(4.5%) withdrew consent prior to receiving study treatment. 
Subject disposition of all screened subjects is presented in Table 10.1-1.  
Table 10.1-1: Subject Disposition (All Screened Subjects) 
 
Overall 
Screen Failure 
2 
Enrolled 
66 
Completed 
63 (95.5%) 
Early Termination (Withdrawal) 
3 (4.5%) 
Reason for Early Termination (Early Withdrawal) 
 
   Death  
0 (0.0%) 
 Adverse Event 
0 (0.0%) 
   Lost to Follow Up 
0 (0.0%) 
   Withdrawal of Subject Consent  
3 (4.5%) 
   Investigator Discretion 
0 (0.0%) 
   Protocol Deviation 
0 (0.0%) 
   Sponsor Discretion 
0 (0.0%) 
   Other 
0 (0.0%) 
Source: Data Table 1 
 
10.2 PROTOCOL DEVIATIONS 
The only protocol deviations noted in this study involved violations of the inclusion/exclusion 
criteria. A total of 5 subjects grouped as NET positive violated the inclusion criteria of having a 
confirmed or suspicion of a NET based on histology/biopsy report. Additionally, one subject, 
subject NET3-SC-0005, was screened but violated the inclusion criteria of being able to 
understand and comply with the procedures and requirements of the study and another screened 
subject, subject NET3-SC-0002, violated the exclusion criteria of having a history of significant 
drug abuse within 1 year prior to screening or use of soft drugs within 3 months prior to the 
screening visit or hard drugs within 1 year prior to screening. Consequently, these two subjects 
were screen failures and not enrolled in the study. 
PET/CT images were acquired outside of the protocol time window for 8 subjects. These 
deviations ranged from 6 minutes earlier to 22 minutes later than the protocol requirement of 60 
± 15 minutes (45-75 minutes). A complete listing of PET-CT image acquisition deviations is 
provided in Appendix 16.1.13. Blood draws were performed outside of the protocol time window 
for 7 subjects. A complete listing of clinical laboratory deviations is provided in Appendix 
16.1.13. 
 


 
 
 
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11 EFFICACY EVALUATION 
11.1 DATA SETS ANALYZED 
The efficacy evaluable (EE) population was used for the primary analysis of all effectiveness 
analyses. The EE population consisted of all subjects who were enrolled in the study and 4 
subjects from the selected dose cohort of the Phase 1 study having the following characteristics: 
had an established SOT, were injected with 64Cu-DOTATATE, and had an image read result 
using 64Cu-DOTATATE by three independent readers. 
11.2 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographics and other baseline characteristics for the safety population are presented in 
Table 11.2-1. The median age of all enrolled subjects was 54 years. Subjects ranged in age from 
25 to 82 years. The mean (SD) age of all subjects was 54.37 (15.65) years and the mean (SD) 
weight was 185.75 (46.70) pounds. The study consisted of 28 (44.4%) men and 35 (55.6%) 
women. The majority of subjects were white (85.7%) and not Hispanic or Latino (82.5%). 
African American subjects comprised 9.5% of the safety population. The remaining subjects 
were Asian (3.2%) or other (1.6%). 
A by-subject listing of demographics is provided in Data Listing 6. Of note, subject 051 had a 
race of other-Latino recorded in error. This subject’s race should have been set to missing and 
therefore the percentage of subjects with a race of Other would be 0% rather than 1.6% (n=1). 
A total of 47 subjects (74.6%) reported at least 1 medical history event. The most common 
medical history events included vascular disorders (39.7%), metabolism and nutrition disorders 
(28.6%), gastrointestinal disorders (23.8%), psychiatric disorders (22.2%), and endocrine 
disorders (17.5%). 
A summary of medical history findings is provided in Data Table 4. A by-subject listing of 
medical history is provided in Data Listing 12. 
 


 
 
 
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Table 11.2-1: Demographics and Baseline Characteristics (Safety Population) 
Characteristic 
Overall 
(N = 63) 
Age (years), n 
 
 Mean (SD) 
54.37 (15.65) 
 Median (min, max) 
54.00 (25.0, 82.0) 
Height (in), n 
 
 Mean (SD) 
67.67 (4.54) 
 Median (min, max) 
68.00 (58.0, 78.7) 
Weight (lb), n 
 
 Mean (SD) 
185.75 (46.70) 
 Median (min, max) 
178.00 (114.0, 327.0) 
Gender, n (%) 
 
 Male 
28 (44.4%) 
 Female 
35 (55.6%) 
Race, n (%) 
 
 American Indian or Alaska Native  
0 (0.0%) 
 Asian 
2 (3.2%) 
 Black or African American  
6 (9.5%) 
 Native Hawaiian or Other Pacific Islander 
0 (0.0%) 
 White 
54 (85.7%) 
 Other 
1 (1.6%) 
Ethnicity, n (%) 
 
 Hispanic or Latino 
11 (17.5%) 
 Not Hispanic or Latino 
52 (82.5%) 
    Unknown 
0 (0.0%) 
 Not Reported 
0 (0.0%) 
Source: Data Table 2 & Data Table 3 
 
11.3 MEASUREMENTS OF TREATMENT COMPLIANCE 
Injection of 64Cu-DOTATATE was performed at the study site under the supervision of the 
investigator. A total of 63 subjects were injected with a mean dose of 4.11 mCi of 64Cu-
DOTATATE. A total of 62 subjects received a dose of 4 mCi ± 10% of 64Cu-DOTATATE. 
Subject AA-NET3-006 received a total injected dose of 3.5756 mCi of 64Cu-DOTATATE. 
A by-patient listing of drug administration is provided in Data Listing 14. 


 
 
 
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11.4 EFFICACY RESULTS AND TABULATIONS OF INDIVIDUAL SUBJECT DATA 
11.4.1 Analysis of Efficacy 
By-patient listings of primary and secondary efficacy are provided in Data Listing 16, Data 
Listing 17, and Data Listing 18. 
11.4.1.1 Primary Endpoint Analysis 
The co-primary effectiveness endpoints of the study were the sensitivity and specificity of 64Cu-
DOTATATE PET-CT imaging when each imaging reader’s subject-level result was compared to 
a SOT for the subject, with primary endpoint success defined as the same two out of three 
readers having sensitivity and specificity results exceeding the specified thresholds. 
Table 11.4.1.1-1 presents the individual reader results for PET imaging versus SOT. All three 
readers demonstrated success on the co-primary effectiveness endpoints with Sensitivity >70% 
and Specificity >60%. All three readers had point estimates of sensitivity of 64Cu-DOTATATE 
to be >90% for detecting disease when disease was present relative to the SOT. Two of the three 
readers had point estimates of specificity greater ≥90% while the third had a point estimate of 
specificity equal to 80% in determining absence of disease when disease was indeed absent. All 
readers passed the sensitivity and specificity hypotheses testing at a one-sided α=0.025 level of 
significance. 
 
