Clinical trial NCT04947137
Conditions: Rheumatoid Arthritis
Keywords: RA Healthy control Tilmanocept
Sponsor: Navidea Biopharmaceuticals
Start date: 2021-05-27; Completion date: 2022-01-21
Enrollment: 134 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will establish a normative database of Tilmanocept Uptake Values (TUVjoint) in healthy controls age-matched to the RA population.

Detailed description:
This is a prospective, open-label, multicenter, single-dose study designed to develop a normative database of TUVjoint in HCs and to assess the feasibility of qualitative and quantitative SPECT/CT assessments in HCs and subjects with active RA.

This study is stratified into 2 arms. Arm 1 is comprised of HCs and Arm 2 is comprised of HCs and clinically diagnosed RA subjects on stable treatment.

Arms: arm 1: The first arm will be comprised of HCs who are deemed to be clinically free of inflammatory diseases, arthropathies, and/or arthroplasties and clinically free of joint pain for at least 28 days prior to the consent date. arm 2: The second arm is comprised of \[1\] disease-free HCs and \[2\] clinically diagnosed RA subjects on stable treatment.
Interventions: intervention 1: Tc99m tilmanocept
Intervention descriptions: intervention 1: Tilmanocept is a radiotracer that accumulates in macrophages by binding to a mannose binding receptor that resides on the surface.

Protocol documents:
Prot_000.pdf: 
 
 
Clinical Trial Protocol: NAV3-35 
Study Title: 
Development of a Normative Database for Rheumatoid Arthritis 
(RA) Imaging with Tc 99m Tilmanocept  
Study Number: 
NAV3-35 
Study Phase: 
Phase 2b 
Product Name: 
Technetium Tc 99m tilmanocept 
IND Number: 
132943 
Investigators: 
Multicenter 
Sponsor: 
Navidea Biopharmaceuticals, Inc. 
4995 Bradenton Ave., Suite 240 
Dublin, OH 43017 
Sponsor 
Contact: 
Rachael Hershey, MS, CCRP 
Clinical Research Project Manager 
(614) 822-2329 
Medical 
Monitor: 
Michael Blue, MD, FACEP 
Senior Medical Director 
(614) 571-4313 
 
 
Date 
Original Protocol: 
17 March 2021 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document and its contents are the property of and confidential to Navidea 
Biopharmaceuticals. Any unauthorized copying or use of this document is prohibited.  


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SYNOPSIS 
Study Title: 
Development of a Normative Database for Rheumatoid Arthritis (RA) Imaging with Tc 
99m Tilmanocept   
Study Number: 
NAV3-35 
Study Phase: Phase 2b 
Primary Objective(s):  
• To establish mean and variance of joint-specific Tilmanocept Uptake Value 
(TUVjoint) in healthy controls (HCs) age-matched to RA population.  
• To assess the feasibility of detecting Tc 99m tilmanocept anatomic localization 
using single photon emission computed tomography/computed tomography 
(SPECT/CT) imaging of hands and wrists in HCs and subjects with active RA.   
Secondary Objective(s): 
• To quantitate Tc 99m tilmanocept anatomic localization based on SPECT/CT 
imaging of hands and wrists in HCs and joints with RA-involved inflammation. 
Safety Objective:  
• To evaluate safety through the examination of adverse event (AE) incidence and 
changes over time in laboratory tests, vital signs, and physical examination 
findings. 


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Inclusion Criteria:   
ALL SUBJECTS 
1. The subject has provided written informed consent with HIPAA (Health 
Information Portability and Accountability Act) authorization before the 
initiation of any study-related procedures. 
2. The subject has agreed to not engage in any diet, lifestyle, or medication changes 
until study completion.  
 
HEALTHY CONTROL SUBJECTS  
3. The subject is 30 years of age or greater at the time of consent. 
4. The subject is deemed to be clinically free of any inflammatory disease(s), auto-
immune disease(s), or arthropathies and has not experienced joint pain for at 
least 28 days prior to the consent date. 
5. The subject is not currently on anti-inflammatory drugs (including non-steroidal 
anti-inflammatory drugs [NSAIDs]) and has not taken any anti-inflammatories 
for at least 28 days prior to the consent date.  
6. For all ongoing concomitant medications, the subject has maintained a stable 
dose for at least 28 days prior to the consent date. 
 
RA SUBJECTS 
3. The subject is at least 18 years of age and was ≥ 18 years of age at the time of 
RA diagnosis. 
4. The subject has moderate to severe RA as determined by the 2010 American 
College of Rheumatology/European League Against Rheumatism 
(ACR/EULAR) Classification Criteria (score of ≥ 6/10). 
5. The subject has a 28-joint disease activity score (DAS28) of ≥ 3.2 (includes the 
Erythrocyte Sedimentation Rate [ESR] test and Visual Analog Scale [VAS]). 
6. Subjects receiving traditional DMARDs must have been on therapy for ≥ 90 
days and at a stable dose for ≥ 30 days prior to the imaging visit (Day 0). 
7. If the subject is receiving bDMARD or janus kinase (JAK) inhibitor therapy, 
they have been at a stable dose > 60 days prior to the imaging visit (Day 0).  
8. If the subject is receiving NSAIDs or oral corticosteroids, the dose has been 
stable for ≥ 28 days prior to the imaging visit (Day 0). The corticosteroid dose 
must be ≤ 10 mg/day of prednisone or an equivalent steroid dose. 
 
Exclusion Criteria:  
1. The subject is pregnant or lactating.  
2. The subject size or weight is not compatible with imaging per the investigator. 
3. The subject is currently receiving radiation therapy or chemotherapy or has 
received radiation therapy or chemotherapy in the past six months. 
4. The subject has had a finger, hand, and/or wrist amputation or hand or wrist joint 
arthroplasty.  
5. The subject has renal insufficiency as demonstrated by a glomerular filtration rate 
of < 60 mL/min. 


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6. The subject has hepatic insufficiency as demonstrated by ALT (alanine 
aminotransferase [SGPT]) or AST (aspartate aminotransferase [SGOT]) greater 
than 2 times the upper limit of normal. 
7. The subject has any severe, acute, or chronic medical conditions and/or psychiatric 
conditions and/or laboratory abnormalities that would impart, in the judgment of 
the investigator, excess risk associated with study participation or study drug 
administration that would deem the subject inappropriate for study participation or 
compromise the safety of the subject or the quality of the data. 
8. The subject has any unstable medical illnesses, including hepatic, renal, 
gastroenterologic, cardiovascular (including ischemic heart disease), 
endocrinologic, neurologic, immunologic, or hematologic disease. 
9. The subject has a known allergy to or has had an adverse reaction to dextran 
exposure. 
10. The subject has received an investigational product within 30 days prior to Tc 99m 
tilmanocept administration (Day 0). 
11. The subject has received intra-articular corticosteroid injections ≤ 8 weeks prior to 
Tc 99m tilmanocept administration (Day 0). 
12. The subject has received any radiopharmaceutical within 7 days or 10 half-lives 
prior to Tc 99m tilmanocept administration (Day 0). 
13. Healthy Controls only: The subject has a positive rheumatoid factor and an 
elevated ESR or CRP. 
 
Study Design: 
This is a prospective, open-label, multicenter, single-dose study designed to develop a 
normative database of TUVjoint in HCs and to assess the feasibility of qualitative and 
quantitative SPECT/CT assessments in HCs and subjects with active RA following Tc 
99m tilmanocept administration. 
Tilmanocept Uptake Value (TUV) is a quantitative imaging metric used to characterize 
Tc 99m tilmanocept uptake on planar imaging. Results from prior Phase 1 and 2 
studies have demonstrated that TUV is a sensitive and specific predictor of visually 
interrogated Tc 99m tilmanocept localization in joint regions with presumed 
inflammatory macrophage activity. A per-joint TUV (TUVjoint) relative ratio will be 
calculated for the each of the 22 DAS-28 joints located in the hands and wrists. A 
subject-level global TUV (TUVglobal) assessed across the 22 joints will be used as an 
indication of overall disease burden. TUV metrics are further described in the NAV3-
35 Statistical Analysis Plan. 
This study is stratified into 2 arms. Arm 1 is comprised of 120 HCs, and Arm 2 is 
comprised of 5 HCs and 10 clinically diagnosed RA subjects on stable treatment.  


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Rationale for Sample Size: 
The study will enroll up to 135 evaluable subjects in Arms 1 and 2 allocated below, 
imaged at up to 8 study centers. Arm 1 will have N = 120 evaluable HC subjects, Arm 2 
will have N = 15 (5 HCs and 10 RA) evaluable subjects. A subject is considered 
evaluable if he/she meets the criteria for the analysis population and has the data 
necessary for computing the primary endpoint. 
The sample size for Arm 1 was determined to provide acceptable precision for the 
estimated 5 and 95 percentiles. These percentiles will be estimated with 95% 
nonparametric confidence intervals. Although the standard error formula for quantile 
estimators is known and quantile estimators obey a central limit theorem, relying on the 
asymptotic Normal distribution seems imprudent. 
The sample will be stratified 3:1, females males to reflect RA incidence in the United 
States. The sex-specific samples will be further stratified by age to reflect the Census 
estimated US population in 2019. The target sample sizes are given below. 
Age Range 
Male 
Female 
Total 
30 to 39 years 
8 
23 
31 
40 to 49 years 
7 
21 
28 
50 to 59 years 
8 
22 
30 
60 to 69 years 
7 
21 
28 
70 years and oldera 
6 
21 
27 
Total 
36 
108 
144 
a An effort will be made to target enrollment in this group to include 2 men and 8 women 80 years old and 
over.  
The existing data for HC subjects was used in a bootstrap procedure to evaluate the width 
of 95% confidence intervals for the 95 percentiles for various sample sizes. The sponsor 
has decided for its business purposes that knowing the percentile to within 0.05 of its 
true value is sufficient. A sample of size N = 144 HC results (this includes the subjects 
from Arm 1 of NAV3-31) in 95% confidence intervals with half-widths less than 0.05. 
The sample size for Arm 2 was determined to be sufficient for the business purposes of 
the sponsor. The sample size for Arm 2 will be 5 HCs and 10 RA subjects.  


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Efficacy 
Assessments: 
Primary Endpoint(s) 
ARM 1 
• The normal limits of TUVjoint (on a per joint basis) in HC subjects, which are 
defined as the 5 and 95 percentiles of TUVjoint of bilateral joints (i.e., bilateral 
wrists, metacarpophalangeal joint [MCPs], proximal interphalangeal [PIPs]). 
The normal range will be determined separately for each of the three blinded 
readers. 
 
ARM 2  
• The qualitative evaluations of SPECT/CT in detecting localization within 
synovial spaces of the bilateral hands and wrists in HCs and RA subjects. 
 
Secondary Endpoints 
ARM 1 
• Applicability of the Normal (Gaussian) distribution to TUVjoint data. 
 
 
ARM 2  
• Quantitative evaluations of Tc 99m tilmanocept localization from SPECT/CT 
within synovial spaces of the bilateral hands and wrists in HCs and RA 
subjects. 
• Normative joint-specific standardized uptake value (SUV). 
 
• Predictive value of planar scans for SPECT/CT scans. 
 
Statistical Methods: 
Primary Endpoint Arm 1 
The distribution of TUVjoint in HC subjects will be summarized with descriptive 
statistics: mean, standard deviation, n, minimum, maximum, and median per reader, 
joint, and view. The 5 and 95 percentiles will be estimated with quantile regression fitting 
an intercept as a fixed term. The lower and upper limits of normal TUVjoint will be 
determined using non-parametric confidence intervals and kernel density-based 
confidence intervals. 
Primary Endpoint Arm 2 
Localization of tilmanocept in the hands and wrists will be summarized with frequency 
counts and percentages by reader and joint. 


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Secondary Endpoint Arm 1 
Normal quantile plots will be provided per joint and reader, along with the p-value for 
the Shapiro-Wilk test of Normality.  
Secondary Endpoints Arm 2 
SUV will be calculated and summarized on both a per-joint and a total of all joints with 
summary statistics: mean, standard deviation, n, minimum, maximum, and median. 
The predictive value of planar scans for SPECT/CT qualitative findings will be 
summarized per joint and reader with a crosstabulation and the uncertainty coefficients 
for row | column, column | row, and symmetric. The planar result will be deemed 
“positive” (i.e., inflamed) if TUVjoint > 95 percentile of the reader results for the same 
joint in Arm 1. Otherwise, the planar result will be deemed “negative”. 
Additional statistical methods are described in Section 9.5 and in the NAV3-35 
Statistical Analysis Plan.  
Date of Original Approved Protocol: 17 March 2021 
 
 
 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
Primary Endpoint Arm 1 ..........................................................................................6 
Primary Endpoint Arm 2 ..........................................................................................6 
Secondary Endpoint Arm 1 ......................................................................................7 
Secondary Endpoints Arm 2.....................................................................................7 
LIST OF IN-TEXT TABLES ..................................................................................................12 
LIST OF IN-TEXT FIGURES.................................................................................................13 
LIST OF APPENDICES ..........................................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................15 
1 
INTRODUCTION ...........................................................................................................18 
1.1 
Background ............................................................................................................18 
1.2 
Previous Nonclinical Research and Clinical Trial Experience in Tc 99m 
Tilmanocept ...........................................................................................................23 
1.2.1 
Nonclinical Evaluations –Subcutaneous Administration.............................23 
1.2.2 
Nonclinical Evaluations – IV Administration..............................................23 
1.2.3 
Clinical Pharmacokinetics (IV)....................................................................25 
1.2.4 
Clinical Efficacy ..........................................................................................26 
1.2.4.1 
NAV3-23 (SC) ...................................................................................26 
1.2.4.2 
NAV3-21 (IV) ....................................................................................27 
1.2.4.3 
NAV3-31 (IV) ....................................................................................27 
1.2.5 
Clinical Safety ..............................................................................................28 
1.2.5.1 
NAV3-23 (SC) ...................................................................................28 
1.2.5.2 
NAV3-21 (IV) ....................................................................................28 
1.2.5.3 
NAV3-31 (IV) ....................................................................................28 
2 
STUDY OBJECTIVES ....................................................................................................29 
2.1 
Primary Objective(s) ..............................................................................................29 
2.2 
Secondary Objective(s) ..........................................................................................29 
2.3 
Safety Objective(s).................................................................................................29 
3 
INVESTIGATIONAL PLAN ..........................................................................................30 
3.1 
Overall Study Design and Plan ..............................................................................30 
3.1.1 
Arm 1: No Inflammatory and/or Joint Disease (HC Subjects) ....................30 
3.1.1.1 
Description of Patient Population ......................................................30 
3.1.1.2 
Overview of Study Procedures ..........................................................30 
3.1.1.3 
Justification for Population ................................................................30 
3.1.2 
Arm 2: HCs and RA Subjects on Stable Anti-Rheumatic Therapy .............31 
3.1.2.1 
Description of Patient Population ......................................................31 
3.1.2.2 
Overview of Study Procedures ..........................................................31 
3.1.2.3 
Justification for Population ................................................................31 
3.2 
Protocol Adherence ................................................................................................32 


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3.3 
Study Duration(s) ...................................................................................................32 
4 
STUDY POPULATION ..................................................................................................33 
4.1 
Study Arms ............................................................................................................33 
4.2 
Eligibility ...............................................................................................................33 
4.2.1 
Inclusion Criteria .........................................................................................33 
4.2.2 
Exclusion Criteria ........................................................................................34 
4.3 
Recruitment ............................................................................................................35 
4.4 
Withdrawal .............................................................................................................35 
4.5 
Replacement ...........................................................................................................36 
4.6 
Screen Failures .......................................................................................................36 
4.7 
Subject Identification .............................................................................................36 
5 
INVESTIGATIONAL PRODUCT ..................................................................................37 
5.1 
Description of Investigational Project ...................................................................37 
5.2 
Investigational Product Dosage and Administration .............................................37 
5.3 
Timing and Frequency of Drug Administration ....................................................38 
5.4 
Packaging and Labeling .........................................................................................38 
5.5 
Drug Logistics and Investigational Product Accountability ..................................38 
6 
THERAPIES OTHER THAN INVESTIGATIONAL PRODUCT .................................39 
6.1 
Prior and Concomitant Therapies ..........................................................................39 
6.2 
Post-Study Therapy ................................................................................................39 
7 
STUDY PROCEDURES .................................................................................................40 
7.1 
Schedule of Evaluations .........................................................................................40 
7.1.1 
Arm 1 ...........................................................................................................40 
7.1.2 
Arm 2 ...........................................................................................................42 
8 
PROCEDURES AND VARIABLES ..............................................................................44 
8.1 
Population Characteristics .....................................................................................44 
8.1.1 
Demographics and Other Baseline Characteristics ......................................44 
8.1.2 
Medical, Rheumatological, and Surgical History ........................................44 
8.1.3 
Prior and Concomitant Medication ..............................................................44 
8.2 
Tc 99m Tilmanocept Administration .....................................................................44 
8.3 
Rheumatological Assessments ...............................................................................44 
8.3.1 
2010 ACR/EULAR Classification Criteria ..................................................44 
8.3.2 
DAS28..........................................................................................................45 
8.3.3 
Other ............................................................................................................45 
8.3.3.1 
28-joint Count (SJC and TJC)............................................................45 
8.3.3.2 
Patient Assessment of Pain (VAS) ....................................................45 
8.3.3.3 
Acute-phase Reactant.........................................................................45 
8.4 
Imaging ..................................................................................................................46 


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8.4.1 
Image Acquisition ........................................................................................46 
8.4.1.1 
Planar Scintigraphy ............................................................................46 
8.4.1.2 
SPECT/CT .........................................................................................46 
8.4.2 
Tilmanocept Uptake Value (TUV) ..............................................................46 
8.5 
Adverse Events ......................................................................................................46 
8.5.1 
Definition of Adverse Event ........................................................................46 
8.5.2 
Categories for Adverse Event Assessment ..................................................47 
8.5.3 
Assessments and Documentation of Adverse Events ..................................48 
8.5.4 
Expected Adverse Events ............................................................................49 
8.5.5 
Serious Adverse Events ...............................................................................50 
8.6 
Physical Examination.............................................................................................51 
8.7 
Vital Signs ..............................................................................................................52 
8.8 
Clinical Laboratory Parameters .............................................................................52 
9 
STATISTICAL METHODS ............................................................................................54 
9.1 
Randomization Methods ........................................................................................54 
9.2 
Safety Variables .....................................................................................................54 
9.3 
Efficacy Variables ..................................................................................................54 
9.4 
Sample Size Justification .......................................................................................55 
9.5 
Statistical Analyses ................................................................................................56 
9.5.1 
Analysis Populations ....................................................................................56 
9.5.2 
Analysis of Baseline and Demographic Characteristics ..............................56 
9.5.3 
Analysis of Efficacy Variables ....................................................................57 
9.5.3.1 
Primary Endpoint Arm 1 ....................................................................57 
9.5.3.2 
Primary Endpoint Arm 2 ....................................................................57 
9.5.3.3 
Secondary Endpoint Arm 1 ................................................................57 
9.5.3.4 
Secondary Endpoints Arm 2 ..............................................................57 
9.5.4 
Analysis of Safety Variables ........................................................................57 
9.5.5 
Handling of Missing Values ........................................................................58 
9.5.6 
Interim Analyses ..........................................................................................58 
10 DATA HANDLING AND QUALITY ASSURANCE ...................................................59 
10.1 
Data Recording ......................................................................................................59 
10.1.1 
CRF Design ..................................................................................................59 
10.2 
Monitoring .............................................................................................................59 
10.3 
Data Processing ......................................................................................................59 
10.4 
Auditing .................................................................................................................59 
10.5 
Archiving ...............................................................................................................60 
10.6 
Premature Termination of the Study ......................................................................60 
10.6.1 
Termination by the Sponsor .........................................................................60 
10.6.2 
Termination by the Investigator ...................................................................60 


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10.6.3 
Study as a Whole .........................................................................................61 
10.6.4 
Center ...........................................................................................................61 
10.6.5 
Study Participant ..........................................................................................61 
11 ETHICAL AND LEGAL ASPECTS...............................................................................62 
11.1 
Ethical and Legal Conduct of the Study ................................................................62 
11.2 
Subject Information and Consent...........................................................................62 
11.3 
Financing/Financial Disclosure .............................................................................63 
11.4 
Publication Policy ..................................................................................................63 
11.5 
Subject Injury .........................................................................................................63 
12 REFERENCES ................................................................................................................64 
 


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LIST OF IN-TEXT TABLES 
Table 1  
Preclinical Tests .........................................................................................24 
Table 2  
Whole Blood PK Parameter Summaries by Group....................................25 
Table 3  
Urine PK Parameter Summaries by Group ................................................26 
Table 4  
Study Arms ................................................................................................30 
Table 5  
Inclusion Criteria Treatment Windows for Recent or Concomitant RA-
specific Treatments ....................................................................................31 
Table 6  
Study Arms ................................................................................................33 
Table 7  
Clinical Laboratory Parameters .................................................................52 
Table 8  
Approximate Amount of Blood Drawn .....................................................53 


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LIST OF IN-TEXT FIGURES 
Figure 1  
Tc 99m tilmanocept and the Mannose Receptor........................................37 
 


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LIST OF APPENDICES 
Appendix 1 
Schedule of Events .....................................................................................69 
Appendix 2 
2010 ACR/EULAR Criteria .......................................................................70 
Appendix 3 
DAS28 Scoring ..........................................................................................72 
Appendix 4 
Sponsor Signatures.....................................................................................73 
Appendix 5 
Investigator’s Signature .............................................................................74 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACPA 
Anti-Citrullinated Peptide Antibody 
ACR 
American College of Rheumatology 
ACR12/24w 
American College of Rheumatology response criteria at 12 ± 1 weeks / 
24 ± 1 weeks of newly initiated bDMARD therapy and baseline 
ACR20/50/70 
American College of Rheumatology response criteria 
ACR/EULAR 
American College of Rheumatology/European League Against 
Rheumatism 
AE 
Adverse event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
bDMARD 
Biological disease-modifying antirheumatic drug 
BMI 
Body Mass Index 
CD206 
Mannose-binding receptor (Ca2+-binding lectin) 
CDAI 
Clinical disease activity index 
CFB 
Change from baseline 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CV 
Coefficient of variation 
DAS28 
Disease activity score -28 for RA describing the severity of RA using 
clinical and laboratory data. 
DMARD 
Disease-modifying antirheumatic drug 
DTPA 
Diethylenetriaminepentaacetic Acid 
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
ESR 
Erythrocyte Sedimentation Rate 
GCP 
Good Clinical Practice 
HC 
Healthy control 