Table 11.4.1.1-1: Summary of Individual Reader Results for 64Cu-DOTATATE PET Imaging 
Versus SOT – EE Population (N=63) 
Reader 
Parameter 
Estimate 
(95% CI) 
p-Value 
Reader Passes 
Sensitivity and 
Specificity 
Hypotheses? 
Reader 1 
Sensitivity 
0.9091 
(0.7643, 0.9686) 
0.0042 
Yes 
 
Specificity 
0.9655 
(0.8282, 0.9939) 
<0.0001 
Yes 
Reader 2 
Sensitivity 
0.9091 
(0.7643, 0.9686) 
0.0042 
Yes 
 
Specificity 
0.8000 
(0.6269, 0.9049) 
0.0172 
Yes 
Reader 3 
Sensitivity 
0.9091 
(0.7643, 0.9686) 
0.0042 
Yes 
 
Specificity 
0.9000 
(0.7438, 0.9654) 
0.0003 
Yes 
Source: Data Table 5 
CI=Confidence Interval 
 


 
 
 
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11.4.1.2 Secondary Endpoint Analysis 
The secondary effectiveness endpoints of the study were the majority of readers sensitivity, 
specificity, PPV, NPV, and accuracy; individual and majority reader sensitivity and specificity in 
distinguishing between localized and metastatic disease; and individual reader accuracy, PPV, 
and NPV. 
The two-way table utilized to compute sensitivity, specificity, PPV, NPV, and accuracy for the 
majority read is provided in Table 11.4.1.2-1. Subject PD-NET3-013 had a Not Evaluable read 
for Reader 1 (Data Listing 18), and therefore, the total number of images in the two-way table is 
1 fewer than the EE population count. Table 11.4.1.2-2 provides the majority read summary 
statistics for 64Cu-DOTATATE PET imaging versus SOT.  
The majority of readers showed statistically significant sensitivity (0.9091, p=0.0042) and 
specificity (0.9655, p<0.0001) in detecting patients positive for disease and patients negative for 
disease, respectively. The probability of disease being present given a positive result with 64Cu-
DOTATATE (PPV) was 0.9677. The probability of disease being absent given a negative result 
with 64Cu-DOTATATE (NPV) was 0.9032. In this study, the majority of readers determined that 
imaging with 64Cu-DOTATATE had an accuracy of 0.9355. 
 
Table 11.4.1.2-1: 64Cu-DOTATATE PET Majority Read Imaging Versus Standard of Truth 
Two-Way Table – EE Population (N=63) 
 
Standard of Truth 
Method of Evaluation 
 
Disease 
No Disease 
Total 
64Cu-DOTATATE Scan Results 
Disease 
30 
1 
31 
 
No Disease 
3 
28 
31 
 
Total 
33 
29 
62 
Source:  Data Table 6 
 
Table 11.4.1.2-2: Summary Statistics for 64Cu-DOTATATE Majority Read Imaging Versus 
Standard of Truth – EE Population (N=63) 
 
Summary Statistics 
Parameter 
Estimate 
95% CI 
p-Value 
Sensitivitya 
0.9091 
(0.7643, 0.9686) 
0.0042 
Positive Predictive Value 
0.9677 
(0.8381, 0.9943) 
 
Specificityb 
0.9655 
(0.8282, 0.9939) 
<0.0001 
Negative Predictive Value 
0.9032 
(0.7510, 0.9665) 
 
Accuracy 
0.9355 
(0.8455, 0.9746) 
 
Source:  Data Table 6 
CI=Confidence Interval 
a One sided α=0.025 test of Ha0:Sens ≤0.70 vs. Ha1:Sens>0.70 
b One sided α=0.025 test of Hb0:Spec ≤0.60 vs. Hb1:Spec>0.60 
 
Individual reader summary statistics for 64Cu-DOTATATE PET imaging versus SOT are 
provided in Table 11.4.1.2-3. All readers demonstrated a level of accuracy ranging from 0.8571 
to 0.9355. Readers 1 and 3 were more accurate in determining the presence or absence of disease 
relative to the SOT than Reader 2.  


 
 
 
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Table 11.4.1.2-3: Individual Reader Summary Statistics for 64Cu-DOTATATE PET Imaging 
Versus SOT – EE Population (N=63) 
Reader 
Parameter 
PPV 
NPV 
Accuracy 
1 
0.9677 
0.9032 
0.9355 
2 
0.8333 
0.8889 
0.8571 
2 
0.9091 
0.9000 
0.9048 
Source:  Data Table 7 
 
Readers who identified an image as positive were asked to further classify the disease as 
localized or metastatic. Sensitivity and specificity were determined relative to the SOT. The 
majority of readers determined from 64Cu-DOTATATE imaging findings that 30 patients were 
positive for disease while the SOT determined 33 patients were positive for disease. Of the 30 
patients identified by the readers via 64Cu-DOTATATE PET imaging as positive for disease, 2 
patients were determined to have localized disease while 28 were determined to have metastatic 
disease. Three instances of localized disease detected by the SOT were not detected by the 
majority read. The majority of readers had a sensitivity of 1.000 and a specificity of 1.000 in 
determining localized or metastatic disease among patients imaged with 64Cu-DOTATATE and 
having an image status of positive for disease (Table 11.4.1.2-4). Individual reader classification 
of localized and metastatic disease is provided in Data Table 8. 
 
Table 11.4.1.2-4: Majority Read Classification of Localized and Metastatic Disease – EE 
Population (N=63) 
Majority of Readers 
Classification 
Standard of Truth 
Sensitivity 
Specificity 
Localized Disease 
(N=5) 
Metastatic Disease 
(N=28) 
Localized Disease 
2 (40.0%) 
0 (0.0%) 
1.0000 
1.0000 
Metastatic Disease 
0 (0.0%) 
28 (100.0%) 
Source:  Data Table 9 
 
11.4.1.3 Tertiary Endpoint Analysis 
For each reader pair (Readers 1&2, Readers 1&3, and Readers 2&3) the inter-reader agreement 
was assessed using a Cohen’s Kappa along with a 95% confidence interval on Cohen’s Kappa. A 
Generalized Fleiss Kappa and associated 95% confidence interval were computed to assess 
overall agreement among the 3 readers. Readers 1&3 were in greatest agreement (Kappa = 
0.8710) among the reader pairs. Overall, the 3 readers demonstrated a relatively high degree of 
agreement  (Kappa = 0.7664). Table 11.4.1.3-1 presents a summary of inter-reader agreement for 
assessment of 64Cu-DOTATATE imaging. 