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ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
ITD 
Intent to Diagnose 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
MCP 
Metacarpophalangeal joint  
NSAID 
Non-steroidal anti-inflammatory drug 
PIP 
Proximal Interphalangeal 
PK 
Pharmacokinetics 
PP 
Per Protocol 
QT 
Interval from the Q wave to the end of the T wave 
QTc 
Corrected QT Interval 
RA 
Rheumatoid arthritis 
RF 
Rheumatoid Factor 
RMSD 
Root mean square difference 
ROC 
Receiver Operating Characteristic 
ROI 
Region of interest 
RR 
Reference region 
RSNA 
Radiological Society of North America 
SAP 
Statistical Analysis Plan 
SJC 
Swollen joint count 
SC 
Sulfur Colloid 
SOC 
System Organ Class 
SPECT 
Single-Photon Emission Computerized Tomography 
SPECT/CT 
Combined Single-Photon Emission Computerized Tomography and 
computed tomography 
SUV 
Standardized Uptake Value 
TJC 
Tender joint count 


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TMF 
Trial Master File 
TNFα 
Tumor necrosis factor alpha 
TUV 
Tilmanocept Uptake Value 
TUVglobal 
Global Tilmanocept Uptake Value 
TUVjoint 
Joint-specific Tilmanocept Uptake Value 
UC 
Uncertainty Coefficient 
ULN 
Upper limit of normal 
VAS 
Visual Analog Scale 
WB  
Whole body 


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1 
INTRODUCTION 
1.1 
Background 
Worldwide, approximately 1 in 200 adults suffer from RA. In the US, 1.3 million adults are 
living with RA. Each year, about 130,000 Americans are newly diagnosed with RA. Persons 
with inadequately controlled RA have significantly shorter life expectancies and frequently 
become disabled, leading to reduced quality of life and severe adverse economic consequences 
[1-4]. 
It has been realized for many years that RA patients who are placed on DMARDs soon after 
they develop arthritis symptoms respond much more favorably to these therapies than do 
patients whose initiation of DMARD therapy is delayed [5]. Many more of these early RA 
patients placed on therapy achieve disease remission than is observed in RA patients who do 
not initiate DMARD therapy until after they have been symptomatic for RA for 6 or more 
months. Furthermore, those early RA patients placed on timely therapy who do not achieve 
remission experience less severe disease [6-8]. Indeed, the early diagnosis of RA affords a 
“window of opportunity” for the greatest probability of effective RA therapy and the possibility 
of disease remission [9]. This window closes 3 to 6 months after patients become symptomatic 
with RA. The problem is that only a portion of patients first presenting with arthritis have RA 
and differentiating those patients who have RA from those who do not is challenging, leading 
frequently to delays in accurately identifying those patients with RA.  
The realization that early diagnosis of RA is critical for delivering the most effective RA 
treatment led to a collaboration between the American College of Rheumatology and the 
European League Against Rheumatism (ACR/EULAR) that resulted in 2010 in the publication 
of new criteria for diagnosing RA [10]. The intent of the ACR/EULAR 2010 criteria was to 
improve the diagnosis of early RA. This intent was only partially realized. There have been 
numerous publications reporting the results of studies evaluating the diagnostic accuracy of 
the ACR/EULAR 2010 criteria for identifying early RA patients. In a meta-analysis of this 
literature [11], it was shown that the ACR/EULAR 2010 criteria has a 73% sensitivity and a 
74% specificity for correctly identifying early RA. If the ACR/EULAR 2010 criteria are used 
to decide who should receive DMARD therapy, this meta-analysis indicates that over a quarter 
of true early RA patients would not be provided with appropriate DMARD therapy during the 
critical window of opportunity for an optimal response. Furthermore, a significant portion of 
arthritis patients who do not have RA would be prescribed DMARD therapies for which they 
would not receive benefit and would be exposed to possible adverse side effects of the drugs. 
Clearly there remains an unmet need for a more accurate means to identify early RA patients, 
to improve aggregate outcomes for early RA patients, and to reduce adverse drug effects and 
healthcare costs associated with unproductive delivery of RA therapies to individuals who do 
not have RA.  
Basic research on the pathobiology of RA has revealed that the inflammation observed in RA 
is the consequence of a self-perpetuating pathological alteration in the expression and 
downstream signaling of a network of cytokines [12, 13]. Frequently, at the center of this 
cytokine network is the overexpression of tumor necrosis factor alpha (TNFα) [14-17]. 


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Recognition of the importance of disturbances in cytokine expression and especially that of 
TNF𝛼𝛼 formed the underlying rationale for the development of many antibody based biologic 
therapies intended to block signaling by TNF𝛼𝛼 or one of the other various inflammatory 
cytokines involved in RA pathology [18-21]. Many of these cytokine-directed RA biologic 
therapies have been granted regulatory approval and are currently commercially available. 
While many RA patients have benefited from recent advances in RA therapies, problems and 
deficiencies remain. Among these problems and deficiencies are: 
• A significant portion of RA patients do not respond to RA therapies or respond 
insufficiently to RA therapies to achieve therapeutic goals [22, 23], 
• All current RA therapies are associated with adverse effects, which can be common 
and/or severe [24],  
• Many current RA therapies, especially the biologic therapies, are exceedingly 
expensive, placing an imposing burden on healthcare costs [25] and affordability [26], 
and 
• Nearly all RA therapies lack an adequate defined diagnostic element that can facilitate 
choosing an individual patient’s therapeutic regimen that provides the highest 
probability of an effective treatment response. 
 
Quantitative assessment of CD206 positivity of inflamed synovia in RA patients is expected 
to remedy, at least partially, all 4 of these problems and deficiencies. Tc 99m tilmanocept is a 
synthetic radiopharmaceutical imaging agent that was purposefully designed to be a high 
affinity ligand for CD206. CD206 is highly upregulated on phenotypically activated 
macrophages that contribute mechanistically to the underlying pathobiology of RA.  It has long 
been recognized that activated macrophages contribute significantly to RA pathology [27-29]. 
Macrophages are common in inflamed synovial tissues when patients are first diagnosed with 
RA [30] and frequently become more numerous as the disease progresses. Activated 
macrophages produce most of the TNFα that, in a significant proportion of cases, drives and 
perpetuates the inflammatory cycle in RA [14]. In the synovial sublining of a joint affected by 
RA, activated macrophages are frequently the dominant cell type [31-33]. Activated 
macrophages significantly contribute to the destruction of bone and cartilage through their 
secretion of proteases [34, 35]. Furthermore, the densities of synovial membrane macrophages 
measured before treatment, and especially the densities of sublining macrophages, have been 
reported to predict future joint damage [36-39]. Not surprisingly, activated synovial 
macrophage numbers—but not the numbers of other immune cell types—correlate with 
radiographically determined joint destruction in RA [36, 37]. Thus, CD206 positivity of 
inflamed synovia in RA patients is expected to provide clinically significant prognostic 
information for RA patients. Another important finding is that activated macrophage numbers 
are reduced by effective RA therapy [38], but do not significantly change over the course of at 
least months if a patient was given ineffective RA therapy [40]. Also, importantly, reductions 
in activated synovial macrophages associated with effective RA therapy typically occur before 
treatment mediated changes in the severity of clinical symptoms can be observed [41]. Thus, 
a change in activated synovial macrophage numbers is now recognized as a biomarker that 
provides an objective and early measure of responses to RA therapies [42, 43].  In fact, a 
change in activated synovial macrophage numbers is considered a more accurate measure of 


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treatment response than clinical assessments, which are highly subjective in nature and prone 
to observer error [42, 44, 45]. Therefore, there is a possibility that future clinical studies may 
show that quantitative assessment of CD206 positivity of inflamed synovia in RA patients 
could be used to monitor the efficacy of RA therapies, providing physicians and patients with 
earlier and more objective criteria to abandon ineffective therapies and adopt alternative 
therapies that may be more effective.  
In recent years, synovial biopsy-enabled studies have greatly increased our understanding of 
the pathological processes occurring within the inflamed joints of RA patients [39].  An 
important finding of these studies has been that the inflammatory cell compositions of RA 
inflamed joints can vary between patients [46, 47]. The biopsy specimens obtained from 
different RA patients can have different numbers and densities of macrophages and monocytes, 
lymphocytes and lymphocyte containing structures, and fibroblast-like synoviocytes [48]. 
These differences in cellular composition suggest that RA inflammation can be divided into 3 
pathotypes, referred to as diffuse myeloid, lympho-myeloid, and fibroid respectively [49, 50]. 
Myeloid pathotype variants have the highest density of macrophages, whereas the fibroid 
pathotype is largely devoid of both macrophages and lymphoid cells. These pathotypes are not 
fully discreet with some overlap occurring. However, they provide a strong basis for temporal 
or cytological compartmentalization in RA disease natural history.  
Current studies utilizing IHC analyses of synovial biopsies are insufficient to determine the 
distribution of the various pathotypes in RA patients but suggest that the diffuse myeloid and 
lympho-myeloid pathotypes are about equally frequent in RA patients with the fibroid 
pathotype being less common. There is growing evidence that patients with different RA 
pathotypes respond differently to various therapies, holding out the possibility that determining 
the RA pathotype of an individual patient’s RA can direct choice of the most effective therapy 
for that patient (i.e., personalized RA therapy) [50]. This is an area of ongoing active 
investigation in RA therapy research [51-53]. However, already there is significant evidence 
indicating that patients with a myeloid-driven RA pathotype and/or with high densities of 
macrophages in their inflamed synovium respond best to anti-TNFα biologic therapy [50, 54], 
whereas patients with a fibroid pathotype do not respond significantly to anti-TNFα therapy. 
Although these results need to be confirmed and elaborated upon in further studies, they 
suggest that determination of the density of activated macrophages in the inflamed synovial 
membranes of patients with RA could facilitate identification of those RA patients who would 
most benefit from anti-TNFα therapy and/or those who would not receive benefit. Additional 
work in this field seeks to determine if similar associations between the efficacies of other 
treatments and synovial pathotypes can identify those treatments that are most effective in 
patients with lympho-myeloid and/or fibroid RA pathotypes. Such results, if attained, would 
provide a great benefit to RA patients by enabling personalized delivery of an optimal 
treatments to all RA patients.  
Previously generated results from clinical imaging studies conducted by Navidea and extensive 
peer reviewed scientific literature strongly indicate that Tc 99m tilmanocept can enable non-
invasive imaging of aggregates of CD206 expressing cells associated with various pathologies 
using planar scintigraphy. While it has been suggested that synovial biopsy and IHC 
evaluations might be translatable to common rheumatological clinical practice, there are 5 


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reasons why quantitative assessment of CD206 positivity enabled by Tc 99m tilmanocept 
imaging may be preferred to synovial biopsies for evaluations of RA patients. 
First, biopsy procedures usually sample a single joint. If variation exists between the 
pathotypes of different joints in the same patient, biopsy studies cannot detect or quantify this 
variation. Current RA therapies and new therapies in development are, by their designed 
targets, likely to be more effective against specific RA pathotypes. If pathotype variation 
occurs within individual RA patients, this could severely limit the ability of pathotype 
determination by biopsy to accurately predict treatment response. A key advantage of Tc 99m 
tilmanocept imaging over synovial biopsies is that Tc 99m tilmanocept imaging can provide a 
global quantitative assessment of all joints, providing Tc 99m tilmanocept imaging with the 
possibility of detecting pathotype variation without biopsies. Navidea’s proposed studies will 
directly assess RA inflammatory variation within individual patients and provide evidence 
relevant to determining the extent to which pathotype variation exists within individual RA 
patients and the ability of Tc 99m tilmanocept imaging to detect this variation.  
The second reason why Tc 99m tilmanocept imaging may be preferred to synovial biopsies for 
evaluations of RA patients is that synovial biopsies are only performed on patients with 
inflamed synovia that have expanded in volume beyond a certain grade, thereby enabling 
extraction of sufficient tissue to assess histologically. This could be a problem when evaluating 
patients in the early phase of symptomatic RA disease when high densities of activated 
macrophages have begun to aggregate into the inflamed synovial membrane but the synovial 
membrane may not yet have expanded (i.e. thickened) sufficiently to permit biopsy sampling. 
As discussed below, there is an urgent need to more accurately identify RA patients as early in 
the disease process as possible and place them on DMARD therapy immediately to provide 
these patients with their best possible therapy responses.  
The third reason why Tc 99m tilmanocept imaging may be preferred to synovial biopsies for 
evaluations of RA patients is that, although synovial biopsy procedures typically extract 6-14 
samples of tissue from each biopsied joint, in about 5% to 10% of cases, they do not provide 
tissue of sufficient quantity or quality to enable adequate histological evaluations of the 
inflamed synovial tissue [31, 51]. It is expected that Tc 99m tilmanocept imaging would not 
fail to quantitatively assess the aggregation of macrophages in RA inflamed joints at this 
frequency.  
The fourth reason is that although more than 1 biopsy procedure can be performed on an 
individual joint, there are likely to be limitations on the number of times or how often a single 
joint can be biopsied. Furthermore, while not discussed in the literature, repeated biopsies may 
alter the inflammatory microenvironment in an inflamed synovial membrane and/or induce its 
own inflammation or wound healing response to trauma. In any event, Tc 99m tilmanocept 
imaging, being non-invasive and non-traumatic, is likely to be more amenable to repeat 
examination and would not affect synovial inflammation through repeated biopsy related 
trauma. These issues may be most significant when considering evaluations of the small joints 
of the hands where there is a limited quantity of inflammatory tissue.  


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The fifth and final reason why Tc 99m tilmanocept imaging will be preferred to synovial 
biopsies is that performing biopsies is challenging and requires extensive training [52]. 
Synovial biopsies have only been performed in research settings and until very recently, only 
in Europe where adequately trained and experienced investigators reside. Training and 
qualifying all physicians in the US who care for RA patients to perform synovial biopsies 
would be a significant barrier to adoption.  
Indeed, Tc 99m tilmanocept quantitative imaging reliably assesses all joints, is not dependent 
on synovial swelling, is non-invasive and non-traumatic, and does not require extensive 
practitioner training. Thus, for all these reasons, Tc 99m tilmanocept imaging is expected to 
provide clinically predictive information about the inflammatory status of inflamed joints in 
RA patients that is not obtainable from synovial biopsies or will be preferred over invasive and 
potentially risky synovial biopsies as a means to evaluate RA patients. 
In diagnostic radiology, quantitative imaging provides a layer of clinically meaningful 
information beyond that of qualitative interrogation. The Radiological Society of North 
America (RSNA) defines quantitative imaging as “the extraction of quantifiable features from 
medical images for the assessment of normal or the severity, degree of change, or status of a 
disease, injury, or chronic condition relative to normal. Quantitative imaging includes the 
development, standardization, and optimization of anatomical, functional, and molecular 
imaging acquisition protocols, data analyses, display methods, and reporting structures. These 
features permit the validation of accurately and precisely obtained image-derived metrics with 
anatomically and physiologically relevant parameters, including treatment response and 
outcome, and the use of such metrics in research and patient care.” [55] 
In nuclear medicine, the SUV (standard uptake value) is an established quantitative imaging 
metric for the assessment of disease-related activity across a variety of neurological, 
cardiovascular, oncological, and immunological conditions. For example, in 18F-labeled 
fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET) imaging, SUV is used 
to measure the proliferative activity of malignant tumors in various cancers through the 
quantification of FDG uptake using the following parameters: r, the radioactivity activity 
concentration [kBq/mL] measured by the PET scanner within a region of interest (ROI), a’, 
the decay-corrected amount of injected radiolabeled FDG [kBq], and w, the weight of the 
patient [g], such that such that SUV = 
r
(a′/w). [56]   
Based on the clinical utility of SUV in 18F-FDG PET imaging, Navidea pursued the 
development of the TUV to quantify CD206 activity on planar gamma camera imaging. TUV 
considers the fundamental principles of SUV and introduces modifications to account for inter- 
and intra-patient variability and disease pathobiology. After the evaluation of several formula 
permutations, Navidea has established TUV as a metric for the measurement of joint-specific 
CD206 activity in RA through the quantification of Tc 99m tilmanocept uptake using the 
following parameters: 𝑥𝑥̅, the average pixel intensity of an ROI, and B, the average pixel 
intensity of the whole hand and part of the forearm on the same view and side as the joint ROI 
(serving as an intra-patient reference region), such that TUV =
xത
B. The overall purpose of this 


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study will be to establish the mean and variance of healthy control joint uptake values for 
reference to be used to assess RA-inflamed joints in patients with RA. 
1.2 
Previous Nonclinical Research and Clinical Trial Experience in Tc 
99m Tilmanocept  
A detailed evaluation of the nonclinical evaluations from subcutaneous (SC) and IV routes of 
administration, clinical pharmacokinetics (PK), clinical efficacy, and clinical safety of Tc 99m 
tilmanocept can be found in the accompanying Investigator’s Brochure supplied by Navidea 
Biopharmaceuticals, Inc.   
1.2.1 
Nonclinical Evaluations –Subcutaneous Administration 
Nonclinical studies of Tc 99m tilmanocept demonstrated that the drug selectively binds to its 
intended receptor (the CD206 mannose binding receptor), and is well tolerated by rats, rabbits, 
guinea pigs, and dogs. 
PK data obtained from nonclinical studies demonstrated rapid absorption into the plasma. 
Urinary excretion was a major pathway of elimination. Tc 99m tilmanocept exhibited rapid 
clearance from the injection site, rapid uptake by the local lymph node, and low uptake by the 
remaining lymph nodes. Tilmanocept was well tolerated at all doses tested in nonclinical safety 
pharmacology studies and in single and repeated dose toxicology studies in rats, rabbits, and 
dogs. In some studies in rabbits and dogs, tilmanocept acted as a local irritant of the subcutis 
or skeletal muscle, and induced mild inflammation and tissue degeneration. The no-observed 
adverse-effect level (NOAEL) was 42μg/kg/day. Tilmanocept was not mutagenic or genotoxic 
in vitro or in vivo. No signs or symptoms of hypersensitivity were observed in a study in guinea 
pigs.  
1.2.2 
Nonclinical Evaluations – IV Administration 
In preparation to initiate the IV route of administration, 11 preclinical tests were conducted to 
assess safety, toxicity, and interaction potential at doses hundreds to thousands of times the 
expected maximum human dose, as summarized in Table 1. The nonclinical evaluations 
yielded safety and pharmacokinetics profiles that were appropriate for initiation of IV dosing 
in clinical trials. Nonclinical study results can be found in the accompanying Investigator’s 
Brochure. 


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Table 1  
Preclinical Tests 
Type of Study / 
Description 
Test System 
Method of 
Administration 
Dosing 
Central nervous system 
safety pharmacology  
Rat 
Intravenous 
37, 190, and 380 µg/animal 
or equivalent 490X and 61X 
the anticipated study doses 
of 50 µg and 400 µg in 
humans 
Expanded single-dose 
toxicology (including 
toxicokinetics and local 
tolerance) 
Rat 
Intravenous 
37, 190, and 380 µg/animal 
or equivalent 490X and 61X 
the anticipated study doses 
of 50 µg and 400 µg in 
humans 
Respiratory Safety 
Pharmacology 
Evaluation Using Head-
Out Plethysmography of 
Tilmanocept following 
Intravenous Bolus 
Injection in Male Rats 
Rat 
Intravenous 
60, 120, and 300 µg/animal 
or equivalent 320X and 41X 
the anticipated study doses 
of 50 µg and 400 µg in 
humans 
In Vitro Evaluation of 
Tilmanocept as an 
Inhibitor of Cytochrome 
P450 (CYP) Enzymes in 
Human Liver 
Microsomes 
Human Liver 
Samples 
In vitro 
0.6 to 600 nM 
In Vitro Evaluation of 
Tilmanocept as an 
Inhibitor of Human ABC 
and SLC Transporters 
Human Liver 
Samples 
In vitro 
0.04, 0.4 µM 
Pharmacokinetics, 
Excretion, and 
Distribution by 
Quantitative Whole-
Body Autoradiography 
Following Intravenous 
Administration of 
99mTc-Tilmanocept in 
Rats 
Rat 
Intravenous 
25 µg in 0.5 mL with 
collection of  blood, urine, 
feces, and carcasses for 
QWBA 
Hemolysis and protein 
flocculation 
Human blood 
samples 
In vitro 
2.5, 25, and 250 µg/mL 
whole human blood 
Target profiling screen 
(K, Na, and Ca ion 
channels) 
Ion Channel 
In vitro 
0.025 to 0.5 mg/mL 
 


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1.2.3 
Clinical Pharmacokinetics (IV) 
Clinical PK was evaluated in IV administered Tc 99m tilmanocept in the Phase 1 and 2 trial 
NAV3-21 (NCT02865434). In this trial, 12 subjects (6 RA/6 HC) were administered the 
maximum dose of 400 mcg tilmanocept radiolabeled with 10 mCi of Tc 99m and urine and 
blood data were non-compartmentally modeled to assess potential differences in drug 
distribution and elimination by disease group (active RA vs. HC). 
Subject-level whole blood PK parameters were assessed between HC subjects (n = 6) and 
subjects with active RA (n = 6) to evaluate potential differences between mean maximum 
concentration (Cmax), mean area under the concentration-time curve (AUC0-t), mean area under 
the concentration-time curve extrapolated to infinity (AUC0-∞), mean clearance, mean half-life 
(t1/2), or mean elimination rate constant (λz) across each disease group (Table 2). The geometric 
mean of whole blood clearance was 26.5 mL/min for HC subjects and 24.8 mL/min for RA 
patients. 
Table 2  
Whole Blood PK Parameter Summaries by Group 
Group 
Statistic 
Clearance 
(mL/min) 
AUC(0-t) 
(min*nCi) 
AUC(0-∞) 
(min*nCi) 
Cmax 
(nCi) 
T1/2 
(min) 
HC 
n 
6 
6 
6 
6 
6 
Mean 
27.3 
235258.0 
370580.1 
1244.2 
759.0 
Std Dev 
7.36 
50010.28 
92535.92 
500.36 
134.20 
CV% 
26.9 
21.3 
25.0 
40.2 
17.7 
Geometric 
Mean 
26.5 
230853.1 
360357.6 
1155.5 
749.3 
Lower 90% 
CI 
21.26 
193698.75 
290005.04 
809.55 
648.36 
Upper 90% 
CI 
33.04 
275134.27 
447777.17 
1649.33 
865.85 
RA 
n 
6 
6 
6 
6 
6 
Mean 
25.5 
268110.7 
396026.4 
2043.8 
719.1 
Std Dev 
6.18 
61667.51 
101351.07 
1211.86 
138.10 
CV% 
24.3 
23.0 
25.6 
59.3 
19.2 
Geometric 
Mean 
24.8 
262309.5 
385984.3 
1761.9 
707.4 
Lower 90% 
CI 
20.11 
217187.41 
315475.79 
1078.28 
598.97 
Upper 90% 
CI 
30.59 
316806.03 
472251.44 
2878.94 
835.46 
 
Similarly, subject-level urinary PK parameters including maximum rate, AUC0-t, or percent 
recovered were assessed for HC subjects (n=6) and subjects with active RA (n=6) to evaluate 
potential differences between disease groups (Table 3). The geometric mean of urine percent 
recovered was 7.4% in HC subjects and 6.7% in RA patients.  


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Table 3  
Urine PK Parameter Summaries by Group 
Group 
Statistic 
Percent 
Recovered a 
AUC(0-t) 
(h*nCi) 
Max Rate 
(nCi/h) b 
HC 
n 
6 
6 
6 
Mean 
7.6 
1468788.9 
949280.7 
Std Dev 
2.07 
432723.27 
236916.28 
CV% 
27.2 
29.5 
25.0 
Geometric Mean 
7.4 
1411786.8 
924858.6 
Lower 90% CI 
5.84 
1088888.09 
752742.08 
Upper 90% CI 
 9.28 
1830437.75 
1136329.94 
RA 
n 
6 
6 
6 
Mean 
6.9 
1384642.0 
841331.0 
Std Dev 
1.74 
313600.65 
227308.94 
CV% 
25.2 
22.6 
27.0 
Geometric Mean 
6.7 
1355137.9 
817282.6 
Lower 90% CI 
5.46 
1123310.11 
659111.71 
Upper 90% CI 
8.33 
1634810.07 
1013410.74 
a Percent recovered is the cumulative amount of radioactivity divided by the dose and multiplied by 100.  
b Maximum observed excretion rate, calculated as (radioactivity*volume)/ (end time – start time). 
 
A comparison of the PK parameters in subjects with active RA and HC subjects does not reveal 
any apparent differences in the elimination of radioactivity from the body. 
1.2.4 
Clinical Efficacy 
1.2.4.1 
NAV3-23 (SC) 
This was an open-label, multicenter study of Tc 99m tilmanocept by subcutaneous injection in 
patients with active RA and healthy controls.  Tilmanocept was administered SC at 1 of 2 mass 
doses: [1] 50 mcg (Cohorts 1 & 3), or [2] 200 mcg (Cohorts 2 & 4). Both mass doses were 
radiolabeled with 2 mCi of Tc 99m. A total of 18 subjects were enrolled and evaluated (9 active 
RA, 9 HC). Imaging was performed 60 ± 15 minutes post injection. The following performance 
conclusions were drawn upon study completion:  
• Based on data from this study and parallel pathology studies, Tc 99m tilmanocept 
localizes to activated macrophage-infiltrated joints at doses of 50 µg and 200 µg 
radiolabeled with 2.0 mCi (74.0 MBq) by SC administration.  
• Across all combined RA subjects, swollen/tender joints demonstrating the highest 
proportions of localization include the wrists and knees.  
• Based on qualitative image evaluation, Tc 99m tilmanocept does not show differences 
in localization between 2 to 3 and 4 to 6-hour planar imaging within dosing groups.  
• Tc 99m tilmanocept demonstrates a greater frequency of localization to swollen/tender 
joints at 200 mcg/2.0 mCi than 50 mcg/2.0 mCi.  
• There is an overall lack of concordance between qualitative observation of Tc 99m 
tilmanocept localization to swollen/tender joints identified in DAS28 joint count 


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assessment. Swollen/tender joints did not appear to be reliable predictors of presumed 
abnormal activated macrophage infiltration and overall disease progression when used 
as an isolated diagnostic system.  
• Increased tilmanocept mass dosing, increased Tc 99m specific activity, and other routes 
of administration may enhance localization and anatomic delineation in tilmanocept-
positive joints of RA patients.  
• The potential for using Tc 99m tilmanocept to delineate macrophage infiltration in RA-
affected joints may allow for earlier RA-specific treatment beyond the current standard 
of care ACR/EULAR criteria. 
 
1.2.4.2 
NAV3-21 (IV) 
This was an open-label, multicenter, dose-escalation safety with PK and dosimetry study of 
Tc 99m tilmanocept by IV injection in HCs and subjects with active RA. Thirty-nine subjects 
were enrolled. A total of 27 subjects with active RA were enrolled to Groups 1 to 9 in the dose 
escalation phase. Group 10 consisted of 6 HCs (3 female and 3 male) and Group 11 consisted 
of 6 subjects with active RA (3 female and 3 male). Tilmanocept was administered IV at 1 of 
3 mass doses: 50 mcg, 200 mcg, or 400 mcg.  Within each mass dose group, tilmanocept was 
radiolabeled with 1 of 3 Tc 99m doses: 1 mCi, 5 mCi, or 10 mCi.  Subjects in Groups 10 and 
11 received the maximum dose of 400 mcg/10 mCi. Imaging was performed 60 ± 15 minutes 
p.i. The following clinical efficacy conclusions were drawn upon study completion: 
• The TUVbrain(average) readout provides an objective means of quantification of Tc 99m 
tilmanocept localization when administered at the calculated optimal dose of 150 
mcg/10 mCi and planar images are acquired 60 to 180 minutes after drug 
administration.  
• Joint-specific localization of activity and joint-specific clinical symptomology were not 
fully concordant. Within the spectrum of RA disease involvement, there may be a 
decoupling of the causal active immune process and subsequent clinical sequelae. We 
surmise that imaging and quantification of Tc 99m tilmanocept uptake may provide a 
fuller and more accurate, responsive, and objective measure of RA disease activity than 
can be obtained from clinical assessments alone. Future studies will examine whether 
the approach to image acquisition and calculation of TUV can be further refined. 
1.2.4.3 
NAV3-31 (IV) 
This is an ongoing open-label, multi-center, single and repeat-dose study designed to 
evaluate the reliability and sensitivity of TUV assessments in HCs and subjects with active 
RA. One-hundred and five evaluable subjects will be enrolled. Tilmanocept is administered 
IV at a dose of 150 mcg tilmanocept radiolabeled with 10 mCi Tc 99m. Clinical efficacy 
conclusions for this study are still in progress.  
 


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1.2.5 
 Clinical Safety 
1.2.5.1 
NAV3-23 (SC)  
The NAV3-23 (NCT02683421) safety evaluation included all trial subjects injected with Tc 
99m tilmanocept (N = 18). The AE monitoring was performed from the time of dose 
administration until completion of onsite safety assessment. There was 1 AE that was possibly 
related to and 1 AE that was probably related to Tc 99m tilmanocept. However, there were no 
AEs that led to trial discontinuation, and no SAEs were observed. There were no deaths on 
trial. 
1.2.5.2 
NAV3-21 (IV) 
The primary safety endpoint of the NAV3-21 study was evaluated by examining the incidence 
of AEs, changes over time in clinical laboratory tests, physical exams, electrocardiogram 
(ECG) parameters, and vital signs. The safety evaluation included all subjects who were 
enrolled in the study and administered Tc 99m tilmanocept (n = 39). There were no Tc 99m 
tilmanocept related AEs. There were no deaths during the trial; no SAEs; and no AEs that led 
to discontinuation from the trial. In addition, radiation exposure was within regulatory and 
safety limits at the doses evaluated. Radiation exposure and pharmacokinetics do not appear 
to differ in subjects with RA and healthy control subjects. 
1.2.5.3 
NAV3-31 (IV) 
This is an ongoing open-label, multi-center, single and repeat-dose study designed to 
evaluate the reliability and sensitivity of TUV assessments in HCs and subjects with active 
RA. One-hundred and five evaluable subjects will be enrolled. Tilmanocept is administered 
IV at a dose of 150 mcg tilmanocept radiolabeled with 10 mCi Tc 99m. Clinical safety 
conclusions for this study are still in progress.  
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective(s)  
• To establish mean and variance of TUVjoint in HCs age-matched to RA population.  
• To assess the feasibility of detecting Tc 99m tilmanocept anatomic localization using 
SPECT/CT imaging of hands and wrists in HCs and subjects with active RA.   
 
2.2 
Secondary Objective(s)  
• To quantitate Tc 99m tilmanocept anatomic localization based on SPECT/CT 
imaging of hands and wrists in HCs and joints with RA-involved inflammation. 
 
2.3 
Safety Objective(s) 
• To evaluate safety through the examination of AE incidence and changes over time in 
laboratory tests, vital signs, and physical examination findings. 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a prospective, open-label, multicenter, single-dose study designed to develop a 
normative database of TUVjoint in HCs and to assess the feasibility of qualitative and 
quantitative SPECT/CT assessments in HCs and subjects with active RA following Tc 99m 
tilmanocept administration. Subjects will be enrolled in 1 of 2 study arms (Table 4) with 
distinct study procedures in accordance with Arm-specific eligibility requirements.  
Table 4  
Study Arms  
Arm 
n 
Subjects 
Evaluation(s) 
1 
120 HCs 
HC subjects clinically free of any 
inflammatory disease and/or joint pain 
Planar image of 
bilateral 
hands/wrists 
2 
5 HCs 
10 RA 
HC subjects clinically free of any 
inflammatory disease and/or joint pain and 
subjects with clinically diagnosed active RA 
who have been on stable anti-rheumatic 
therapy  
Planar image of 
bilateral 
hands/wrists 
 
SPECT/CT of 
bilateral 
hands/wrists 
 
3.1.1 
Arm 1: No Inflammatory and/or Joint Disease (HC Subjects) 
3.1.1.1 
Description of Patient Population 
This arm will be comprised of 120 HCs who are deemed to be clinically free of inflammatory 
disease(s) and/or arthropathies and clinically free of joint pain for at least 28 days prior to the 
consent date. These subjects will not receive any anti-inflammatory treatment(s) (including 
NSAIDs) during study participation and will not have taken any such drugs at least 28 days 
prior to the consent date. All other concomitant medications (for non-inflammatory conditions) 
will have been maintained at a stable dose for at least 28 days prior to consent. 
3.1.1.2 
Overview of Study Procedures 
Subjects in this arm will have a total of two on-site visits and one telephone safety assessment. 
The maximum possible study duration for these subjects will be 39 days.  
3.1.1.3 
Justification for Population 
The reason for the inclusion of this study population is to establish mean and variance for 
TUVjoint values in HCs to develop a normative database to which the inflamed joints of subjects 
with active RA can be compared. By determining the upper limit of normal (ULN) for average 
anterior or posterior TUVjoint for right and left joints of the bilateral hands and wrists, these 


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assessments can be further investigated for their utility in providing clinically meaningful 
reference data for symptomatic individuals presenting to the clinic.  
3.1.2 
Arm 2: HCs and RA Subjects on Stable Anti-Rheumatic Therapy  
3.1.2.1 
Description of Patient Population 
This arm will include five (5) HCs who are deemed to be clinically free of inflammatory 
disease(s) and/or arthropathies and clinically free of joint pain for at least 28 days prior to the 
consent date. These subjects will not receive any anti-inflammatory treatment(s) (including 
NSAIDs) during study participation and will not have taken any such drugs at least 28 days 
prior to the consent date. All other concomitant medications (for non-inflammatory conditions) 
will have been maintained at a stable dose for at least 28 days prior to consent. 
This arm will also include ten (10) subjects with clinically diagnosed active RA on stable anti-
inflammatory and/or anti-rheumatic therapy. All subjects’ RA diagnoses will be moderate to 
severe in accordance with a 2010 ACR/EULAR score of 6 or higher. All subjects receiving 
traditional DMARDs must have been on therapy for ≥ 90 days and at a stable dose for ≥30 
days prior to the first imaging visit; all subjects receiving bDMARDs must have been on 
therapy for at least 60 days prior to the first imaging visit; and all subjects receiving NSAIDs 
and/or oral corticosteroids must have been on therapy for at least 28 days prior to the first 
imaging visit (Table 7).  
Table 5  
Inclusion Criteria Treatment Windows for Recent or Concomitant 
RA-specific Treatments 
Drug Class 
Window 
Traditional DMARDs 
On therapy ≥ 90 days and at a stable dose ≥ 30 days prior to 
the imaging visit (Day 0) 
bDMARDs 
> 60 days prior to the imaging visit (Day 0) 
JAK inhibitors 
> 60 days prior to the imaging visit (Day 0) 
NSAIDs/Corticosteroids 
≥ 28 days prior to the imaging visit (Day 0) 
 
3.1.2.2 
Overview of Study Procedures 
Subjects in this arm will have a total of two on-site visits and one telephone safety assessment. 
The maximum possible study duration for these subjects will be 39 days.  
3.1.2.3 
Justification for Population 
The reason for the inclusion of this study population is to assess the feasibility of qualitative 
and quantitative SPECT/CT assessments following Tc 99m tilmanocept administration. HCs 
will provide control data to which data from RA subjects on stable therapy can be compared. 
Planar imaging from these subjects will be utilized for comparison to SPECT/CT results and 
will be pooled with data from this and previous Navidea RA trials for TUV evaluations.   


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3.2 
Protocol Adherence 
Strict adherence to all specifications outlined in this protocol is required for all aspects of the 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol. If protocol modifications are necessary, all alterations that are not solely of an 
administrative nature require a formal protocol amendment for the involvement of Institutional 
Review Board(s) (IRB(s)). 
If an investigator has deviated from the protocol in order to eliminate an immediate hazard to 
subjects or for other inevitable medical reasons, the investigator shall document all such 
deviations, including the reasons thereof, and submit the document to the sponsor and the IRB 
as applicable. 
3.3 
Study Duration(s) 
The maximum possible study duration for Arm 1 or 2 subjects is 39 days. 
 


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4 
STUDY POPULATION  
4.1 
Study Arms 
The study population will be comprised of HCs and subjects with clinically diagnosed active 
RA on stable anti-rheumatic therapy. Subjects will be enrolled in 1 of 2 study arms (Table 6): 
Table 6  
Study Arms  
Arm 
n 
Subjects 
Evaluation(s) 
1 
120 HCs 
HC subjects clinically free of any 
inflammatory disease and/or joint pain 
Planar image of 
bilateral 
hands/wrists 
2 
5 HCs 
10 RA 
HC subjects clinically free of any 
inflammatory disease and/or joint pain and 
subjects with clinically diagnosed active RA 
who have been on stable anti-rheumatic 
therapy  
Planar image of 
bilateral 
hands/wrists 
 
SPECT/CT of 
bilateral 
hands/wrists 
 
4.2 
Eligibility 
All inclusion/exclusion criteria must be verified before any subject is considered eligible for 
enrollment and for administration of Tc 99m tilmanocept and imaging (Day 0 procedures). 
Subjects will be considered enrolled once injected with Tc 99m tilmanocept  (Day 0). Written 
and dated (with time-noted) informed consent will be obtained from all subjects. A subject 
who withdraws consent prior to receiving Tc 99m tilmanocept injection on Day 0 will be 
considered a screen failure.   
4.2.1 
Inclusion Criteria 
ALL SUBJECTS 
1. The subject has provided written informed consent with HIPAA authorization before 
the initiation of any study-related procedures. 
2. The subject has agreed to not engage in any diet, lifestyle, or medication changes until 
study completion.  
 
HEALTHY CONTROL SUBJECTS  
3. The subject is 30 years of age or greater at the time of consent. 
4. The subject is deemed to be clinically free of any inflammatory disease(s), auto-
immune disease(s), or arthropathies and has not experienced joint pain for at least 28 
days prior to the consent date. 


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5. The subject is not currently on anti-inflammatory drugs (including NSAIDs) and has 
not taken any anti-inflammatories for at least 28 days prior to the consent date.  
6. For all ongoing concomitant medications, the subject has maintained a stable dose for 
at least 28 days prior to the consent date. 
 
CLINICALLY DIAGNOSED ACTIVE RA SUBJECTS 
3. The subject is at least 18 years of age and was ≥ 18 years of age at the time of RA 
diagnosis. 
4. The subject has moderate to severe RA as determined by the 2010 ACR/EULAR 
Classification Criteria (score of ≥ 6/10). 
5. The subject has a DAS28 of ≥ 3.2 (includes the ESR test and VAS). 
6. If the subject is receiving traditional DMARDs, they have been on therapy for 
≥ 90 days and at a stable dose for ≥ 30 days prior to the imaging visit (Day 0). 
7. If the subject is receiving bDMARD or JAK inhibitor therapy, they have been at a 
stable dose > 60 days prior to the imaging visit (Day 0).  
8. If the subject is receiving NSAIDs or oral corticosteroids, the dose has been stable for 
≥ 28 days prior to the imaging visit (Day 0). The corticosteroid dose must be ≤ 
10mg/day of prednisone or an equivalent steroid dose. 
 
4.2.2 
Exclusion Criteria 
1. The subject is pregnant or lactating.  
2. The subject size or weight is not compatible with imaging per the investigator. 
3. The subject is currently receiving radiation therapy or chemotherapy or has received 
radiation therapy or chemotherapy in the past six months. 
4. The subject has had a finger, hand, and/or wrist amputation or hand or wrist joint 
arthroplasty. 
5. The subject has renal insufficiency as demonstrated by a glomerular filtration rate of 
< 60 mL/min. 
6. The subject has hepatic insufficiency as demonstrated by ALT (alanine 
aminotransferase [SGPT]) or AST (aspartate aminotransferase [SGOT]) greater than 
2 times the upper limit of normal. 
7. The subject has any severe, acute, or chronic medical conditions and/or psychiatric 
conditions and/or laboratory abnormalities that would impart, in the judgment of the 
investigator, excess risk associated with study participation or study drug 
administration that would deem the subject inappropriate for study participation or 
compromise the safety of the subject or the quality of the data. 
8. The subject has any unstable medical illnesses, including hepatic, renal, 
gastroenterologic, cardiovascular (including ischemic heart disease), endocrinologic, 
neurologic, immunologic, or hematologic disease. 


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9. The subject has a known allergy to or has had an adverse reaction to dextran exposure. 
10. The subject has received an investigational product within 30 days prior to Tc 99m 
tilmanocept administration (Day 0). 
11. The subject has received intra-articular corticosteroid injections ≤ 8 weeks prior to Tc 
99m tilmanocept administration (Day 0). 
12. The subject has received any radiopharmaceutical within 7 days or 10 half-lives prior 
to Tc 99m tilmanocept administration (Day 0). 
13. Healthy Controls only: The subject has a positive rheumatoid factor and an elevated 
ESR or CRP. 
 
4.3 
Recruitment 
Healthy control subjects will be recruited via clinical research sites and clinically assessed for 
the “absence” of painful and/or swollen joints. RA subjects will be recruited from 
rheumatology practices in accordance with the inclusion and exclusion criteria listed above. 
Candidate subjects will be asked by their treating physician about their willingness to 
participate in the study.  
4.4 
Withdrawal 
In accordance with the Declaration of Helsinki, each subject is free to withdraw from the study 
at any time and without providing a reason.  
A subject who withdraws consent prior to receiving Tc 99m tilmanocept injection on Day 0 
will be considered a screen failure.  
Should a subject withdraw after administration of the investigational product, all efforts will 
be made to complete and report the observations up to the time of withdrawal as thoroughly as 
possible. An explanation should be given of why the subject is withdrawing or being 
withdrawn from the study. 
The investigator may withdraw a subject from the study at any time at the discretion of the 
investigator for any of the following reasons:  
• A protocol violation occurs  
• A serious or intolerable AE occurs  
• A clinically significant change in a laboratory parameter occurs  
• At the investigator’s/sponsor’s discretion as long as it is in the best interest of the 
subject  
• The sponsor or investigator terminates the study  
• The subject requests to be discontinued from the study  
 


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4.5 
Replacement 
Subjects will be replaced if they have not completed all study procedures necessary for the 
primary endpoint(s) relevant to their study arm or their data are determined to be not evaluable. 
A subject is considered evaluable if he/she meets the criteria for the analysis population and 
has the data necessary for computing the primary endpoint. 
 
4.6 
Screen Failures 
Subjects who sign an informed consent form (ICF) but are ultimately not injected will be 
considered a screen failure. Subjects will be assigned a study identification number at the time 
the ICF is signed. eCRFs for Informed Consent, Inclusion, Exclusion, Demographics, Adverse 
Events, and final disposition should be completed for all screen failure subjects. 
4.7 
Subject Identification 
After the subject provides written informed consent, the site will assign the subject a 7-digit 
subject number. Subject numbers are to be assigned in a sequential manner using the following 
format:  
Digits 1 to 2: Study number “35”  
 
Digits 3 to 4: Site number (e.g., “01”)  
 
Digits 5 to 7: Sequential subject number (e.g., “001”, “002”, “003”)  
For example, the first subject consented at Site 01 is subject number “35-01-001.”  
 
Subjects will maintain the same number given at screening for the entire study. If a subject is 
a screen failure, the number will not be used for any other subject. 


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5 
INVESTIGATIONAL PRODUCT 
5.1 
Description of Investigational Project 
Technetium Tc 99m tilmanocept is a scintigraphic imaging radiotracer that binds to CD206 
(mannose-binding receptor) on the surface of macrophages and other inflammatory cells. It is 
comprised of multiple units of DTPA (diethylenetriaminepentaacetic acid) and mannose, each 
synthetically attached to a 10 kDa dextran backbone (Figure 1). The mannose acts as a 
substrate for the receptor and the DTPA serves as a chelating agent for labeling with Tc 99m. 
Tilmanocept has a diameter of about 7 nm, which permits enhanced diffusion into lymph nodes 
and blood capillaries.  
Figure 1  
Tc 99m tilmanocept and the Mannose Receptor 
 
 
5.2 
Investigational Product Dosage and Administration 
Tc 99m tilmanocept will be administered through an IV route of injection. A 150-mcg dose 
containing 10 mCi of Tc 99m in 3 mL will be delivered using 1 syringe. The dose will be 
injected as a slow push into the IV catheter. At the completion of the injection, a 10-mL sterile 
normal saline flush will be administered. The preferred site of IV placement will be between 
the left or right antecubital vein. 
The final administered dose will be ± 20% of the tilmanocept mass dose and radiolabel mCi 
dose. 