 
 
 
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Table 11.4.1.3-1: Summary of Inter-Reader Agreement for Assessment of 64Cu-DOTATATE 
Imaging – EE Population (N=63). 
Reader Pair 
n 
Kappa (SE) 
95% CI on Kappa 
1 vs. 2 
62 
0.7419 (0.0844) 
(0.5764, 0.9074) 
1 vs. 3 
62 
0.8710 (0.0623) 
(0.7489, 0.9930) 
2 vs. 3 
63 
0.7123 (0.0883) 
(0.5392, 0.8855) 
Overall 
63 
0.7664 (0.0732) 
(0.6229, 0.9099) 
Source:  Data Table 11 
SE=Standard Error 
CI=Confidence Interval 
 
Intra-reader variability was assessed using n=7 randomly chosen study images that were re-read 
by the readers. Cohen’s Kappa was computed for each reader on the pairs of re-reads for each 
image. A 95% confidence interval on Cohen’s Kappa was computed. A generalized Kappa and 
95% confidence interval were computed in order to assess overall intra-reader reliability. 
Readers 1 and 3 demonstrated perfect intra-reader agreement upon image re-read. Table 
11.4.1.3-2 presents a summary of intra-reader agreement of 64Cu-DOTATATE PET imaging. 
 
Table 11.4.1.3-2: Summary of Intra-Reader Agreement of 64Cu-DOTATATE PET Imaging – 
EE Population (N=63) 
 
Summary Statistics 
Reader 
Parameter 
Estimate 
95% CI 
1 
Kappa 
1.0000 
(1.0000, 1.0000) 
 
Uncorrected Agreement 
1.0000 
(0.5904, 1.0000) 
2 
Kappa 
0.5333 
(0.0596, 1.0000) 
 
Uncorrected Agreement 
0.7143 
(0.2904, 0.9633) 
3 
Kappa 
1.0000 
(1.0000, 1.0000) 
 
Uncorrected Agreement 
1.0000 
(0.5904, 1.0000) 
Source:  Data Table 10 
CI=Confidence Interval 
11.4.1.4 Pharmacokinetic Analysis 
The results of the PK assessment are presented in Section 16.1.11. 
11.4.2 Statistical and Analytical Summary 
11.4.2.1 Adjustments for Covariates 
Not applicable. 


 
 
 
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11.4.2.2 Handling of Dropouts or Missing Data 
In the statistical analysis of the primary effectiveness endpoints of the study, only subjects with 
evaluable endpoints were used in the statistical analyses (i.e., a complete case analysis). 
11.4.2.3 Interim Analysis and Data Monitoring 
No interim analysis was planned or performed for this study. 
11.4.2.4 Use of an “Efficacy Subject” of Subjects 
Not applicable. 
11.4.2.5 Examination of Subgroups 
No subgroup analyses were planned or performed. 
11.4.3 Drug Dose, Drug Concentration, and Relationship to Response 
All subjects in this study received the same intended dose of 64Cu-DOTATATE. Therefore, no 
drug-dose or drug-concentration response was expected. 
11.4.4 Drug-Drug and Drug-Disease Interactions 
There do not appear to be any drug-drug or drug-disease interactions related to the use of 64Cu-
DOTATATE in this study. 
11.4.5 By-Subject Displays 
Not applicable. 
11.4.6 Efficacy Conclusions 
• A total of 68 subjects were screened for this study. Of these, 66 were enrolled and 63 
(95.5%) completed the study. Three subjects (4.5%) withdrew consent. A total of 63 
subjects were injected with a mean dose of 4.11 mCi of 64Cu-DOTATATE. 
• Based on the individual reader analysis, all three readers demonstrated success on the co-
primary effectiveness endpoints with Sensitivity >70% and Specificity >60%. 
• The majority read analysis showed statistically significant sensitivity (0.9091, p=0.0042) 
and specificity (0.9655, p<0.0001) in detecting patients positive for disease and patients 
negative for disease, respectively. The probability of disease being present given a positive 
result with 64Cu-DOTATATE (PPV) was 0.9677. The probability of disease being absent 
given a negative result with 64Cu-DOTATATE (NPV) was 0.9032. In this study, the 
majority read analysis determined that imaging with 64Cu-DOTATATE had an accuracy 
of 0.9355. 
• The majority read analysis had a sensitivity of 1.000 and a specificity of 1.000 in 
distinguishing between localized or metastatic disease among patients imaged with 64Cu-
DOTATATE and having an image status of positive for disease. 
• All readers demonstrated a level of accuracy ranging from 0.8571 to 0.9355. Readers 1 and 
3 were more accurate in determining the presence or absence of disease relative to the SOT 


 
 
 
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than Reader 2. Reader 1 had a PPV of 0.9677, NPV of 0.9032, and accuracy of 0.9355; 
Reader 2 had a PPV of 0.8333, NPV of 0.8889, and accuracy of 0.8571; and Reader 3 had 
a PPV of 0.9091, NPV of 0.9000, and accuracy of 0.9048. 
• Overall, the 3 readers demonstrated a high degree of inter-reader agreement (Kappa = 
0.7664). 
• Relative to the 7 images that were re-read, Readers 1 and 3 demonstrated perfect intra-
reader agreement upon image re-read (Kappa = 1.000). 
• It can be concluded that 64Cu-DOTATATE is an effective imaging agent in detecting the 
presence or absence of a NET. 
 
 


 
 
 
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12 SAFETY EVALUATION 
12.1 EXTENT OF EXPOSURE 
All 63 subjects were injected with a single dose of  64Cu-DOTATATE. A mean (SD) dose of 
4.11 (0.17) mCi of 64Cu-DOTATATE was delivered. Doses ranged from 3.6 mCi to 4.4 mCi. 
Table 12.1-1 provides a summary of 64Cu-DOTATATE dose administration. 
A by-subject listing of drug administration is provided in Data Listing 14 and a by-subject listing 
of the PET imaging procedure is provided in Data Listing 15. 
Table 12.1-1: Summary of 64Cu-DOTATATE Dose Administration 
 
Mean 
SD 
n 
Min 
Max 
Median 
64Cu-DOTATATE Delivered (mCi) 
4.11 
0.17 
63 
3.6 
4.4 
4.13 
Mass dose of 64Cu-DOTATATE Delivered (mcg) 
17.48 
6.27 
63 
8.5 
38.3 
16.10 
Source:  Data Table 12 
12.2 ADVERSE EVENTS 
12.2.1 Display of Adverse Events 
Overall there were 9 adverse events experienced by 5 subjects. The most common adverse events 
were gastrointestinal disorders (4.8%), nervous system disorders (3.2%), vascular disorders 
(3.2%), and skin and subcutaneous tissue disorders (1.6%). 
The number and percentage of subjects with adverse events are summarized by preferred term 
and system organ class in Table 12.2.1-1. Adverse events summarized in this table include all 
events recorded in the Adverse Events CRF. For a complete list of events and other symptoms 
recorded in the database see Data Listing 7. 