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5.3 
Timing and Frequency of Drug Administration 
Subjects in either arm will receive the study-defined dose of 150 mcg tilmanocept radiolabeled 
with 10 mCi of Tc 99m on Day 0 Visit 2.  
 
5.4 
Packaging and Labeling 
Tilmanocept cartons ready for radiolabeling will be shipped and stored at the study-assigned 
radiopharmacy. Tilmanocept is provided in a vial. Vials are packaged as a kit. A carton (kit) 
contains 5 vials of tilmanocept.  
A detailed Radiolabeling protocol will be provided to each radiopharmacy for instructions on 
how to radiolabel the vials and prepare the final tilmanocept product for injection. Quality 
Control worksheets will also be provided. 
5.5 
Drug Logistics and Investigational Product Accountability 
The investigator (or designated personnel) will confirm receipt of the investigational product 
in writing and will use the investigational product only within the framework of this clinical 
study and in accordance with this study protocol. For each subject, he/she will keep a record 
of the investigational product dispensed and store all other forms that accompanied the delivery 
of the radiolabeled product to the clinical site. These documents are to be filed in the 
investigator site file. Overall drug accountability and reconciliation will be completed by the 
sponsor or its representative. A list of investigational product vials and other materials that 
were returned, or destroyed, must be recorded and signed by the PI or an appropriately 
qualified designee as documented in the study site responsibility sheet. An overall 
accountability and reconciliation form of the investigational product will be prepared and 
completed. If there are any discrepancies, they must be investigated and their resolution 
documented. All unused study kits will be destroyed in accordance with institutional 
destruction procedures. 


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6 
THERAPIES OTHER THAN INVESTIGATIONAL PRODUCT 
6.1 
Prior and Concomitant Therapies 
All medications taken 30 days prior to Tc 99m tilmanocept injection through the post-injection 
safety follow-up must be documented and maintained at a stable dose according to the 
inclusion criteria. Subjects receiving radiation therapy or chemotherapy are not eligible for 
participation in the trial. If applicable, the subject’s history of RA treatments for up to 6 months 
will also be collected. 
6.2 
Post-Study Therapy 
There are no post-study therapy restrictions. 


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7 
STUDY PROCEDURES 
A schedule of evaluations is provided in the schedule of events (Appendix 1). 
7.1 
Schedule of Evaluations 
7.1.1 
Arm 1  
Visit 1 (Screening; Day -30 to Day -1) 
• Preliminary review of inclusion and exclusion criteria 
• Obtain signed informed consent for study participation 
• Allocation of unique subject number; this number will be used to document the subject 
data in the case report forms (CRFs) and enrollment log 
• Demography – date of birth, gender, race, ethnicity  
• Medical surgical history – all relevant prior medical and surgical conditions will be 
recorded in the CRF. Documented medical conditions will also note the month and year 
of onset if the condition is still active. 
• Concomitant medications (within 30 days before injection). 
• Vital signs (body temperature, heart rate, blood pressure, and respiratory rate after at 
least 1 minute in a resting position) 
• Physical examination will include an assessment of height, weight, and examination of 
general appearance, skin, eyes, ears, nose, throat, head and neck (including thyroid), 
lungs, heart, abdomen, lymph nodes, musculoskeletal, and nervous system. Any 
clinically relevant finding is to be documented as a baseline finding. Physical exams 
that are conducted as standard of care prior to signing informed consent may be used if 
they are performed within 30 days of injection. 
• Clinical laboratory tests – study subjects will have blood obtained for hematology, 
chemistry, and an RA panel (see Table 7)  
• Urine collection for routine analysis 
• Urine pregnancy test for women of child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who 
are not of childbearing potential will not require a pregnancy test. 
• 2010 ACR/EULAR: to confirm that the subject is clinically free of inflammatory 
disease and joint pain Swollen and tender joints will be identified and documented 
during physical examination as established by the 2010 ACR/EULAR.  
 


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Visit 2 (Tc 99m Tilmanocept Administration and Imaging; Day 0) 
All subjects will be assessed for adverse events in an ongoing manner from the day of injection 
through the end of participation.  
Pre-Tc 99m Tilmanocept Administration 
 
The following procedures will be completed for all subjects on the day of injection prior to the 
administration of Tc 99m tilmanocept: 
• A urine pregnancy test for women of child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who 
are not of childbearing potential will not require a pregnancy test. 
• Assessment of adverse events 
• Concomitant medication review 
• Vital signs after at least 1 minute in a resting position (body temperature, heart rate, 
blood pressure, and respiratory rate) within 30 minutes prior to administration of Tc 
99m tilmanocept 
 
Tc 99m Tilmanocept Administration 
 
IV administration of Tc 99m tilmanocept will be at study time 00:00. The preferred site of IV 
placement will be the left or right antecubital vein. The filled syringe will be connected to the 
catheter for a slow push injection (30-60 seconds). At the completion of the injection, a 10-mL 
sterile normal saline flush will be administered. The IV administration will be performed in 
the nuclear medicine department by an onsite Certified Nuclear Medicine Technologist or 
Nuclear Medicine Physician. Subjects will be continuously monitored for adverse events. 
0-30 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• Vital signs after at least 1 minute in a resting position (body temperature, heart rate, 
blood pressure, and respiratory rate) 
 
60 - 75 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• Image acquisition: Planar scan of the bilateral hands and wrists acquired per NAV3-35 
Image Acquisition Guidelines 
 
Visit 3 (Day 5 ± 3; Follow-up Telephone Safety Assessment) 
• Review of concomitant medications 
• Assessment of adverse events 
 


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7.1.2 
Arm 2  
Visit 1 (Screening; Day -30 to Day -1) 
• Preliminary review of inclusion and exclusion criteria 
• Obtain signed informed consent for study participation 
• Allocation of unique subject number; this number will be used to document the subject 
data in the case report forms (CRFs) and enrollment log 
• Demography – date of birth, gender, race, ethnicity  
• Medical surgical history – all relevant prior medical and surgical conditions will be 
recorded in the CRF. Documented medical conditions will also note the month and year 
of onset if the condition is still active. 
• Concomitant medications (within 30 days before injection). 
• Vital signs (body temperature, heart rate, blood pressure, and respiratory rate after at 
least 1 minute in a resting position) 
• Physical examination will include an assessment of height, weight, and an examination 
of general appearance, skin, eyes, ears, nose, throat, head and neck (including thyroid), 
lungs, heart, abdomen, lymph nodes, musculoskeletal, and nervous system. Any 
clinically relevant finding is to be documented as a baseline finding. Physical exams 
that are conducted as standard of care prior to signing informed consent may be used if 
they are performed within 30 days of injection. 
• Clinical laboratory tests – study subjects will have blood obtained for hematology, 
chemistry, and an RA panel (Section 8.8 )  
• Urine collection for routine analysis 
• Urine pregnancy test for women of child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who 
are not of childbearing potential will not require a pregnancy test. 
• RA Evaluations: Swollen and tender joints will be identified and documented during 
physical examination as established by the 2010 ACR/EULAR for both HCs and RA 
subjects. RA subjects will also undergo a DAS28 evaluation and a review of RA history 
including previous treatments, date of symptom onset, and date of diagnosis.  
 
Visit 2 (Day 0; Tc 99m Tilmanocept Administration and Imaging) 
All subjects will be assessed for adverse events in an ongoing manner from the day of injection 
through the end of participation.  
Pre-Tc 99m Tilmanocept Administration 
 
The following procedures will be completed for all subjects on the day of injection prior to the 
administration of Tc 99m tilmanocept: 
• A urine pregnancy test for women of child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 


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oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who 
are not of childbearing potential will not require a pregnancy test. 
• Assessment of adverse events 
• Concomitant medication review 
• Vital signs after at least 1 minute in a resting position (body temperature, heart rate, 
blood pressure, and respiratory rate) within 30 minutes prior to administration of Tc 
99m tilmanocept 
 
Tc 99m Tilmanocept Administration 
 
IV administration of Tc 99m tilmanocept will be at study time 00:00. The preferred site of IV 
placement will be the left or right antecubital vein. The filled syringe will be connected to the 
catheter for a slow push injection (30-60 seconds). At the completion of the injection, a 10-mL 
sterile normal saline flush will be administered. The IV administration will be performed in 
the nuclear medicine department by an onsite Certified Nuclear Medicine Technologist or 
Nuclear Medicine Physician. Subjects will be continuously monitored for adverse events. 
0 to 30 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• Vital signs after at least 1 minute in a resting position (body temperature, heart rate, 
blood pressure, and respiratory rate) 
 
60 - 75 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• Image acquisition (in the following order): 
1. Planar scan of the bilateral hands and wrists acquired per NAV3-35 Image 
Acquisition Guidelines followed by preparation (up to 10 minutes) for the 
subsequent scan; 
2. SPECT/CT of the bilateral hands and wrists acquired per NAV3-35 Image 
Acquisition Guidelines 
 
Visit 3 (Day 5 ± 3; Follow-up Telephone Safety Assessment) 
• Review of concomitant medications 
• Assessment of adverse events 
 
 


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8 
PROCEDURES AND VARIABLES 
8.1 
Population Characteristics 
8.1.1 
Demographics and Other Baseline Characteristics 
One-hundred and thirty-five (135) evaluable subjects will be enrolled across the 2 study arms. 
Arm 1 will be comprised of 120 male or female HC subjects who are clinically free of any 
inflammatory and/or joint disease. Arm 2 will be comprised of 15 subjects. Ten (10) subjects 
in Arm 2 will be male or female individuals with clinically diagnosed active RA who are on 
stable anti-inflammatory and/or anti-rheumatic therapy. Five (5) subjects in Arm 2 will be male 
or female HCs who are clinically free of any inflammatory and/or joint disease. Enrolled HCs 
in either Arm will be categorized by age and sex to ensure intended distributions are met for 
the normative database, as described in Section 9.4. 
8.1.2 
Medical, Rheumatological, and Surgical History 
Relevant medical, rheumatological, and surgical histories will be obtained on all study 
subjects.  As part of the medical history, the date of the last spontaneous menstruation will be 
recorded if childbearing potential is not excluded by surgical sterilization. Rheumatological 
history will include date of RA diagnosis as well as the timing, dose, administration frequency, 
and administration route (when available) of all RA-specific drugs taken in the last 6 months. 
8.1.3 
Prior and Concomitant Medication 
All prior non-RA medications used up to 30 days before the first screening examination 
through the follow-up safety visit will be documented. In addition to the summarization of 
prior RA-specific treatments, recent or concomitant treatments taken for RA in the last 6 
months must be collected. 
 
8.2 
Tc 99m Tilmanocept Administration 
Tc 99m tilmanocept must be ordered from the study-assigned radiopharmacy once the subject 
has been scheduled for IV administration and imaging. The preferred site of IV placement will 
be the left or right antecubital vein. The filled syringe will be connected to the catheter for a 
slow push injection. Immediately after the completion of the injection, a 10-mL sterile normal 
saline flush will be administered. Injection of Tc 99m tilmanocept will be at study time 0:00. 
8.3 
Rheumatological Assessments 
8.3.1 
2010 ACR/EULAR Classification Criteria 
All subjects will be evaluated at screening using the 2010 ACR/EULAR Classification Criteria 
as part of eligibility and inclusion (Aletaha et. al 2010). The 2010 ACR/EULAR classification 
criteria includes 4 components: number and site of involved joints, serologic abnormality, 
elevated acute-phase response and symptom duration. See Appendix 5 for details. A total score 


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of 6 or higher (out of a possible 10) combined with clinical synovitis not better explained by 
another disease confirms a diagnosis of “definite RA”. 
8.3.2 
DAS28 
RA subjects in Arm 2 will receive the DAS28 evaluation (Prevoo et. al 1995) at screening as 
part of eligibility and inclusion. DAS28 is calculated from 4 components: tender joint count 
(TJC), swollen joint count (SJC), visual analogue scale (VAS) of the subject’s global health, 
and the laboratory parameter erythrocyte sedimentation rate (ESR), such that: 
𝐷𝐷𝐷𝐷𝐷𝐷28 = 0.56ඥ𝑇𝑇𝑇𝑇𝑇𝑇+ 0.28ඥ𝑆𝑆𝑆𝑆𝑆𝑆+ 0.7 ln(𝐸𝐸𝐸𝐸𝐸𝐸) + 0.014(𝑉𝑉𝑉𝑉𝑉𝑉) 
A DAS28 score of higher than 5.1 is indicative of high disease activity whereas a DAS28 
below 3.2 indicates low disease activity. A subject with a DAS28 lower than 2.6 is considered 
to be in remission. For consistent scoring, the following calculator should be utilized: 
https://qxmd.com/calculate/.  See Appendix 3 for details. 
8.3.3 
Other 
8.3.3.1 
28-joint Count (SJC and TJC) 
The 28-joint count will be performed for swollen and/or tender joints in the following: 
shoulder, elbow, wrist, MCP and PIP, and knee. Joint swelling is defined as soft tissue swelling 
that is detectable along the joint margins. Joint tenderness is defined as the presence of pain in 
a joint at rest with pressure or on movement of the joint [57]. This assessment will be used as 
an input parameter for 2010 ACR/EULAR score and DAS28 score. 
8.3.3.2 
Patient Assessment of Pain (VAS) 
Patient assessment of pain will be evaluated using the visual analog scale (VAS). Using a ruler, 
the score will be determined by measuring the distance (mm) on the 10-cm line between the 
‘no pain’ anchor and the patient’s mark, providing a range of scores from 0 to 100. This 
assessment will be used as an input parameter for DAS28 score. 
8.3.3.3 
Acute-phase Reactant 
ESR and CRP will be obtained in the RA-specific laboratory panel (see Table 7). This 
assessment will be used as an input parameter for 2010 ACR/EULAR score and DAS28 
score. 


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8.4 
Imaging 
8.4.1 
Image Acquisition 
8.4.1.1 
Planar Scintigraphy 
Bilateral hand and wrist planar image acquisition occurs in Arm 1 and 2 subjects beginning 
60-75 minutes following Tc 99m tilmanocept injection. Refer to the NAV3-35 Image 
Acquisition Guidelines for all required imaging technical specifications and acquisitions. 
8.4.1.2 
SPECT/CT 
SPECT/CT is performed for Arm 2 subjects on the bilateral hands and wrists only following 
the planar scan. Refer to the NAV3-35 Image Acquisition Guidelines for all required imaging 
technical specifications and acquisitions. SUV will be calculated for DAS28 joints of interest 
according to standard methods. See the NAV3-35 Image Review Charter and Statistical 
Analysis Plan for more details. 
8.4.2 
Tilmanocept Uptake Value (TUV) 
TUV is a quantitative imaging metric used to characterize the amount of CD206 activity on 
planar imaging. Results from prior Phase 1 and 2 studies have demonstrated that TUV is a 
sensitive and specific predictor of visually interrogated Tc 99m tilmanocept localization in 
joint regions with presumed inflammatory macrophage activity. A per-joint TUV (TUVjoint) 
relative ratio will be calculated for the each of the 22 DAS-28 joints located in the hands and 
wrists. A subject-level global TUV (TUVglobal) assessed across the 22 joints will be used as an 
indication of overall disease burden.  
For all subjects, delegated trained imaging scientists blinded to all clinical subject information 
will perform semi-automated ROI drawing on planar images of the bilateral hands and wrists 
to derive relevant count statistics, which are input parameters for TUVjoint and TUVglobal. TUV 
metrics are further described in the NAV3-35 Statistical Analysis Plan. 
8.5 
Adverse Events 
8.5.1 
Definition of Adverse Event 
The definitions below follow International Conference on Harmonization (ICH) – Good 
Clinical Practice (GCP) (see also ICH Guideline for Clinical Safety Data Management:  
Definitions and Standards for Expedited Reporting). 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product.  


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Any clinically significant change in a condition (worsening) from screening that results in a 
change in subject management will be considered an AE and will be recorded on the AE page 
of the CRF. 
By definition for this study, all untoward medical occurrences beginning on the Visit 2 (Day 
0) until the final visit (variable per arm) are to be reported as AEs.  AEs continuing after study 
completion will be followed to normalization or stabilization. Additionally, untoward medical 
events occurring prior to the day of Tc 99m tilmanocept administration will be collected and 
added to the subject’s medical history unless they are related to a study procedure, in which 
case the event will be recorded as an AE. SAEs will be reported from the time of consent 
through the end of participation. 
8.5.2 
Categories for Adverse Event Assessment 
The severity of an AE is classified according to the following categories, taking into account 
the possible range of the intensity of the event: 
• Mild  
The adverse event is transient and easily tolerated by the subject. 
• Moderate   The adverse event causes the subject discomfort and interrupts the 
subject’s usual activities 
• Severe  
The adverse event causes considerable interference with the subject’s 
usual activities and may be incapacitating or life-threatening. 
 
Specific drug treatment 
Any specific drug treatment will be documented.  
Causal relationship to investigational product 
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of investigational product:  
Definitely related: 
Event can be fully explained by administration of the 
investigational product. 
Probably related: 
Event is most likely to be explained by administration of the 
investigational product rather than the subject’s clinical state or 
other agents/therapies. 
Possibly related: 
Event may be explained by administration of the investigational 
product or by the subject’s clinical state or other agents/therapies. 
Probably not related: 
Event is most likely to be explained by the subject’s clinical state 
or other agents/therapies, rather than the investigational product. 


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Definitely not related: 
Event can be fully explained by the subject’s clinical state or other 
agents/therapies. 
For causality assessments, events meeting the categories of definitely, probably, or possibly 
related will be considered to be related to investigational product. 
Causal relationship to study procedure 
The investigator will use the following definitions to assess the relationship of the adverse 
event to study procedure:  
Definitely related: 
Event can be fully explained by the study procedure. 
Probably related: 
Event is most likely to be explained by the study rather than the 
subject’s clinical state or other agents/therapies. 
Possibly related: 
Event may be explained by the study procedure or by the subject’s 
clinical state or other agents/therapies. 
Probably not related: 
Event is most likely to be explained by the subject’s clinical state 
or other agents/therapies, rather than the study procedure. 
Definitely not related: 
Event can be fully explained by the subject’s clinical state or other 
agents/therapies. 
For causality assessments, events meeting the categories of definitely, probably, or possibly 
related will be considered to be related to study. 
8.5.3 
Assessments and Documentation of Adverse Events 
Attention shall be paid to the occurrence of AEs for the duration of subject participation. Events 
occurring prior to Visit 2 (Day 0) will be recorded in the subject’s medical history unless 
related to study procedure, in which case the event will be recorded as an AE. Untoward 
medical events beginning on Visit 2 (Day 0) until the final visit (variable per arm) will be 
reported as adverse events.     
Any AE (observed, volunteered, or elicited) should be recorded in detail in the source 
documentation. 
The following information is required: 
• The date and time of onset of any AE. 
• The duration (the entire duration of an event or symptom, calculated from date of onset 
to date of end, if not recorded directly). 
• The seriousness of the AE will be assessed by the investigator.  If the investigator 
deems that an AE qualifies as an SAE, a special form provided by the sponsor should 
be completed and the event must be immediately reported to the sponsor.  A definition 
of serious adverse events is provided in Section 8.5.5. 


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• The maximum intensity (mild, moderate, or severe). 
• Whether drug treatment was administered for the event, any specific drug treatment 
must be documented. 
• The relationship of the AE to the investigational product and to study conduct (for 
definitions, see above). 
• The outcome of the AE (resolved, resolved with sequelae, not resolved, unknown, 
death). 
 
AEs will be coded according to an internationally recognized dictionary (Medical Dictionary 
for Regulatory Activities [MedDRA]). 
8.5.4 
Expected Adverse Events 
Investigational Product-Related Risks 
In all completed studies of Lymphoseek (Tc 99m tilmanocept), involving 553 subjects, only 3 
events (breast pain and injection site pain reported by subjects with breast cancer and injection 
site irritation reported by a subject with head and neck squamous cell cancer) were deemed 
definitely related to the administration of Lymphoseek by the investigator. The most common 
adverse reactions (incident < 1%) have been lack of effect (< 0.067%), injection site pain (< 
0.02%) and rash (< 0.02%). Adverse events from the radioactive dose are not expected, since 
the applied radiation doses are far below doses that can cause acute effects in human tissues. 
Routes of administration included: subcutaneous, intradermal, and peritumoral. 
In addition to the Lymphoseek pre-approval clinical studies, post-marketing surveillance 
shows that Lymphoseek has been administered to more than 450,000 patients with not a single 
drug-related SAE. Routes of administration included: subcutaneous, intradermal, and 
peritumoral.  
The intended route of administration in this study is intravenous. There have been 
approximately 280 IV administrations of Tc 99m tilmanocept to date, and no SAEs or AEs 
related to the product have been reported to date.  
Risks of Imaging Procedures 
Radiation dose considerations from Tc 99m Tilmanocept planar and SPEC/CT scans – Patients 
enrolled in this trial will have hand/wrist planar gamma camera scans following Tc 99m 
Tilmanocept injection, with subjects enrolled in Arm 2 also receiving one hand/wrist 
SPECT/CT scan.   
The average effective radiation dose per 10 mCi Tc 99m Tilmanocept injection is calculated 
to be 2.7 mSv (equivalent to about ten months of natural background radiation received in the 
US). Subjects enrolled in Arm 1 will receive one injection, equal to 2.7 mSv total; subjects 
enrolled in Arm 2 will receive one injection plus one SPECT/CT scan- with an estimated 
effective dose of 1 mSv for the CT portion- amounting to 3.7 mSv total. Therefore, the 
maximum possible dose of ~3.7 mSv for any enrolled subject (no one will cross over into more 


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than one study arm) is considered to be a minor to intermediate risk level corresponding to the 
benefit to the patient [category IIb based on the International Commission on Radiological 
Protection 62 (ICRP62)] and is balanced against the possible substantial societal benefit that 
can be gained from the trial (European Commission Radiation Protection 99, 1998 and ICRP 
62, 1992). For further reference, the effective dose from a standard CT abdomen and pelvis, 
with and without contrast, is up to 20 mSv.  
Precautionary Measures 
Special precautionary measures are not considered necessary for this study.  In case of 
emergency, standard emergency procedures will be employed. 
Unexpected Adverse Events 
An unexpected adverse event is defined as an adverse reaction that in nature and severity is 
not consistent with the applicable product information (e.g., Investigator’s Brochure).  Any 
adverse experience that is not listed in the current Investigator’s Brochure or which is, with 
regard to the specificity or severity, not consistent with the risk information shall be regarded 
as unexpected.  
Examples would be (a) acute renal failure listed in the Investigator’s Brochure with a 
subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant 
hepatitis.  “Unexpected” as used in this definition refers to an adverse drug experience that has 
not been previously observed and included in the Investigator’s Brochure, rather than from the 
perspective of such experience not being anticipated from the pharmacological properties of 
the investigational product. 
8.5.5 
Serious Adverse Events 
Definition of Serious Adverse Events 
The following SAE definition is based on ICH guidelines and the final rule issued by the Food 
and Drug Administration (FDA) and effective 06 Apr 1998.   
An SAE is classified as any untoward medical occurrence that at any dose: 
• results in death, or 
• is life threatening, or 
• requires inpatient hospitalization or prolongation of existing hospitalization, or 
• results in persistent or significant disability/incapacity, or 
• is a congenital anomaly/birth defect, or 
• is an important medical event (see paragraphs below). 
 
The term ‘life threatening’ in the definition refers to an event in which the subject was at risk 
of death at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe. 


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Medical and scientific judgment should be exercised in deciding whether it is appropriate to 
report an AE as serious also in other situations, such as important medical events that may not 
be immediately life threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the definition 
above.  These should also usually be considered serious.  Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm or blood dyscrasias or 
convulsions that do not result in subject hospitalization. 
Actions and reporting obligations in case of serious adverse events 
The investigator should take appropriate diagnostic and therapeutic measures to minimize the 
risk to the subject.   
If any SAE occurs over the course of the study, investigators or other site personnel will inform 
Navidea Biopharmaceutical representatives within 1 day (i.e., within 24 hours) of becoming 
aware of the SAE. Written notification of the SAE will be emailed to Navidea 
Biopharmaceuticals Pharmacovigilance at safety@navidea.com. For fatal or life-threatening 
adverse events where important or relevant information is missing, active follow-up is 
undertaken immediately. 
Pregnancy will have the same time reporting obligations to the sponsor as SAEs. Upon 
notification, Navidea will provide a form for collection of pregnancy information. 
All SAEs must also be recorded on the Adverse Event eCRFs. 
Notification of the IRB(s) 
The sponsor and/or the investigator will notify the IRB(s) about all relevant events (e.g., 
serious adverse events [SAEs] and Suspected, Unexpected, Serious Adverse Reactions 
[SUSARs]) according to all applicable regulations. 
Notification of the authorities 
The sponsor will process and report all relevant events (e.g., SAEs, SUSARs) to the authorities 
according to all applicable regulations. 
Sponsor’s notification of the investigators 
The sponsor will inform all investigators about reported relevant events (e.g., SAEs, SUSARs) 
according to all applicable regulations. 
8.6 
Physical Examination 
Complete physical examinations will be conducted at screening including height and weight 
assessments. A physical exam that has been conducted as standard of care prior to signing 
informed consent may be used if it was performed within 30 days of injection. 


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Physical examinations will be performed for the following body systems: 
• General Appearance 
• Skin/dermatological 
• Eyes, ears, nose, throat 
• Head and neck (including thyroid) 
• Lungs 
• Heart 
• Abdomen (liver, kidney, spleen, gastrointestinal) 
• Lymph nodes 
• Musculoskeletal 
• Nervous system 
 
8.7 
Vital Signs 
Vital signs comprise the measurement of body temperature, heart rate, respiration, systolic and 
diastolic blood pressure. All measurements will be taken after the subject has been in a resting 
position for at least 1 minute. Vital signs will be measured at screening, within 30 minutes 
before investigational product injection, and within 30 minutes post injection. Any clinically 
significant change from screening (worsening) that results in a change in subject management 
will be considered an AE and will be recorded on the AE page of the CRF. 
8.8 
Clinical Laboratory Parameters 
Table 7  
Clinical Laboratory Parameters 
Hematology 
Hemoglobin (Hgb), hematocrit (HCT), platelets, neutrophils, 
basophils, lymphocytes, monocytes, red blood cells (RBC), white 
blood cells (WBC) 
Serum chemistry  
Aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase, total bilirubin, creatinine, chloride, 
potassium, sodium, total protein, albumin, carbon dioxide 
(CO2)/bicarbonate, blood urea nitrogen (BUN), glucose  
Urinalysis 
pH, specific gravity 
Rheumatoid Panel 
Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), 
rheumatoid factor (RF); anti-citrullinated peptide antibody 
(ACPA) 
 
All laboratory reports must be promptly reviewed for clinical significance by the investigator, 
and upon review, initialed and dated by the investigator. 
Good clinical practice would suggest that a copy of the laboratory results also be provided to 
the subject’s referring physician. 


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Only abnormal laboratory values that are evaluated as being clinically significant will be 
collected in the electronic database. Any change in a laboratory value, which results in a change 
in subject management (additional controls or treatment required), will be reported as a 
clinically significant change. Clinically significant changes in laboratory parameters, which 
are not the result of laboratory error, are to be recorded as AEs. 
Any clinically significant changes in laboratory values are to be followed up with repeated 
tests at appropriate intervals (as determined by the investigator) until the values return to 
baseline level or until the abnormality is explained by the investigator. The expected amount 
of blood to be drawn is shown in Table 8. 
Table 8  
Approximate Amount of Blood Drawn  
Timepoint 
Test (Sample Volume) 
Total Blood Drawn at Timepoint 
Visit 1 (Day -30 to -1) 
Chemistry (5 mL) 
Hematology (4 mL) 
RA panel (4 mL) 
13 mL (2.6 teaspoons) 
Visit 2 (Day 0) 
Chemistry (5 mL) 
Hematology (4 mL) 
9 mL (1.8 teaspoons) 
Total  
22 mL (~4.5 teaspoons) 
 


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9 
STATISTICAL METHODS 
This is a prospective, open-label, multicenter study of the patterns of variation in planar 
imaging using IV injected Tc 99m tilmanocept for the quantitative detection of disease activity 
in the skeletal joints of HC subjects and subjects with active RA. In addition to quantitative 
assessments, this study will also include qualitative (i.e., visual) evaluations of SPECT/CT in 
detecting localization within synovial spaces of the bilateral hands and wrists.   
The study is stratified into 2 groups. Arm 1 consists of HC subjects. Arm 2 consists of HC 
subjects and RA subjects on stable therapy. 
9.1 
Randomization Methods 
This study is not randomized.  
9.2 
Safety Variables 
The safety analysis variables are defined as follows: 
• Adverse events (AEs) 
• Clinical laboratory tests (hematology, serum chemistry, urinalysis, and RA panel) 
• Vital signs 
 
9.3 
Efficacy Variables 
The efficacy variables for this study are defined below: 
• Quantitative determination of TUVjoint and TUVglobal  
• Qualitative (i.e., visual) determination of tilmanocept localization in planar and 
SPECT/CT images of the bilateral hands and wrists; 
• Quantitative determination of tilmanocept localization in planar and SPECT/CT 
images of the bilateral hands and wrists. 
 
It is presumed that the presence of radiotracer uptake for a joint indicates the presence of 
activated macrophages. The use of the term “localization” is synonymous with radiotracer 
uptake. 
The efficacy endpoints for this study, by arm, are as follows: 
Primary Endpoint(s) 
ARM 1 
• The normal limits of TUVjoint (on a per joint basis) in HC subjects, which are defined 
as the 5 and 95 percentiles of TUVjoint of bilateral joints (i.e., bilateral wrists, 
metacarpophalangeal joint [MCPs], proximal interphalangeal [PIPs]). The normal 
range will be determined separately for each of the three blinded readers. 
 


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ARM 2  
• The qualitative evaluations of SPECT/CT in detecting localization within synovial 
spaces of the bilateral hands and wrists in HCs and RA subjects. 
 
Secondary Endpoints 
ARM 1 
• Applicability of the Normal (Gaussian) distribution to TUVjoint data. 
 
 
ARM 2  
 
• Quantitative evaluations of Tc 99m tilmanocept localization from SPECT/CT within 
synovial spaces of the bilateral hands and wrists in HCs and RA subjects. 
• Normative joint-specific SUV. 
 
• Predictive value of planar scans for SPECT/CT scans. 
9.4 
Sample Size Justification 
The study will enroll up to 135 evaluable subjects in Arms 1 and 2 allocated below, imaged at 
up to 8 study centers. Arm 1 will have N = 120 evaluable HC subjects, Arm 2 will have N = 
15 (5 HCs and 10 RA) evaluable subjects. A subject is considered evaluable if he/she meets 
the criteria for the analysis population and has the data necessary for computing the primary 
endpoint. 
The sample size for Arm 1 was determined to provide acceptable precision for the estimated 5 
and 95 percentiles. These percentiles will  be estimated with 95% nonparametric confidence 
intervals. Although the standard error formula for quantile estimators is known and quantile 
estimators obey a central limit theorem, relying  on the asymptotic Normal distribution seems 
imprudent. 
The sample will be stratified 3:1, females:males to reflect RA incidence in the United States 
[58, 59]. The sex-specific samples will be further stratified by age to reflect the Census 
estimated US population in 2019 (U.S. Census Bureau, 2020 [60]). The target sample sizes are 
given below.  


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Age Range 
Male 
Female 
Total 
30 to 39 years 
8 
23 
31 
40 to 49 years 
7 
21 
28 
50 to 59 years 
8 
22 
30 
60 to 69 years 
7 
21 
28 
70 years and oldera 
6 
21 
27 
Total 
36 
108 
144 
a An effort will be made to target enrollment in this group to include 2 men and 8 women 80 years old and over.  
The existing data for HC subjects was used in a bootstrap procedure to evaluate the width of 
95% confidence intervals for the 95 percentiles for various sample sizes. The sponsor has 
decided for its business purposes that knowing the percentile to within 0.05 of its true value is 
sufficient. A sample of size N = 144 HC results (this includes the subjects from Arm 1 of 
NAV3-31) in 95% confidence intervals with half-widths less than 0.05. 
The sample size for Arm 2 was determined to be sufficient for the business purposes of the 
sponsor. The sample size for Arm 2 will be 5 HCs and 10 RA subjects.  
9.5 
Statistical Analyses 
9.5.1 
Analysis Populations 
The following populations are defined for this study: 
Intent-to-Diagnose (ITD) Population – the ITD population includes all subjects who have 
been enrolled in the study, injected with Tc 99m tilmanocept, and received all imaging and 
evaluations necessary for the primary endpoint(s) appropriate to their respective arm. 
Per-Protocol (PP) Population – the PP population consists of all ITD subjects without major 
protocol violations. 
Safety Population – The safety population includes all subjects who have been enrolled in the 
study and injected with Tc 99m tilmanocept. 
9.5.2 
Analysis of Baseline and Demographic Characteristics 
Baseline and demographic characteristics of the safety population will be summarized by 
subject status and overall.  Continuous variables (age, height, and weight) will be summarized 
via mean, standard deviation, minimum, maximum, and number of non-missing responses. 
Categorical variables (gender, race and ethnicity) will be summarized via counts and 
percentages. 


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9.5.3 
Analysis of Efficacy Variables 
All efficacy analyses will be conducted on both the ITD and PP populations. The ITD 
population will be the primary analysis set. 
9.5.3.1 
Primary Endpoint Arm 1 
The distribution of TUVjoint in HC subjects will be summarized with descriptive statistics: 
mean, standard deviation, n, minimum, maximum, and median per reader, joint, and view. The 
5 and 95 percentiles will be estimated with quantile regression fitting an intercept as a fixed 
term. The lower and upper limits of normal TUVjoint will be determined using non-parametric 
confidence intervals and kernel density-based confidence intervals. 
9.5.3.2 
Primary Endpoint Arm 2 
Localization of tilmanocept in the hands and wrists will be summarized with frequency counts 
and percentages by reader and joint. 
9.5.3.3 
Secondary Endpoint Arm 1 
Normal quantile plots will be provided per joint and reader, along with the p-value for the 
Shapiro-Wilk test of Normality.  
9.5.3.4 
Secondary Endpoints Arm 2 
SUV will be calculated and summarized on both a per-joint and a total of all joints with 
summary statistics: mean, standard deviation, n, minimum, maximum, and median. 
The predictive value of planar scans for SPECT/CT qualitative findings will be summarized 
per joint and reader with a crosstabulation and the uncertainty coefficients for row | column, 
column | row, and symmetric. The planar result will be deemed “positive” (i.e., inflamed) if 
TUVjoint > 95 percentile of the reader results for the same joint in Arm 1. Otherwise, the planar 
result will be deemed “negative”. 
Additional efficacy analyses may be described in the NAV3-35 Statistical Analysis Plan 
(SAP).  
 
9.5.4 
Analysis of Safety Variables 
All safety analyses will be conducted on the safety population. 
All AEs will be observed for each subject from the time of signing of informed consent until 
study completion. A treatment-emergent AE (TEAE) is defined as an AE whose start date is 
on or after the initial procedure date. If the procedure date or the AE start date is missing, the 
AE will be considered treatment emergent. 
Prior to analysis all AEs will be coded using the MedDRA coding dictionary. Based on the 
coded terms, TEAEs will summarized by cohort and overall as follows: 


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• By system organ class (SOC) and preferred term (PT); 
• By SOC and PT and relation to the study drug; 
• By SOC and PT and severity. 
 
Observed and change from baseline vital sign parameters and hematology, clinical chemistry 
and urinalysis parameters will be summarized using descriptive statistics (mean, standard 
deviation, median, and range) for each Arm and overall at each time point. 
Other safety analyses may be described in the SAP for the study. 
9.5.5 
Handling of Missing Values 
The analysis of the efficacy variables will be carried out on the observed data, i.e. a complete 
case analysis.  
9.5.6 
Interim Analyses 
No interim analyses will be performed for this study.  


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10 DATA HANDLING AND QUALITY ASSURANCE  
10.1 Data Recording 
Data required according to this protocol is captured in the subject’s source documentation and 
are to be entered onto the electronic CRFs (provided by the sponsor) as soon as possible. 
10.1.1 CRF Design 
Electronic CRFs (eCRFs) will be used for collecting all data generated during the trial. CRF 
completion details will be documented in a separate document that will be provided by the sponsor 
and maintained in the TMF. 
10.2 Monitoring 
This study will be monitored regularly by a clinical research associate (CRA) from the sponsor 
or a contract research organization (CRO).  Monitoring procedures include 1 or more visits 
designed to clarify all prerequisites before the study starts.  Interim monitoring visits will take 
place on a regular basis according to a schedule fixed by mutual agreement.  During these 
visits, the CRA will check for completion of the entries on the CRFs, their compliance with 
the protocol and with GCP, and will compare the CRF entries with the source data. 
All data recorded in the CRF will be captured in the source documentation. 
The CRA will verify the correct use of the investigational product.  The investigational product 
will not be supplied to the investigator site prior to a favorable opinion from the IRB and the 
regulatory authority and, if appropriate, from the radiation protection authorities. In addition, 
the CRA will determine whether all AEs or SAEs have been appropriately reported (including 
adherence to the time periods required for SAEs).   
10.3 Data Processing 
Study data documentation will be maintained specifying all relevant aspects of data processing 
for the study (including data validation, cleaning, correcting, releasing).  This documentation 
will be stored in the TMF. 
For data coding (e.g., AEs, medication, medical/surgical history), internationally recognized 
and accepted dictionaries will be used.  These and the processes used for coding will be 
specified in the data management plan 
10.4 Auditing 
A member of the sponsor’s (or a designated CRO) quality assurance unit may arrange to visit 
the investigator in order to audit the performance of the study at the study site and the study 
documents originating there.  The auditor(s) will usually be accompanied by a CRA or the 
study team leader.  The investigator will be informed about the outcome of the audit. 


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In addition, inspections by health authority representatives and IRB(s) are possible at any time.  
The investigator is to notify the sponsor of any such inspection immediately. 
10.5 Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.  Patient (hospital) files will be archived 
according to local regulations and in accordance with the maximum period of time permitted 
by the hospital, institution, or private practice.  Where the archiving procedures do not meet 
the minimum timelines required by the sponsor, alternative arrangements must be made to 
ensure the availability of the source documents for the required period. 
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g., relocation or transfer of ownership). 
The investigator site file is not to be destroyed without the sponsor’s approval. 
The investigator’s contract will contain all regulations relevant for the study center. 
Imaging data will be archived by the central imaging core lab according to the NAV3-35 
WorldCare Project Plan (WorldCare Clinical, Boston, MA).  
10.6 Premature Termination of the Study 
10.6.1 Termination by the Sponsor 
The Sponsor may terminate the study at any time for any of the following reasons: 
1. Failure to enroll subjects 
2. Protocol violations 
3. Inaccurate or incomplete data 
4. Unsafe or unethical practices 
5. Questionable safety of the investigational product 
6. Suspected lack of efficacy of the investigational product 
7. Administrative decision 
 
10.6.2 Termination by the Investigator 
If the Investigator terminates the study prematurely, the Investigator must do the following: 
• Return all unused investigational products and related study materials to the Sponsor. 
• Provide the IRB(s) and the sponsor with a written statement describing why the study 
was terminated prematurely.  Prompt compliance with this requirement is essential so 
that the sponsor may comply with its regulatory obligations. 
 


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10.6.3 Study as a Whole 
The sponsor retains the right to prematurely terminate the study as a whole at any time.   
At the discretion of the sponsor, the entire study may be canceled for medical reasons.  In 
addition, the sponsor retains the right to end the study at any time if the study cannot be carried 
out as agreed upon in the protocol. In case of early termination or suspension of the study, the 
principal investigator/sponsor will promptly inform the investigator/institutions, regulatory 
authorities, and IRB of the termination or suspension and the reason for that. 
10.6.4 Center 
At any time, the study may be terminated at an individual center if:  
• The center cannot comply with the requirements of the protocol. 
• It is not possible for the center to comply with GCP standards. 
 
10.6.5 Study Participant 
Individual subjects may be withdrawn from the study according to the criteria specified in 
Section 4.4. 


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11 ETHICAL AND LEGAL ASPECTS 
11.1 Ethical and Legal Conduct of the Study 
The planning and conduct of this clinical study are subject to national laws. Only when all of 
the requirements of the appropriate regulatory authority have been fulfilled will the study 
begin. The study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki and the ICH-GCP Guidelines of 17 Jan 1997. At the 
discretion of the investigator, the entire study may be canceled for medical reasons. In addition, 
the sponsor retains the right to end the study for medical-scientific or GCP-relevant reasons. 
In case of premature termination the investigators, IRB(s) and Regulatory Authorities will be 
informed by the Study Manager. As required by local law, current safety-relevant information 
will be provided to the IRB(s) and the regulatory authorities by the sponsor. The sponsor will 
also inform all investigators about relevant safety events according to the applicable 
regulations. 
11.2 Subject Information and Consent 
All relevant information on the study will be summarized in the subject consent form and 
additionally as required by the investigator’s institution in an integrated subject information 
and consent sheet. A sample informed consent form (ICF) is provided as a document separate 
to this protocol. 
Based on this subject ICF, the investigator will explain all relevant aspects of the study to each 
subject, before entry into the study (i.e., before examinations and procedures associated with 
selection for the study are performed).  
The investigator will also mention that written approval of the IRB has been obtained.  Each 
subject will have ample time and opportunity to ask questions and will be informed about the 
right to withdraw from the study at any time without any disadvantage and without having to 
provide reasons for this decision.  Following this informative discussion, the subject will be 
asked if he/she is willing to sign and personally date a statement of informed consent.  Only if 
the subject voluntarily agrees to sign the ICF and has done so, may he/she enter the study.  
Additionally, the investigator or his/her designee will personally sign and date the form.  The 
subject will receive a duplicate of the signed and dated form.  
The investigator will record in the source documentation the consent process including the 
time and date of obtaining informed consent. In the event that informed consent is obtained on 
the date that baseline study procedures are performed, the study record or subject's clinical 
record must clearly show that informed consent was obtained prior to these procedures.  
The ICF and any other written information provided to subjects will be revised whenever 
important new information becomes available that may be relevant to the subject’s consent, or 
there is an amendment to the protocol which necessitates a change to the content of the subject 
information and/or the written ICF. The investigator will inform the subject of changes in a 
timely manner and will ask the subject to confirm his/her participation in the study by signing 


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the revised ICF. Any revised written ICF and written information must receive the IRB’s 
approval/favorable opinion in advance of use. 
11.3 Financing/Financial Disclosure 
Each investigator (including principal and/or any subinvestigators; as well as their spouses and 
dependent children) who is directly involved in the treatment or evaluation of research subjects 
has to provide a financial disclosure according to all applicable legal requirements. All relevant 
documentation will be filed in the sponsor trial master file and the investigator site file, as 
appropriate. 
11.4 Publication Policy 
The sponsor will be responsible for determining when any trial results should be published.  
The sponsor will work jointly with the investigator(s) to publish information in a timely 
manner.  The investigator(s) shall not submit any information gleaned under the direct support 
or sponsorship of the sponsor to journals or professional societies without the prior written 
approval of the sponsor.  A “publication” is meant to include any abstract, letter, manuscript 
or public announcement in any form or length that contains information gleaned under the 
direct support or sponsorship of the sponsor. 
11.5 Subject Injury 
In general, if a subject is injured as a direct result of the investigational product but not due to 
medical negligence on the part of the principal investigator or study staff, the sponsor will pay 
for reasonable and necessary medical treatment for the injury, to the extent the expenses are 
not covered by the subject’s medical insurance, a government program, or other responsible 
third party.  If laws or regulations of the locality in which the study is taking place require 
additional payment of expenses, the sponsor shall comply with such law or regulation.  Where 
applicable, the sponsor has taken specific national insurance. 