 
 
 
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Table 12.2.1-1: Number and Percentage of Subjects with Adverse Events (Safety Population) 
Adverse Event Category 
Overall 
(N=63) 
Total Number of Adverse Events 
9 
Subjects with at Least One Adverse Event 
5 (7.9%) 
Gastrointestinal Disorders 
3 (4.8%) 
   Nausea 
1 (1.6%) 
   Vomiting 
2 (3.2%) 
Nervous System Disorders 
2 (3.2%) 
   Headache 
1 (1.6%) 
   Syncope 
1 (1.6%) 
Skin and Subcutaneous Tissue Disorders 
1 (1.6%) 
   Melanoderma 
1 (1.6%) 
Vascular Disorders 
2 (3.2%) 
   Flushing 
1 (1.6%) 
   Hypertension 
1 (1.6%) 
Source: Data Table 13 
 
 
12.2.2 Analysis of Adverse Events 
12.2.2.1 Adverse Events by Severity 
Adverse events by severity are presented in Data Table 14. A total of 4 subjects (6.3%) 
experienced 7 adverse events that were mild in severity and 2 subjects (3.2%) experienced 2 
adverse events that were moderate in severity. There were no adverse events that were severe, 
life-threatening or disabling, or that resulted in death. Adverse events that were mild in severity 
included nausea, vomiting, headache, melanoderma, and flushing. Adverse events that were 
moderate in severity included syncope and hypertension. 
12.2.2.2 Adverse Events by Relationship 
Adverse events by relationship to treatment are presented in Data Table 15. A total of 5 subjects 
(7.9%) experienced 8 adverse events that were determined to be probably not related to treatment 
with 64Cu-DOTATATE. These adverse events included nausea, vomiting, headache, syncope, 
melanoderma, and flushing. One subject (1.6%) experienced an adverse event of hypertension 
that was determined to be definitely not related to treatment with 64Cu-DOTATATE. 
12.2.3 Listing of Adverse Events by Subject 
A by-subject data listing of all AEs for the safety population is provided in Data Listing 7.  
12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT 
ADVERSE EVENTS 


 
 
 
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No deaths, other serious adverse events, or other significant adverse events occurred during the 
course of this study.  
12.4 CLINICAL LABORATORY EVALUATIONS 
There were no clinically significant changes from baseline in mean serum chemistry or 
hematology values that occurred post-injection with 64Cu-DOTATATE or at the Day 1-2 follow-
up visit. Of note, shift tables for creatinine presented a shift from a normal value at baseline to a 
high value at the Day 1-2 visit in 6 subjects (9.5%) (Data Table 30). Shift tables for glucose 
presented a shift from a normal value at baseline to a high value post-injection in 5 subjects 
(7.9%) and a shift from a normal value at baseline to a high value at the Day 1-2 visit in 13 
subjects (20.6%) (Data Table 31). Shift tables for sodium presented a shift from a normal value 
pre-injection to a low value post-injection in 9 subjects (14.3%) which had resolved by the Day 
1-2 visit (Data Table 34). 
A by-subject listing of serum chemistry and hematology laboratory profiles are provided in Data 
Listing 9 and Data Listing 10, respectively. 
12.5 VITAL SIGNS, PHYSICAL EXAMINATIONS, AND OTHER OBSERVATIONS 
RELATED TO SAFETY 
12.5.1 Vital Signs 
There were no clinically significant changes from baseline in mean vital signs occurring at 5-, 
10-, 30-, or 60- minutes post-injection or at discharge. Mean systolic blood pressure was elevated 
at all time points from pre-injection to discharge and fluctuated from a mean low of 130.48 
mmHg pre-injection to a mean high of 137.10 mmHg at 60 minutes post-injection. Upon 
discharge, the mean systolic blood pressure was 132.97 mmHg. 
A by-subject listing of vital signs is provided in Data Listing 8. 
12.5.2 Physical Examinations 
All physical exam findings were normal with the exception of 2 subjects. Subject GG-NET3-023 
had mild high blood pressure at screening and subject MS-NET3-044 had controlled 
hypertension at screening. 
A by-subject listing of physical exam findings is provided in Data Listing 13. 
12.5.3 ECG Parameters 
There were no shifts observed in ECG parameters from baseline to 1 hour post-injection of 64Cu-
DOTATATE. 
A summary of ECG shift is provided in Data Table 18.  
12.5.4 Concomitant Medications 
A by-subject listing of concomitant medications is provided in Data Listing 11. 
12.6 SAFETY CONCLUSIONS 


 
 
 
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The following conclusions can be drawn from the safety analyses: 
• 
Overall there were 9 adverse events experienced by 5 subjects. The most common adverse 
events by MedDRA system organ class were gastrointestinal disorders (4.8%), nervous 
system disorders (3.2%), vascular disorders (3.2%), and skin and subcutaneous disorders 
(1.6%). 
• 
All adverse events were either mild or moderate in severity. There were no adverse events 
that were severe, life-threatening or disabling, or that resulted in death. Adverse events that 
were mild in severity included nausea, vomiting, headache, melanoderma, and flushing. 
Adverse events that were moderate in severity included syncope and hypertension. 
• 
All adverse events were either probably not related or definitely not related to injection of 
a single dose of 64Cu-DOTATATE. No adverse events were considered definitely related, 
probably related, or possibly related to 64Cu-DOTATATE injection. 
• 
There were no serious adverse events reported in subjects injected with 64Cu-DOTATATE. 
• 
There were no clinically significant changes from baseline in mean serum chemistry or 
hematology values that occurred post-injection with 64Cu-DOTATATE or at the Day 1-2 
follow-up visit. 
• 
There were no clinically significant changes from baseline in mean vital signs occurring at 
5-, 10-, 30-, or 60- minutes post-injection or at discharge. 
• 
There were no shifts observed in ECG parameters from baseline to 1 hour post-injection of 
64Cu-DOTATATE. 
• 
Injection of a single dose of 64Cu-DOTATATE appears to be safe and well tolerated in this 
patient population. 
 
 


 
 