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Appendix 1 
Schedule of Events  
Evaluation 
Visit 1 
Screening 
(Day -30 to -1) 
Visit 2 
(Day 0) 
Visit 3 
Telephone 
(Day 5 ± 3) 
- 00:30 
to 
- 00:01 
00:00 
Injection 
 
00:01 
to 
00:30 
60 - 75 min 
After Imaging 
Informed consent 
1, 2 
 
 
 
 
 
 
Entry criteria 
1, 2 
 
 
 
 
 
 
Medical History, RA history, demography 
1, 2 
 
 
 
 
 
 
Physical examination 
1, 2 
 
 
 
 
 
 
Clinical laboratory evaluation: chemistry, 
hematology, urinalysis 
1, 2 
 
 
 
 
1, 2 
 
RA panel 
1, 2 
 
 
 
 
 
 
Urine pregnancy test (women of CBP only) 
1, 2 
1, 2 
 
 
 
 
 
2010 ACR/EULAR 
1, 2 
 
 
 
 
 
 
DAS28 (RA subjects only) 
 2 
 
 
 
 
 
 
Vital signs  
1,2 
1, 2 
 
1, 2 
 
 
 
Tc 99m tilmanocept administration 
 
 
1, 2 
 
 
 
 
Planar scan of bilateral hands/wrists 
 
 
 
 
1, 2 
 
 
SPECT/CT of bilateral hands/wrists 
 
 
 
 
2 
 
 
Concomitant medications 
1, 2 
1, 2 
 
 
 
 
1, 2 
AE monitoring 
1, 2 
1, 2 
1, 2 
1, 2 
1, 2 
 
1, 2 
1   Arm 1 
2   Arm 2 
1,2 Arms 1 and 2 


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Appendix 2 
2010 ACR/EULAR Criteria 
 Score 
Target population (Who should be tested?): Patients who 
 
1) Have at least 1 joint with definite clinical synovitis (swelling)* 
 
2) With the synovitis not better explained by another disease† 
 
Classification criteria for RA (score-based algorithm: add score of categories A-D; 
 
A score of ≥ 6/10 is needed for classification of a patient as having definite RA)‡ 
 
A. Joint involvement§ 
 
1 large joint 
0 
2 – 10 large joints 
1 
1 – 3 small joints (with or without involvement of large joints) 
2 
4- 10 small joints (with or without involvement of large joints) 
3 
> 10 joints (at least 1 small joint)** 
5 
B. Serology (at least 1 test result is needed for classification)‡‡ 
 
Negative RF and negative ACPA 
0 
Low-positive RF or low-positive ACPA 
2 
High-positive RF or high-positive ACPA 
3 
C. Acute-phase reactants (at least 1 test result is needed for classification) ‡‡ 
 
Normal CRP and normal ESR 
0 
Abnormal CRP or abnormal ESR 
1 
D. Duration of symptoms§§ 
 
< 6 weeks 
0 
≥ 6 weeks 
1 
* The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease 
typical of rheumatoid arthritis (RA) with a history compatible with prior fulfillment of the 2010 criteria should 
be classified as having RA. Patients with longstanding disease, including those whose disease is inactive (with or 
without treatment) who, based on retrospectively available data, have previously fulfilled the 2010 criteria should 
be classified as having RA.  
† Differential diagnoses vary among patients with different presentations, but may include conditions such as 
systemic lupus erythematosus, psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses 
to consider, an expert rheumatologist should be consulted.  
‡ Although patients with a score of < 6/10 are not classifiable as having RA, their status can be reassessed and 
the criteria might be fulfilled cumulatively over time.  
§ Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging 
evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal 
joints are excluded from assessment. Categories of joint distribution are classified according to the location and 
number of involved joints, with placement into the highest category possible based on the pattern of joint 
involvement.  
“Large joints” refers to shoulders, elbows, hips, knees, and ankles.  
 “Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth 
metatarsophalangeal joints, thumb interphalangeal joints, and wrists.  


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** In this category, at least 1 of the involved joints must be a small joint; the other joints can include any 
combination of large and additional small joints, as well as other joints not specifically listed elsewhere (e.g., 
temporomandibular, acromioclavicular, sternoclavicular, etc.).  
†† Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the laboratory 
and assay; low-positive refers to IU values that are higher than the ULN but ≤ 3times the ULN for the laboratory 
and assay; high-positive refers to IU values that are > 3 times the ULN for the laboratory and assay. Where 
rheumatoid factor (RF) information is only available as positive or negative, a positive result should be scored as 
low-positive for RF. ACPA = anti-citrullinated protein antibody. 
‡‡ Normal/abnormal is determined by local laboratory standards. CRP = C-reactive protein; ESR = erythrocyte 
sedimentation rate.  
§§ Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (e.g., pain, 
swelling, tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status. 
Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of 
Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 
2010;62(9):2569-2581. 


Technetium Tc 99m tilmanocept 
 
Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-35 
 
17 March 2021 
 
 
 
 
Confidential 
Page 72 of 74 
 
Appendix 3 
DAS28 Scoring 
Courtesy of http://www.iche.edu/newsletter/DAS28.pdf 


Technetium Tc 99m tilmanocept 
Clinical Trial Protocol: NA V3-35 
Sponsor Signatures 
Navidea Biopharmaceuticals, Inc. 
17 March 2021 
Appendix 4 
Study Title: 
Development of a Normative Database for Rheumatoid Arthritis 
(RA) Imaging with Tc99m Tilmanocept. 
Study Number: 
NAV3-35 
Original Date: 
17 March 2021 
This clinical study protocol was s bject o critical review and has been approved by the 
sponso,---;;;~~ con ;:::::iting and/or app~;ing this p:
col: 
Signed: 
Date: 
W1 /Mr 
2-1 
William Regan 
Chief Compliance Officer 
Navidea Biopharmaceuticals, Inc. 
Signed:~ 6._~ Date: 231\1l11.,yZot,j 
Michael Blue, MD, FACEP 
Senior Medical Director 
Navidea Biopharmaceuticals, Inc. 
Signed: ~,{ IL\\olo~ 
Bonnie Abbruzzese, MS,C 
Senior Director, Clinical Research & Development 
Navidea Biopharmaceuticals, Inc. 
Signed: ~ ~  
Michael Rosol, PhD 
Chief Medical Officer 
Navidea Biopharmaceuticals, Inc. 
Confidential 
Page 73 of74 
Date: 3 / 2-~ / 2,-0~ 
I 
I 
Date: 3/~3/.J__) 


Technetium Tc 99m tilmanocept 
 
Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-35 
 
17 March 2021 
 
 
 
 
Confidential 
Page 74 of 74 
 
Appendix 5 
Investigator’s Signature 
Study Title: 
Development of a Normative Database for Rheumatoid Arthritis 
(RA) Imaging with Tc99m Tilmanocept  
Study Number: 
NAV3-35 
Original Date: 
17 March 2021 
I have read the protocol described above. I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  
 
 
Signed: 
 
 
Date:  
 
 

SAP_001.pdf: 
Statistical Analysis Plan (SAP) 
Development of a Normative Database for Rheumatoid 
Arthritis (RA) Imaging with Tc 99m Tilmanocept 
Study No: NAV3-35 
Version 1.0 
July 14, 2022 
Prepared for 
Navidea Biopharmaceuticals, Inc. 
4995 Bradenton Avenue, Suite 240 
Dublin, OH  43017 
Prepared by 
STATKING Clinical Services 
759 Wessel Drive 
Fairfield, OH  45014 
513-858-2989
www.statkingclinical.com STATKING Clinical Services






Statistical Analysis Plan 
 
Study No. NAV3-35 
 
 
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Revision History 
 
Not Applicable. 
 
 
 


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List of Abbreviations and Definitions of Terms  
 
Term 
Definition 
Δ 
Greek letter delta, used to represent the change in a 
particular variable 
g 
microgram 
ACPA 
anti-citrullinated protein/peptide antibody 
ACR/EULAR 
American College of Rheumatology/ European League 
Against Rheumatism 
AE 
adverse event 
Anti-TNF- 
bDMARD 
Anti-Tumor Necrosis Factor  biological Disease Modifying 
Anti-Rheumatic Drug 
CDAI 
Clinical Disease Activity Index 
CFB 
change from baseline 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
CT 
X-ray computed tomography 
CV 
coefficient of variation 
DAS28 
Disease activity score used with the ACR/EULAR 2010 RA 
guidelines 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
HAQ-DI 
Health Assessment Questionnaire Disability Index 
HC(s) 
healthy control(s)  
ICH 
International Conference on Harmonization 
ITD 
intent-to-diagnose  
IV 
intravenous 
mCi 
milliCurie (37x106 becquerels; 37megabecquerels) 
MCP 
metacarpophalange 
MedDRA 
Medical Dictionary for Regulatory Activities 
NPV 
Negative Predictive Value 
OA 
Osteoarthritis or Overall Accuracy, depending on context 
PIP 
proximal interphalange 
PP 
per protocol 
PPV 
Positive Predictive Value 
RA 
rheumatoid arthritis 
ROI 
region of interest 
RR 
reference region  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SPECT 
single photon emission computed tomography 


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Term 
Definition 
Tc 99m 
technetium-99m metastable isotope; -emitting (half-life  
6.02 h) 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
tilmanocept 
DTPA Mannosyl Dextran (the US Adopted Name for the 
drug substance of Lymphoseek) 
TUV 
Tilmanocept uptake value 
US 
United States 
𝑋̅𝐵𝑅𝐴𝐼𝑁 
the decay-corrected average voxel intensity of the brain 
RR of a subject at the anterior view at 1 or 3-hours post-
injection 
𝑋̅𝑅𝑂𝐼 
the decay-corrected average voxel intensity of a region of 
interest 
 
 
 


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Table of Contents 
 
APPROVAL PAGE ............................................................................................ 1 
REVISION HISTORY ......................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................... 5 
INTRODUCTION ................................................................................................ 9 
1.0 SYNOPSIS OF STUDY DESIGN/PROCEDURES ....................................... 9 
1.1 Design and Treatment .......................................................................................................................10 
1.2 Study Procedures ...............................................................................................................................10 
1.3 Sample Size .........................................................................................................................................11 
2.0  DATA ANALYSIS CONSIDERATIONS .................................................... 12 
2.1 Types of Analyses ...............................................................................................................................12 
2.2 Analysis Populations ..........................................................................................................................12 
2.3 Missing Data Conventions .................................................................................................................13 
2.4 Interim Analyses ................................................................................................................................13 
2.5 Calculation of TUV ............................................................................................................................13 
2.6 Study Center Considerations in the Data Analysis .........................................................................14 
2.7 Documentation and Other Considerations ......................................................................................14 
3.0 ANALYSIS OF BASELINE PATIENT CHARACTERISTICS ..................... 15 
4.0 ANALYSIS OF EFFICACY ........................................................................ 15 
4.1 Description of Efficacy Endpoints ....................................................................................................15 
4.2 Analysis of Efficacy Variables ..........................................................................................................17 
5.0  ANALYSIS OF SAFETY ........................................................................... 18 
5.1 Description of Safety Variables ........................................................................................................18 


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5.2 Description of Safety Analysis ..........................................................................................................18 
6.0  OTHER RELEVANT DATA ANALYSES/SUMMARIES ........................... 20 
6.1 Patient Completion ............................................................................................................................20 
6.3 Study Drug Administration...............................................................................................................20 
6.4 RA Evaluation ....................................................................................................................................20 
6.5 Concomitant Medications..................................................................................................................20 
7.0  LIST OF ANALYSIS TABLES, FIGURES AND LISTINGS ...................... 21 
8.0  REFERENCES .......................................................................................... 25 
APPENDIX A – TABLES, FIGURES AND LISTING SPECIFICATIONS ........ 26 
APPENDIX B – TABLE SHELLS .................................................................... 28 
 
 
 


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INTRODUCTION 
 
Description 
 
This Statistical Analysis Plan (SAP) is consistent with the final study protocol 
(dated 17 March 2021) and includes the latest details of efficacy and safety 
summaries to be included in the clinical study report (CSR). 
The preparation of this SAP was done in accordance with STATKING Clinical 
Services SOP SCI 02-54, Statistical Analysis Plans. 
 
1.0 Synopsis of Study Design/Procedures 
 
This is a prospective, open-label, multicenter, single-dose study designed to 
develop a normative database of joint-specific Tilmanocept Uptake Values 
(TUVjoint) in healthy controls (HCs) and to assess the feasibility of qualitative and 
quantitative single photon emission computed tomography/ computed 
tomography (SPECT/CT) assessments in HCs and subjects with active 
rheumatoid arthritis RA following Tc 99m tilmanocept administration. 
 
Tilmanocept Uptake Value (TUV) is a quantitative imaging metric used to 
characterize Tc 99m tilmanocept uptake on planar imaging. A per-joint TUV 
(TUVjoint) relative ratio will be calculated for the each of the 22 DAS28 joints 
located in the hands and wrists. A subject-level global TUV (TUVglobal) assessed 
across the 22 joints will be used as an indication of overall disease burden in RA 
patients.  
 
The study is stratified into two arms. Arm 1 consists of HC subjects. Arm 2 
consists of HCs and clinically diagnosed RA patients on stable therapy.  
The objectives of the study are: 
Primary Objectives: 
• To establish mean and variance of TUVjoint in HCs age-matched to RA 
population.  
• To assess the feasibility of detecting Tc 99m tilmanocept anatomic 
localization using SPECT/CT imaging of hands and wrists in HCs and 
subjects with active RA.   
 
 


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Secondary Objectives: 
• To quantitate Tc 99m tilmanocept anatomic localization based on 
SPECT/CT imaging of hands and wrists in HCs and joints with RA-
involved inflammation. 
Safety Objective: 
• To evaluate safety through the examination of adverse event (AE) 
incidence and changes over time in laboratory tests, vital signs, and 
physical examination findings.  
1.1 Design and Treatment 
 
Subjects will receive the administration of Tc 99m tilmanocept through an IV 
route of administration. All subjects will receive a 150 g mass dose of 
tilmanocept labeled with 10 mCi of Tc 99m in a 3 ml volume. Following injection 
a 10 ml sterile normal saline flush will be administered. The preferred site of IV 
placement will be the left or right antecubital vein.  
Table 1 Study arms 
Arm 
Subjects 
Evaluations 
1 
HC subjects clinically free of any 
inflammatory disease and/or joint pain. 
Planar image of 
bilateral 
hands/wrists. 
 
2 
HC subjects clinically free of any 
inflammatory disease and/or joint pain. 
Subjects with clinically diagnosed RA who 
have been on stable anti-rheumatic 
therapy. 
Planar image of 
bilateral 
hands/wrists followed 
by 
SPECT/CT 
of 
bilateral hands/wrists. 
 
1.2 Study Procedures 
 
Subjects will visit the study site (Visit 1) for screening procedures up to 30 days 
(Day -30 to Day -1) before enrollment into the study. Screening procedures 
(demographics, vital signs, medical history, blood and urine samples for clinical 
labs, RA specific labs, urine pregnancy testing for subjects of childbearing 
potential, and physical exam) will be completed along with the 2010 ACR/EULAR 
score. RA subjects will also undergo a DAS28 evaluation and a review of RA 
history including previous treatments, date of symptom onset, and date of 
diagnosis. 


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Subjects arriving for Study Day 0 (Visit 2) will be considered enrolled in the study. 
On Day 0 subjects will receive Tc 99m injection and imaging procedures. A urine 
pregnancy test will be administered (pre-injection) to all subjects with 
childbearing potential. Up to 30 minutes prior to drug administration assessment 
of vital signs and AEs will be performed. After pre-injection procedures are 
completed subjects will receive a single IV dose with 150 g of tilmanocept 
radiolabeled with 10 mCi of Tc 99m. Within 30 minutes of injection, subjects will 
receive vital sign and AE check. For all subjects, planar images of the bilateral 
hands and wrists will be taken at 60 - 75 minutes for 10 – 13 minutes. After 
preparation up to 10 minutes, for Arm 2, SPECT/CT of the bilateral hands and 
wrists will be acquired for 25-30 minutes. 
On Study Day 5 (+ 3 days) (Visit 3) a safety follow-up telephone call will include 
a review of concomitant medications and assessment of adverse events. 
Subjects have completed the study at this point. 
For all subjects, delegated trained imaging scientists blinded to all clinical subject 
information will perform semi-automated region-of-interest ROI drawing on 
planar images of the bilateral hands and wrists to derive relevant count statistics, 
which are input parameters for TUVjoint and TUVglobal. 
 
1.3 Sample Size 
 
The study will enroll up to 135 evaluable subjects in Arms 1 and 2 allocated 
below, imaged at up to 8 study centers.  
 
Arm 1 will have up to N = 120 evaluable HC subjects, Arm 2 will have up to  N = 
15 evaluable subjects; 5 HCs and 10 RA subjects.  
 
A subject is considered evaluable if he/she meets the criteria for the analysis 
population and has the data necessary for computing the primary endpoint(s) 
relevant to his/her study Arm. 
 
The sample will be stratified 3:1, females to males ratio to reflect RA incidence 
in the United States. The sex-specific samples will be further stratified by age to 
reflect the Census estimated US population in 2019. 
 
 
 
 
 
 
 
 
 


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The target sample sizes are given below. 
 
Age Range 
Male 
Female 
Total 
30 to 39 years 
8 
23 
31 
40 to 49 years 
7 
21 
28 
50 to 59 years 
8 
22 
30 
60 to 69 years 
7 
21 
28 
70  years and older 
 6 
 21 
 27  
Total 
36 
108 
144 
 
An effort will be made to target enrollment in this group to include 2 men and 8 
women 80 years old and over. 
 
The existing data for HC subjects was used in a bootstrap procedure to evaluate 
the width of 95% confidence intervals for the 95 percentiles for various sample 
sizes. The sponsor has decided for its business purposes that knowing the 
percentile to within 0.05 of its true value is sufficient. A sample of size N = 144 
HC results (this includes the subjects from Arm 1 of NAV3-31) in 95% confidence 
intervals with half-widths less than 0.05. 
 
The sample size for Arm 2 was determined to be sufficient for the business 
purposes of the sponsor. The sample size for Arm 2 will be 5 HCs and 10 RA 
subjects. 
 
2.0  Data Analysis Considerations 
 
2.1 Types of Analyses 
 
Data analyses described in this SAP will consist of analyzing efficacy and safety 
data.  
 
2.2 Analysis Populations 
 
The following analysis populations will be used in the study: 
 
Safety Population – The safety population includes all patients that have been 
enrolled in the study and injected with Tc 99m tilmanocept. 
 
Intent-to-Diagnose (ITD) Population – The ITD population includes all subjects 
that have been enrolled in the study, injected with Tc 99m tilmanocept, and 


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received all imaging and evaluations necessary for the primary endpoint(s) 
appropriate to their respective arm. 
 
Per Protocol (PP) Population: The PP population will include all ITD subjects 
without major protocol violations. All protocol violations will be classified as major 
or minor prior to database lock. 
 
All efficacy analyses will be carried out on the ITD and PP populations with the 
ITD population being the primary analysis set. All analyses of safety data and 
baseline subject characteristics will be carried out on the safety population. A 
data listing displaying the patients excluded from each population will be created, 
as shown in Appendix B.   
 
2.3 Missing Data Conventions 
 
No missing value imputation will be used in this analysis.  All analyses will be 
based on the observed data. 
 
2.4 Interim Analyses 
     
There are no interim analyses planned for this study.      
 
2.5 Calculation of TUV 
 
All calculations are done on a reader-specific basis. That is, there is no statistical 
aggregation of the reader results. 
 
Calculating Joint TUV  
 
For an individual joint, TUVjoint is defined as the average pixel intensity of the joint 
(ROI) divided by the average pixel intensity of the whole hand and part of the 
forearm on the same view and side as the joint ROI. 
 
Calculating Global TUV 
 
For each independent blind reader, determine the average TUVjoint and 95% 
prediction interval of both the anterior and posterior views of the wrists, MCPs, 
and PIPs in healthy individuals. For all following calculations, reader specific 
average TUVjoint and 95% prediction intervals will be used.  
 
For each RA subject do the following. 
Step 1: Calculate TUVjoint for each of the 22 DAS28 joints for which data are 
collected. 


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Step 2: Identify all imaged joints with TUVjoint > upper limit of normal for the 
anatomically similar joint and view. These will be referred to as inflamed joints 
(IJ). Each joint has an anterior and posterior view: a joint is considered an IJ if 
either view has a TUVjoint higher than the upper bound from the normative data 
set. 
Step 3: Calculate the macrophage-involved contribution (MI) to Tc 99m 
tilmanocept localization for each IJ. This is done by expressing the TUV for the 
IJ as a fractional change from the mean TUV for the anatomically equivalent joint 
and view. That is, if TUVjoint and H̅joint represent the joint and view specific TUV 
and the mean TUV for the anatomically equivalent joint and view from the 
normative data set respectively, the macrophage contribution to TUV is MIjoint: 
MIjoint =
TUVjoint −H̅joint
H̅joint
. 
Step 4: TUVglobal is the total of the macrophage-involved contributions for the IJs. 
(Note that MIk is effectively 0 if TUVjoint is less than or equal to the upper limit of 
normal from the normative data set.) That is, 
TUVglobal = ∑MIIJ
All IJs
= ∑MI𝑘
22
𝑘=1
. 
Arms 1 and 2: 
 
Precision endpoints for both arms will be assessed estimating the mean, 
standard deviation, n, minimum, median, and maximum of TUV for each 
evaluated DAS28 joint. 
 
2.6 Study Center Considerations in the Data Analysis 
 
A study center is defined as a treatment administration site or group of treatment 
administration sites under the control and supervision of the same Principal 
Investigator (PI). There will be no selective pooling of study centers. 
 
2.7 Documentation and Other Considerations 
 
The data analyses described in this SAP will be conducted using SAS© Software, 
version 9.4 or later.   
 


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3.0 Analysis of Baseline Patient Characteristics 
 
Baseline and demographic characteristics of the safety population will be 
summarized by subject arm and overall.  Continuous variables (age, height, and 
weight) will be summarized via mean, standard deviation, minimum, maximum, 
and number of non-missing responses. Categorical variables (gender, race, and 
ethnicity) will be summarized via counts and percentages.   
 
A detailed listing of baseline data for each patient in the safety population will 
also be provided, as shown in Appendix B. 
 
4.0 Analysis of Efficacy 
 
4.1 Description of Efficacy Endpoints 
     
The efficacy variables for this study are as follows: 
• Quantitative determination of TUVjoint and TUVglobal. 
• Qualitative determination of tilmanocept localization in planar images and 
SPECT/CT images of the bilateral hands and wrists. 
• Quantitative determination of tilmanocept localization in planar and 
SPECT/ CT images of the bilateral hands and wrists 
The presence of radiotracer uptake for a joint indicates the presumed presence 
of activated macrophages.  The use of the term “localization” in this SAP is 
synonymous with the presence of radiotracer uptake.   
TUV is defined as: 
TUVjoint = 𝑋̅𝑗𝑜𝑖𝑛𝑡
𝑋̅RR
; 
  
where 
 
• 𝑋̅joint is the average voxel intensity of a particular joint of a subject at the 
anterior or posterior views at 1 hour post-injection. 
• 𝑋̅RR is the average voxel intensity of the reference region (RR) of a subject 
at the anterior or posterior views at 1 hour post-injection.  
 
4.1.1 Primary Efficacy Endpoints 
The primary efficacy endpoints of this study are: 


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Arm 1: 
The normal limits of TUVjoint per joint basis in HC subjects, which are 
defined as the 5 and 95 percentiles of TUVjoint of bilateral joints (i.e., 
bilateral 
wrists, 
metacarpophalangeal 
joint 
[MCPs], 
proximal 
interphalangeal [PIPs]). The normal range will be determined separately 
for each of the three blinded readers. 
Arm 2: 
The qualitative evaluations of planar and SPECT/CT in detecting 
localization within synovial spaces of the bilateral hands and wrists in HCs 
and RA subjects. 
4.1.2 Secondary efficacy Endpoints 
The Secondary efficacy endpoints of this study are: 
Healthy Controls in Both Arms 1 and 2: 
• Applicability of the Normal (Gaussian) distribution to TUVjoint data. 
• Relationship between TUVjoint and age by joint. 
• Relationship between the variance of TUVjoint and age. 
• Relationship between TUVjoint and sex (male vs female). 
• Relationship between TUVjoint and BMI. 
Arm 2: 
• Quantitative evaluations of Tc 99m tilmanocept localization from 
SPECT/CT within synovial spaces of the bilateral hands and wrists in HCs 
and RA subjects. 
• Normative joint-specific standardized uptake value (SUV). 
• Predictive value of planar scans for SPECT/CT scans. 
 
 
 
 
 


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4.2 Analysis of Efficacy Variables 
 
4.2.1 Analysis of Primary Efficacy Variables 
 
Arm 1: 
 
All TUVjoint data will be analyzed with summary statistics (mean, standard 
deviation, n, minimum, median, maximum) by reader, joint and view. 
 
The 5 and 95 percentiles will be estimated with quantile regression fitting an 
intercept as a fixed term. The lower and upper limits of normal TUVjoint will be 
determined using non-parametric confidence intervals and kernel density-based 
confidence intervals. 
 
Arm 2: 
 
Localization of tilmanocept in the hands and wrists will be summarized with 
frequency counts and percentages by reader and joint.  
 
4.2.2 Analysis of Secondary Efficacy Variables 
 
Healthy Controls in Both Arms 1 and 2: 
Normal quantile plots will be provided per-joint and reader, along with the p-value 
for the Shapiro-Wilk test of Normality. 
 
Scatter plots of TUVjoint by age per-joint will be provided, along with the 
correlation coefficients and p-values. The hypotheses for the p-value to test the 
correlation coefficient are: H0: ρ = 0 vs H1: ρ ≠ 0, where ρ is the correlation 
coefficient. The p-value evaluating age in the regression model will be provided 
in the figure. 
 
Scatter plots of TUVjoint by BMI will be provided, along with the correlation 
coefficients and p-values. The hypotheses for the p-value to test the correlation 
coefficient are: H0: ρ = 0 vs H1: ρ ≠ 0, where ρ is the correlation coefficient. The 
p-value evaluating BMI in the regression model will be provided in the figure. 
 
Scatter plots of TUVjoint by sex will be provided. 
 
To check the relationship between the variance of TUVjoint and age, a quantile 
regression model will be fitted with an intercept as a fixed term.The plot of the 
residuals on the y-axis and age on the x-axis will be provided.  
 
 
 


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Arm 2: 
 
SUV will be calculated and summarized on both a per-joint and a total of all joints 
with summary statistics: mean, standard deviation, n, minimum, maximum, and 
median. The formula for SUV is:  
𝑆𝑈𝑉= 
𝑟
(𝑎′/𝑤) ; 
where: 
r: The radioactivity activity concentration [kBq/mL]  
a’: The decay-corrected amount of injected radiolabeled FDG [kBq] 
w: The weight of the patient [g] 
The predictive value of planar scans for SPECT/CT qualitative findings will be 
summarized per joint and reader with a crosstabulation and the uncertainty 
coefficients for row | column, column | row, and symmetric. The planar result will 
be deemed “positive” (i.e., inflamed) if TUVjoint > 95 percentile of the reader. 
 
5.0  Analysis of Safety  
 
5.1 Description of Safety Variables  
 
The safety analysis variables are defined as follows: 
 
• Adverse Events (AEs) 
• Clinical Laboratory Tests (hematology, serum chemistry, urinalysis, RA 
panel) 
• Vital Signs 
 
 
5.2 Description of Safety Analysis 
 
The following describes the safety analyses to be performed for the study. All 
safety analyses will be performed on the safety population. Follow up timing will 
vary by arm as noted above. 
 
Adverse Events  
Adverse events will be observed for each subject from signing of informed 
consent until termination from the study. AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA®). A treatment-emergent AE 
(TEAE) is defined as an AE whose start date is on or after the initial procedure 
date. Based on the coded terms, frequencies of each TEAE will be summarized 
by MedDRA® preferred term within system organ class (SOC), by severity grade, 
and by relationship to Tc 99m Tilmanocept for each arm and overall. 
 
 


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A summary of TEAEs will be constructed showing the following by arm and 
overall: 
 
• Number of subjects with at least one TEAE 
• TEAEs by arm and severity grade 
• TEAE by arm and relationship to Tc 99m tilmanocept 
• TEAEs by arm and relationship of TEAE to study procedure 
• Number of subjects with at least one treatment emergent serious adverse 
event 
 
Treatment-emergent serious adverse events (TESAEs) will be tabulated by 
MedDRA® preferred term within SOC by arm and overall. 
 
A by-patient AE data listing of all AEs including verbatim term, coded term, grade, 
and relation to study drug will be provided.   
 
Clinical Laboratory Tests  
Clinical laboratory tests will be performed at screening (baseline) and after the 
final image acquisition on the imaging day. Only abnormal laboratory values and 
RA lab values will be assessed for clinical significance as applicable. For each 
quantitative laboratory test, summary statistics (mean, standard deviation, 
median, range, n) on the raw as well as their changes from baseline will be 
presented by timepoint, by arm, and overall.  A shift table will also be produced 
to show the changes in lab values over time relative to the normal ranges.   
 
If multiple labs were performed at a given visit, then the latest results will be 
summarized in the analysis tables. All collected lab data will be listed.  
 
Vital Signs 
Vital signs will be performed at screening, just prior to and just after injection.  
Height and weight will be measured only at screening and will be summarized as 
part of the baseline and demographic information. For each vital sign (respiration 
rate, systolic blood pressure, diastolic blood pressure, heart rate and 
temperature), summary statistics (mean, standard deviation, minimum, 
maximum, n) on the raw as well as their changes from baseline will be presented 
by timepoint, by arm, and overall. The baseline value for each of the post-
injection vital sign parameters will be the corresponding pre-injection time point.  
If there are multiple vital signs taken at any time point, then the latest set of vital 
signs will be used for the analysis. All vital sign data will be listed.   
 
 


Statistical Analysis Plan 
 
Study No. NAV3-35 
 
 
Page 20 of 75 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                              July 14, 2022
 
                                                                                                             
6.0  Other Relevant Data Analyses/Summaries 
 
6.1 Patient Completion  
 
A table will be constructed with counts of screen failures and enrolled subjects.  
Of those enrolled, counts and percentages of patients withdrawing from the study 
before study completion and the number completing the study  will be displayed.  
For those subjects that withdraw before completion of the study, counts and 
percentages of the reasons for withdrawal will be tabulated. The table will include 
summary counts and percentages by study arm and overall. A data listing of all 
subject completion and withdrawal data will also be constructed. 
 
6.2 Physical Exam  
 
Physical exams will be performed at screening. All physical exam data will be 
listed. 
 
6.3 Study Drug Administration 
 
The volume, the calculated mass dose, and radioactivity of Tc 99m tilmanocept 
injected will be summarized by arm and overall. All study drug administration 
data will be listed. 
 
6.4 RA Evaluation  
 
Each RA subject will undergo a DAS28 evaluation during screening. The swollen 
and tender joints will be identified and documented during the physical 
examination.   Results of all DAS28 evaluations will be listed. 
 
6.5 Concomitant Medications 
 
Prior and concomitant medications will be collected for 30 days prior to Day 0, 
and all RA medications will be collected for 6 months prior to Day 0. All prior and 
concomitant medications will be listed, as shown in Appendix B. A separate data 
listing will be created to show only those medications that were taken for RA 
within the 6 months prior to Day 0 injection.  
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
Study No. NAV3-35 
 
 
Page 21 of 75 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                              July 14, 2022
 
                                                                                                             
7.0  List of Analysis Tables, Figures and Listings 
 
 
Table 
No. 
 
 
Table Title 
Included 
in Final 
Tables 
Shown in 
Appendix 
B 
 
 
 
 
1 
Subject Disposition by Study Arm 
X 
X 
2 
Demographics and Baseline Data Summary Statistics by Arm – 
Continuous Variables (Safety Population) 
X 
X 
3 
Demographics and Baseline Data Summary Statistics by Arm – 
Categorical Variables (Safety Population) 
X 
X 
4 
Summary of Study Drug Administration by Arm (Safety 
Population) 
X 
X 
5 
Summary of TUVjoint on both Arms Per Reader, Joint, and View 
(ITD population) 
X 
X 
6 
Summary of TUVjoint on both Arms Per Reader, Joint, and View 
(PP Population) 
X 
 
7 
Summary of SUV on Arm 2 per Joint and a Total of All Joints 
(ITD population) 
X 
X 
8 
Summary of SUV on Arm 2 per Joint and a Total of All Joints 
(PP Population) 
X 
 
9 
Normal Range of TUVjoint for the Three Blinded Readers in All 
Arm 1 and 2 Healthy Control Subjects (ITD Population) 
X 
X 
10 
Normal Range of TUVjoint for the Three Blinded Readers in All 
Arm 1 and 2 Healthy Control Subjects (PP Population) 
X 
 
11 
Correlation Between TUVjoint and Age and BMI – All Arm 1 and 2 
Healthy Control Subjects (ITD Population) 
X 
X 
12 
Correlation Between TUVjoint and Age and BMI – All Arm 1 and 2 
Healthy Control Subjects (PP Population) 
X 
 
13 
Frequency Counts and Percentage of Localization in SPECT/ 
CT Imaging in RA Subjects (ITD Population) 
X 
X 
14 
Frequency Counts and Percentage of Localization in SPECT/ 
CT Imaging in RA Subjects (PP Population) 
X 
 
15 
Shapiro-Wilk P-Value for Normality Test for TUVjoint Data – All 
Arm 1 and 2 Healthy Control Subjects (ITD Population) 
X 
X 
16 
Shapiro-Wilk P-Value for Normality Test for TUVjoint Data – All 
Arm 1 and 2 Healthy Control Subjects (PP Population) 
X 
 
17 
Predictive Value of Planar Scans for SPECT/CT Per Joint and 
Reader (ITD Population) 
X 
X 
18 
Predictive Value of Planar Scans for SPECT/CT Per Joint and 
Reader (PP Population) 
X 
 
19 
Number and Percentage of Subjects with TEAEs (Safety 
Population) 
X 
X 
20 
Summary of TEAEs (Safety Population) 
X 
X 
21 
Number and Percentage of Subjects with TESAEs (Safety 
Population) 
X 
X 
22 
Number and Percentage of Subjects With TEAEs by Severity 
Grade (Safety Population) 
X 
X 
23 
Number and Percentage of Subjects With TEAEs by Level of 
Relationship to Tc 99m Tilmanocept  (Safety Population) 
X 
X 
24 
Number and Percentage of Subjects With TEAEs by Level of 
Relationship to Procedure (Safety Population) 
X 
 


Statistical Analysis Plan 
 
Study No. NAV3-35 
 
 
Page 22 of 75 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                              July 14, 2022
 
                                                                                                             
 
Table 
No. 
 
 
Table Title 
Included 
in Final 
Tables 
Shown in 
Appendix 
B 
25 
Serum Chemistry Clinical Laboratory Parameters Summary 
Statistics by Arm (Safety Population) 
X 
X 
26 
Hematology Clinical Laboratory Parameters Summary Statistics 
by Arm (Safety Population) 
X 
 
27 
Urinalysis Clinical Laboratory Parameters Summary Statistics by 
Arm (Safety Population) 
X 
 
28 
Serum Chemistry Clinical Laboratory Parameters Shift Table by 
Arm (Safety Population) 
X 
X 
29 
Hematology Clinical Laboratory Parameters Shift Table by Arm 
(Safety Population) 
X 
 
30 
Urinalysis Clinical Laboratory Parameters Shift Table by Arm 
(Safety Population) 
X 
 
31 
Vital Signs Summary Statistics by Arm (Safety Population) 
X 
X 
 
Figure 
No. 
 
 
Figure Title 
Included 
in Final 
Figures 
 
Shown in 
Appendix 
B 
Fig1 
Normal QQ plot for TUVjoint Data – All Arm 1 and 2 Healthy 
Control Subjects (ITD Population) 
X 
X 
Fig2 
Normal QQ plot for TUVjoint Data – All Arm 1 and 2 Healthy 
Control Subjects (PP Population) 
X 
 
Fig3 
Scatter Plot of TUVjoint Distribution of the Right Hand – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
X 
Fig4 
Scatter Plot of TUVjoint Distribution of the Right Hand – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig5 
Scatter Plot of TUVjoint Distribution of the Left Hand – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
X 
Fig6 
Scatter Plot of TUVjoint Distribution of the Left Hand – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig7 
Scatter Plot of TUVjoint Distribution for MCP1 by Age – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
X 
Fig8 
Scatter Plot of TUVjoint Distribution for MCP1 by Age – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig9 
Scatter Plot of TUVjoint Distribution for MCP2 by Age – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
 
Fig10 
Scatter Plot of TUVjoint Distribution for MCP2 by Age – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig11 
Scatter Plot of TUVjoint Distribution for MCP3 by Age – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
 
Fig12 
Scatter Plot of TUVjoint Distribution for MCP3 by Age – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig13 
Scatter Plot of TUVjoint Distribution for MCP4 by Age – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
 
Fig14 
Scatter Plot of TUVjoint Distribution for MCP4 by Age – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig15 
Scatter Plot of TUVjoint Distribution for MCP5 by Age – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
 


Statistical Analysis Plan 
 
Study No. NAV3-35 
 
 
Page 23 of 75 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                              July 14, 2022
 
                                                                                                             
Figure 
No. 
 
 
Figure Title 
Included 
in Final 
Figures 
 
Shown in 
Appendix 
B 
Fig16 
Scatter Plot of TUVjoint Distribution for MCP5 by Age – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig17 
Scatter Plot of TUVjoint Distribution for PIP1 by Age – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
 
Fig18 
Scatter Plot of TUVjoint Distribution for PIP1 by Age – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig19 
Scatter Plot of TUVjoint Distribution for PIP2 by Age – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
 
Fig20 
Scatter Plot of TUVjoint Distribution for PIP2 by Age – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig21 
Scatter Plot of TUVjoint Distribution for PIP3 by Age – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
 
Fig22 
Scatter Plot of TUVjoint Distribution for PIP3 by Age – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig23 
Scatter Plot of TUVjoint Distribution for PIP4 by Age – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
 
Fig24 
Scatter Plot of TUVjoint Distribution for PIP4 by Age – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig25 
Scatter Plot of TUVjoint Distribution for PIP5 by Age – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
 
Fig26 
Scatter Plot of TUVjoint Distribution for PIP5 by Age – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig27 
Scatter Plot of TUVjoint Distribution for Wrist by Age – All Arm 1 
and 2 Healthy Control Subjects (ITD Population) 
X 
 
Fig28 
Scatter Plot of TUVjoint Distribution for Wrist by Age – All Arm 1 
and 2 Healthy Control Subjects (PP Population) 
X 
 
Fig29 
Scatter Plot of TUVjoint Distribution by Sex – All Arm 1 and 2 
Healthy Control Subjects (ITD Population) 
X 
 
Fig30 
Scatter Plot of TUVjoint Distribution by Sex – All Arm 1 and 2 
Healthy Control Subjects (PP Population) 
X 
 
Fig31 
Scatter Plot of TUVjoint Distribution by BMI – All Arm 1 and 2 
Healthy Control Subjects (ITD Population) 
X 
 
Fig32 
Scatter Plot of TUVjoint Distribution by BMI – All Arm 1 and 2 
Healthy Control Subjects (PP Population) 
X 
 
Fig33 
Scatter Plot of Residuals by Age – All Arm 1 and 2 Healthy 
Control Subjects (ITD Population) 
X 
X 
Fig34 
Scatter Plot of Residuals by Age – All Arm 1 and 2 Healthy 
Control Subjects (PP Population) 
X 
 
 
 
Listing 
No. 
 
 
Data Listing Title 
Included 
in Final 
Listings 
 
Shown in 
Appendix 
B 
 
 
 
 
DL1 
Subject Disposition Data Listing 
X 
X 
DL2 
Inclusion/Exclusion Data Listing 
X 
X 
DL3 
Protocol Deviations Data Listing 
X 
X 
DL4 
Demographics Data Listing   
X 
X 


Statistical Analysis Plan 
 
Study No. NAV3-35 
 
 
Page 24 of 75 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                              July 14, 2022
 
                                                                                                             
 
Listing 
No. 
 
 
Data Listing Title 
Included 
in Final 
Listings 
 
Shown in 
Appendix 
B 
DL5 
Subjects Excluded from ITD Population Data Listing 
X 
X 
DL6 
Subjects Excluded from PP Population Data Listing 
X 
X 
DL7 
Subjects Excluded from Safety Population Data Listing 
X 
X 
DL8 
Medical History Data Listing 
X 
X 
DL9 
Prior and Concomitant Medications Data Listing 
X 
X 
DL10 
Prior and Concomitant RA Medications Data Listing 
X 
X 
DL11 
Adverse Events Data Listing 
X 
X 
DL12 
Subject Laboratory Profiles – Hematology Data Listing 
X 
X 
DL13 
Subject Laboratory Profiles – Serum Chemistry Data Listing 
X 
 
DL14 
Subject Laboratory Profiles – Urinalysis Data Listing 
X 
 
DL15 
Subject Laboratory Profiles – Rheumatology Panel Data Listing 
X 
 
DL16 
Physical Exam Data Listing 
X 
X 
DL17 
ACR/EULAR 2010 Classification Data Listing 
X 
X 
DL18 
DAS-28 by Joint Data Listing – Arm 2 RA Subjects 
X 
X 
DL19 
DAS-28 by Subject Data Listing – Arm 2 RA Subjects 
X 
X 
DL20 
Vital Signs Data Listing 
X 
X 
DL21 
Study Drug Administration Data Listing 
X 
X 
DL22 
Post-Injection Imaging Data Listing 
X 
X 
DL23 
SPECT/CT Reader Results Data Listing – Hands and Wrists 
X 
X 
DL24 
TUV Data Listing 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
Study No. NAV3-35 
 
 
Page 25 of 75 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                              July 14, 2022
 
                                                                                                             
8.0  References 
 
Food & Drug Administration Center for Drug Evaluation and Research and 
Center for Biologics Evaluation and Research (September 1998). Guidance for 
Industry: ICH E9 Statistical Principles for Clinical Trials. 
 
Forkman, J. (2009) Estimator and Tests for Common Coefficients of Variation in 
Normal Distributions. Communications in Statistics: Theory and Methods. 38:2, 
pp233- 251. 
 


Statistical Analysis Plan 
 
Study No. NAV3-35 
 
 
Page 26 of 75 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                              July 14, 2022
 
                                                                                                             
Appendix A – Tables, Figures and Listing Specifications 
 
Orientation 
 
Tables and figures will be displayed in landscape.  
 
Margins  
 
Margins will be 1 inch on all sides.  Table and listing boundaries will not extend 
into the margins. 
 
Font 
 
Courier New, 8 point. 
 
Headers 
 
The table number will be on the first line of the title.  The title area will contain 
the Sponsor name, the study number, and the name of the table.  The title area 
will contain the page number (Page x of y) on the far right, 1 line above the 
name of the table. 
 
Footers 
 
- The first line will be a solid line. 
- Next will be any footnotes regarding information displayed in the table. 
- Below these footnotes will be displayed “STATKING Clinical Services (DD-
MMM-YYYY)” on the far left. 
- The last line will display the name of the SAS program that generated the 
table and (if applicable) the source data reference. 
 
Table Disclaimer 
 
The format of the mock tables shown in the appendix of this SAP will be the 
format of the deliverable tables to the extent that Word document constructed 
tables can match production tables produced by SAS.  This formatting includes 
the content and format of the header and footer areas of the tables.  The 
Sponsor agrees to the format of the tables as shown in the appendix. 
 
Further programming charges will be applicable for changes in the format of 
tables (including title statements, notes, data dependent footnotes, etc.) made 
after the approval of the SAP. 
 
 


Statistical Analysis Plan 
 
Study No. NAV3-35 
 
 
Page 27 of 75 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                              July 14, 2022
 
                                                                                                             
Missing Values 
 
All missing values will be displayed on the output tables/listings as blanks. 
 