 
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13 DISCUSSION AND OVERALL CONCLUSIONS 
13.1 DISCUSSION 
The primary objective of this study was to assess the performance (sensitivity and specificity) of 
64Cu-DOTATATE PET-CT imaging in subjects with known or suspected NETs, when 
comparing individual reader results to a standard of truth for each subject. Success was defined 
as the same two out of three readers having sensitivity and specificity results exceeding the 
specified thresholds. All three readers demonstrated success on the co-primary effectiveness 
endpoints with individual sensitivity >70% and individual specificity >60%.  
Additionally, the study sought to characterize the predictive value of 64Cu-DOTATATE PET-CT 
imaging when comparing an imaging reader-majority rule determination to the SOT for each 
subject and also when the comparison was performed on an individual reader basis. The majority 
of readers showed statistically significant sensitivity (0.9091, p=0.0042) and specificity (0.9655, 
p<0.0001) in detecting patients positive for disease and patients negative for disease, 
respectively. The probability of disease being present given a positive result with 64Cu-
DOTATATE (PPV) was 0.9677. The probability of disease being absent given a negative result 
with 64Cu-DOTATATE (NPV) was 0.9032. In this study, the majority of readers determined that 
imaging with 64Cu-DOTATATE had an accuracy of 0.9355.  
In evaluating the imaging performance (sensitivity and specificity) of 64Cu-DOTATATE when 
comparing an imaging reader-majority rule determination to the SOT for each subject the 
majority of readers had a sensitivity of 1.000 and a specificity of 1.000 in determining localized 
or metastatic disease. Overall, the readers demonstrated a level of accuracy ranging from 0.8571 
to 0.9355. 
Furthermore, intra-reader and inter-reader agreement were evaluated. Overall, the three readers 
demonstrated a relatively high degree of inter-reader agreement (Kappa=0.7664). Readers 1 and 
3 demonstrated perfect intra-reader agreement (Kappa=1.0000). 
It is important to note that failures in detecting disease were retrospectively reviewed by the 
investigators after the database was locked. Upon review of these failures it was noted that three 
SOT image reads determined to be positive for disease by the oncologist were in fact negative 
for disease. Included in these miscalls were subjects 42, 43, and 51. Each of these subjects had 
their primary tumor resected prior to determining the SOT and as such should have had a SOT 
negative for disease. The oncologists have included a note-to-file, provided in Section 16.1.12, 
describing this error. Taking this into account Readers 1 & 3 and the Majority Read would have 
a sensitivity of 1.000, a specificity of 0.9688, PPV of 0.9677. NPV of 1.000, and accuracy of 
0.9839. Reader 2 would have a sensitivity of 1.000, specificity of 0.8182, PPV of 0.8333, NPV 
of 1.000, and accuracy of 0.9048. 
The safety of 64Cu-DOTATATE was measured by evaluating adverse events, vital signs, clinical 
laboratory parameters, and ECG recordings. There were 9 reported adverse events experienced 
by 5 subjects of which all were mild to moderate in severity and none were related to injection of 
64Cu-DOTATATE. There were no adverse events that were severe, life-threatening or disabling, 
or that resulted in death. Additionally, no serious adverse events were reported during the course 
of this study. There were no clinically significant changes from baseline in mean serum 
chemistry or hematology values that occurred post-injection of 64Cu-DOTATATE or at the Day 
1-2 follow-up visit nor were there clinically significant changes from baseline in mean vital signs 


 
 
 
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at 5-, 10-, 30-, or 60- minutes post-injection or at discharge. Furthermore, there were no observed 
shifts in ECG parameters from baseline to 1-hour post-injection of 64Cu-DOTATATE.  
Safety data from this study are consistent with safety data reported from the two prior clinical 
studies of 64Cu-DOTATATE. Subjects in the retrospective study were observed for adverse 
events. Upon conclusion of that study there were no adverse events or clinically detectable 
pharmacologic effects observed. Adverse events, vital signs, clinical laboratory parameters, and 
ECG recordings were collected in the dose ranging study. At the conclusion of that study there 
were no adverse events related to treatment with 64Cu-DOTATATE nor were there any safety 
concerns based upon ECG parameters, vital signs, or clinical laboratory values. 
This study demonstrates that 64Cu-DOTATATE appears to be an effective agent in detecting the 
presence or absence of a NET as well as for distinguishing between localized and metastatic 
disease. Injection of a single dose of 64Cu-DOTATATE appears to be safe and was well tolerated 
by study subjects. 
13.2 CONCLUSIONS 
The following conclusions were elicited from the results of this study: 
• 
64Cu-DOTATATE has both a high sensitivity and specificity in detecting patients with and 
without NETs, respectively. 
• 
64Cu-DOTATATE has a high sensitivity and specificity in determining localized or 
metastatic disease. 
• 
64Cu-DOTATATE PET-CT image reads have a high level of inter-reader and intra-reader 
agreement. 
• Imaging with 64Cu-DOTATATE appears to be safe, effective, and well tolerated. 


 
 
 
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14 TABLES AND FIGURES NOT INCLUDED IN THE TEXT (SOME REFERRED AS 
SOURCE) 
Table 1 
Subject Completion/Withdrawal 
Table 2 
Demographics and Baseline Data Summary Statistics – Continuous Variables 
Table 3 
Demographics and Baseline Data Summary Statistics – Categorical Variables 
Table 4 
Summary of Medical History Findings 
Table 5 
Summary of Individual Reader Results for 64Cu-DOTATATE PET Imaging Versus 
Standard Of Truth 
Table 6 
Majority Read Summary Statistics for 64Cu-DOTATATE PET Imaging Versus 
Standard Of Truth 
Table 7 
Individual Reader Summary Statistics for 64Cu-DOTATATE PET Imaging Versus 
Standard Of Truth, Secondary Endpoints 
Table 8 
Reader Classification of Localized and Metastatic Disease 
Table 9 
Majority Read Classification of Localized and Metastatic Disease 
Table 10 
Summary of Intra-reader Agreement of 64Cu-DOTATATE PET Imaging 
Table 11 
Summary of Inter-Reader Agreement for Assessment of 64Cu-DOTATATE Imaging 
Table 12 
Summary of 64Cu-DOTATATE Dose Administration 
Table 13 
Number and Percentage of Subjects with Adverse Events 
Table 14 
Number and Percentage of Subjects with Adverse Effects by Severity 
Table 15 
Number and Percentage of Subjects with Adverse Effects by Relation to Treatment 
Table 16 
Number and Percentage of Subjects with Serious Adverse Events 
Table 17 
Vital Signs Summary Statistics 
Table 18 
ECG Shift Summary Table 
Table 19 
Clinical Laboratory Parameters Summary Statistics – Serum Chemistry 
Table 20 
Clinical Laboratory Parameters Summary Statistics – Hematology 
Table 21 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Alanine 
Aminotransferase (ALT) 
Table 22 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Albumin (ALB) 
Table 23 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Alkaline Phosphatase 
(ALP) 
Table 24 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Aspartate 
Aminotransferase (AST) 
Table 25 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Blood Urea Nitrogen 
(BUN) 
Table 26 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – BUN/Creatinine 
Table 27 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Calcium (CA) 
Table 28 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Carbon Dioxide (CO2) 
Table 29 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Chloride (CL) 
Table 30 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Creatinine (CREAT) 
Table 31 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Glucose (GLUC) 
Table 32 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Potassium (K) 
Table 33 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Protein (PROT) 
Table 34 
Clinical Laboratory Parameter Shift Table– Serum Chemistry – Sodium (SODIUM) 
Table 35 
Clinical Laboratory Parameter Shift Tables– Serum Chemistry – Glomerular Filtration 
Rate 
Table 36 
Clinical Laboratory Parameter Shift Tables – Hematology – Basophils 
Table 37 
Clinical Laboratory Parameter Shift Tables – Hematology – Bilirubin 
Table 38 
Clinical Laboratory Parameter Shift Tables – Hematology – Eosinophils 


 
 
 
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Table 39 
Clinical Laboratory Parameter Shift Tables – Hematology – Erythrocyte Mean 
Corpuscular HGB Concentration 
Table 40 
Clinical Laboratory Parameter Shift Tables – Hematology – Erythrocyte Mean 
Corpuscular Hemoglobin 
Table 41 
Clinical Laboratory Parameter Shift Tables – Hematology – Erythrocyte Mean 
Corpuscular Volume 
Table 42 
Clinical Laboratory Parameter Shift Tables – Hematology – Erythrocytes 
Table 43 
Clinical Laboratory Parameter Shift Tables – Hematology – Erythrocyte Distribution 
Width 
Table 44 
Clinical Laboratory Parameter Shift Tables – Hematology – Hematocrit 
Table 45 
Clinical Laboratory Parameter Shift Tables – Hematology – Hemoglobin 
Table 46 
Clinical Laboratory Parameter Shift Tables – Hematology – Leukocytes 
Table 47 
Clinical Laboratory Parameter Shift Tables – Hematology – Lymphocytes 
Table 48 
Clinical Laboratory Parameter Shift Tables – Hematology – Monocytes 
Table 49 
Clinical Laboratory Parameter Shift Tables – Hematology – Neutrophils 
Table 50 
Clinical Laboratory Parameter Shift Tables – Hematology – Platelets 
 
 


 
 
 
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15 REFERENCE LIST 
1. de Jong M. et al. Comparison of (111)In-labeled somatostatin analogues for tumor 
scintigraphy and radionuclide therapy. Cancer Research 1998; 58: 437-441. 
2. Esser 
JP, 
Krenning 
EP, 
Teunissen 
JJM, 
et 
al. 
Comparison 
of 
[177Lu-
DOTA0,Tyr3]octreotate and [177Lu-DOTA0,Tyr3]octreotide: which peptide is preferable 
for PRRT? European Journal of Nuclear Medicine 2006; 33: 1346-1351. 
3. Fauci AB, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL, eds. 
Harrison’s Principles of Oncology, 14th Edition, New York, NY: McGraw-Hill, New York, 
NY; 1998. 
4. Görges R, Kahaly G, Müller-Brand J, Mäcke H, Roser HW, Bockisch A. Radionuclide-
labeled somatostatin analogues for diagnostic and therapeutic purposes in nonmedullary 
thyroid cancer. Thyroid 2001; 11: 47-659. 
5. Horton KM, Kamel I, Hofmann L, Fishman EK. Carcinoid tumors of the small bowel: a 
multitechnique imagining approach. Am J Roentgenol 2004; 182: 559-567. 
6. Hoyer D, Lubbert H, Bruns C. Molecular pharmacology of somatostatin receptors. Naunyn 
Schmeideberg’s Archives of Pharmacology 1994; 350: 441-453. 
7. Karashima T, Cai RZ, Schally AV. Effects of highly potent octapeptide analogs of 
somatostatin on growth hormone, insulin and glucagon release. Life Sci 1987; 41: 1011-
1019. 
8. Krenning EP. Et al. Somatostatin receptor: scintigraphy and radionuclide therapy. 
Digestion 1996; 57 (Suppl 1): 57-61. 
9. Kwekkeboom DJ et al. Treatment of subjects with gastro-entero-pancreatic (GEP) tumours 
with the novel radiolabeled somatostatin analogue [177Lu-DOTA(0), Tyr3]octreotate. 
European Journal of Nuclear Medicine and Molecular Imaging 2003; 30: 417-422. 
10. Lewis J, Lewis M, Cutler P, Srinivasan A, Schmidt M, Schwarz S, Morris M, Miller J, 
Anderson C. Radiotherapy and dosimetry of 64Cu-TETA-Tyr3-ocreotate in a somatostatin 
receptor-positive, tumor-bearing rat model. Clin Cancer Res. 1999; 5(11):3608-3616. 
11. Lewis J, Laforest R, Buettner T, Song SK, et al. Copper-64-diacetyl-bis(N4-
methylthiosemicarbazone): An agent for radiotherapy”. PNAS. 2001, 98 (3): 1206-1211. 
12. Pfeifer A, Knigge U, Mortensen J, Oturai P, et al. Clinical PET of Neuroendocrine Tumors 
Using 64Cu-DOTATATE: First-in-Humans Study. J Nucl Med. 2012, 53, 1207-1215. 
13. Pfeifer A, Knigge U, Binderup T, Mortensen J, et al. 64Cu-DOTATATE PET for 
Neuroendocrine Tumors: a Prospective Head-to-Head Comparison with 111In-DTPA-
octreotide in 112 Patients. J Nucl Med. 2015, 56, 847-854 
14. Raut CP, Kulke MH, Glickman JN, Swanson RS, Ashely SW. Carcinoid tumors. Curr 
Probl Surg 2006; 43: 383-450. 
15. Reubi JC et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of 
somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. European 
Journal of Nuclear Medicine 2000; 27: 273-282. 
16. Robertson RG, Geiger WJ, David NB. Carcinoid tumors. Am Fam Physician 2006; 74: 
429-434. 
17. Serri O, Brazeau P, Kachra Z. Octreotide inhibits insulin-like growth factor-I hepatic gene 
expression in hypophysectomized rat: evidence for a direct and indirect mechanism of 
action. Endocrinology 1992; 130: 1816-1821. 


 
 
 
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18. Stetter H, Frank W. Coplex Formation with tetraazacycloalkane-N,N’,N’’,N’’’-tetraacetic 
acids as a function of ring size. Angewandte Chemie International Edition in English 1976; 
15: 686-689. 
 
 
 


 
 
 
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16 APPENDICES 
16.1 STUDY INFORMATION 
16.1.1 Protocol 
The final protocol dated 15 October 2018 reflecting 2 amendments is attached. 
Original 
The original protocol was dated 05 June 2018, and was amended on the following dates: 
Amendments 
• Amendment 1: 05 October 2018  
• Amendment 2: 15 October 2018 


 
 
 
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16.1.2 Sample Case Report Forms (CRFs) 
A blank casebook of CRFs is attached. 
 


 
 
 
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16.1.3 Institutional Review Board and Subject Consent and Information 
16.1.3.1 Name and Address of Institutional Review Board 
Biomedical Research Alliance of New York 
1981 Marcus Avenue, Suite 210 
Lake Success, New York 11042 
16.1.3.2 Sample Informed Consent Form (ICF) 
The sample ICF approved by the IRB is attached. 
 


 
 
 
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16.1.4 Description of Investigators, Investigator CVs, and FDA 1572 
16.1.4.1 Investigators and Locations 
Principal Investigator and location for this study were as follows, for the 1 active site: 
Excel Diagnostics and Nuclear Oncology Center 
Principal Investigator:  Rodolfo Nunez, M.D. 
9701 Richmond Ave. 
Houston, TX 77042 
16.1.4.2 Curriculum Vitae of Principal Investigators and FDA 1572 
Curriculum vitae and FDA 1572 from the principal investigator named in Appendix 16.1.4.1 are 
attached. 


 
 
 
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16.1.5 Signature of Sponsor’s Responsible Officer or Medical Representative 
FINAL APPROVAL 
To the best of my knowledge, this clinical study report accurately describes the conduct and the 
results of this clinical study. 
 
  David Ranganathan, PhD 
  Senior Scientist 
RadioMedix, Inc. 
Signature  
 
Date 
 
 
  Ebrahim S. Delpassand, MD, FACNM 
  Chairman and CEO 
RadioMedix, Inc. 
Signature  
 
Date 
 


 
 
 
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16.1.6 Listing of Patients Receiving Test Drug(s)/Investigational Product(s) from Specific 
Batches, Where More Than One Batch Was Used 
A listing of batch numbers is attached. 


 
 
 
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16.1.7 Subject Randomization Scheme and Codes 
Not applicable. 


 
 
 
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16.1.8 Audit Certificates (if available) 
Not applicable. 


 
 
 
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16.1.9 Documentation of Statistical Methods 
The final SAP (Version 1.1; 07 November 2018) is attached. 


 
 
 
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16.1.10 Documentation of Inter laboratory Standardization Methods and Quality 
Assurance Procedures, if Used 
Documentation of laboratory QA methods is attached. 


 
 
 
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16.1.11 Pharmacokinetic Assessment Report 
The PK Assessment Report is attached. 
 
 


 
 
 
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16.1.12 Oncologist Note to File 
The Oncologist Note to File discussed in Section 13.1 is attached. 


 
 
 
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16.1.13 Clinical Laboratory and PET Imaging Deviations 
The listing of PET-CT image acquisition deviations is attached. 
The listing of clinical laboratory deviations is attached. 


 
 
 
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16.1.14 Publications Based on the Study 
Not applicable. 


 
 
 
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16.1.15 Important Publications Referenced in the Report 
Important publications referenced in the report are attached via the links in Section 15. 
 


 
 
 
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16.2 SUBJECT DATA LISTINGS 
Listing 1 
Subject Completion/Withdrawal 
Listing 2 
Inclusion Criteria Violations 
Listing 3 
Exclusion Criteria Violations 
Listing 4 
Subjects Excluded from Safety Population 
Listing 5 
Subjects Excluded from EE Population 
Listing 6 
Demographics 
Listing 7 
Adverse Events 
Listing 8 
Vital Signs 
Listing 9 
Subject Laboratory Profiles – Serum Chemistry 
Listing 10 
Subject Laboratory Profiles – Hematology 
Listing 11 
Concomitant Medications 
Listing 12 
Medical History 
Listing 13 
Physical Exam 
Listing 14 
Drug Administration 
Listing 15 
PET Imaging Procedure 
Listing 16 
Standard of Truth Data Listing 
Listing 17 
Central Radiology Data Listing 
Listing 18 
Efficacy Data Listing 


 
 
 
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16.3 CASE REPORT FORMS 
Completed CRFs for all screened subjects are attached. 


 
 
 
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16.4 INDIVIDUAL SUBJECT DATA LISTINGS 
Individual subject data listings were not generated for this study.  Subject-level data are 
presented in the subject data listings in Section 16.2 and contained in the final study database.   

SAP_001.pdf: 
 
 
 
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1 TITLE PAGE 
STUDY TITLE: 
An Open-label, Single-dose, Single-arm, Single-center Clinical Trial of 
64Cu-DOTATATE (NETMedix™) PET-CT Scan for Imaging Patients 
with Known or Suspected Somatostatin Receptor-positive Neuroendocrine 
Tumors (NETs) 
PROTOCOL NUMBER: 
NCT Number 
RMX-18-22 
NCT03673943 
STUDY PHASE: 
Phase 3 
IVESTIGATIONAL 
PRODUCT: 
NETMedix™ (64Cu-DOTATATE) injection, for intravenous use 
DRUG SUBSTANCE 
64Cu-DOTATATE 
STUDY DATES: 
January 22, 2018 to December 2, 2018 
INDICATION: 
Imaging of patients with known or suspected somatostatin receptor-
positive neuroendocrine tumors 
SPONSOR CONTACT 
INFORMATION: 
 
Ebrahim S. Delpassand, MD, FACNM 
RadioMedix, Inc. 
9701 Richmond Avenue, Suite 222 
Houston, TX 77042 
+1 (713) 358-6570 
REPORT DATE: 
March 6, 2019 
LEAD INVESTIGATOR: 
Rodolfo Nunez, M.D. 
GCP COMPLIANCE: 
The investigators agreed to conduct the study in compliance with the study 
protocol, the International Conference on Harmonisation (ICH) of 
Technical Requirements for Registration of Pharmaceuticals for Human 
Use guidance for industry entitled “E6 Good Clinical Practice (GCP): 
Consolidated Guidance”, the “Declaration of Helsinki: Ethical Principles 
for Research Involving Human Subjects” (World Medical Association), 
and applicable law and regulatory requirements. 
 


 
 
 
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2 SYNOPSIS 
Statistical Methods: 
Analysis Populations 
The following analysis populations were defined: 
Efficacy Evaluable (EE) Population – The EE population consisted of all subjects who were enrolled in the 
study (plus 4 subjects from the selected dose cohort of the Phase 1 study having the same radiation dose (4.0 
mCi) as used in this study), had an established SOT, were injected with 64Cu-DOTATATE, and had an image 
read result using 64Cu-DOTATATE by three independent readers.  
Safety Population – The safety population consisted of all subjects who were enrolled in the study and had 
been injected with 64Cu-DOTATATE. 
General Statistical Methodology 
A table was constructed with counts and percentages of the number of subjects who were screen failures, the number 
of subjects enrolled in the study, the number of subjects withdrawn from the study before study completion, and the 
number who completed the study. For those subjects who withdrew before completion of the study, counts and 
percentages of the reasons for withdrawal were tabulated.   
The continuous demographic characteristics at screening were summarized for all subjects in the safety population 
using descriptive statistics (mean, standard deviation, median, minimum, maximum, and number of non-missing 
observations). The categorical baseline characteristics were summarized for the safety population using frequency 
counts and percentages. 
The study was powered with respect to the co-primary endpoints of sensitivity and specificity.   
In order to have at least an 80% probability of showing that the sensitivity was at least 70% and the specificity was 
at least 60% a sample of n1 = 42 positive subjects and n2 = 21 negative subjects was necessary. This sample size 
was derived under the assumptions that (1) the readers were reading the same images and that their reads were 
correlated at r = 0.70; (2) exact binomial tests were used with an alpha level of 0.025 for the hypotheses 
Ha0: Sensitivity ≤ 70% vs Ha1: Sensitivity > 70% 
and 
Hb0: Specificity ≤ 60% vs Hb1: Specificity > 60% 
 (3) the actual sensitivity was 0.90; and, (4) the actual specificity was 0.90. In order to assure a power of at least 
0.80 for two tests together, the individual tests were powered at 0.90.  
The PK assessment was performed on 6 subjects as an exploratory study. 
Primary Efficacy Analysis 
The EE population was the primary analysis set for all effectiveness analyses. The co-primary effectiveness 
endpoints were computed as follows: 
sensitivity = (# true positive)/(# true positive + # false negative) 
specificity = (# true negative)/(# true negative + # false positive) 
Each hypothesis test was conducted at the one-sided α = 0.025 level of significance. Point estimates of sensitivity 
and specificity were calculated with a 95% confidence limits. Confidence limits for all binomial parameters 
(sensitivity, specificity, PPV, NPV and accuracy) were calculated using Wilson’s score method with continuity 
correction (the score method). 
The sensitivity and specificity were calculated on a by-reader basis. Success upon the primary endpoints was 
declared if two of the three independent readers achieved sensitivity and specificity results in excess of the 
thresholds designated above. That is, the same two out of three readers must have achieved success upon sensitivity 
and specificity. 
Safety Analysis 
The safety population was used for the analysis of all safety variables and baseline characteristics. Prior to analysis, 
all AEs were coded using the MedDRA coding dictionary. Based on these coded terms, TEAEs were summarized 
using system organ class and preferred terms, as well as by relationship to 64Cu-DOTATATE. All AEs were listed, 
regardless of whether or not they were study treatment related. 


 
 
 
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Vital signs were summarized using descriptive statistics (mean, standard deviation, median, minimum, maximum, 
and number of non-missing observations) by time point. Changes from baseline were also summarized by post-dose 
time point. 
Clinical laboratory parameters were summarized using descriptive statistics (mean, standard deviation, median, 
minimum, maximum, and number of non-missing observations) by time point. Changes from baseline were also 
summarized by post-dose time point.  In addition, a shift table was constructed to show the shifts in laboratory 
results by parameter relative to the normal ranges. The number and percentage of subjects with the following shifts 
was presented: normal/normal, normal/low, normal/high, low/low, low/normal, low/high, high/low, high/normal, 
and high/high. 
A shift table was constructed to show the shifts in ECG interpretations between the pre-dose recording and the post-
dose recoding. The number and percentage of subjects with the following shifts were presented: normal/normal, 
normal/abnormal, abnormal/normal, and abnormal/abnormal. 
Pharmacokinetic Analysis 
Analysis of the PK data are provided in a separate PK report, included in Appendix 16.1.11 of this report. 
DISCUSSION AND OVERALL CONCLUSIONS 
13.1 DISCUSSION 
The primary objective of this study was to assess the performance (sensitivity and specificity) of 
64Cu-DOTATATE PET-CT imaging in subjects with known or suspected NETs, when 
comparing individual reader results to a standard of truth for each subject. Success was defined 
as the same two out of three readers having sensitivity and specificity results exceeding the 
specified thresholds. All three readers demonstrated success on the co-primary effectiveness 
endpoints with individual sensitivity >70% and individual specificity >60%.  
Additionally, the study sought to characterize the predictive value of 64Cu-DOTATATE PET-CT 
imaging when comparing an imaging reader-majority rule determination to the SOT for each 
subject and also when the comparison was performed on an individual reader basis. The majority 
of readers showed statistically significant sensitivity (0.9091, p=0.0042) and specificity (0.9655, 
p<0.0001) in detecting patients positive for disease and patients negative for disease, 
respectively. The probability of disease being present given a positive result with 64Cu-
DOTATATE (PPV) was 0.9677. The probability of disease being absent given a negative result 
with 64Cu-DOTATATE (NPV) was 0.9032. In this study, the majority of readers determined that 
imaging with 64Cu-DOTATATE had an accuracy of 0.9355.  
In evaluating the imaging performance (sensitivity and specificity) of 64Cu-DOTATATE when 
comparing an imaging reader-majority rule determination to the SOT for each subject the 
majority of readers had a sensitivity of 1.000 and a specificity of 1.000 in determining localized 
or metastatic disease. Overall, the readers demonstrated a level of accuracy ranging from 0.8571 
to 0.9355. 
Furthermore, intra-reader and inter-reader agreement were evaluated. Overall, the three readers 
demonstrated a relatively high degree of inter-reader agreement (Kappa=0.7664). Readers 1 and 
3 demonstrated perfect intra-reader agreement (Kappa=1.0000). 
It is important to note that failures in detecting disease were retrospectively reviewed by the 
investigators after the database was locked. Upon review of these failures it was noted that three 
SOT image reads determined to be positive for disease by the oncologist were in fact negative 
for disease. Included in these miscalls were subjects 42, 43, and 51. Each of these subjects had 
their primary tumor resected prior to determining the SOT and as such should have had a SOT 


 
 
 
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negative for disease. The oncologists have included a note-to-file, provided in Section 16.1.12, 
describing this error. Taking this into account Readers 1 & 3 and the Majority Read would have 
a sensitivity of 1.000, a specificity of 0.9688, PPV of 0.9677. NPV of 1.000, and accuracy of 
0.9839. Reader 2 would have a sensitivity of 1.000, specificity of 0.8182, PPV of 0.8333, NPV 
of 1.000, and accuracy of 0.9048. 
The safety of 64Cu-DOTATATE was measured by evaluating adverse events, vital signs, clinical 
laboratory parameters, and ECG recordings. There were 9 reported adverse events experienced 
by 5 subjects of which all were mild to moderate in severity and none were related to injection of 
64Cu-DOTATATE. There were no adverse events that were severe, life-threatening or disabling, 
or that resulted in death. Additionally, no serious adverse events were reported during the course 
of this study. There were no clinically significant changes from baseline in mean serum 
chemistry or hematology values that occurred post-injection of 64Cu-DOTATATE or at the Day 
1-2 follow-up visit nor were there clinically significant changes from baseline in mean vital signs 
at 5-, 10-, 30-, or 60- minutes post-injection or at discharge. Furthermore, there were no observed 
shifts in ECG parameters from baseline to 1-hour post-injection of 64Cu-DOTATATE.  
Safety data from this study are consistent with safety data reported from the two prior clinical 
studies of 64Cu-DOTATATE. Subjects in the retrospective study were observed for adverse 
events. Upon conclusion of that study there were no adverse events or clinically detectable 
pharmacologic effects observed. Adverse events, vital signs, clinical laboratory parameters, and 
ECG recordings were collected in the dose ranging study. At the conclusion of that study there 
were no adverse events related to treatment with 64Cu-DOTATATE nor were there any safety 
concerns based upon ECG parameters, vital signs, or clinical laboratory values. 
This study demonstrates that 64Cu-DOTATATE appears to be an effective agent in detecting the 
presence or absence of a NET as well as for distinguishing between localized and metastatic 
disease. Injection of a single dose of 64Cu-DOTATATE appears to be safe and was well tolerated 
by study subjects. 
13.2 CONCLUSIONS 
The following conclusions were elicited from the results of this study: 
• 
64Cu-DOTATATE has both a high sensitivity and specificity in detecting patients with and 
without NETs, respectively. 
• 
64Cu-DOTATATE has a high sensitivity and specificity in determining localized or 
metastatic disease. 
• 
64Cu-DOTATATE PET-CT image reads have a high level of inter-reader and intra-reader 
agreement. 
• Imaging with 64Cu-DOTATATE appears to be safe, effective, and well tolerated.