Display of Study Dates 
 
The date format to be used is dd-mmm-yyyy.  Missing parts of dates are not 
shown (i.e., for a missing day value, the value displayed is in yyyy-mm format).   
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 28 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
Appendix B – Table Shells  
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 29 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
 
Page x of y 
 
Table 1. Subject Disposition by Study Arm  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
 
 
 
 
 
  
 
 
 
Arma 
 
 
 
HC-1 
(N = xxx) 
HC-2 
(N = xxx) 
RA 
(N = xxx) 
Overall 
(N = xxx) 
Screen Failures 
 
 
 
 
xx 
 
 
 
 
 
 
Enrolled 
 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Completed 
 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
 
 
 
 
 
Withdrawn  
 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
 
 
 
 
 
Withdrawal Reason 
Adverse Event 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Protocol Violation 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Lost to Follow Up 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Withdrawal of Consent 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Sponsor Discretion 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Investigator Discretion xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Death 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Other 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
The denominator for all percentages in the table is the number of enrolled subjects in the respective arm and overall. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 30 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 2. Demographics and Baseline Data Summary Statistics by Arm – Continuous Variables 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
             
 
Variable 
 
Arma 
 
Mean 
 
Std Dev 
 
n 
 
Min 
 
Max 
 
Median 
 
 
 
 
 
 
 
 
Age (years) 
HC-1 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
HC-2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
Height (inches) 
HC-1  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
HC-2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
Weight (pounds) 
HC-1  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
HC-2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
BMI (kg/m^2) 
HC-1  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
HC-2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 31 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 3. Demographics and Baseline Data Summary Statistics by Arm – Categorical Variables 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N= xxx) 
 
 
Arma 
 
Variable 
 
Category 
HC-1 
 (N= xxx) 
HC -2 
 (N= xxx) 
RA 
(N= xxx) 
 
 
 
 
 
Gender 
Male 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Female With Childbearing Potential 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Female With No Childbearing Potential 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
Race 
American Indian or Alaska Native 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Asian 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Black or African American 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Native Hawaiian or Other Pacific Islander 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
White 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Other 
 
 
 
 
 
 
 
 
Ethnicity 
Hispanic or Latino 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Not Hispanic or Latino 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
Handedness 
Right Handed 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Left Handed 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Ambidextrous 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 32 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 4. Summary of Study Drug Administration by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N= xxx) 
 
 
 
 
 
 
Arma 
Mean 
Std Dev 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
Tc 99m Dose (mCi) 
HC-1 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
HC-2 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
RA 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mass Dose (µg) 
HC-1 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
HC-2 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
RA 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
Total Volume of Tc 99m Tilmanocept Injected (mL) 
HC-1 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
HC-2 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
RA 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 33 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 5. Summary of TUVjoint on both Arms Per Reader, Joint, and View 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
ITD Population (N=xxx) 
 
 
 
 
Arma 
Reader 
View 
Joint 
Mean 
Std Dev 
n 
Min 
Max 
 
Median 
 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxxxxxxxxxx  
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xxxxxxxxxxxxxxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx 
xxxxxxxxxxxxxxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xxxxxxxxxxxxxxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for the PP population.   


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 34 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 7. Summary of SUV on Arm 2 per Joint and Total of All Joints 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
ITD Population (N=xxx) 
 
 
 
 
Arm 2a 
Joint 
Mean 
Std Dev 
n 
Min 
Max 
 
Median 
 
 
 
 
 
 
 
 
HC-2 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
Total of All 
Joints 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
RA 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
Total of All 
Joints 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for the PP population.   


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 35 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 9. Normal Range of TUVjoint for the Three Blinded Readers in All Arm 1 and 2 Healthy Control 
Subjects 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
ITD Population (N=xxx) 
 
 
Joint 
View 
Reader 
Number of 
Joints 
 
Mean 
Standard 
Deviation 
Estimated 
 5 %tile 
Estimated 
 95 %tile 
 
 
 
 
 
 
 
 
xxxxxxxxxxxxx 
xx 
xx 
xxx 
xxx.xx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
xxx 
xxx.xx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
xxx 
xxx.xx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
xx 
xxx 
xxx.xx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
xxx 
xxx.xx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
xxx 
xxx.xx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
If there are no major protocol deviations, then analysis tables for the ITD and PP populations will contain identical results. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for the PP population 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 36 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 11. Correlation Between TUVjoint and Age and BMI – All Arm 1 and 2 Healthy Control Subjects 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
ITD Population (N=xxx) 
 
 
 
Variable 
 
TUV 
 
P-valuea 
 
 
 
AGE 
xx.xxx 
x.xxxx 
 
 
 
 
 
 
BMI 
xx.xxx 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a P-value testing H0: Correlation Coefficient = 0 vs H1: Correlation Coefficient ≠ 0. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for the PP population 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 37 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 13. Frequency Counts and Percentage of Localization in SPECT/CT Imaging in RA Subjects 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
ITD Population (N=xxx) 
 
 
 
 
Localized on SPECT/CT 
 
Joint 
Reader 
 
No 
 
Yes 
 
Total 
 
 
 
 
 
xxxxxxxxxxxxx 
xx 
xxx 
xxx 
xxx 
 
 
xx.x% 
xx.x% 
 
 
 
 
 
 
 
xx 
xxx 
xxx 
xxx 
 
 
xx.x% 
xx.x% 
 
 
 
 
 
 
 
xx 
xxx 
xxx 
xxx 
 
 
xx.x% 
xx.x% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for the PP population. 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 38 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
Page x of y 
Table 15. Shapiro-Wilk P-Value for Normality Test for TUVjoint Data - All Arm 1 and 2 Healthy Control 
Subjects 
Navidea Biopharmaceuticals - Study No. NAV3-35 
ITD Population (N=xxx) 
 
 
 
 
 
 
 
 
Test for Normality 
Test 
 
Statistic 
 
P-Value 
 
 
 
Shapiro-Wilk 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
All Table format is repeated for the PP population 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 39 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 17. Predictive Value of Planar Scans for SPECT/CT Per Joint and Reader 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
SPECT/CT 
(Standard of Truth) 
 
 
 
Reader  
Joint  
Planar Scans 
 
Positive 
Negative 
 
 
Total 
Uncertainty 
Coefficients 
Estimated 
 95 %tile 
xx 
xxx 
TUVjoint > 95 (Positive) 
xxx 
xxx 
xxx 
xxx 
 xxx 
 
 
Negative 
xxx 
xxx 
xxx 
 
 
 
 
Total 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxx 
TUVjoint > 95 (Positive) 
xxx 
xxx 
xxx 
xxx 
 xxx 
 
 
Negative 
xxx 
xxx 
xxx 
 
 
 
 
Total 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
xx 
xxx 
TUVjoint > 95 (Positive) 
xxx 
xxx 
xxx 
xxx 
 xxx 
 
 
Negative 
xxx 
xxx 
xxx 
 
 
 
 
Total 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
xxx 
TUVjoint > 95 (Positive) 
xxx 
xxx 
xxx 
xxx 
 xxx 
 
 
Negative 
xxx 
xxx 
xxx 
 
 
 
 
Total 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
xxx 
TUVjoint > 95 (Positive) 
xxx 
xxx 
xxx 
xxx 
 xxx 
 
 
Negative 
xxx 
xxx 
xxx 
 
 
 
 
Total 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
xxx 
TUVjoint > 95 (Positive) 
xxx 
xxx 
xxx 
xxx 
 xxx 
 
 
Negative 
xxx 
xxx 
xxx 
 
 
 
 
Total 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
If there are no major protocol deviations, then analysis tables for the ITD and PP populations will contain identical results. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
All Table format is repeated for the PP population 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 40 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 19. Number and Percentage of Subjects with TEAEs 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N= xxx) 
 
 
 
 
Arma 
 
Adverse Event Categoryb: 
HC-1 
HC-2 
RA 
Overall 
 
 
 
 
 
Total Number of TEAEs 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Subjects with at Least One TEAE 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
  System Organ Class 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
  System Organ Class 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
b Adverse events coded with MedDRA Coding Dictionary Version XXX 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 41 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 20. Summary of TEAEs  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
Arma 
 
 
HC-1 
HC-2 
RA 
Overall 
 
 
 
 
 
Subjects With at Least One TEAE 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Maximum TEAE Severity Grade 
 
 
 
 
    Mild 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Moderate 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Severe 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
Highest Relationship of TEAE to Tc 99m tilmanocept 
 
 
 
 
    Definitely Not [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Probably Not [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Possibly [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Probably [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Definitely [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
Highest Relationship of TEAE to Study Procedure 
 
 
 
 
    Definitely Not [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Probably Not [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Possibly [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Probably [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Definitely [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
Subjects with at Least One TESAE 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 42 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 21. Number and Percentage of Subjects with TESAEs  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
Arma 
 
 
Adverse Event Categoryb: 
HC-1 
HC-2 
RA 
Overall 
 
 
 
 
 
Total Number of TESAEs 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Subjects with at Least One TESAE 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
  System Organ Class 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
  System Organ Class 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
b Adverse events coded with MedDRA Coding Dictionary Version XXX 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 43 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 22. Number and Percentage of Subjects With TEAEs by Severity Grade 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
Part 1 of 4 – HC-1a 
 
 
 
 
 
 
Severity Grade 
Adverse Event Categoryb: 
Mild 
Moderate 
Severe 
 
 
 
 
Total Number of TEAEs 
xxx 
xxx 
xxx 
 
 
 
 
Subjects with at Least One TEAE 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
  System Organ Class 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
  System Organ Class 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
b Adverse events coded with MedDRA Coding Dictionary Version XXX 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
 
Table format repeats for HA-2, RA (Parts 2 and 3) and overall (Part 4). 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 44 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
 
Table 23. Number and Percentage of Subjects With TEAEs by Level of Relationship 
to Tc 99m Tilmanocept  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
Part 1 of 4 : HC-1a 
 
 
 
 
 
 
Level of Relationship 
Adverse Event Categoryb: 
Definitely 
Not 
Probably 
Not 
Possibly 
Related 
Probably 
Related 
Definitely 
Related 
 
 
 
 
 
 
Total Number of TEAEs 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Subjects with at Least One TEAE 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
  System Organ Class 1 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
  System Organ Class 2 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
b Adverse events coded with MedDRA Coding Dictionary Version XXX 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
Table format repeats for HC-2, RA (Parts 2 and 3) and overall (Part 4). Full Table (all parts) repeats for Table 24. 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 45 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 25.  Serum Chemistry Clinical Laboratory Parameters Summary Statistics by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
                                 
 
Parameter(units) 
Arma 
Visit  
Data Typeb 
Mean 
Std 
Dev 
n 
Min 
Max 
Median 
xxxxxxxx(xxx) 
HC-1 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 (Visit 2)      
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
HC-2 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 (Visit 2) 
RAW 
 
 
 
 
 
 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 (Visit 2) 
RAW 
 
 
 
 
 
 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx(xxx) 
HC-1 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 (Visit 2) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
HC-2 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 (Visit 2) 
RAW 
 
 
 
 
 
 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 (Visit 2) 
RAW 
 
 
 
 
 
 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
b RAW = data recorded in database; CFB = change from baseline= (parameter value at the current time point)-(Baseline parameter value) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Table format repeats for Tables 26 and 27. 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 46 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 28. Serum Chemistry Clinical Laboratory Parameters Shift Table by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 1 of 3: HC-1a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for Tables 29 (Hematology) and 30 (Urinalysis) 
 
 
 
 
Baseline Result/ 
Post-Injection Result 
 
Panel/Parameter 
(units) 
Low/ 
Low 
Low/ 
Normal 
Low/ 
High 
Normal/ 
Low 
Normal/ 
Normal 
Normal/ 
High 
High/ 
Low 
High/ 
Normal 
High/ 
High 
 
 
 
 
 
 
 
 
 
 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 47 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
 
Page x of y 
 
Table 28. Serum Chemistry Clinical Laboratory Parameters Shift Table by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 2 of 3: HC-2a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for Tables 29 (Hematology) and 30 (Urinalysis) 
 
 
 
 
Baseline Result/ 
Post-Injection Result 
 
Panel/Parameter 
(units) 
Low/ 
Low 
Low/ 
Normal 
Low/ 
High 
Normal/ 
Low 
Normal/ 
Normal 
Normal/ 
High 
High/ 
Low 
High/ 
Normal 
High/ 
High 
 
 
 
 
 
 
 
 
 
 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 48 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 28. Serum Chemistry Clinical Laboratory Parameters Shift Table by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 3 of 3: RAa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
Table format is repeated for Tables 29 (Hematology) and 30 (Urinalysis) 
 
 
 
 
Baseline Result/ 
Post-Injection Result 
 
Panel/Parameter 
(Units) 
 
Low/ 
Low 
Low/ 
Normal 
Low/ 
High 
Normal/ 
Low 
Normal/ 
Normal 
Normal/ 
High 
High/ 
Low 
High/ 
Normal 
High/ 
High 
 
 
 
 
 
 
 
 
 
 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 49 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Table 31.  Vital Signs Summary Statistics by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
                                 
Vital Sign 
Parameter (units) 
Arma 
Visit 
Data 
Typeb 
Mean 
Std Dev 
n 
Min 
Max 
Median 
xxxxxxxxx (xxx) 
HC-1 
Screening  
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
HC-2 
Day 0 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
HC-2 
Screening  
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
HC-2 
Day 0 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
RA 
Screening  
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA 
Day 0 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________     
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
b RAW = data recorded in database; CFB = change from baseline= (parameter value at the current time point)-(Baseline parameter value). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 50 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Figure 1. Normal QQ plot for TUVjoint Data - All Arm 1 and 2 Healthy Control Subjects 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Figure format is repeated for the PP population.  


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 51 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Figure 3. Scatter Plot of TUVjoint Distribution of the Right Hand - All Arm 1 and 2 Healthy Control Subjects 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Figure format is repeated for the PP population.  
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 52 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Figure 5. Scatter Plot of TUVjoint Distribution of the Left Hand - All Arm 1 and 2 Healthy Control 
Subjects 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Figure format is repeated for the PP population. 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 53 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Figure 7. Scatter Plot of TUVjoint Distribution for MCP1 by Age – All Arm 1 and 2 Healthy Control Subjects 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Figure format is repeated per joint and again for the PP population per joint. Repeat for Sex and BMI. 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 54 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Figure 33. Scatter Plot of Residuals by Age – All Arm 1 and 2 Healthy Control Subjects 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
 
 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Figure format is repeated the PP Population.  
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 55 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 1. Subject Disposition Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
 
 
 
 
 
 
 
 
 
                        
 
                                                                                                                                       
 
Arma 
 
Subject 
No. 
 
 
Disposition Status 
 
Date of 
Completion or 
Withdrawal 
 
 
Withdrawal Reason 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 56 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 2. Inclusion/Exclusion Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Arma 
 
 
Subject 
No. 
 
Did Subject 
Meet All 
Eligibility 
Criteria? 
Criterion Category 
 
 
Criterion 
Was a 
Waiver 
Granted? 
Is Subject a 
Screen 
Failure? 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
xxxxxx 
xxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
xxxxxx 
xxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
xxxxxx 
xxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 57 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 3. Protocol Deviations Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Arma 
 
 
Subject 
No. 
Date of 
Deviation 
Deviation Description  
 
 
Deviation Category 
(Major/Minor) 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 58 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 4. Demographics Data Listing  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=135) 
 
 
 
 
 
 
 
                        
 
                                                                                                                             
 
 
 
 Arma 
 
 
Subject 
No. 
 
Informed 
Consent 
Date/Time 
 
Date 
of 
Birth 
Height 
(inches) 
Weight 
(pounds) 
 
 
Age 
(yrs) 
 
 
 
Gender 
 
 
 
Race 
 
 
 
Ethnicity Handedness 
WOCBP? 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________  
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 59 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 5. Subjects Excluded from ITD Population Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
All Enrolled Subjects (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Arma 
 
 
Subject No. 
 
 
Reason for Exclusion 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 60 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 6. Subjects Excluded from PP Population Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
All Enrolled Subjects (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Arma 
 
 
Subject No. 
 
 
Reason for Exclusion 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 61 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 7. Subjects Excluded from Safety Population Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
All Enrolled Subjects (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Arma 
 
 
Subject No. 
 
 
Reason for Exclusion 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 62 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 8. Medical History Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
Arma 
Subject 
No. 
MedDRA System Organ Classb/ 
MedDRA Preferred Term/ 
CRF Verbatim Term 
Start Date  
Resolution/Stop 
Date 
Ongoing? 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
b Medical history terms coded with MedDRA Coding Dictionary Version xxx. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 63 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 9. Prior and Concomitant Medications Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
Arma 
Subject 
No. 
Drug Preferred Termb/ 
Verbatim/ 
ATC Level 1 Text/ 
ATC Level 4 Text 
Indication Frequency 
Start 
Date 
Stop 
Date 
Route Ongoing? 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_______________________________________________________________________________________________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
b Medications coded with WHO Coding Dictionary xxxxxxxxx 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 64 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 10. Prior and Concomitant RA Medications Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
Arma 
 
 
Subject 
No. 
 
 
Drug Preferred Termb/ 
Verbatim/ 
ATC Level 1 Text/ 
ATC Level 4 Text 
Indication Frequency 
 
 
 
 
 
Start 
Date 
 
 
 
 
 
 
Stop 
Date 
 
 
 
 
 
 
Route 
 
 
 
 
 
 
Ongoing? 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
b Medications coded with WHO Coding Dictionary xxxxxxxxx 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 65 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 11. Adverse Events Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
Arma 
 
 
Subject 
No. 
Start 
Date and 
Time/ 
End Date 
and Time 
Start Date 
and Time of 
tilmanocept 
Injection 
Treatment 
Emergent? 
MedDRA System Organ 
Classb/ 
MedDRA Preferred 
Term/ 
CRF Verbatim Term 
Severity  
Relation to 
Tc-99m 
tilmanocept/ 
Procedure 
Serious? 
Outcome 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxxx 
xxxxxxx 
xxxxxxx/ 
xxxxxxx 
xxxxxxx 
xxxxxxx  
xxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxx 
xxxxxxxx/ 
xxxxxxxx 
 
xxx 
 
xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxxx 
xxxxxxx 
xxxxxxx/ 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxx 
xxxxxxxx/ 
xxxxxxxx 
 
xxx 
 
xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
b Adverse events coded with MedDRA Coding Dictionary Version xxx 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 66 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 12. Subject Laboratory Profiles - Hematology Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Normal Range 
 
 
Arma 
Subject 
No. 
 
Visit 
Sample Date 
and Time 
Lab Parameter (Units) 
 
Result 
 
Lab Low 
 
Lab High 
Clin. Sig? 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxx 
xxxxxxxx / xx:xx 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for Serum Chemistry, Urinalysis, and Rheumatology Panel Listings (Listings 13, 14, 15). 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 67 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 16. Physical Exam Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
Arma 
 
 
Subject 
No. 
 
 
 
 
 
Visit 
 
 
 
 
Date 
Conducted 
 
 
 
 
 
Body System 
 
 
 
 
 
Result 
 
 
 
 
 
Abnormality 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxx 
General Appearance 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Skin 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Eyes, Ears, Nose, Throat 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Head and Neck 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Lungs 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Heart 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Abdomen 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Lymph Nodes 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Musculoskeletal 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Nervous System 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Other: XXXXXX 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 68 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 17. ACR/EULAR 2010 Classification Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
ACR/EULAR 2010 
 
 
Arma 
 
 
Subject 
No. 
 
 
 
 
Visit 
 
 
 
 
Date 
Joint 
Involvement 
Serology 
Acute-
Phase 
Reactants 
Duration 
of 
Symptoms 
Total Score 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
xxxxxx 
xxxx 
xxxxxxx 
 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 69 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 18. DAS-28 by Joint Data Listing – Arm 2 RAa Subjects 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
 
 
DAS28 Joint Classification 
 
 
Subject 
No. 
 
Visit 
 
 
Date 
Joint 
Result  
(Right Body) 
Result  
(Left Body) 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxx 
xxxxxxxxx 
xxx 
xxx 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
xxxxxxxxx 
xxx 
xxx 
xxxx 
xxxxxxx 
xxxxxxx 
xxxxxxxxx 
xxx 
xxx 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 70 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 19. DAS-28 by Subject Data Listing – Arm 2 RAa Subjects  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
 
DAS28 
 
 
Subject 
No. 
 
Visit 
 
 
Date 
Tender 
Joint 
Count 
Swollen 
Joint 
Count 
Patient 
VAS 
Global 
(mm) 
Erythrocyte 
Sedimentation 
Rate (ESR; 
mm/hr) 
DAS28 
Score 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 71 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 20. Vital Signs Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
Arma 
 
 
Subject 
No. 
 
 
 
 
Visit 
 
 
 
 
Date 
 
 
 
 
Time  
 
 
 
Temp. 
(°F) 
 
Systolic 
Blood 
Pressure 
(mmHg) 
Diastolic 
Blood 
Pressure 
(mmHg) 
Heart 
Rate 
(bpm) 
 
 
 
Respirations 
per Minute 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
 
xxxxxxx 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
 
xxxxxxx 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 72 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
Page x of y 
 
Data Listing 21. Study Drug Administration Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
 
Arma 
 
 
Subject 
No. 
Date/ 
Time of 
Injection  
 
 
 
Anatomic 
Location 
of 
Injection 
 
Pre-Injection 
Radioactivity 
(mCi)/Time of 
Measurement 
 
Post-
Injection 
Radioactivity 
(mCi)/Time of 
Measurement 
 
Calculated 
Amount of 
Administered 
Radioactivity 
(mCi) 
Source 
Recorded 
Administered 
Radioactivity 
(mCi) 
Calculated 
Mass Dose 
(µg) 
Volume 
Injected  
(mL) 
 
 
 
Lot  
Number 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxx/ 
xxxx 
xxxxxxxx 
xxx/ 
xxxx 
xxx/ 
xxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxx/ 
xxxx 
xxxxxxxx 
xxx/ 
xxxx 
xxx/ 
xxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx/ 
xxxx 
xxxxxxxx 
xxx/ 
xxxx 
xxx/ 
xxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2)STATKING 
Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 73 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
  
 
Page x of y 
 
Data Listing 22. Post-Injection Imaging Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
 
Arma,b 
Subject 
No. 
 
Visit 
Date of 
Imaging  
Start Time 
of Planar 
Imaging 
End Time 
of Planar 
Imaging 
Start Time  
of SPECT/CT 
Imaging 
End Time  
of SPECT/CT 
Imaging 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxx 
xxxxxx 
xx:xx 
xx:xx 
xx:xx 
xx:xx 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxx 
xxxxxx 
xx:xx 
xx:xx 
xx:xx 
xx:xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
b SPECT/CT imaging performed only in study Arm 2 - RA 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 74 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
                                                  
 
 
Page x of y 
 
Data Listing 23. SPECT/CT Reader Results Data Listing – Hands and Wrists 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
Arma 
Subject 
No. 
Post-Injection 
Imaging Time Point 
Joint 
SPECT/CT 
Localization? 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxxxxxxx 
xxxx 
 
 
 
xxxxxxxxxxxx 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxxxxxxx 
xxxx 
 
 
 
xxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-35 
 
Page 75 of 75 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                            July 14, 2022 
 
 
 
Page x of y 
 
Data Listing 24. TUV Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-35 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
Arma 
Subject 
No. 
 
Visit 
Date/Time 
Region of 
Interestb 
TUV 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxxxxxxxxx 
xxxxxx 
xxxxx 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxxxxxxxxx 
xxxxxx 
xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC-1 = healthy control–Arm 1, HC-2 = healthy control–Arm 2, RA = rheumatoid arthritis (stable treatment regimen; Arm 2) 
b Region of Interest is joint for all arms, and joint or Global for the Arm 2 - RA. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas