Clinical trial NCT04078191
Conditions: Rheumatoid Arthritis
Keywords: tilmanocept RA imaging synovial biopsy
Sponsor: Navidea Biopharmaceuticals
Start date: 2021-09-14; Completion date: 2024-07-09
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is a comparison of quantitative Tc 99m tilmanocept imaging with IHC analysis of CD206 expression in synovial tissue of RA subjects.

Detailed description:
This is a Manocept Platform phase 2b, open-label, multi-center, multinational, non-randomized, single-dose study designed to assess the relationship between quantitative Tc 99m tilmanocept planar imaging and synovial histopathology in subjects clinically diagnosed with RA.

Arms: arm 1: RA subjects who are on stable treatment will receive a single dose of 150 mcg tilmanocept radiolabeled with 10 mCi Tc 99m.
Interventions: intervention 1: Tc 99m 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:
SAP_002.pdf: 
 
 
Statistical Analysis Plan (SAP) 
 
 
A Comparison of Tc 99m Tilmanocept Quantitative 
Imaging with Immunohistochemical (IHC) Analysis of 
CD206 Expression in Synovial Tissue from Subjects 
Clinically Diagnosed with Rheumatoid Arthritis (RA) 
 
Study No: NAV3-32  
 
 
 
Version 1.0 
 
September 15, 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 
 
 






Statistical Analysis Plan 
 
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Revision History 
 
N/A 
 
 


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List of Abbreviations and Definitions of Terms  
 
Term 
Definition 
g 
microgram 
ACR/EULAR 
American College of Rheumatology/European League 
Against Rheumatism 
ADR 
adverse drug reaction 
AE 
adverse event 
Anti TNF- 
bDMARD 
Anti-Tumor Necrosis Factor  biological Disease Modifying 
Anti-Rheumatic Drug 
CDAI 
Clinical Disease Activity Index 
CRF 
case report form 
CSR 
clinical study report 
CT 
X-ray computed tomography 
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 
healthy controls  
ICH 
International Conference on Harmonization 
ITA 
intent-to-assay 
IV 
intravenous 
mCi 
milliCurie (37x106 becquerels; 37megabecquerels) 
MCP 
metacarpophalangeal 
MedDRA 
Medical Dictionary for Regulatory Activities 
OA 
osteoarthritis 
PIP 
proximal interphalangeal 
PP 
per protocol 
PT 
preferred term 
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 
Tc 99m 
technetium-99m metastable isotope; γ-emitting (half-life  
6.02 h) 
tilmanocept 
DTPA Mannosyl Dextran (the US Adopted Name for the 
drug substance of Lymphoseek) 
TUV 
Tilmanocept uptake value 
US 
United States 


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Term 
Definition 
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 ...............................................................................................................................11 
1.3 Sample Size .........................................................................................................................................12 
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 
2.6 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 Variables .....................................................................................................15 
4.2 Analysis of Efficacy Variables ..........................................................................................................16 
5.0 ANALYSIS OF SAFETY ............................................................................ 20 
5.1 Description of Safety Variables ........................................................................................................20 
5.2 Description of Safety Analysis ..........................................................................................................20 


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6.0 OTHER RELEVANT DATA ANALYSES/SUMMARIES ............................ 21 
6.1 Patient Completion ............................................................................................................................21 
6.3 Study Drug Administration...............................................................................................................22 
6.4 RA Evaluation and Screening Physical Exam .................................................................................22 
6.5 Concomitant Medications..................................................................................................................22 
7.0 LIST OF ANALYSIS TABLES, FIGURES AND LISTINGS ....................... 23 
8.0 REFERENCES ........................................................................................... 28 
APPENDIX A – TABLES, FIGURES AND LISTING SPECIFICATIONS ........ 29 
APPENDIX B – TABLE SHELLS .................................................................... 30 
 
 


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INTRODUCTION 
 
Description 
 
This Statistical Analysis Plan (SAP) is consistent with the study protocol 
Amendment 6 (dated 24 June 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 is done in accordance with STATKING Clinical 
Services SOP SCI 02-54, Statistical Analysis Plans. 
 
1.0 Synopsis of Study Design/Procedures 
 
This is a Phase 2b, open-label, multi-center, multinational, non-randomized, 
single-dose study designed to assess the relationship between quantitative Tc 
99m tilmanocept planar imaging and synovial histopathology in subjects clinically 
diagnosed with RA.  
 
The objectives of the study are: 
 
Primary Objectives: 
 
• Assessment of the relationship between joint-specific tilmanocept uptake 
value (TUVjoint) and synovial anatomic pathology.  
• IHC assessment of macrophage expression of the CD206 receptor.  
 
Secondary Objectives: 
 
• Assessments of CD68 and CD163 receptor expression levels through IHC 
microscopy.  
• Classification of synovial anatomic pathology as  
o Lympho-myeloid  
o Diffuse myeloid  
o Pauci-immune fibroid  
 
Exploratory Objectives: 
 
• Determine the relationship between TUVjoint and mRNA expression 
profiles of CD68, CD163, and CD206 as determined by RNA sequencing 
(RNA-seq).  
• Determine the relationship between TUVjoint and the number, size, and 
intensity of CD68, CD163, and CD206 as determined by (optional) flow 
cytometry.  
• Evaluate synovial expression of CD3, CD20, CD55, and TE-7 and CD206 
in synovial tissue biopsy specimens.  


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• Assessment of the relationship between global tilmanocept uptake value 
(TUVglobal) and synovial anatomic pathology.  
 
Safety Objective: 
 
• Evaluate safety through the examination of adverse event (AE) incidence, 
physical examination findings, and changes over time in laboratory tests, 
electrocardiograms (ECGs), and vital signs.  
 
1.1 Design and Treatment 
 
Subjects will receive the administration of Tc 99m tilmanocept through an 
intravenous (IV) route of administration. All subjects will receive a 150 g mass 
dose of tilmanocept radiolabeled with 10 mCi of Tc 99m and will be at study time 
00:00. 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.  
 
Subjects will undergo an imaging assessment of the bilateral hands and wrists 
followed by an ultrasound-guided synovial biopsy of a select joint at a subsequent 
visit. Tissue samples from the synovial biopsy procedure will be used for 2 
mandatory anatomic pathology evaluations, [1] IHC and [2] RNA-seq, and 
optional flow cytometry, to provide quantitative and semi-quantitative information 
regarding joint-specific disease activity. Results from each anatomic pathology 
evaluation will be correlated with TUVjoint on planar imaging to mechanistically 
assess the relationship between synovial anatomic pathology and TUVjoint.  
 
All joints selected for biopsy will be required to have an ultrasound synovial 
thickness score of ≥ 2. In instances where more than 1 joint qualifies for biopsy, 
the candidate joint will be selected based on TUVjoint. 
 
Table 1 Biopsy Selection Options 
Option 
Description 
1 
The 
subject 
has 
only 
1 
metacarpophalangeal (MCP) joint or 
wrist joint with an ultrasound gray-
scale synovitis score of ≥ 2. This joint 
will be selected for biopsy. 
2 
The subject has 2 or more MCP 
and/or wrist joints with an ultrasound 
gray-scale synovitis score of ≥ 2. The 
joint for biopsy will be selected based 
on 
evaluation 
of 
corresponding 
TUVjoint. In the first subject with 
multiple qualifying joints, the joint with 


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the highest TUVjoint will be selected; in 
the second subject with multiple 
qualifying joints, the joint with the 
lowest TUVjoint will be selected. 
Selection will proceed in this fashion, 
alternating 
between 
highest 
and 
lowest TUVjoint. 
 
1.2 Study Procedures 
 
Subjects will be “on study” for up to 45 days depending on the screening window 
(up to 30 days). The first visit is for the screening (Day -30 to -1). Screening 
procedures (demographics, vital signs, medical and surgical history, concomitant 
medications, blood and urine samples for clinical labs, RA specific labs, urine 
pregnancy testing for subjects of childbearing potential, ultrasound synovitis 
assessment, AE assessment, and physical exam) will be completed along with 
RA evaluations including the 2010 ACR/EULAR classification criteria and DAS28 
evaluation.  
 
On Day 0 (visit 2) subjects will receive Tc 99m injection and imaging procedures. 
Pre-injection procedures include the following: Urine pregnancy testing for all 
women of childbearing potential. Up to 30 minutes prior to study drug 
administration, an ECG will be performed, followed by assessment of vital signs, 
AEs, and concomitant medications. After pre-injection procedures are 
completed, subjects will receive a single IV dose of 150 g of tilmanocept 
radiolabeled with 10 mCi of Tc 99m. Within 30 minutes after injection, an ECG 
will be performed, followed by assessment of vital signs and AEs. Between 60 
and 75 minutes after injection, subjects will receive an AE assessment and a 
static gamma camera scan of bilateral hands and wrists. Blood will be drawn for 
clinical laboratory evaluations after the image acquisition has been completed. 
Subjects who are administered Tc 99m tilmanocept on Day 0 will be considered 
to be enrolled in the study. 
 
On the third visit (24-72 hours post-injection), a safety follow-up telephone call 
will include a review of concomitant medications and an AE check.   
 
On the fourth visit (3-7 days post-injection), subjects will be given an ultrasound 
assessment of synovitis and then a tissue biopsy of the selected joint in 


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accordance with Table 1 as described in Section 1.1. In addition, an AE check 
and a review of concomitant medications will be conducted.  
 
On the fifth and final visit (5 ± 2 days post-biopsy), a safety follow-up telephone 
call will include a review of concomitant medications and an AE check. 
 
For the entire study, end of study is defined as last subject last visit.  
 
1.3 Sample Size 
 
The sample size is expected to be approximately 12 to 24 joints. The final sample 
size will be determined after the completion of an interim analysis including at 
least 4 subjects in each pathotype (diffuse myeloid, lympho-myeloid and pauci-
immune fibroid). The final sample size will be chosen based on the sponsor’s 
business requirements regarding precision for the estimated correlation between 
CD206 expressing macrophage density and TUVjoint. The final sample size will 
be at least N = 12. If the rarest pathotype has 25% prevalence in the study patient 
pool, the expected number of subjects at the interim analysis is N = 16. These 
needs may be further increased because synovial biopsy fails to recover enough 
tissue for histological analysis in about 15% of cases.  
 
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 subjects who have been 
enrolled in the study and injected with Tc 99m tilmanocept regardless of imaging 
or biopsy status.  
 
Intent-to-Assay (ITA) Population – The ITA population includes all subjects 
that have been enrolled in the study, injected with Tc 99m tilmanocept, received 
all imaging procedures, and have been biopsied.  
 
Per-Protocol (PP) Population: The PP population will include all ITA subjects 
without major protocol violations. At least 4 evaluable synovial biopsy samples 
must be available for a subject to be included in the PP population.  
 


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2.3 Missing Data Conventions 
 
The analysis of the efficacy and safety variables will be carried out on the 
observed data (i.e., a complete case analysis). For the regression and correlation 
analyses, a subject must have valid values for all variables to be used in the 
analysis.  
 
2.4 Interim Analyses 
     
An interim analysis will be performed after 4 subjects in each of the 3 pathotypes 
(diffuse myeloid, lympho-myeloid, and pauci-immune fibroid) have been imaged. 
The final sample size will be recalculated after completion of the interim analysis.  
 
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 intrasubject ratio of the average 
pixel intensity of a joint to the average pixel intensity of the reference region, such 
that: 
 
𝑇𝑈𝑉𝑗𝑜𝑖𝑛𝑡= 𝑥̅𝐽𝑜𝑖𝑛𝑡 𝑅𝑂𝐼
𝑥̅𝑅𝑅
 
where 
 
• 𝑋̅𝐽𝑜𝑖𝑛𝑡 𝑅𝑂𝐼 is the average pixel intensity of a region of interest (ROI) of a 
subject at the anterior or posterior view at the time of imaging (nominally 
60 minutes); 
• 𝑋̅𝑅𝑅 is the average pixel intensity of the reference region (RR) of a subject 
at the anterior or posterior view at the time of imaging (nominally 60 
minutes). 
 
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
, 
TUVglobal = ∑MI𝑘
22
𝑘=1
. 
 
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. 
 
2.6 Study Center Considerations in the Data Analysis 
 
Up to 10 Centers which include sites in the US, UK, and EU. Analysis will be 
conducted on the pooled data from all 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. 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 Variables 
 
4.1.1 Primary efficacy variables 
The primary efficacy variables for this study are:  
 
• Tc 99m tilmanocept uptake values (TUVjoint) for the biopsied joints;  
• IHC assessment of macrophage expression of the CD206 receptor. 
 
The primary endpoint is: 
 
• The correlation between joint-specific tilmanocept uptake value (TUVjoint) 
and the number and area fraction of CD206 expression as determined by 
IHC assessment.  
 
4.1.2 Secondary efficacy variables 
 
The secondary variables for this study are:  
 
• IHC and immunofluorescence assessment of macrophage expression 
and co-expression of the CD68 and CD163 receptors. 
• Pathotype classification of RA disease as lympho-myeloid, diffuse 
myeloid, or pauci-immune fibroid, based on TUVjoint.  
 
The secondary endpoints are: 
 
• The correlation between TUVjoint and the number and area fraction of 
CD68 and CD163 determined by IHC assessments.  
• Classification of synovial anatomic pathology into Lympho-myeloid, 
Diffuse myeloid, and Pauci-immune fibroid types as a function of CD68, 
CD163, CD206, CD3, CD20, CD55, and TE7 expression determined by 


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IHC assessments using a multinomial logistic regression model with 
TUVjoint as a covariate.  
• The correlation between the expression of CD68, CD163, and CD206.  
 
4.1.3 Exploratory efficacy variables 
 
The exploratory variables for this study are:  
 
• IHC assessment of macrophage expression of the CD3, CD20, CD55, and 
TE7 biomarkers. 
• mRNA levels in synovial tissue for the CD206, CD163, and CD68 
biomarkers. 
• Flow cytometry measurements of CD206, CD163, and CD68 biomarker 
expression and co-expression.  
• Tc 99m tilmanocept global uptake values (TUVglobal) per subject.  
• IHC assessment of the expression of a biomarker (e.g., CD206, TE7) is 
determined from immunofluorescent microscopy, specifically: 
o The ratio of the total fluorescent stained area to the total field area 
under 4x and 10x power magnification. 
• Pathotype classification of RA disease as lympho-myeloid, diffuse 
myeloid, or pauci-immune fibroid, based on TUVglobal. 
 
The exploratory endpoints for this study are:  
 
• The correlation of the expression of CD3, CD20, CD55, and TE7 with 
CD206 as measured through IHC.  
• The correlation of TUVjoint with the expression of CD206, CD163, and 
CD68 as measured through RNA-seq.  
• The number and size of CD206, CD163, and CD68 expressing 
macrophages as measured through (optional) flow cytometry and their 
correlation with TUVjoint.  
• The correlation between TUVglobal and synovial anatomic pathology as 
determined by IHC assessments.  
• Classification of synovial anatomic pathology into Lympho-myeloid, 
Diffuse myeloid, and Pauci-immune fibroid types using a multinomial 
logistic regression model with TUVglobal as a covariate. 
 
4.2 Analysis of Efficacy Variables 
 
All efficacy analyses will be conducted on both the ITA and PP populations. The 
ITA population will be the primary analysis set.  
 
 
 
 


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4.2.1 Primary Efficacy Variables 
 
The primary endpoint will be analyzed by computing the Pearson (product-
moment) and Spearman (rank) correlation coefficient between the TUV for the 
biopsied joint and the final CD206 expressing macrophage count. The CD206 
expressing macrophage count is derived from the IHC histopathology and 
ultrasound imaging: 
 
• The fraction of CD206 expressing macrophages under 4x and 10x power 
magnification, defined as the ratio of the total fluorescent stained area to 
total field area. Specifically, area fraction (AF) is defined as 
 
𝐴𝐹= 𝑇𝑜𝑡𝑎𝑙 𝑆𝑡𝑎𝑖𝑛𝑒𝑑 𝐴𝑟𝑒𝑎
𝑇𝑜𝑡𝑎𝑙 𝐹𝑖𝑒𝑙𝑑 𝐴𝑟𝑒𝑎 × 100%. 
 
• The volume of synovial tissue in the biopsied joint, defined as the 
ultrasound synovial thickness score (Vol). The CD206 macrophage count 
will be the product of these 2 variables (that is, CD206 = AF*Vol). 
 
CD206 expressing macrophage fraction and TUVjoint will be summarized with 
descriptive statistics (number of data pairs, means, standard deviations, minima, 
medians, and maxima as well as the Pearson correlation between the variables). 
The ultrasound synovitis score will be summarized with a frequency table. 
Defining ρ to be the population correlation coefficient, a test of the hypotheses 
 
H𝑜: 𝜌≤0 
H𝑎: 𝜌> 0 
 
will be performed using Fisher’s Z-transformation and its Normal approximation. 
A 95% confidence interval for the population correlation coefficient (ρ) based on 
the Fisher Z-transformation (the inverse hyperbolic tangent) and its normal 
approximation will be provided. The joint distribution of the CD206 macrophage 
count and TUVjoint will be summarized graphically with a scatter diagram of the 
data pairs with the least-squares regression line superimposed on the graph. The 
joint distribution of the component variables of CD206 macrophage count will be 
graphically summarized with box plots showing the conditional distribution of 
TUVjoint for each category of synovitis score. 
 
4.2.2 Secondary Efficacy Variables 
 
Co-expression of the CD68, CD163, and CD206 markers will be analyzed by 2 
methods. First, by providing the product-moment and Spearman rank correlation 
matrices of the IHC field measurements (that is, the fraction of macrophages 
expressing the markers will not be multiplied by the synovitis score). Descriptive 
statistics of the data triplets used to calculate the correlation matrices will be 


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provided (number of data triplets, means, standard deviations, minima, medians, 
and maxima). In the second method, histological sections will undergo 
immunofluorescent staining for the 3 markers and DAPI. For each section 
evaluated, up to 50 cells from the synovial sublining will be identified for each of 
the 3 markers. For each identified cell (up to 150/section), the rate of co-
expression of the 3 markers will be determined. For sections with sparse marker 
expressing cells, four microscope fields will be randomly selected. Co-expression 
of the markers will be quantified for any cell observed expressing a marker. 
 
The ability of TUVjoint to discriminate among lympho-myeloid, diffuse myeloid, 
and pauci-immune fibroid RA disease types will be evaluated with a multinomial 
logistic regression model. The model in terms of the logit (log odds) of the 
outcome is defined as: 
 
𝑙𝑛
𝜋𝑗
1 −𝜋𝑗
= 𝛼𝑗+ 𝛽𝑗𝑋 
where 
j = category of the outcome  
 
𝜋𝑗
1−𝜋𝑗 = odds 
α = intercept 
β = slope 
X = TUVjoint 
 
RA type will be the response variable and TUVjoint will be the explanatory variable. 
ROC curves will be generated using the lympho-myeloid type as the base class. 
The marginal distribution of disease type will be summarized with a frequency 
table, while the marginal distribution of TUVjoint will be summarized with 
descriptive statistics (number of data pairs, mean, standard deviation, minimum, 
median and maximum). The joint distribution will be graphically summarized with 
box plots showing the conditional distribution of TUVjoint for each disease type.  
 
4.2.3 Exploratory Efficacy Endpoints 
 
Expression of CD3, CD20, CD55, CD68, CD163, CD206, and TE7 biomarkers 
and their association with TUVjoint will be assessed with the Pearson (product-
moment) and the Spearman (rank) correlation matrices calculated for each 
measurement of expression (IHC, RNAseq, and [optional] flow cytometry). The 
marginal distributions will be summarized with descriptive statistics (number of 
complete data points, means, standard deviations, minima, medians, and 
maxima). The joint distribution will be presented graphically in a windowpane plot 
of the scatter diagrams. 
 
Expression of CD206, CD163, and CD68 genes in mRNA will be measured with 
cDNA probes. The TUVjoint values concentrations will be regressed on the mRNA 


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abundance as determined by RNA-seq values. The marginal distributions will be 
summarized with descriptive statistics (number of complete data points, means, 
standard deviations, minima, medians, and maxima). The joint distribution will be 
presented with a windowpane plot of the scatter diagrams. The regression 
coefficients will be presented with the estimated residual covariance matrix.  
The number, size, and co-expression of CD68, CD163, and CD206 expressing 
macrophages measured by flow cytometry and their relationship with TUVjoint will 
be assessed with the Pearson (product-moment) and Spearman (rank) 
correlation matrices. The marginal distributions of all variables will be 
summarized by descriptive statistics (number of complete data points, means, 
standard deviations, minima, medians, and maxima). The joint distributions will 
be presented graphically in a windowpane plot of the scatter diagrams. 
 
The ability of TUVglobal to discriminate among lympho-myeloid, diffuse myeloid, 
and pauci-immune fibroid RA disease types will be evaluated with a multinomial 
logistic regression model. The model in terms of the logit of the outcome is 
defined as: 
 
𝑙𝑛
𝜋𝑗
1 −𝜋𝑗
= 𝛼𝑗+ 𝛽𝑗𝑋 
where 
j = category of the outcome 
 
𝜋𝑗
1−𝜋𝑗 = odds 
α = intercept 
β = slope 
X = TUVglobal 
 
RA type will be the response variable and TUVglobal will be the explanatory 
variable. ROC curves will be generated using the lympho-myeloid type as the 
base class. The marginal distribution of disease type will be summarized with a 
frequency table, while the marginal distribution of TUVglobal will be summarized 
with descriptive statistics (number of data pairs, mean, standard deviation, 
minimum, median and maximum). The joint distribution will be graphically 
summarized with box plots showing the conditional distribution of TUVglobal for 
each disease type.  
 
If it is found (based on the ROC curves from the multinomial logistic regressions) 
that TUVjoint and TUVglobal can discriminate between the three RA disease types, 
then no additional analyses will be performed. However, if this is not the case, 
then two binary logistic regression analyses, with fibroid vs. non-fibroid disease 
type as the response and TUVjoint and TUVglobal as predictors, respectively, will 
also be conducted. 


Statistical Analysis Plan 
 
Study No. NAV3-32 
 
 
Page 20 of 84 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                   September 15, 2022                                  
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) 
• ECG Parameters 
• Vital Signs 
 
All adverse events (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 date of the first 
tilmanocept injection. If the first injection date or the AE start date is missing, the 
AE will be considered treatment emergent. 
 
Prior to analysis to all AEs will be coded using the MedDRA coding dictionary. 
Based on the coded terms, TEAEs will be summarized as follows: 
 
• 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. 
 
 
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.   
 
Observed and change from baseline for vital sign parameters, ECG parameters, 
hematology, clinical chemistry, and urinalysis parameters will be summarized 
using descriptive statistics (n, mean, standard deviation, min, median, and max) 
at each timepoint.  
 
A data listing will be prepared that reflects the occurrence of TEAEs associated 
with each concomitant medication or class of medications to examine whether a 
drug interaction signal is detectable.  
 
Clinical Laboratory Tests  
Clinical laboratory tests will be performed at screening and after image 
acquisition. Abnormal laboratory values will be assessed for clinical significance. 
For each quantitative laboratory test, descriptive statistics (mean, standard 


Statistical Analysis Plan 
 
Study No. NAV3-32 
 
 
Page 21 of 84 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                   September 15, 2022                                  
deviation, median, range, n) on the raw, as well as their changes from baseline, 
will be presented by timepoint. 
 
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.  
 
ECG Parameters 
A standard 12-lead ECG will be obtained up to 30 minutes before investigational 
product administration and within 30 minutes after investigational product 
administration. The ECG will be performed with the subject in a resting position 
for at least 1 minute. Continuous ECG monitoring is not required. At a minimum, 
the heart rate, QRS, PR, and QT intervals will be collected. QTc will be calculated 
using the Fridericia formula.  
 
Vital Signs 
Vital signs will be performed at screening, up to 30 minutes before, and within 30 
minutes  after investigational product administration.  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), descriptive 
statistics (mean, standard deviation, minimum, maximum, n) on the raw, as well 
as their changes from baseline, will be presented by timepoint. 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.   
 
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. 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. 
 


Statistical Analysis Plan 
 
Study No. NAV3-32 
 
 
Page 22 of 84 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                   September 15, 2022                                  
6.3 Study Drug Administration 
 
The volume, calculated mass dose, and radioactivity of Tc 99m Tilmanocept 
injected will be summarized with descriptive statistics. All study drug 
administration data will be listed. 
 
6.4 RA Evaluation and Screening Physical Exam 
 
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 
 
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. NAV3-32 
 
 
Page 23 of 84 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                   September 15, 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  
X 
X 
2 
Demographics and Baseline Data Descriptive Statistics 
- Continuous Variables (Safety Population) 
X 
X 
3 
Demographics and Baseline Data Descriptive Statistics 
– Categorical Variables (Safety Population) 
X 
X 
4 
Descriptive Statistics of TUVjoint and the CD206 
Expressing Macrophage Fraction (ITA population) 
X 
X 
5 
Descriptive Statistics of TUVjoint and the CD206 
Expressing Macrophage Fraction (PP Population) 
X 
 
6 
Number and Percent of Subject’s Ultrasound Synovitis 
Scores (ITA Population)   
X 
X 
7 
Number and Percent of Subject’s Ultrasound Synovitis 
Scores (PP Population) 
X 
 
8 
Pearson (Product-Moment) Correlation between CD68, 
CD163, and CD206 of IHC Measurements (ITA 
Population) 
X 
X 
9 
Pearson (Product-Moment) Correlation between CD68, 
CD163, and CD206 of IHC Measurements (PP 
Population) 
X 
 
10 
Spearman (Rank) Correlation between CD68, CD163, 
and CD206 of IHC Measurements (ITA Population) 
X 
 
11 
Spearman (Rank) Correlation between CD68, CD163, 
and CD206 of IHC Measurements (PP Population) 
X 
 
12 
Descriptive Statistics of CD68, CD163, and CD206 from 
IHC Measurements (ITA Population) 
X 
X 
13 
Descriptive Statistics of CD68, CD163, and CD206 from 
IHC Measurements (PP population) 
X 
 
14 
Number and Percent of Subjects in Each RA Disease 
Type - TUVjoint (ITA Population) 
X 
X 
15 
Number and Percent of Subjects in Each RA Disease 
Type - TUVjoint (PP Population) 
X 
 
16 
Number and Percent of Subjects in Each RA Disease 
Type – TUVglobal (ITA Population) 
X 
 
17 
Number and Percent of Subjects in Each RA Disease 
Type – TUVglobal (PP Population) 
X 
 
18 
Descriptive Statistics of the Marginal Distribution of 
TUVjoint (ITA Population) 
X 
X 
19 
Descriptive Statistics of the Marginal Distribution of 
TUVjoint (PP Population) 
X 
 
20 
Descriptive Statistics of the Marginal Distribution of 
TUVglobal (ITA Population) 
X 
 
21 
Descriptive Statistics of the Marginal Distribution of 
TUVglobal (PP Population) 
X 
 
22 
Pearson (Product-Moment) Correlation of CD3, CD20, 
CD55, CD68, CD163, CD206, and TE7 Biomarkers 
Association with TUVjoint Measured by IHC 
Measurement (ITA Population) 
X 
X 


Statistical Analysis Plan 
 
Study No. NAV3-32 
 
 
Page 24 of 84 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                   September 15, 2022                                  
 
Table 
No. 
 
 
Table Title 
Included 
in Final 
Tables 
Shown in 
Appendix 
B 
23 
Pearson (Product-Moment) Correlation of CD3, CD20, 
CD55, CD68, CD163, CD206, and TE7 Biomarkers 
Association with TUVjoint Measured by IHC 
Measurement (PP Population) 
X 
 
24 
Pearson (Product-Moment) Correlation of CD3, CD20, 
CD55, CD68, CD163, CD206, and TE7 Biomarkers 
Association with TUVjoint Measured by RNAseq (ITA 
Population) 
X 
 
25 
Pearson (Product-Moment) Correlation of CD3, CD20, 
CD55, CD68, CD163, CD206, and TE7 Biomarkers 
Association with TUVjoint Measured by RNAseq (PP 
Population) 
X 
 
26 
Pearson (Product-Moment) Correlation of CD3, CD20, 
CD55, CD68, CD163, CD206, and TE7 Biomarkers 
Association with TUVjoint Measured by Flow Cytometry 
(ITA Population) 
X 
 
27 
Pearson (Product-Moment) Correlation of CD3, CD20, 
CD55, CD68, CD163, CD206, and TE7 Biomarkers 
Association with TUVjoint Measured by Flow Cytometry 
(PP Population) 
X 
 
28 
Spearman (Rank) Correlation of CD3, CD20, CD55, 
CD68, CD163, CD206, and TE7 Biomarkers 
Association with TUVjoint Measured by IHC 
Measurement (ITA Population) 
X 
X 
29 
Spearman (Rank) Correlation of CD3, CD20, CD55, 
CD68, CD163, CD206, and TE7 Biomarkers 
Association with TUVjoint Measured by IHC 
Measurement (PP Population) 
X 
 
30 
Spearman (Rank) Correlation of CD3, CD20, CD55, 
CD68, CD163, CD206, and TE7 Biomarkers 
Association with TUVjoint Measured by RNAseq (ITA 
Population) 
X 
 
31 
Spearman (Rank) Correlation of CD3, CD20, CD55, 
CD68, CD163, CD206, and TE7 Biomarkers 
Association with TUVjoint Measured by RNAseq (PP 
Population) 
X 
 
32 
Spearman (Rank) Correlation of CD3, CD20, CD55, 
CD68, CD163, CD206, and TE7 Biomarkers 
Association with TUVjoint Measured by Flow Cytometry 
(ITA Population)  
X 
 
33 
Spearman (Rank) Correlation of CD3, CD20, CD55, 
CD68, CD163, CD206, and TE7 Biomarkers 
Association with TUVjoint Measured by Flow Cytometry 
(PP Population) 
X 
 
34 
Descriptive Statistics of CD3, CD20, CD55, CD68, 
CD163, CD206, and TE7 Biomarkers Association with 
TUVjoint Measured by IHC Measurement (ITA 
Population) 
X 
X 
35 
Descriptive Statistics of CD3, CD20, CD55, CD68, 
CD163, CD206, and TE7 Biomarkers Association with 
X 
 


Statistical Analysis Plan 
 
Study No. NAV3-32 
 
 
Page 25 of 84 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                   September 15, 2022                                  
 
Table 
No. 
 
 
Table Title 
Included 
in Final 
Tables 
Shown in 
Appendix 
B 
TUVjoint Measured by IHC Measurement (PP 
Population) 
36 
Descriptive Statistics of CD3, CD20, CD55, CD68, 
CD163, CD206, and TE7 Biomarkers Association with 
TUVjoint Measured by RNAseq (ITA Population) 
X 
 
37 
Descriptive Statistics of CD3, CD20, CD55, CD68, 
CD163, CD206, and TE7 Biomarkers Association with 
TUVjoint Measured by RNAseq (PP Population) 
X 
 
38 
Descriptive Statistics of CD3, CD20, CD55, CD68, 
CD163, CD206, and TE7 Biomarkers Association with 
TUVjoint Measured by Flow Cytometry (ITA Population) 
X 
 
39 
Descriptive Statistics of CD3, CD20, CD55, CD68, 
CD163, CD206, and TE7 Biomarkers Association with 
TUVjoint Measured by Flow Cytometry (PP Population) 
X 
 
40 
Descriptive Statistics of CD68, CD163, and CD206 
Genes in mRNA (ITA Population) 
X 
X 
41 
Descriptive Statistics of CD68, CD163, and CD206 
Genes in mRNA (PP Population) 
X 
 
42 
Estimated Residual Covariance with the Regression 
Coefficients of the CD68, CD163, and CD206 Genes in 
mRNA (ITA Population) 
X 
X 
43 
Estimated Residual Covariance with the Regression 
Coefficients of the CD68, CD163, and CD206 Genes in 
mRNA (PP Population) 
X 
 
44 
Pearson (Product-Moment) Correlation of CD68, 
CD163, CD206 Expressing Macrophages Measured by 
Flow Cytometry and Their Relationship to TUVjoint (ITA 
Population) 
X 
X 
45 
Pearson (Product-Moment) Correlation of CD68, 
CD163, CD206 Expressing Macrophages Measured by 
Flow Cytometry and Their Relationship to TUVjoint (PP 
Population) 
X 
 
46 
Spearman (Rank) Correlation of CD68, CD163, CD206 
Expressing Macrophages Measured by Flow Cytometry 
and Their Relationship to TUVjoint (ITA Population) 
X 
 
47 
Spearman (Rank) Correlation of CD68, CD163, CD206 
Expressing Macrophages Measured by Flow Cytometry 
and Their Relationship to TUVjoint (PP Population) 
X 
 
48 
Descriptive Statistics of CD68, CD163, and CD206 
Expressing Macrophages Measured by Flow Cytometry 
(ITA Population) 
X 
X 
49 
Descriptive Statistics of CD68, CD163, and CD206 
Expressing Macrophages Measured by Flow Cytometry 
(PP Population) 
X 
 
50 
Descriptive Statistics of TUVglobal by Pathology Type 
(ITA Population) 
X 
X 
51 
Descriptive Statistics of TUVglobal by Pathology Type (PP 
Population) 
X 
 
52 
Vital Signs Descriptive Statistics (Safety Population) 
X 
X 
53 
Clinical Laboratory Tests Descriptive Statistics (Safety 
Population) 
X 
X 


Statistical Analysis Plan 
 
Study No. NAV3-32 
 
 
Page 26 of 84 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                   September 15, 2022                                  
 
Table 
No. 
 
 
Table Title 
Included 
in Final 
Tables 
Shown in 
Appendix 
B 
54 
ECG Parameters Descriptive Statistics (Safety 
Population) 
X 
X 
55 
Summary of Treatment Emergent Adverse Events 
(Safety Population) 
X 
X 
56 
Number and Percent of Subjects with TEAEs (Safety 
Population) 
X 
X 
57 
Descriptive Statistics of TUVjoint by Fibroid vs. Non-
Fibroid Type (ITA Population) 
X 
X 
58 
Descriptive Statistics of TUVjoint by Fibroid vs. Non-
Fibroid Type (PP Population) 
X 
 
59 
Descriptive Statistics of TUVglobal by Fibroid vs. Non-
Fibroid Type (ITA Population) 
X 
 
60 
Descriptive Statistics of TUVglobal by Fibroid vs. Non-
Fibroid Type (PP Population) 
X 
 
 
Figure 
No. 
 
 
Figure Title 
Included 
in Final 
Figures 
 
Shown in 
Appendix 
B 
Fig1 
Scatterplot of the Joint Distribution of CD206 
Macrophage Count and TUVjoint  
X 
X 
Fig2 
Boxplots of the Conditional Distribution of TUVjoint for 
Each Category of Synovitis Score 
X 
X 
Fig3 
Boxplots of the Conditional Distribution of TUVglobal for 
Each Category of Synovitis Score 
X 
 
Fig4 
ROC Curves by RA Disease Type, Logistic Regression 
with TUVjoint 
 
X 
X 
Fig5 
ROC Curves by RA Disease Type, Logistic Regression 
with TUVglobal 
X 
 
Fig6 
Conditional Distribution of TUVjoint by RA Disease Type    
X 
X 
Fig7 
Joint Distribution of CD3, CD20, CD55, CD68, CD163, 
CD206, and TE7 Biomarkers Association with TUVjoint  
X 
X 
Fig8 
Joint Distribution of CD68, CD163, and CD206 in mRNA  
X 
X 
Fig9 
Joint Distribution of CD68, CD163, and CD206 
Measured by Flow Cytometry 
X 
X 
 
 


Statistical Analysis Plan 
 
Study No. NAV3-32 
 
 
Page 27 of 84 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                   September 15, 2022                                  
 
Data 
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 
DL5 
Subjects Excluded from ITA 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 
Occurrence of TEAEs Associated with Concomitant 
Medications or Class of Medications 
X 
X 
DL13 
Subject Laboratory Profiles – Hematology Data Listing 
X 
X 
DL14 
Subject Laboratory Profiles – Serum Chemistry Data 
Listing 
X 
 
DL15 
Subject Laboratory Profiles – Urinalysis Data Listing 
X 
 
DL16 
Subject Laboratory Profiles – Rheumatology Panel Data 
Listing 
X 
 
DL17 
Physical Exam Data Listing 
X 
X 
DL18 
ACR/EULAR 2010 Classification Data Listing 
X 
X 
DL19 
DAS-28 by Joint Data Listing 
X 
X 
DL20 
DAS-28 by Subject Data Listing 
X 
X 
DL21 
Vital Signs Data Listing 
X 
X 
DL22 
ECG Parameters Data Listing 
X 
X 
DL23 
Study Drug Administration Data Listing 
X 
X 
DL24 
Post-Injection Imaging Data Listing 
X 
X 
DL25 
TUV Data Listing 
X 
X 
DL26 
TUV by Pathology Type 
X 
X 
DL27 
Biomarkers Data Listing 
X 
X 


Statistical Analysis Plan 
 
Study No. NAV3-32 
 
 
Page 28 of 84 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                   September 15, 2022                                  
8.0 References 
 
N/A 


Statistical Analysis Plan 
 
Study No. NAV3-32 
 
 
Page 29 of 84 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 1.0                                                                                                   September 15, 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. NAV3-32 
 
Page 30 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
Appendix B – Table Shells  
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 31 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
 
Page x of y 
 
Table 1. Subject Disposition  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
 
 
 
 
 
 
  
 
 
 
 
Overall 
Screen Failures 
 
xx 
 
 
 
Enrolled 
 
xx 
 
 
 
Completed 
 
xx (xxx%) 
 
 
 
Withdrawn  
 
xx (xxx%) 
 
 
 
Reason for Withdrawal 
Adverse Event 
xx (xxx%) 
 
Protocol Violation 
xx (xxx%) 
 
Lost to Follow-Up 
xx (xxx%) 
 
Withdrawal of Consent 
xx (xxx%) 
 
Sponsor Discretion 
xx (xxx%) 
 
Investigator Discretion 
xx (xxx%) 
 
Death 
xx (xxx%) 
 
Other 
xx (xxx%) 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas  
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 32 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 2. Demographics and Baseline Data Descriptive Statistics – Continuous Variables 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
Mean 
 
Std Dev 
 
n 
 
Min 
 
Max 
 
Median 
 
 
 
 
 
 
 
Age (years) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Height (inches) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Weight (pounds) 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 33 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 3. Demographics and Baseline Data Descriptive Statistics – Categorical Variables 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
Variable 
 
Category 
 
 
Overall 
 
 
 
Gender 
Male 
xx (xxx%) 
 
Female 
xx (xxx%) 
 
 
 
Race 
American Indian or Alaska Native 
xx (xxx%) 
 
Asian 
xx (xxx%) 
 
Black or African American 
xx (xxx%) 
 
Native Hawaiian or Other Pacific Islander 
xx (xxx%) 
 
White 
xx (xxx%) 
 
Other 
xx (xxx%) 
 
 
 
Ethnicity 
Hispanic or Latino 
xx (xxx%) 
 
Not Hispanic or Latino 
xx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
  
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 34 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
 
Page x of y 
 
Table 4. Descriptive Statistics of TUVjoint and the CD206 Expressing Macrophage Fraction 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a 95% Confidence limits for the Pearson (Product-Moment) Correlation Coefficient are based on the Fisher Z-Transformation  
(the inverse hyperbolic tangent) and its normal approximation. 
b 95% Confidence limits for the Spearman (Rank) Correlation Coefficient are based on the Fisher Z-Transformation (the  
inverse hyperbolic tangent) and its normal approximation. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table Format is Repeated for the PP Population (Table 5) 
 
 
 
 
 
Measure 
/Biomarker 
 
 
 
 
Mean 
 
 
 
Std 
Dev 
 
 
 
 
n 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Median 
 
 
Pearson (Product-
Moment) Correlation 
Coefficient 
 
 
 
95% Confidence 
Limitsa 
 
 
Spearman (Rank) 
Correlation 
Coefficient 
 
 
 
95% Confidence 
Limitsb 
 
 
 
 
 
 
 
 
 
 
 
CD206 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x.xxx 
(x.xxx, x.xxx) 
x.xxx 
(x.xxx, x.xxx) 
TUVjoint 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 35 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
 
Page x of y 
 
Table 6. Number and Percent of Subject’s Ultrasound Synovitis Scores 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
Ultrasound 
Synovitis Score 
 
 
Visit 
Number 
(Percentage) 
 
2  
 
1 
 
xxx(xxx%)  
2 
4 
xxx(xxx%) 
3  
1 
xxx(xxx%) 
3 
4 
xxx(xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Table Format is Repeated for the PP Population (Table 7) 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 36 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 8. Pearson (Product-Moment) Correlation between CD68, CD163, and CD206  
of IHC Measurements 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Number of data pairs 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table will be repeated for the Spearman (Rank) Correlation Matrix (Table 10). Tables are repeated for the PP Population (Tables 9, 
11). 
 
 
Biomarker 1 
 
 
Biomarker 2 
Pearson (Product-
Moment) Correlation 
Coefficient 
 
95% Confidence 
Limits 
 
 
na 
 
 
 
 
 
CD68 
CD163 
x.xxx 
x.xxx 
xxx 
CD163 
CD206 
x.xxx 
x.xxx 
xxx 
CD206 
CD68 
x.xxx 
x.xxx 
xxx 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 37 of 84 
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Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 12. Descriptive Statistics of CD68, CD163, and CD206 from IHC Measurements 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Number of data triplets 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table Format is Repeated for the PP Population (Table 13) 
 
 
 
Biomarker 
 
Mean 
 
Std Dev 
 
na 
 
Min 
 
Max 
 
Median 
 
 
 
 
 
 
 
CD68 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
CD163 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
CD206 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 38 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 14. Number and Percent of Subjects in Each RA Disease Type - TUVjoint 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
 
RA Disease Type 
Number (Percent) 
of Subjects  
 
Lympho-Myeloid  
 
xxx(xxx) 
Diffuse Myeloid 
xxx(xxx) 
Pauci-immune Fibroid 
xxx(xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table will be repeated for TUVglobal (Table 16). Tables are repeated for the PP Population (Tables 15, 17). 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 39 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 18. Descriptive Statistics of the Marginal Distribution of TUVjoint 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-32 
 
 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Number of complete data points 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Table will be repeated for TUVglobal (Table 20). Tables are repeated for the PP Population (Tables 19, 21). 
 
 
 
 
Mean 
 
Std Dev 
 
na 
 
Min 
 
Max 
 
Median 
 
 
 
 
 
 
 
TUVjoint 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 40 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 22. Pearson (Product-Moment) Correlation of CD3, CD20, CD55, CD68, CD163, CD206, and TE7 
Biomarkers Association with TUVjoint Measured by IHC Measurement 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
 
 
Measure 
/Biomarker 
Pearson 
(Product-Moment) 
Correlationa 
95% Confidence 
Limitsb 
 
 
nc 
 
 
 
 
TUVjoint 
-- 
-- 
xxx 
 
 
 
 
CD3 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
CD20 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
xxx 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
CD206 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
TE7 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Pearson (Product-Moment) correlation between TUVjoint and the indicated measurement/biomarker. 
b Confidence limits calculated using the Fisher Z-transformation. 
c Number of complete data points. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table Format is Repeated for RNAseq and Flow Cytometry (Tables 24, 26). Each table will be repeated for the PP Population (Tables 23, 
25, 27). 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 41 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 28. Spearman (Rank) Correlation of CD3, CD20, CD55, CD68, CD163, CD206, and TE7 Association with 
TUVjoint Measured by IHC Measurement 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
 
 
 
Measure 
/Biomarker 
Spearman (Rank) 
Correlationa 
95% Confidence 
Limitsb 
 
nc 
 
 
 
 
TUVjoint 
-- 
-- 
xxx 
 
 
 
 
CD3 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
CD20 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
xxx 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
CD206 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
TE7 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Spearman (Rank) correlation between TUVjoint and the indicated measurement/biomarker. 
b Confidence limits calculated using the Fisher Z-transformation. 
c Number of complete data points. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table Format is Repeated for RNAseq and Flow Cytometry (Tables 30, 32). Each table will be repeated for the PP Population (Tables 29, 
31, 33). 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 42 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 34. Descriptive Statistics of CD3, CD20, CD55, CD68, CD163, CD206, and TE7 Biomarkers Association 
with TUVjoint Measured by IHC Measurement 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
 
 
Measure 
/Biomarker 
na 
Mean 
Std Dev 
 
 
 
Min  
 
 
 
Max 
 
 
 
Median 
 
 
 
 
 
 
 
TUVjoint 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
CD3 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
CD20 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
CD206 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
TE7 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Number of complete data points. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table Format is Repeated for RNAseq and Flow Cytometry (Tables 36, 38). Each table will be repeated for the PP Population (Tables 35, 
37, 39). 
  


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 43 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 40. Descriptive Statistics of CD68, CD163, and CD206 Genes in mRNA 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Number of complete data points 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
Table Format is Repeated for the PP Population (Table 41) 
 
Biomarker 
na 
Mean 
Std Dev 
 
Min 
 
Max 
 
Median 
 
 
 
 
 
 
 
CD68 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
CD163 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
CD206 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 44 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 42. Estimated Residual Covariance with the Regression Coefficients of the CD68, CD163, and CD206 
Genes in mRNA 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
A least-squares regression model will be implemented with TUVjoint values concentrations as the independent variable and the mRNA 
abundance as determined by RNAseq values as the dependent variables.  
a COV = Covariance (i.e. COV(CD163,CD68) = Covariance of CD163 and CD68) 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Table Format is Repeated for the PP Population (Table 43) 
Covariance Parametera 
Covariance Parameter 
Estimates 
Regression 
Coefficient 
 
 
 
COV(CD68,CD68) 
x.xxx 
x.xxx 
COV(CD163,CD68) 
x.xxx 
 
COV(CD163,CD163) 
x.xxx 
x.xxx 
COV(CD206,CD68) 
x.xxx 
 
COV(CD206,CD163) 
x.xxx 
 
COV(CD206,CD206) 
x.xxx 
x.xxx 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 45 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 44. Pearson (Product-Moment) Correlation of CD68, CD163, CD206 Expressing Macrophages Measured by 
Flow Cytometry and Their Relationship to TUVjoint 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
 
 
Measure 
/Biomarker 
Pearson 
(Product-Moment) 
Correlationa 
95% Confidence 
Limitsb 
 
 
nc 
 
 
 
 
TUVjoint 
-- 
-- 
xxx 
 
 
 
 
CD68 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
CD163 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
CD206 
x.xxx 
(x.xxx, x.xxx) 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Pearson (Product-Moment) correlation between TUVjoint and the indicated measurement/biomarker. 
b Confidence limits calculated using the Fisher Z-transformation. 
c Number of complete data points. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table Format is Repeated for the Spearman (Rank) Correlation Matrix (Table 46). Tables will be repeated for the PP Population (Tables 
45, 47). 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 46 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 48. Descriptive Statistics of CD68, CD163, and CD206 Expressing Macrophages Measured by Flow 
Cytometry 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
Biomarker 
n 
Mean 
Std Dev 
 
Min 
 
Max 
 
Median 
 
 
 
 
 
 
 
CD68 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
CD163 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
CD206 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Table Format is Repeated for the PP Population (Table 49) 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 47 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 50. Descriptive Statistics of TUVglobal by Pathology Type 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Number of complete data points 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
Table Format is Repeated for the PP Population (Table 51)  
 
Pathology Type 
na 
Mean 
Std Dev 
 
Min 
 
Max 
 
Median 
 
 
 
 
 
 
 
Lympho-myeloid 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
Diffuse myeloid 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
Pauci-immune fibroid 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 48 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 52. Vital Signs Descriptive Statistics 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a 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 
 
 
 
Vital Sign Parameter 
(units) 
 
Visit 
Data 
Typea 
 
 
n 
 
Std 
Dev 
 
 
Mean 
 
 
Min 
 
 
Max 
 
 
Median 
 
 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxxxx (xxx) 
Screening 
Raw 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
30 Minute Pre Admin 
Raw 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
30 Minute Post Admin 
Raw  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxxxxxxxxxxxxxxxx (xxx) 
Screening 
Raw 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
30 Minute Pre Admin 
Raw 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
30 Minute Post Admin 
Raw  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxxxxxxxxxxxxxxxx (xxx) 
Screening 
Raw 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
30 Minute Pre Admin 
Raw 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
30 Minute Post Admin 
Raw  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 49 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 53. Clinical Laboratory Tests Descriptive Statistics 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a 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 
 
 
 
Laboratory Test  
 
Visit 
Data 
Typea 
 
 
n 
 
Std 
Dev 
 
 
Mean 
 
 
Min 
 
 
Max 
 
 
Median 
 
 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxxxx  
Screening 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Day 0 – 60 to 75 Minutes Post Admin 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxxxxxxxxxxxxxxxx  
Screening 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Day 0 – 60 to 75 Minutes Post Admin 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxxxxxxxxxxxxxxxx  
Screening 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Day 0 – 60 to 75 Minutes Post Admin 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 50 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 54. ECG Parameters Descriptive Statistics 
Navidea Biopharmaceuticals - Study No. NAV3-32 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a 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 
 
 
 
ECG Parameter (units) 
 
Visit 
Data 
Typea 
 
 
n 
 
Std 
Dev 
 
 
Mean 
 
 
Min 
 
 
Max 
 
 
Median 
 
 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxxxx (xxx) 
Baseline 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
30 Minute Post Admin 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxxxxxxxxxxxxxxxx (xxx) 
Baseline 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
30 Minute Post Admin 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxxxxxxxxxxxxxxxx (xxx) 
Baseline 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
30 Minute Post Admin 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxxxxxxxxx (xxx) 
 
Baseline 
30 Minute Post Admin 
CFB 
RAW  
RAW 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 51 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 55. Summary of Treatment Emergent Adverse Events 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
Overall 
 
 
Subjects with at Least One Treatment Emergent 
Adverse Event (TEAE) 
xxx (xxx%) 
 
 
Maximum TEAE Severity Grade  
 
    Mild 
xxx (xxx%) 
    Moderate 
xxx (xxx%) 
    Severe 
xxx (xxx%) 
 
 
Highest Relationship of TEAE to Study Drug 
 
    Definitely Not [n(%)] 
xxx (xxx%) 
    Probably Not [n(%)] 
xxx (xxx%) 
    Possibly [n(%)] 
xxx (xxx%) 
    Probably [n(%)] 
xxx (xxx%) 
    Definitely [n(%)] 
xxx (xxx%) 
 
 
Highest Relationship of TEAE to Study 
Procedure 
 
    Definitely Not [n(%)] 
xxx (xxx%) 
    Probably Not [n(%)] 
xxx (xxx%) 
    Possibly [n(%)] 
xxx (xxx%) 
    Probably [n(%)] 
xxx (xxx%) 
    Definitely [n(%)] 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 52 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Table 56. Number and Percent of Subjects with TEAEs 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Adverse Event Categorya: 
Overall 
 
 
Total Number of Treatment Emergent Adverse Events 
(TEAEs) 
xxx 
 
 
Subjects with at Least One TEAE 
xxx (xxx%) 
 
 
  System Organ Class 1 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
 
 
  System Organ Class 2 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a Adverse events coded with MedDRA Coding Dictionary Version XXX. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 53 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
Table 57. Descriptive Statistics of TUVjoint by Fibroid vs. Non-Fibroid Type 
Navidea Biopharmaceuticals - Study No. NAV3-32 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Number of complete data points 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
Table Format is Repeated for TUVglobal (Table 59). Tables will be repeated for the PP Population (Tables 58, 60). 
 
 
Type 
na 
Mean 
Std Dev 
 
Min 
 
Max 
 
Median 
 
 
 
 
 
 
 
Fibroid 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
non-Fibroid 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 54 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Figure 1. Scatterplot of the Joint Distribution of CD206 Macrophage Count and TUVjoint 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
0.2
0.4
0.6
0.8
TUVjoint
50
100
150
200
250
300
CD206 Macrophage Count
CD206 Macrophage Count
Regression


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 55 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Figure 2. Boxplots of the Conditional Distribution of TUVjoint by Synovitis Score 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table Format is Repeated for TUVglobal (Figure 3). 
 
2
3
Synovitis Score
0.2
0.4
0.6
0.8
1.0
TUVjoint


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 56 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Figure 4. ROC Curves by RA Disease Type, Logistic Regression with TUVjoint 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Table Format is Repeated for TUVglobal (Figure 5). 
0.00
0.25
0.50
0.75
1.00
Sensitivity
0.00
0.25
0.50
0.75
1.00
1 - Specificity
Pauci-Immune Fibroid  (0.7540)
Diffuse Myeloid  (0.8172)
Lympho-Myeloid  (0.7715)
ROC Curve (Area)
ROC Curves for Comparisons


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 57 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
 
Page x of y 
 
Figure 6. Conditional Distribution of TUVjoint by RA Disease Type 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Diffuse Myeloid
Lympho-Myeloid
Pauci-Immune Fibroid
RA Disease Type
0.2
0.4
0.6
0.8
TUVjoint


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 58 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Figure 7. Joint Distribution of CD3, CD20, CD55, CD68, CD163, CD206, and TE7 Biomarkers  
Association with TUVjoint 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
TE7
CD206
CD163
CD68
CD55
CD20
CD3
TE7
CD206
CD163
CD68
CD55
CD20
CD3


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 59 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Figure 8. Joint Distribution of CD68, CD163, and CD206 in mRNA 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
CD206
CD163
CD68
CD206
CD163
CD68


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 60 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Figure 9. Joint Distribution of CD68,  CD163, and CD206 Measured by Flow Cytometry 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
ITA Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
CD206
CD163
CD68
CD206
CD163
CD68


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 61 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
 
Page x of y 
 
Data Listing 1. Subject Disposition Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
Subject 
No. 
 
 
Disposition Status 
 
Date of 
Completion/ 
Withdrawal/Screen 
Fail 
 
 
Withdrawal Reason 
 
 
 
 
xxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 62 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
 
Page x of y 
 
Data Listing 2. Inclusion/Exclusion Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Subject 
No. 
 
Did Subject 
Meet All 
Eligibility 
Criteria? 
Criterion Category 
 
 
Criterion 
Was a 
Waiver 
Granted? 
Is Subject a 
Screen 
Failure? 
 
 
 
 
 
 
xxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
xxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
xxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
xxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 63 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
 
 
Page x of y 
 
Data Listing 3. Protocol Deviations Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Subject 
No. 
Date of 
Deviation 
Deviation Description  
 
 
Deviation Category 
(Major/Minor) 
 
 
 
 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 64 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
 
 
Page x of y 
 
Data Listing 4. Demographics Data Listing  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
                        
 
                                                                                                                             
 
 
 
Subject 
No. 
 
Informed 
Consent 
Date/Time 
 
Date 
of 
Birth 
Height 
(inches) 
Weight 
(pounds) 
 
 
Age 
(yrs) 
 
 
 
Gender 
 
 
 
Race 
 
 
 
Ethnicity 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 65 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 5. Subjects Excluded from ITA Population Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
All Enrolled Subjects (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Subject No. 
 
 
Reason for Exclusion 
 
 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 66 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 6. Subjects Excluded from PP Population Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
All Enrolled Subjects (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Subject No. 
 
 
Reason for Exclusion 
 
 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 67 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 7. Subjects Excluded from Safety Population Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
All Enrolled Subjects (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Subject No. 
 
 
Reason for Exclusion 
 
 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 68 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 8. Medical History Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
Subject 
No. 
MedDRA System Organ Classa/ 
MedDRA Preferred Term/ 
CRF Verbatim Term 
Start Date  
Resolution/Stop 
Date 
Ongoing? 
 
 
 
 
 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a 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. NAV3-32 
 
Page 69 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 9. Prior and Concomitant Medications Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
Subject 
No. 
Drug Preferred Terma/ 
Verbatim/ 
ATC Level 1 Text/ 
ATC Level 4 Text 
Indication Frequency 
Start 
Date 
Stop 
Date 
Route Ongoing? 
 
 
 
 
 
 
 
 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_______________________________________________________________________________________________________________________________________________________________________________________________________________________ 
a Medications coded with WHO Coding Dictionary xxxxxxxxx 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 70 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 10. Prior and Concomitant RA Medications Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
Subject 
No. 
 
 
Drug Preferred Terma/ 
Verbatim/ 
Indication/ 
ATC Level 1 Text/ 
ATC Level 4 Text 
Frequency 
 
 
 
 
 
Start 
Date 
 
 
 
 
 
 
Stop 
Date 
 
 
 
 
 
 
Route 
 
 
 
 
 
 
Ongoing? 
 
 
 
 
 
 
 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Medications coded with WHO Coding Dictionary xxxxxxxxx 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 71 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 11. Adverse Events Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
Subject 
No. 
Start 
Date and 
Time/ 
End Date 
and Time 
Start Date 
and Time of 
Nearest 
Previous 
tilmanocept 
Injection 
MedDRA System 
Organ Classa/ 
MedDRA Preferred 
Term/ 
CRF Verbatim Term 
Severity  
Relation to 
Tc-99m 
tilmanocept/ 
Procedure 
Serious? 
Outcome 
 
 
 
 
 
 
 
 
xxxxxxxxx 
xxxxxxx 
xxxxxxx/ 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxx 
xxxxxxxx/ 
xxxxxxxx 
 
xxx 
 
xxxxxxxx 
 
 
 
 
 
 
 
 
xxxxxxxxx 
xxxxxxx 
xxxxxxx/ 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxx 
xxxxxxxx/ 
xxxxxxxx 
 
xxx 
 
xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a Adverse events coded with MedDRA Coding Dictionary Version xxx. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 72 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 12. Occurrence of TEAEs Associated with Concomitant Medication or Class of Medications 
Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a Adverse events coded with MedDRA Coding Dictionary Version xxx. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
Subject 
No. 
Start 
Date and 
Time/ 
End Date 
and Time 
Start Date 
and Time of 
Nearest 
Previous 
tilmanocept 
Injection 
MedDRA System 
Organ Classa/ 
MedDRA Preferred 
Term/ 
CRF Verbatim Term 
Concomitant Medication or 
Class of Medications 
Associated with AE 
 
 
 
 
 
xxxxxxxxx 
xxxxxxx 
xxxxxxx/ 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxx 
 
 
 
 
 
xxxxxxxxx 
xxxxxxx 
xxxxxxx/ 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxx 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 73 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
 
Page x of y 
 
Data Listing 13. Subject Laboratory Profiles - Hematology Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Normal Range 
 
Subject 
No. 
 
Visit 
Sample Date 
and Time 
Lab Parameter (Units) 
 
Result 
 
Lab Low 
 
Lab High 
Clin. Sig? 
 
 
 
 
 
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for Serum Chemistry, Urinalysis, and Rheumatology Panel Listings (Listings 14, 15, 16). 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 74 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 17. Physical Exam Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
Subject 
No. 
 
 
 
 
 
Visit 
 
 
 
 
Date 
Conducted 
 
 
 
 
 
Body System 
 
 
 
 
 
Result 
 
 
 
 
 
Abnormality 
 
 
 
 
 
 
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 
    
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 75 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 18. ACR/EULAR 2010 Classification Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
   
 
 
 
ACR/EULAR 2010 
 
 
Subject 
No. 
 
 
 
 
Visit 
 
 
 
 
Date 
Joint 
Involvement 
Serology 
Acute-
Phase 
Reactants 
Duration 
of 
Symptoms 
Total Score 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
xxxx 
xxxxxxx 
 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 76 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
 
Page x of y 
 
Data Listing 19. DAS-28 By Joint Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
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 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 77 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
 
Page x of y 
 
Data Listing 20. DAS-28 By Subject Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
 
DAS28 
 
 
Subject 
No. 
 
Visit 
 
 
Date 
Tender 
Joint 
Count 
Swollen 
Joint 
Count 
Patient 
VAS 
Global 
(mm) 
C-reactive 
Protein (CRP; 
mg/L) 
DAS28 
Score 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 78 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 21. Vital Signs Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
Subject 
No. 
 
 
 
 
Visit 
 
 
 
 
Date 
 
 
 
 
Time  
 
 
 
Temp. 
(°F) 
 
Systolic 
Blood 
Pressure 
(mmHg) 
Diastolic 
Blood 
Pressure 
(mmHg) 
Heart 
Rate 
(bpm) 
 
 
 
Respirations 
per Minute 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
 
xxxxxxx 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
 
xxxxxxx 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 79 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 22. ECG Parameters Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
Subject 
No. 
 
 
 
Visit 
 
 
 
Date 
 
 
 
Time 
Heart Rate  
 
 
PR Interval 
QRS 
Interval 
QT Interval  
 
QTcF 
Interval 
 
 
Overall 
Interpretation 
 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxx 
xxxxx 
xxxxxx 
xxxxxx 
xxxxxxxx 
xxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 80 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 23. Study Drug Administration Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
 
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) 
Calculated 
Mass Dose 
(µg) 
Volume 
Injected  
(mL) 
 
 
 
Lot  
Number 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxxx/ 
xxxx 
xxxxxxxx 
xxx/ 
xxxx 
xxx/ 
xxxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxxx/ 
xxxx 
xxxxxxxx 
xxx/ 
xxxx 
xxx/ 
xxxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx/ 
xxxx 
xxxxxxxx 
xxx/ 
xxxx 
xxx/ 
xxxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 81 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
    
 
Page x of y 
 
Data Listing 24. Post-Injection Imaging Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
 
Subject 
No. 
 
Visit 
Date of 
Imaging  
Start Time 
of Imaging 
Planar Imaging 
Performed? 
 
 
 
 
 
xxxx 
xxxxxxxx 
xxxxxx 
xx:xx 
xxx 
 
 
 
 
 
xxxx 
xxxxxxxx 
xxxxxx 
xx:xx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 82 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 25. TUV Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
Subject 
No. 
 
Visit 
Date / Time 
Region of 
Interesta 
TUV 
Upper Limit of 
Normal 
Mean of 
Normal 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxxx / xx:xx 
xxxxxx 
xxxxx 
xxx 
xxx 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxxx / xx:xx 
xxxxxx 
xxxxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a Region of Interest is joint or global. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 83 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
 
Page x of y 
 
Data Listing 26. TUVglobal by Pathology Type Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
Subject 
No. 
 
Visit 
Date / Time 
Pathology Type 
TUVglobal 
Upper Limit of 
Normal 
Mean of 
Normal 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxxx / xx:xx 
xxxxxx 
xxxxx 
xxx 
xxx 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxxx / xx:xx 
xxxxxx 
xxxxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
 
 
                                Study No. NAV3-32 
 
Page 84 of 84 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 1.0 
                                                                                                                                                                             September 15, 2022 
 
 
Page x of y 
 
Data Listing 27. Biomarkers Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-32 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
Subject 
No. 
 
Visit 
Date / Time 
 
 
Biomarker 
 
Anatomic Pathology 
Evaluation 
Result 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxxx / xx:xx 
xxxxx 
xxxxx 
xxxxx 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxxx / xx:xx 
xxxxx 
xxxxx 
xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 

ICF_001.pdf: 
Navidea Version 1.0: 18SEP2020  
Page 1 of 10 
 
RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
 
 
Title:  
A Comparison of Tc 99m Tilmanocept Quantitative Imaging with 
Immunohistochemical (IHC) Analysis of CD206 Expression in 
Synovial Tissue from Subjects Clinically Diagnosed with 
Rheumatoid Arthritis (RA) 
 
 
Protocol:  
NAV3-32 
 
 
 
Sponsor: 
Navidea Biopharmaceuticals, Inc.  
 
4995 Bradenton Avenue, Suite 240 
 
Dublin, Ohio 43017 
 
United States 
 
Investigator:  
XXX XXXX  
 
Investigator Phone Number: «PhoneNumber» or «ERPhone» (for after hours) 
 
 
Site:  
«SiteName» 
 
 


Navidea Version 1.0: 18SEP2020  
Page 2 of 10 
 
This consent form may contain words that you do not understand.  Please ask the study doctor or 
the study staff to explain any words or information that you do not clearly understand.  You may 
take home an unsigned copy of this consent form to think about or discuss with family or friends 
before making your decision. 
 
Why is this study being done?  
This study is being done to determine the ability of technetium Tc 99m tilmanocept (study drug) 
to find inflammatory cells in your joints with rheumatoid arthritis (RA) and to determine the 
relationship with the different types of cells present in one of your joints affected by your RA. You 
are being asked to participate in this study because you are currently undergoing evaluation and 
treatment for RA. 
 
Description of the study 
Patients participating in this study will receive 150 mcg of the study drug radiolabeled with 10 
mCi (370 MBq). The study drug will be administered one time through an intravenous (IV) 
injection in your arm. The study drug is a radioactive mapping drug that binds to certain types of 
cells and can be seen in images (pictures) taken using a SPECT gamma camera (scan). The SPECT 
scanner is an instrument that detects the radiation given off by the decay of the study drug and 
produces images of where the study drug has located in your body. There is no pain associated 
with the use of the camera.  
 
Participants will also undergo a synovial (joint) tissue biopsy, where small samples of tissue will 
be removed from the soft tissue surrounding a joint in the hand or wrist to examine the activity of 
RA. This procedure involves the use of a needle to remove the tissue samples. A small percentage 
of this patient population has reported small amounts of pain and discomfort after the procedure. 
 
Participant Selection 
Up to 24 subjects will take part in this study at up to 10 centers in the United States, United 
Kingdom, and European Union. 
 
Voluntary Participation 
Your decision to participate in this study is entirely voluntary. It is your choice to participate or 
not. If you choose not to consent, there will be no penalty or loss of benefits to you and all of the 
medical care you would normally receive will continue and nothing will change.  
 
You can change your mind later and stop your participation in the study, even if you agreed earlier. 
Your decision to withdraw from this study will not cause any penalty or loss of benefits to you, 
nor will it affect the medical care that you would receive. If you decide to withdraw from 
participation, no additional follow up will be required for the study.  
 
Information on Study Drug  
The study drug is made by Navidea Biopharmaceuticals, Inc. Navidea is working with your study 
doctor to test the study drug in patients with RA.  The study drug has been tested in approximately 
16 clinical trials. The study drug is also called Lymphoseek® and is approved by the Food and 
Drug Administration (FDA) in the United States and by the European Medicines Agency (EMA) 
in the European Union for use in mapping lymph nodes. The study drug is investigational (being 


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used for research) in this study because it is being used for a different purpose and at a different 
amount.  
 
If I agree to join the study, what will I need to do? 
Most of the procedures in this study are not part of the routine care that you would normally receive 
for the evaluation of your RA. The use of tilmanocept is for research and is not part of your routine 
care. 
 
How long will I be in the study? 
Total participation in this study may last up to 45 days. If you choose to participate in this study, 
after you sign this informed consent document, your participation would include the following 
procedures and events: 
 
Visit 1: Screening  
• The screening visit will take approximately 3 hours and may occur over more than one day. 
The information gathered during this visit will help your doctor confirm you are an 
appropriate candidate for the study. 
• You will be asked questions about your medical and surgical history, medications and 
demographic information (such as age, gender, and race). 
• You will have a physical examination (routine examination of your body including 
assessing your height and weight). 
• Vital signs, which include assessing your body temperature, blood pressure, heart rate, and 
breathing rate, will be recorded. 
• Your blood will be taken (about 2.5 teaspoons) for routine testing and RA testing. 
• Your urine will be collected for routine urinalysis.  
• If you are able to get pregnant, your blood will be taken for a serum pregnancy test. If you 
are pregnant, you will not be able to participate. 
• You will have an ultrasound assessment of the hands and wrists to evaluate inflammation. 
• You will have an evaluation of your joints including your shoulders, elbows, hands, wrists, 
and knees. 
• You will answer questions about your RA and health. 
 
Visit 2: Administration of Study Drug and Imaging 
This visit will take about 2 and a half hours 
 
• Before administration of the study drug: 
• If you are able to get pregnant, you must have a negative urine pregnancy test within 
48 hours before the tilmanocept administration. If you are pregnant, you will not be 
able to participate. 
• You will have an ECG (electrocardiogram), which records the electrical activity 
of your heart. 
• Your vital signs will be taken. 
• You will be asked about any changes in your health and medications since your last 
visit. 
• Study drug administration 


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• You will receive the injection of tilmanocept through an IV placed in your arm. The 
amount of tilmanocept injection is small, less than a teaspoon. 
• After study drug administration (within 30 minutes) 
• You will be assessed for any adverse events 
• You will have an ECG  
• Your vital signs will be repeated 
• SPECT Scanning 
• You will have scanning of your hands and wrists at about 60 minutes after 
injection. Your hands and wrists will be positioned on the scanner bed while you 
rest sitting. The SPECT part of the scanner detects the radiation in the study drug 
to create a picture of the study drug in your body. The scan should take 
approximately 15 minutes to complete. 
• At the completion of imaging: 
• You will be assessed for any adverse events. 
• Your blood will be taken (about 2 teaspoons) for safety testing. 
• Your urine will be collected for routine urinalysis.  
 
Visit #3: Safety Telephone Follow-Up Call (24-48 hours after Study Drug administration) 
• You will be asked about changes in your health and medication. 
• You will be asked about any adverse events. 
 
Visit #4: Synovial Tissue Biopsy  
This visit will take about 2 hours to complete 
• You will have an ultrasound assessment of the hands and wrists to evaluate inflammation. 
• An ultrasound-guided synovial tissue biopsy will be performed on a single joint in the hand 
or wrist to analyze RA tissue cells. This procedure will be completed via validated 
ultrasound-guided biopsy methods. The RA tissue obtained from the biopsy will be sent to 
a lab for further testing. 
• 
You will be asked about any adverse events.  
 
Visit #5 Safety Telephone Follow-up Call (5±2 days post-biopsy) 
• You will be asked about changes in your health and medication. 
• You will be asked about any adverse events. 
 
What side effects or risks can I expect from being in the study? 
While the possibility of adverse (bad) reactions happening during this study is very low, it is 
possible that you may experience adverse reactions or discomfort. Every person taking part in the 
study will be watched carefully for any side effects. Doctors don’t know all of the side effects that 
might happen. It is important that you talk to your study doctor about any changes in health that 
you experience while taking part in this study. All side effects or changes in your normal health 
should be reported, even those changes you might not consider to be important. 
 
In other clinical trials with the study drug injected subcutaneously (between the skin and the fat), 
no patients experienced serious adverse reactions and the most common adverse reactions were 
injection site irritation and/or pain (<1%).  The study drug has been available commercially for 
other medical uses since May 2013 and since that time about 400,000 patients have received this 


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drug. The most commonly reported adverse reactions have been injection site pain (<0.02%) and 
rash (<0.02%). 
 
To date, there have been approximately 280 IV injections with the study drug with no adverse 
drug reactions. 
 
You will receive the study drug IV in your arm. IV insertion may cause slight pain or discomfort. 
You may experience tenderness, warmth, or redness along the vein or at the injection site. 
Inflammation of the vein is common and may occur after the insertion of the IV catheter (tube). 
Bruising may occur from an unsuccessful IV insertion or during removal of an IV. In rare cases, 
an infection can occur at the IV site. 
 
You will receive a biopsy of a selected hand joint, where around 12 samples of small tissue, 
approximately 1-2 mm2, will be removed from the joint with a needle. A needle will be placed 
into the joint under local anesthetic guided by ultrasound scanning. This is performed in a sterile 
(germ-free) setting. It should be noted that a small percentage of participants in this type of 
procedure have reported small amounts of pain and discomfort after the procedure, and this can 
be discussed with your study doctor. The samples of tissue are then taken to the laboratory and 
used for the research purposes described. The majority of patients have no adverse reaction to the 
procedure, and it is generally well tolerated. Approximately 15% of patients will have minor 
discomfort after the procedure.  Discomfort, swelling/bruising, or worsening of RA have been 
observed from this procedure, and this can be discussed with your study doctor. Other possible 
complications which are uncommon include infection of the joint or skin, bleeding, pain, and 
rarely nerve or tendon damage (less than 1:100,000 risk). The synovial biopsy procedure used in 
this study is not considered a part of routine RA management; however, the technique is very 
well tolerated in those who have chosen to participate, and the doctors performing the procedure 
are fully trained.  
 
 
Your blood will be collected for routine testing. You may experience mild pain or discomfort, 
bruising, or swelling at the site where the blood is drawn. Some people may experience fainting, 
dizziness or light headedness during or immediately after the blood draw. In rare cases, the 
puncture site may become infected and cause the site to become red or swollen. 
 
The study drug used in this study will expose you to ionizing radiation.  Radiation occurs naturally 
in the environment and is also used in treating and examining patients for medical reasons.  The 
natural radiation we are exposed to all the time from the sun and the earth (natural background 
radiation) is around 300 mrem each year or 3mSv.  The radiation from the study drug 
(2.7mSv/266mrem) is approximately equal to 10.6 months of exposure to natural background 
radiation. Radiation exposure increases other health risks including cancer. The risk of developing 
health problems or cancer from this radiation exposure is small, but the risk may be cumulative 
(adds up over time). If you have additional questions about radiation exposure, or have had 
additional scans using radiation recently, you should ask to speak to your study doctor. 
 


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What will happen to any samples I give?   
All blood and urine samples that are taken for the purposes of this study will be analyzed at the 
hospital where you are participating in this trial and will not be stored for further analyses.  
 
All biopsy tissue samples that are taken for the purposes of this study will be sent to the Centre 
for Experimental Medicine and Rheumatology at Queen Mary University of London (QMUL) 
for analysis.  Following completion of the study, they will be stored at the bio-bank facility at 
Experimental Medicine and Rheumatology department, QMUL (Registered as part of the Barts 
Health Human Tissue Resource Centre). These samples will be used to investigate markers of 
different types of cells, to better understand the mechanisms which lead to RA and potentially 
new treatment targets. The samples may also be used for future analysis in other projects which 
will have ethical approval.   These samples will be considered as a gift to QMUL and will be 
stored securely by them indefinitely. If you decide to participate in this study, you agree to give/ 
“gift” your sample/s to the researchers who will then be able to use your sample/s for academic 
and/or commercial research purposes. You will not own the results generated using your 
sample/s, and you will not be entitled to any interest in or share of any profit that might arise 
from research using the sample/s.  
 
 
What if I am pregnant or want to have a baby? 
Whether you are male or female, your participation in this protocol includes treatment which may 
present unknown risks to a fetus or embryo.  You must avoid becoming pregnant or avoid causing 
a pregnancy while you are participating in this study. You should discuss a method of birth control 
that is best for you to use during the study with your doctor. You should tell your doctor 
immediately if you or your partner becomes pregnant. 
 
Examples of birth control methods that could be used by you and your partner include: 
• Oral birth control pills  
• Birth control patch  
• Implanted (injectable contraceptive hormones or mechanical products such as intrauterine 
device) 
• Barrier methods (diaphragm or condoms) 
• Tubal ligation or vasectomy 
• Abstinence (no sexual intercourse)  
 
For Women: 
If you are pregnant, you may not participate in this study. There may be risks to you and your 
unborn baby.  Breastfeeding (nursing) mothers will not be included in this study; the study drug 
could be passed on to a baby through breast milk.   
 
If you are a female of childbearing potential (able to become pregnant), you will be given a 
pregnancy test at screening (blood test) and before your injection (urine test) at no cost. 
 
Tell one of the study doctors right away if: 
• You are pregnant 


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• You get pregnant 
• You are breastfeeding 
 
For Men: 
We do not know what the study drug could do to your sperm. Should you get a woman pregnant, 
there could be harm to the unborn baby. You and your partner should use an effective form of birth 
control if you are having sexual intercourse with a woman of childbearing potential while 
participating in this trial and for 30 days after participating in the trial. 
 
Are there benefits to taking part in this study? 
You will not receive any medical benefit as a result of being in this study, but the information 
obtained in this study may benefit other patients. 
 
What are the costs of taking part in this study? 
The study drug and all study procedures are at no cost to you. The procedures or tests performed 
for the study are not part of your routine medical care and will not be charged to you, your 
insurance company, or third-party payer. Your routine medical care that is not part of this study 
will continue to be billed to you and your insurance company, or other third-party payers. You can 
ask your study doctor to confirm the costs that will or will not be covered by the study sponsor.  
 
Will I be paid for taking part in this study? 
You will receive a stipend for the time that is required to complete the study visits. You will receive 
the following amounts for each completed visit: 
 
Visit 1: $ [Amount] 
Visit 2: $ [Amount] 
Visit 3: $ [Amount] 
Visit 4: $ [Amount] 
Visit 5: $ [Amount] 
 
If you feel that the payment listed may interfere with your making a good decision about whether 
or not you should volunteer to be in this study, you should not agree to participate. You will be 
paid at the end of your participation for each completed visit. 
 
You may be required to report the payment received for this study to the Internal Revenue Service 
as taxable income. You have to provide your social security number because the IRS may be told 
how much you were paid to take part in this study. 
 
 
Use and disclosure of your personal health information 
“Patient Information” means the health information contained within your medical or other 
healthcare records, which also includes personal identifying information such as your name, 
address, or birthdate. The information that we collect from this study will be kept confidential. 
[Site Name] will take appropriate steps to keep your personal health information private.  
However, there is no guarantee of absolute privacy.  Any information about you will have a number 
on it instead of your name. Only the research team at [Site Name] will be able to link the assigned 


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number to your name.  In order to ensure the scientific value of the study, other parties will be able 
to view your study information. 
 
The following parties may view your identifying information:  
 
Navidea Biopharmaceuticals, Inc.  
Representatives of Navidea Biopharmaceuticals, Inc. 
The Food and Drug Administration (FDA) 
The Office for Human Research Protections (OHRP) - a regulatory agency that oversees research 
in humans 
Other governmental agencies, including those governmental agencies in other countries 
WIRB, An Independent Review Board (IRB) is a group of people that reviews research studies.  
The main goal of this review is to protect the rights and well-being of the human subjects 
participating in research studies. 
Officials of [Site Name] 
 
Will the results of this study be shared? 
Yes, when the study is finished, the results of this study will be shared with professionals in the 
research community and with the public.  You will not be identified in any of the results of the 
study. 
 
Right to Refuse or Withdraw 
You do not have to agree to participate in this study if you do not wish to do so. Refusing to 
participate will not affect your treatment at [Site Name]. If you want to stop your participation in 
this study, you may do so at any time. Withdrawing from the study will not affect your regular 
care at [Site Name]. There are no special procedures that must occur for you to withdraw from this 
study. 
 
What other choices do I have if I do not participate in this study? 
The alternative to participating is to not participate. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor if you feel that you have been injured because you 
took part in the study. You would receive medical treatment for any injury just as you would if 
you did not participate in this study. 
 
In the event that you are injured as a direct result of study conduct, the study sponsor will reimburse 
you for the reasonable medical costs of your medical treatment. In order for the sponsor to 
reimburse you, the study drug must have been administered in accordance with applicable laws, 
regulations, and the study plan (protocol) and the costs must not be covered by insurance or any 
third-party coverage. 
 
Who is paying for the study? 
Navidea is paying your study doctor and the hospital to do this study. 
 
What if new information becomes available? 


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If there is new information or any important new findings that could relate to your willingness to 
continue your participation in this study, we will tell you.  
 
You can then decide if you still want to be in the study.  If the FDA or Navidea makes changes to 
the study before the study starts, the study staff will try to notify you before you check-in.  If 
changes are made after the study has started, the study staff will tell you about them as soon as 
they have been approved.  You can use this information to decide if you want to stay in the study. 
 
Are there reasons we might take you out of the study? 
Even if you want to stay in the study, there may be reasons we need to take you out of it. You may 
be taken out of this study if: 
• We find out it is not safe for you to stay in the study. For example, your health may worsen 
or we may find out that the study drug might harm you. 
• Your healthcare is not being managed properly or you are not coming for study visits as 
scheduled. 
• The study doctor feels it is not in your best interest to continue. 
• If the sponsor or study doctor decides that the study or your participation should be stopped 
for any reason. 
 
Who do I contact if I have questions or concerns about the study? 
If you have any questions, concerns, complaints, or if at any time you feel you have had a research-
related injury or a reaction to the study drug, contact your study doctor:  
 
[PI Name and Contact Information] 
 
If you have questions about your rights as a research subject or have other questions, concerns, or 
complaints about the research, you can contact [IRB Name] at [IRB Phone Number]. A description 
of this clinical trial will be available at http://www.ClinicalTrials.gov, as required by U.S. Law. 
This website will not include information that can identify you. At most, the web site will include 
a summary of the results. You can search this Web site at any time. A description of the trial will 
also be available on the EudraCT website, located at https://eudract.ema.europa.eu/.  
 
In the event of an emergency, dial 911 (US) immediately. If you require emergency care, be sure 
to tell the emergency care provider about your participation in this study. Contact the study doctor 
as soon as possible. 
 
 


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INFORMED CONSENT: 
 
I have been given a chance to ask questions about this research study.  These questions have been 
answered to my satisfaction.  I may contact Dr. [Last Name] if I have any more questions about 
taking part in this study.  I understand that Dr. [LastName] or the company he/she is employed by 
is being paid by the sponsor for my participation in this study. 
I understand that my participation in this research project is voluntary.  I know that I may quit the 
study at any time without harming my future medical care or losing any benefits to which I might 
be entitled.  I also understand that the investigator in charge of this study may decide at any time 
that I should no longer participate in this study. 
By signing this informed consent document, I have not waived any of my legal rights. 
By signing this informed consent document, I acknowledge that I can read, understand, and speak 
English and that I understand the information in this informed consent document.  I understand 
that my study-related medical records may be reviewed by the company sponsoring the study and 
by government authorities. I have read and understand the above information.  I agree to participate 
in this study.  I understand that I will be given a copy of this signed and dated form for my own 
records. 
 
IF YOU DO NOT AGREE WITH THE STATEMENT ABOVE, YOU SHOULD NOT 
SIGN THIS INFORMED CONSENT DOCUMENT. 
 
 
__________________________________  
 
__________ 
Study Participant (signature) 
  
 
 
Date 
 
__________________________________ 
Participant’s Name (print name)  
 
__________________________________  
 
__________ 
Person who explained this study (signature)  
 
Date 
 
__________________________________ 
Person who explained this study (print name) 
 
__________________________________ 
 

Prot_000.pdf: 
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. 
 
Clinical Trial Protocol: NAV3-32 
Study Title: 
A Comparison of Tc 99m Tilmanocept Quantitative Imaging with 
Immunohistochemical (IHC) Analysis of CD206 Expression in 
Synovial Tissue from Subjects Clinically Diagnosed with 
Rheumatoid Arthritis (RA) 
Study Number: 
NAV3-32 
Study Phase: 
2b 
Product Name: 
Tc 99m tilmanocept 
IND Number: 
132943 
EudraCT Number: 
2018-003418-41 
Investigators: 
Multicenter, multinational  
Sponsor: 
Navidea Biopharmaceuticals, Inc. 
4995 Bradenton Ave., Suite 240 
Dublin, OH 43017 
 
Navidea Biopharmaceuticals, Ltd. 
30 Upper High Street 
Thame OX9 3EZ, United Kingdom  
 
Sponsor Contact: 
Rachael Hershey, MS, CCRP 
Associate Director, Clinical Research and Operations 
+1 (614) 822-2329 
Medical Monitor: 
Michael Blue, MD, FACEP 
Senior Medical Director 
+1 (614) 571-4313 
 
 
 
 
 
 
 
 
 
 
 
Date 
Original Protocol (Version 1.0) 
12 June 2019 
Amendment #1 (Version 2.0) 
28 October 2019 
Amendment #2 (Version 3.0) 
11 February 2020 
Amendment #3 (Version 4.0) 
29 April 2020 
Amendment #4 (Version 5.0) 
17 September 2020 
Amendment #5 (Version 6.0) 
07 April 2021 
Amendment #6 (Version 7.0) 
24 June 2021 
Amendment #7 (Version 8.0) 
25 October 2022 


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SYNOPSIS 
Study title 
A Comparison of Tc 99m Tilmanocept Quantitative Imaging with 
Immunohistochemical (IHC) Analysis of CD206 Expression in 
Synovial Tissue from Subjects Clinically Diagnosed with 
Rheumatoid Arthritis (RA)  
Study phase 
Phase 2b 
Study objective(s) 
Primary  
• Assessment of the relationship between joint-specific 
tilmanocept uptake value (TUVjoint) and synovial anatomic 
pathology. 
• IHC assessment of macrophage expression of the CD206 
receptor. 
Secondary  
• Assessments of CD68 and CD163 receptor expression levels 
through IHC microscopy. 
• Classification of synovial anatomic pathology as 
• Lympho-myeloid 
• Diffuse myeloid 
• Pauci-immune fibroid 
Exploratory 
• Determine the relationship between TUVjoint and mRNA 
expression profiles of CD68, CD163, and CD206 as determined 
by RNA sequencing (RNA-seq). 
• Determine the relationship between TUVjoint and the number, 
size, and intensity of CD68, CD163, and CD206 as determined 
by (optional) flow cytometry. 
• Evaluate synovial expression of CD3, CD20, CD55, and TE-7 
and CD206 in synovial tissue biopsy specimens.  
• Assessment of the relationship between global tilmanocept 
uptake value (TUVglobal) and synovial anatomic pathology. 
Safety 
• Evaluate safety through the examination of adverse event (AE) 
incidence, physical examination findings, and changes over time 
in laboratory tests, electrocardiograms (ECGs), and vital signs.  


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Study duration 
Up to 45 days 
Study drug 
Tc 99m tilmanocept  
Dose(s) and Route 
of administration 
Dose: Tilmanocept will be administered at a dose of 150-mcg 
radiolabeled with 10 mCi (370 MBq) Tc 99m. 
Route of Administration: Tc 99m tilmanocept will be administered 
through an intravenous (IV) route of administration in 3 mL using a 
single syringe, with the dose injected as a slow push into the IV 
catheter. The preferred site of IV placement will be the left or right 
antecubital vein. At the completion of Tc 99m tilmanocept 
administration, a 10-mL sterile normal saline flush will be 
administered.  
Inclusion criteria 
1. The subject has provided written informed consent with 
HIPAA (Health Information Portability and Accountability 
Act) or equivalent authorization before the initiation of any 
study-related procedures. 
2. Women and men of reproductive potential must use adequate 
birth control measures (e.g., abstinence, oral contraceptives, 
intrauterine device, barrier method with spermicide, or 
surgical sterilization) for the duration of the study.  
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 RA as determined by the 2010 American 
College of Rheumatology/European League Against 
Rheumatism (ACR/EULAR) Classification Criteria (score of 
≥ 6/10 at or before screening). 
5. The subject has a 28-joint disease activity score (DAS28) of ≥ 
3.2 (includes the C-reactive protein [CRP] 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 first imaging visit (Day 0). 
7. If the subject is receiving biologic disease-modifying 
antirheumatic drug (bDMARD) or janus kinase (JAK) 
inhibitor therapy, they have been at a stable dose > 60 days 
prior to the imaging visit (Day 0). bDMARD therapy should 
not be administered less than 4 days prior to the imaging visit. 
8. If the subject is receiving NSAIDs (nonsteroidal anti-
inflammatory drug) or oral corticosteroids, the dose has been 
at a stable dose for ≥ 28 days prior to imaging. The 


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corticosteroid dose should be ≤ 10 mg/day of prednisone or 
an equivalent steroid dose. 
9. The subject has a hand or wrist joint with a minimum 
ultrasound gray-scale synovitis score of 2 (range 0 to 3). 
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 or chemotherapy 
within the past 5 years. 
4. 
The subject has an active malignancy or a history of 
malignancy within the past 5 years.  
5. 
The subject has had a finger, hand, and/or wrist amputation or 
hand or wrist joint arthroplasty.  
6. 
The subject has renal insufficiency as demonstrated by a 
glomerular filtration rate of < 60 mL/min.  
7. 
The subject has hepatic insufficiency as demonstrated by 
ALT (alanine aminotransferase [SGPT]) or AST (aspartate 
aminotransferase [SGOT]) greater than 3 times the upper 
limit of normal. 
8. 
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. 
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 the Tc 99m tilmanocept administration (Day 0). 
11. The subject has received injectable (e.g., intra-articular, 
intramuscular, etc.) corticosteroids ≤ 8 weeks prior to 
imaging (Day 0). 
12. The subject has received any radiopharmaceutical within 
7 days or 10 half-lives prior to the administration of Tc 99m 
tilmanocept (Day 0). 
13. The subject has an intolerance to anesthetic and antiseptic 
agents indicated for the synovial biopsy procedure.   


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14. The subject is currently receiving anticoagulants (oral anti-
platelet agents are permitted) or has a condition that is 
contraindicated with ultrasound-guided synovial biopsy e.g., 
needle phobia.  
15. The subject has heart failure [New York Heart Association 
(NYHA) Class III-IV], a demyelinating disorder, or a 
chronic/latent infection [e.g., +Purified Protein Derivative 
(PPD) test, Human Immunodeficiency Virus (HIV), 
Hepatitis B].  
Study design 
This is a phase 2b, open-label, multi-center, multinational, non-
randomized, single-dose study designed to assess the relationship 
between quantitative Tc 99m tilmanocept planar imaging and 
synovial histopathology in subjects clinically diagnosed with RA.  
Subjects will undergo an imaging assessment of the bilateral hands 
and wrists followed by an ultrasound-guided synovial biopsy of a 
select joint at a subsequent visit. Tissue samples from the synovial 
biopsy procedure will be used for 2 mandatory anatomic pathology 
evaluations, [1] IHC and [2] RNA-seq, and optional flow cytometry, 
to provide quantitative and semi-quantitative information regarding 
joint-specific disease activity. Results from each anatomic pathology 
evaluation will be correlated with TUVjoint on planar imaging to 
mechanistically assess the relationship between synovial anatomic 
pathology and TUVjoint.  
The quantitative characterization of Tc 99m tilmanocept uptake will 
be defined using the standardized computation of TUVjoint and 
TUVglobal by a central imaging laboratory. TUVjoint and TUVglobal 
metrics are further described in the NAV3-32 Imaging Manual and 
NAV3-32 Statistical Analysis Plan.  Results from  Phase 1 and 2 
studies have revealed that TUVjoint is a sensitive and specific 
identifier of Tc 99m tilmanocept localization in joint regions with 
presumed inflammatory macrophage activity. 
Anatomic pathology evaluations, including IHC and RNA-seq, will 
be performed by a central pathology laboratory in accordance with 
standardized operating procedures (SOPs). Synovial 
immunofluorescence evaluations will be used to determine the 
degree of expression of various immune markers including CD3, 
CD20, CD55, TE-7, CD68, CD163, and CD206. These markers will 
be evaluated in tandem to observe trends in co-expression and will 
also be compared with corresponding TUVjoint(s). IHC evaluations 
will also be used to characterize the pathotype of the corresponding 
synovial specimens (as diffuse myeloid, lympho-myeloid, or pauci-


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v8.0  25 October 2022 
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immune fibroid), which will then be evaluated against TUVjoint and 
TUVglobal to assess the discriminatory capacity of TUV for pathotype 
designation. RNA-seq will be used for the exploratory quantitative 
assessment of CD68, CD163, and CD206 mRNA expression, which 
will then be evaluated against corresponding TUVjoint(s). Flow 
cytometry will be performed (optionally) by a local pathology 
laboratory in accordance with standardized SOPs for the exploratory 
analysis of TUVjoint and the number and size of CD68, CD163, and 
CD206.  
All joints selected for biopsy will be required to have an ultrasound 
synovial thickness score of ≥ 2. In instances where more than 1 joint 
qualifies for biopsy, the candidate joint will be selected based on 
TUVjoint (as described in Table 1 below). 
Table 1 
Biopsy Selection Options 
Option Description 
1 
The subject has only 1 metacarpophalangeal (MCP) 
joint or wrist joint with an ultrasound gray-scale 
synovitis score of ≥ 2. This joint will be selected for 
biopsy. 
2 
The subject has 2 or more MCP and/or wrist joints with 
an ultrasound gray-scale synovitis score of ≥ 2. The 
joint for biopsy will be selected based on evaluation of 
corresponding TUVjoint. In the first subject with 
multiple qualifying joints, the joint with the highest 
TUVjoint will be selected; in the second subject with 
multiple qualifying joints, the joint with the lowest 
TUVjoint will be selected. Selection will proceed in this 
fashion, alternating between highest and lowest 
TUVjoint. 
 
  
Visit #1 (Screening; Day -30 to Day -1) 
• Informed consent 
• Review of study eligibility 
• Collection of medical history (including medications) 
• Vital sign assessment 
• Physical examination (including height and weight) 
• Clinical labs 


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• RA-specific labs 
• Urinalysis 
• Urine pregnancy for subjects of childbearing potential 
• 2010 ACR/EULAR score 
• DAS28 evaluation 
• Ultrasound synovitis assessment 
• AE assessment 
 
Visit #2 (Day 0; Tc 99m Tilmanocept Administration and 
Imaging) 
Pre-Tc 99m Tilmanocept Administration 
• Urine pregnancy test for women of child-bearing potential  
• ECG up to 30 minutes prior to drug administration 
• Post-ECG vital sign assessment 
• AE assessment  
• Review of concomitant medications 
 
Tc 99m Tilmanocept Administration: Subjects will receive a single 
IV dose of 150 mcg tilmanocept radiolabeled with 10 mCi (370 
MBq) of Tc 99m. 
 
0-30 Minutes Post-Tc 99m Tilmanocept Administration 
• ECG 
• Post-ECG vital sign assessment 
• AE assessment 
 
60 to 75 Minutes Post-Tc 99m Tilmanocept Administration  
• AE assessment 
Image acquisition: Static gamma camera scan of bilateral 
hands and wrists 
• Clinical labs (after imaging) 
 
Visit #3 (24-72 hours Post-Tc 99m Tilmanocept Administration; 
Follow-up Telephone Safety Assessment) 
• Review of concomitant medications 
• AE assessment 
 


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Visit #4 (Day 3-7; Synovial Tissue Biopsy) 
• Ultrasound assessment of synovitis 
• Synovial tissue biopsy of selected joint in accordance with 
Table 1 
• AE assessment 
• Review of concomitant medications 
 
Visit #5 (5 ± 2 days Post-Biopsy; Follow-up Telephone Safety 
Assessment) 
• Review of concomitant medications 
• AE assessment 
Planned study 
dates 
Start of study recruitment / 
February 2021 
End of Recruitment/ December 
2023 
End of Study/ March 2024 
Planned number of 
study centers 
Up to 10 centers which include sites in the US, UK, and EU  
Sample size 
Approximately 12 to 24 joints (final number based on an interim 
analysis and adaptive design) 
Justification of 
sample size 
The proposed sample size is sufficient to provide an acceptable 
standard error (approximately 0.15) on the Fisher Z scale and yield an 
acceptable confidence interval width on the population correlation. 
Primary endpoint 
• The correlation between joint-specific tilmanocept uptake value 
(TUVjoint) and the number and area fraction of CD206 
expression as determined by IHC assessment. 
Secondary 
endpoints 
• The correlation between TUVjoint and the number and area 
fraction of CD68 and CD163 determined by IHC assessments. 
• Classification of synovial anatomic pathology into  
• Lympho-myeloid 
• Diffuse myeloid 
• Pauci-immune fibroid 
types as a function of CD68, CD163, CD206, CD3, CD20, CD55, 
and TE7 expression determined by IHC assessments using a 
multinomial logistic regression model with TUVjoint as a 
covariate.  
• The correlation between the expression of CD68, CD163, and 
CD206. 


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Exploratory 
endpoints 
• The correlation of the expression of CD3, CD20, CD55, and 
TE7 with CD206 as measured through IHC.  
• The correlation of TUVjoint with the expression of CD206, 
CD163, and CD68 as measured through RNA-seq. 
• The number and size of CD206, CD163, and CD68 expressing 
macrophages as measured through (optional) flow cytometry and 
their correlation with TUVjoint. 
• The correlation between TUVglobal and synovial anatomic 
pathology as determined by IHC assessments. 
• Classification of synovial anatomic pathology into Lympho-
myeloid, Diffuse myeloid, and Pauci-immune fibroid types using 
a multinomial logistic regression model with TUVglobal as a 
covariate. 
Safety Evaluations 
Adverse events, clinical laboratory results (hematology, serum 
chemistry, vital signs, ECG) 
Plan for statistical 
analysis   
 
The following populations will be defined for the study: 
• Intent-to-Assay (ITA) population – the ITA population 
includes all subjects who have been enrolled in the study, 
injected with Tc 99m tilmanocept, received all imaging 
procedures, and have been biopsied. 
• Per Protocol (PP) population – Consists of all members of 
the ITA population without major protocol violations. At least 
4 evaluable synovial biopsy samples must be available for a 
subject to be included in the PP population. 
• Safety population – Consists of all subjects who are enrolled 
in the study and injected with Tc 99m tilmanocept regardless 
of imaging or biopsy status. 
All safety analyses will be conducted on the safety population. All 
efficacy analyses will be conducted on both the ITA population and 
PP population. 
Distributions of all baseline and demographic variables will be 
summarized for the safety population. Quantitative variables will be 
summarized by the mean, standard deviation, median, and range. 
Categorical variables will be summarized by counts and percentages. 


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Primary Efficacy Analysis 
The primary endpoint will be analyzed by computing the Pearson 
(product-moment) and Spearman (rank) correlation between the 
TUVjoint for the biopsied joint and 2 measures of macrophage 
prevalence: 
• The fraction of CD206-expressing macrophages visible in the 
microscope field under 4x and 10x power magnification, 
measured as the area fraction (AF) 
𝐴𝐴𝐴𝐴= Total Stained Area
Total Field Area × 100%. 
• The volume of synovial tissue in the biopsied joint derived from 
the ultrasound synovitis score (Vol). The final CD206-
expressing macrophage count is defined as the product of Vol 
and AF defined above. 
A 95% confidence interval for the population correlation coefficient 
measuring the association between TUV and CD206 expression (as 
measured via IHC) will be computed using the Fisher’s Z-
transformation method (Z = tanh-1 r) and its asymptotic Normal 
approximation. Statistical summaries of the marginal distributions of 
TUVjoint and CD206 macrophage count will be provided (mean, 
standard deviation, number of cases, median, and range). 
Secondary Efficacy Analyses 
The degree of co-expression of CD68, CD163, and/or CD206 
macrophage types will be assessed by calculating the Pearson 
(product-moment) correlations and Spearman rank correlations 
among these variables. The marginal distributions will be 
summarized by calculating the mean, standard deviation, number of 
cases, median, and range for each variable. 
The ability of TUVjoint to discriminate among lympho-myeloid, 
diffuse myeloid, and pauci-immune fibroid types will be assessed by 
fitting a multinomial logistic regression model with RA pathotype as 
the response variable and TUVjoint as the explanatory variable. ROC 
curves will be generated for the multinomial logistic model using the 
lympho-myeloid type as the base class. No inferential statistics will 
be generated for this endpoint. 


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Exploratory Efficacy Analyses 
The expression of CD68, CD163, and CD206 biomarkers as assessed 
using specific modules by RNA-seq in synovial tissue specimens will 
be measured by calculating the Pearson and Spearman correlation 
matrices for these variables with TUVjoint. Descriptive statistics for 
the variables (mean, number of complete cases, standard deviation) 
will be provided. 
The expression of CD68, CD163, and CD206 biomarkers as 
measured with optional flow cytometry in synovial tissue specimens 
will be measured by calculating the Pearson and Spearman correlation 
matrices for these variables with TUVjoint. Descriptive statistics for 
the variables (mean, number of complete cases, standard deviation) 
will be provided. 
The Pearson and Spearman correlation matrices for CD3, CD20, 
CD55, CD68, CD163, CD206, and TE7 biomarker expressions will 
be computed for each measurement method (IHC, RNA-seq, and 
optional flow cytometry). The marginal distributions of all variables 
will be summarized with descriptive statistics (number of complete 
data points, means, standard deviations, minima, medians, and 
maxima).  
The ability of TUVglobal to discriminate among lympho-myeloid, 
diffuse myeloid, and pauci-immune fibroid types will be assessed by 
fitting a multinomial logistic regression model with RA pathotype as 
the response variable and TUVglobal as the explanatory variable. 
ROC curves will be generated for the multinomial logistic model 
using the lympho-myeloid type as the base class. No inferential 
statistics will be generated for this endpoint. 


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Safety Analyses 
The safety of Tc 99m tilmanocept will be summarized by tabulating 
the number and percentage of subjects experiencing AEs, treatment 
emergent AEs (TEAEs), and serious TEAEs. AEs, TEAEs and 
serious TEAEs will tabulated by system organ class (SOC) and 
preferred term (PT). 
Vital signs, clinical laboratory results, and ECG parameters will be 
summarized with descriptive statistics (mean, standard deviation, n, 
median, and range) for the observed values and the change from the 
baseline value. 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF IN-TEXT FIGURES.................................................................................................16 
LIST OF APPENDICES ..........................................................................................................16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................17 
1 
INTRODUCTION ...........................................................................................................21 
1.1 
Background and Significance ................................................................................21 
1.2 
Previous Nonclinical and Clinical Trial Experience in Tc 99m Tilmanocept .......26 
1.2.1 
Clinical Pharmacokinetics (IV)....................................................................26 
1.2.2 
Clinical Efficacy ..........................................................................................28 
1.2.2.1 
NAV3-23 (SC) ...................................................................................28 
1.2.2.2 
NAV3-21 (IV) ....................................................................................29 
1.2.3 
Clinical Safety ..............................................................................................29 
1.2.3.1 
NAV3-23 (SC) ...................................................................................29 
1.2.3.2 
NAV3-21 (IV) ....................................................................................29 
2 
STUDY OBJECTIVES ....................................................................................................30 
2.1 
Primary Objectives.................................................................................................30 
2.2 
Secondary Objectives.............................................................................................30 
2.3 
Exploratory Objectives ..........................................................................................30 
2.4 
Safety Objective .....................................................................................................30 
3 
INVESTIGATIONAL PLAN ..........................................................................................31 
3.1 
Overall Study Design and Plan ..............................................................................31 
3.2 
Justification for Study Design and Population.......................................................31 
3.3 
Protocol Adherence ................................................................................................31 
3.4 
Study Duration and Dates ......................................................................................32 
4 
STUDY POPULATION SELECTION ...........................................................................33 
4.1 
Study Population ....................................................................................................33 
4.2 
Inclusion Criteria ...................................................................................................33 
4.3 
Exclusion Criteria ..................................................................................................33 
4.4 
Recruitment ............................................................................................................34 
4.5 
Withdrawal .............................................................................................................34 
4.6 
Screen Failures .......................................................................................................35 
4.7 
Subject Identification .............................................................................................35 
5 
INVESTIGATIONAL PRODUCT ..................................................................................36 
5.1 
Description of Investigational Product ..................................................................36 
5.2 
Investigational Product Dosage and Administration .............................................36 
5.3 
Timing and Frequency of Drug Administration ....................................................37 


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5.4 
Drug Logistics and Investigational Product Accountability ..................................37 
6 
THERAPIES OTHER THAN INVESTIGATIONAL PRODUCT .................................38 
6.1 
Prior and Concomitant Therapies ..........................................................................38 
6.2 
Post-Study Therapy ................................................................................................38 
7 
STUDY PROCEDURES .................................................................................................39 
7.1 
Schedule of Evaluations .........................................................................................39 
7.1.1 
Visit 1, Screening (Day -30 to Day -1) ........................................................39 
7.1.2 
Visit 2, Tc 99m Tilmanocept Administration and Imaging (Day 0) ...........40 
7.1.3 
Visit 3, Follow-up Telephone Safety Assessment (24 to 72 hours post-
Tc 99m tilmanocept administration) ............................................................41 
7.1.4 
Visit 4, Synovial Tissue Biopsy (Day 3 to 7 post-Tc 99m tilmanocept 
administration) .............................................................................................41 
7.1.5 
Visit 5, Follow-up Telephone Safety Assessment (5 ± 2 days post-
biopsy)..........................................................................................................41 
7.1.6 
End of Study ................................................................................................41 
8 
PROCEDURES AND VARIABLES ..............................................................................42 
8.1 
Population Characteristics .....................................................................................42 
8.1.1 
Demographics and Other Baseline Characteristics ......................................42 
8.1.2 
Medical, Rheumatological, and Surgical History ........................................42 
8.1.3 
Prior and Concomitant Medication ..............................................................42 
8.2 
Tc 99m Tilmanocept Administration .....................................................................42 
8.3 
Rheumatological Assessments ...............................................................................42 
8.3.1 
2010 ACR/EULAR Classification Criteria ..................................................42 
8.3.2 
DAS28..........................................................................................................43 
8.3.3 
Other ............................................................................................................43 
8.3.3.1 
28-joint Count (Swollen Joint Count [SJC] and Tender Joint 
Count [TJC]) ......................................................................................43 
8.3.3.2 
Visual Analog Scale (VAS) ...............................................................43 
8.3.3.3 
Acute-phase Reactant.........................................................................43 
8.4 
Imaging ..................................................................................................................43 
8.4.1 
Planar Image Acquisition .............................................................................43 
8.4.2 
Image Evaluation .........................................................................................44 
8.4.2.1 
Tilmanocept Uptake Value (TUV) ....................................................44 
8.5 
Synovial Biopsy .....................................................................................................44 
8.5.1 
Joint Selection ..............................................................................................44 
8.5.2 
Biopsy Procedure .........................................................................................45 
8.6 
Pathology Evaluation of Synovial Tissue ..............................................................45 
8.6.1 
Preparation and Shipping of Synovial Tissue Samples to Central 
Laboratory ....................................................................................................45 


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8.6.2 
Central Pathology Laboratory Processing of Samples – IHC and RNA-
seq ................................................................................................................46 
8.6.3 
Local Laboratory Processing of Samples – Flow Cytometry ......................46 
8.7 
Safety .....................................................................................................................46 
8.7.1 
Adverse Events ............................................................................................46 
8.7.1.1 
Definition of Adverse Event ..............................................................46 
8.7.1.2 
Categories for Adverse Event Assessment ........................................47 
8.7.1.3 
Assessments and Documentation of Adverse Events ........................48 
8.7.1.4 
Expected Adverse Events ..................................................................49 
8.7.1.5 
Serious Adverse Events .....................................................................50 
8.7.2 
Vital Signs ....................................................................................................52 
8.7.3 
Electrocardiogram ........................................................................................52 
8.7.4 
Clinical Laboratory Parameters ...................................................................52 
9 
PLANNED STATISTICAL METHODS ........................................................................54 
9.1 
Randomization Methods ........................................................................................54 
9.2 
Safety Variables .....................................................................................................54 
9.3 
Efficacy Variables ..................................................................................................54 
9.4 
Sample Size and Justification ................................................................................56 
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 ....................................................................56 
9.5.3.1 
Primary Endpoint ...............................................................................57 
9.5.3.2 
Secondary Endpoints .........................................................................57 
9.5.3.3 
Exploratory Endpoints .......................................................................58 
9.5.4 
Analysis of Safety Variables ........................................................................58 
9.5.5 
Handling of Missing Values ........................................................................59 
9.5.6 
Interim Analysis ...........................................................................................59 
10 DATA HANDLING AND QUALITY ASSURANCE ...................................................60 
10.1 
Data Recording ......................................................................................................60 
10.1.1 
CRF Design ..................................................................................................60 
10.2 
Monitoring .............................................................................................................60 
10.3 
Data Processing ......................................................................................................60 
10.4 
Auditing .................................................................................................................60 
10.5 
Archiving ...............................................................................................................61 
10.6 
Premature Termination of the Study ......................................................................61 
10.6.1 
Termination by the Sponsor .........................................................................61 
10.6.2 
Termination by the Investigator ...................................................................61 
10.6.3 
Study as a Whole .........................................................................................62 


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10.6.4 
Center ...........................................................................................................62 
10.6.5 
Study Participant ..........................................................................................62 
11 ETHICAL AND LEGAL ASPECTS...............................................................................63 
11.1 
Ethical and Legal Conduct of the Study ................................................................63 
11.2 
Subject Information and Consent...........................................................................63 
11.3 
Financing/Financial Disclosure .............................................................................64 
11.4 
Publication Policy ..................................................................................................64 
11.5 
Subject Injury .........................................................................................................64 
12 REFERENCE LIST .........................................................................................................65 
 
LIST OF IN-TEXT TABLES 
Table 1     
Biopsy Selection Options ...............................................................................6 
Table 2  
Whole Blood PK Parameter Summaries by Group......................................27 
Table 3  
Urine PK Parameter Summaries by Group ..................................................28 
Table 4  
Biopsy Selection Options .............................................................................45 
Table 5  
Clinical Laboratory Parameters ...................................................................52 
Table 6  
Approximate Amount of Blood Drawn per Subject ....................................53 
 
LIST OF IN-TEXT FIGURES 
Figure 1  
Tc 99m tilmanocept and the Mannose Receptor..........................................36 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................69 
Appendix 2 
NAV3-32 Study Workflow ................................................................70 
Appendix 3 
2010 ACR/EULAR Classification Criteria ........................................71 
Appendix 4 
DAS28 Scoring ..................................................................................73 
Appendix 5 
Sponsor Signatures.............................................................................74 
Appendix 6 
Investigator’s Signature .....................................................................75 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
18F-FDG PET 
18F-labeled fluoro-2-deoxyglucose positron emission tomography 
ACR 
American College of Rheumatology 
ACR/EULAR 
American College of Rheumatology/European League Against 
Rheumatism 
ADR 
Adverse drug reaction  
AE 
Adverse event 
AF 
Area fraction 
ALT 
Alanine aminotransferase  
ACPA 
Anti-citrullinated peptide antibody  
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the curve 
BUN 
Blood urea nitrogen 
bDMARD 
Biologic disease modifying antirheumatic drug 
CD206 
Mannose-binding receptor (Ca2+-binding lectin) 
CI 
Confidence interval 
CRF 
Case report form 
CRP 
C-reactive protein 
CRA 
Clinical research associate 
CRO 
Contract research organization  
CT 
Computed tomography 
CV 
Coefficient of variation 
DAS28 
Disease activity score used with the ACR/EULAR 2010 guidelines 
DMARD 
Disease-modifying antirheumatic drug 
DTPA 
diethylenetriaminepentaacetic acid 
ESR 
Erythrocyte sedimentation rate 
ECG 
Electrocardiogram  
eCRF 
Electronic case report form 
EU 
European Union  


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UK 
United Kingdom 
FDA 
Food and Drug Administration 
FDG 
Fluoro-2-deoxyglucose 
GCP 
Good Clinical Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HIPAA 
Health Information Portability and Accountability Act 
HC 
Healthy control 
IAP 
Interim analysis plan 
ICF 
Informed consent form 
IEC 
Independent ethics committee 
ICH 
International Conference on Harmonisation  
IHC 
Immunohistochemistry 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
ITA 
Intent-to-assay 
IV 
Intravenous 
JAK 
Janus kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCP  
metacarpophalangeal joint 
NSAID 
Non-steroidal anti-inflammatory drug 
PET 
Positron emission tomography 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PP 
Per protocol 
PIP 
Proximal interphalangeal  
PT 
Preferred term  
QC 
Quality control  
QT 
Interval from the Q wave to the end of the T wave 


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QTc 
Corrected QT interval 
RBC 
Red blood cell (count) 
ROI 
Region of interest 
RA 
Rheumatoid arthritis  
RF 
Rheumatoid factor  
RR 
Reference region 
RSNA 
Radiological Society of North America 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SJC  
Swollen joint count  
SUV 
Standard uptake value  
SUSAR 
Suspected unexpected serious adverse reactions 
SOC 
System organ class 
SOP 
Standardized operating procedures 
t1/2 
Mean half-life 
TEAE 
Treatment emergent adverse event 
TJC 
Tender joint count  
TMF 
Trial Maser File  
TNFα 
Tumor necrosis factor alpha 
TUV 
Tilmanocept uptake value 
TUVglobal 
Global tilmanocept uptake value 
TUVjoint 
Joint-specific tilmanocept uptake value 
VAS 
Visual analog scale 
Vol 
ultrasound synovial thickness score 
US 
United States 
ULN 
Upper limit of normal  


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WBC 
White blood cell (count) 
λz 
Mean elimination rate constant  


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1 
INTRODUCTION 
1.1 
Background and Significance 
Worldwide, approximately 1 in 200 adults suffers from RA. In the US and UK, there are 
1.3 million and 400,000 adults living with RA, respectively. Each year, about 130,000 
Americans are newly diagnosed with RA. In the UK, the incidence of RA is 
3.81/10,000 person-years (Abhishek 2017). Individuals with inadequately controlled RA have 
significantly shorter life expectancies and frequently become disabled, leading to reduced 
quality of life and severe adverse economic consequences (Lassere 2013, Uhlig 2014, 
Verstappen 2015, Michelsen 2018). 
It has been realized for many years that RA patients who are placed on disease-modifying 
antirheumatic drugs (DMARDs) soon after they develop arthritis symptoms respond much 
more favorably to these therapies than do patients whose initiation of DMARD therapy is 
delayed (Demoruelle 2012). 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 
(Anderson 2000, Nell 2004, van der Linden 2010). 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 (Cush 2007). 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 (Aletaha 2010). 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 (Sakellariou 2013), it was shown that the ACR/EULAR 2010 criteria have 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.  


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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 (Olszewski 2001, Meyer 2010). Frequently, 
at the center of this cytokine network is the overexpression of tumor necrosis factor alpha 
(TNFα) (Leizer 1990, Keffer 1991, Choy 2001, Westra 2004). 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 (Kalden 2002, Chen 2006, Scott 2010, Vivar 2014). 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 (Furst 2011, Salliot 2011), 
• All current RA therapies are associated with adverse effects, which can be common 
and/or severe (Tran 2013),  
• Many current RA therapies, especially the biologic therapies, are exceedingly 
expensive, placing an imposing burden on healthcare costs (Hresko 2018) and 
affordability (Heidari 2018), 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 
(Ishikawa 1976, Firestein 1990, Kinne 2007). Macrophages are common in inflamed synovial 
tissues when patients are first diagnosed with RA (Smolen 2018) 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 (Choy 
2001). In the synovial sublining of a joint affected by RA, activated macrophages are 
frequently the dominant cell type (Cutolo 1993, Kraan 2002, Kennedy 2011). Activated 
macrophages significantly contribute to the destruction of bone and cartilage through their 
secretion of proteases (Bresnihan 1999, Ma 2005). 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 (Yanni 1994, Mulherin 1996, 
Vieira-Sousa 2011, Orr 2017). Not surprisingly, activated synovial macrophage numbers—but 
not the numbers of other immune cell types—correlate with radiographically determined joint 
destruction in RA (Yanni 1994, Mulherin 1996). Thus, CD206 positivity of inflamed synovia 
in RA patients is expected to provide clinically significant prognostic information for RA 


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patients. Another important finding is that activated macrophage numbers are reduced by 
effective RA therapy (Vieira-Sousa 2011), but do not significantly change over the course of 
at least months if a patient was given ineffective RA therapy (Baeten 2006). 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 
(Filkova 2016). 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 
(Smith 2001, Bresnihan 2009).  In fact, a change in activated synovial macrophage numbers is 
considered a more accurate measure of treatment response than clinical assessments, which are 
highly subjective in nature and prone to observer error (Wijbrandts 2007, Bresnihan 2009, van 
de Sande 2012). 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. Navidea’s current clinical development plan for Tc 99m tilmanocept 
includes Phase 2 and Phase 3 studies evaluating the safety and efficacy of Tc 99m tilmanocept 
imaging of RA patients initiating an anti-TNFα therapy and to provide an early indication of 
response to therapy in this patient population before clinical symptoms have improved. Success 
of this clinical trials program would provide physicians and RA 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 (Orr 2017).  An 
important finding of these studies has been that the inflammatory cell compositions of RA 
inflamed joints can vary between patients (Townsend 2014, van de Sande 2016). 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 (Orr 2017). 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 (Dennis 2014, Astorri 2015). High densities of macrophages 
can occur in both the myeloid and lymphoid pathotypes, whereas the fibroid pathotype is 
largely devoid of both macrophages and lymphoid cells. These pathotypes are not fully 
discrete, 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 the choice of the most effective 
therapy for that patient (i.e., personalized RA therapy) (Dennis 2014). This is an area of 
ongoing active investigation in RA therapy research (Pitzalis 2013, Donlin 2018, Mandelin 
2018). However, already there is significant evidence indicating that patients with a myeloid-


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driven RA pathotype and/or with high densities of macrophages in their inflamed synovium 
respond best to anti-TNFα biologic therapy (Wijbrandts 2008, Dennis 2014), 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 optimal treatments to all RA 
patients. The study to be conducted (NAV3-32) is designed to establish the correlation between 
Tc 99m tilmanocept localization to RA inflamed joints and the number and density of CD206 
expressing cells (i.e., macrophages) in the inflamed joints as determined by IHC evaluations 
of synovial biopsy specimens. If this study is successful, Tc 99m tilmanocept imaging may be 
able to discriminate the fibroid pathotype from the myeloid and lymphoid pathotypes and may 
be able discriminate all 3 pathotypes from each other. 
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 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 


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membrane may not yet have expanded (i.e., thickened) sufficiently to permit biopsy sampling. 
As discussed above, 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 to 
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 (Kraan 2002, Pitzalis 2013). 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 one 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 repeated 
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.  
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 (Mandelin 
2018). 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.  
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 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 


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anatomically and physiologically relevant parameters, including treatment response and 
outcome, and the use of such metrics in research and patient care.” (RSNA 2018) 
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 𝑆𝑆𝑆𝑆𝑆𝑆= 
𝑟𝑟
(𝑎𝑎′/𝑤𝑤). (Kinahan 2010)   
Based on the clinical utility of SUV in 18F-FDG PET imaging, Navidea pursued the 
development of the TUV (tilmanocept uptake value) 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 a ROI, 
and B, the pixel intensity of an anatomically defined within-patient reference region, such that 
𝑇𝑇𝑇𝑇𝑇𝑇=
𝑥𝑥̅
𝑅𝑅𝑅𝑅× 100. Thus, another purpose of this study will be to test the reliability and clinical 
utility of TUV. 
1.2 
Previous Nonclinical and Clinical Trial Experience in Tc 99m 
Tilmanocept  
A detailed evaluation of 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 
Clinical Pharmacokinetics (IV) 
Pharmacokinetics 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 healthy control [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) including 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), and mean elimination 
rate constant (λz) to evaluate potential differences between disease groups (Table 2). The 


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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 subjects.  


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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 HCs and subjects with active RA does not reveal any 
apparent differences in the elimination of radioactivity from the body.   
1.2.2 
 Clinical Efficacy 
1.2.2.1 
NAV3-23 (SC) 
This was an open-label, multicenter study of Tc 99m tilmanocept by SC administration in HCs 
and in subjects with active RA.  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 and 180 ± 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-hour 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.  


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• There is an overall lack of concordance between qualitative observation of Tc 99m 
tilmanocept localization to swollen/tender joints identified in DAS28 joint count 
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. 
 
1.2.2.2 
NAV3-21 (IV) 
This was an open-label, multicenter, dose-escalation safety with PK and dosimetry study of 
Tc 99m tilmanocept by IV administration in HCs and in 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 maximum dose of 400 mcg/10 mCi. Imaging was performed 
60 ± 15 minutes and 180 ± 15 minutes post-injection. Clinical efficacy conclusions for this 
study are still under review.  
1.2.3 
 Clinical Safety 
1.2.3.1 
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 serious adverse events (SAEs) were observed. 
There were no deaths on trial.   
1.2.3.2 
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. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objectives of this study are: 
• Assessment of the relationship between joint-specific tilmanocept uptake value 
(TUVjoint) and synovial anatomic pathology. 
• IHC assessment of macrophage expression of the CD206 receptor. 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
• Assessments of CD68 and CD163 receptor expression levels through IHC 
microscopy. 
• Classification of synovial anatomic pathology as 
• Lympho-myeloid 
• Diffuse myeloid 
• Pauci-immune fibroid 
2.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
• Determine the relationship between TUVjoint and mRNA expression profiles of CD68, 
CD163, and CD206 as determined by RNA sequencing (RNA-seq). 
• Determine the relationship between TUVjoint and the number, size, and intensity of 
CD68, CD163, and CD206 as determined by (optional) flow cytometry. 
• Evaluate synovial expression of CD3, CD20, CD55, and TE-7 and CD206 in synovial 
tissue biopsy specimens.  
• Assessment of the relationship between TUVglobal and synovial anatomic pathology. 
 
2.4 
Safety Objective 
The safety objective of this study is: 
• Evaluate safety through the examination of adverse event (AE) incidence, physical 
examination findings, and changes over time in laboratory tests, electrocardiograms 
(ECGs), and vital signs. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a phase 2b, open-label, multicenter, multinational, non-randomized, single-dose study 
designed to assess the relationship between quantitative Tc 99m tilmanocept planar imaging 
and synovial histopathology in subjects clinically diagnosed with RA. This study will take 
place in up to 10 centers in the US, UK, and EU. 
Subjects will undergo an imaging assessment of the bilateral hands and wrists followed by an 
ultrasound-guided synovial biopsy of a select joint at a subsequent visit. Tissue samples from 
the synovial biopsy procedure will be used for 2 mandatory anatomic pathology evaluations, 
[1] IHC and [2] RNA-seq, with optional flow cytometry, to provide quantitative and semi-
quantitative information regarding joint-specific disease activity. Results from each of the 3 
anatomic pathology evaluations will be correlated with TUVjoint on planar imaging to 
mechanistically assess the relationship between synovial anatomic pathology and TUVjoint.  
The Schedule of Events (Appendix 1) contains a list of all study procedures and time points. 
Study activities are described in detail in Section 7.  
3.2 
Justification for Study Design and Population 
This study is designed to evaluate the correlation between TUVjoint and the number and area 
fraction of CD206 expression as determined by IHC assessment in the synovium of subjects 
clinically diagnosed with RA who are not receiving anti-rheumatic treatment or who are on 
stable anti-rheumatic treatment. The ability of Tc 99m tilmanocept imaging to detect and 
discriminate RA pathotypes is being evaluated in these subjects with the goal of supporting 
personalized therapy. A complete rationale for evaluating Tc 99m tilmanocept in this subject 
population is discussed in Section 1.1. 
3.3 
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)] or Independent Ethics Committee(s) [IEC(s)]. 
If an investigator has deviated from the protocol 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 or IEC as 
applicable. 


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3.4 
Study Duration and Dates 
Subjects will be “on study” for up to 45 days depending on the screening window (up to 
30 days). 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
This study will evaluate subjects clinically diagnosed with RA who are on stable therapy. 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study. 
1. The subject has provided written informed consent with HIPAA (Health Information 
Portability and Accountability Act) or equivalent authorization before the initiation of 
any study-related procedures. 
2. Women and men of reproductive potential must use adequate birth control measures 
(e.g., abstinence, oral contraceptives, intrauterine device, barrier method with 
spermicide, or surgical sterilization) for the duration of the study.  
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 RA as determined by the 2010 ACR/EULAR Classification Criteria 
(score of ≥ 6/10 at or before screening). 
5. The subject has a DAS28 of ≥ 3.2 (includes the C-reactive protein [CRP] 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 first 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). bDMARD 
therapy should not be administered less than 4 days prior to the imaging visit. 
8. If the subject is receiving NSAIDs or oral corticosteroids, the dose has been at a stable 
dose for ≥ 28 days prior to imaging. The corticosteroid dose should be ≤ 10 mg/day of 
prednisone or an equivalent steroid dose. 
9. The subject has a hand or wrist joint with a minimum ultrasound gray-scale synovitis 
score of 2 (range 0 to 3). 
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
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 or chemotherapy within the past 5 years. 
4. 
The subject has an active malignancy or a history of malignancy within the past 5 years. 


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5. 
The subject has had a finger, hand, and/or wrist amputation or hand or wrist joint 
arthroplasty.  
6. 
The subject has renal insufficiency as demonstrated by a glomerular filtration rate of 
< 60 mL/min.  
7. 
The subject has hepatic insufficiency as demonstrated by ALT (alanine 
aminotransferase [SGPT]) or AST (aspartate aminotransferase [SGOT]) greater than 
3 times the upper limit of normal. 
8. 
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. 
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 the Tc 99m 
tilmanocept administration (Day 0). 
11. The subject has received injectable (e.g., intra-articular, intramuscular, etc.) 
corticosteroids ≤ 8 weeks prior to imaging (Day 0). 
12. The subject has received any radiopharmaceutical within 7 days or 10 half-lives prior 
to the administration of Tc 99m tilmanocept (Day 0). 
13. The subject has an intolerance to anesthetic and antiseptic agents indicated for the 
synovial biopsy procedure.   
14. The subject is currently receiving anticoagulants (oral anti-platelet agents are 
permitted) or has a condition that is contraindicated with ultrasound-guided synovial 
biopsy, e.g., needle phobia. 
15. The subject has heart failure (NYHA Class III-IV), a demyelinating disorder, or a 
chronic/latent infection (e.g., +PPD, HIV, Hepatitis B). 
 
4.4 
Recruitment 
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. 
4.5 
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.  
Should a subject withdraw after administration of Tc 99m tilmanocept, 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. 


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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 if 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  
 
4.6 
Screen Failures 
Subjects who sign a patient informed consent form (ICF/PCF) but are ultimately not injected 
with Tc 99m tilmanocept will be considered a screen failure. 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 “32”  
 
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 “32-01-001.”  
 
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 Product 
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 
comprises multiple units of diethylenetriaminepentaacetic acid (DTPA) 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 a single syringe, with the dose 
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 the left or 
right antecubital vein.  


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5.3 
Timing and Frequency of Drug Administration 
This is an open-label, non-randomized study in which all subjects will receive the 
study-defined dose of 150 mcg tilmanocept radiolabeled with 10 mCi of Tc 99m at a single 
occurrence on Day 0 (Visit 2). 
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 
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.  
5.4 
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 principal investigator (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 administration through biopsy and 
post-biopsy telephone safety assessment must be documented, and a stable dose of the 
medication must be maintained for RA medications through the end of trial participation 
according to the inclusion criteria. Subjects who have received or are currently 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. 
Dosing of a bDMARD or injectable corticosteroid should be avoided particularly between 
Visit 2 and Visit 4 (i.e., between imaging and biopsy) for subjects on such therapies. Visit 2 
should be scheduled at least 4 days following a subject’s last dose of a bDMARD. Injectable 
corticosteroids (e.g., intra-articular, intramuscular, etc.) should be avoided for at least 8 weeks 
prior to imaging (Day 0).  
6.2 
Post-Study Therapy 
There are no post-study therapy restrictions. 


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7 
STUDY PROCEDURES 
7.1 
Schedule of Evaluations 
A schedule of evaluations is provided in the Schedule of Events (Appendix 1) and Study 
Work Flow (Appendix 2). 
7.1.1 
Visit 1, Screening (Day -30 to Day -1) 
• Preliminary review of inclusion and exclusion criteria 
• 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 
• Medical and 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 (administered within 30 days prior to Tc 99m tilmanocept 
administration); RA concomitant medications administered within 6 months prior to 
Tc 99m tilmanocept administration will be recorded. 
• 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 Tc 99m 
tilmanocept administration. 
• Clinical laboratory tests – study subjects will have blood obtained for hematology, 
chemistry, and an RA panel (see Table 5)  
• 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:  
o Swollen and tender joints as established by the 2010 ACR/EULAR Classification 
Criteria and DAS28 will be identified and documented during physical 
examination.  


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• An ultrasound of the hands and wrist joints will be obtained to assess synovitis. 
Subjects must have at least 1 joint with a minimum gray-scale synovitis score of 2 
(range 0 to 3) to be eligible for the study. 
• Assessment of AEs 
 
7.1.2 
Visit 2, Tc 99m Tilmanocept Administration and Imaging (Day 0) 
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 AEs 
• Concomitant medication review 
• ECG (see Section 8.7.3) within 30 minutes prior to administration of Tc 99m 
tilmanocept 
• 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. 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 AEs. 
0 to 30 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of AEs 
• ECG (completed before vital signs) 
• Vital signs after at least 1 minute in a resting position (body temperature, heart rate, 
blood pressure, and respiratory rate) 
 
60 to 75 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of AEs 
• Image acquisition: Static gamma camera scan of the bilateral hands and wrists  
• Clinical Labs (at conclusion of the imaging session) 


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7.1.3 
Visit 3, Follow-up Telephone Safety Assessment (24 to 72 hours post-
Tc 99m tilmanocept administration) 
• Review of concomitant medications 
• Assessment of AEs 
 
7.1.4 
Visit 4, Synovial Tissue Biopsy (Day 3 to 7 post-Tc 99m tilmanocept 
administration) 
• Ultrasound assessment of synovitis 
• Ultrasound-guided synovial tissue biopsy of selected joint in accordance with Table 4 
• AE assessment 
• Review of concomitant medications 
 
7.1.5 
Visit 5, Follow-up Telephone Safety Assessment (5 ± 2 days post-biopsy) 
• Review of concomitant medications 
• AE assessment 
 
7.1.6 
End of Study  
For the entire study, end of study is defined as last subject last visit. 


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8 
PROCEDURES AND VARIABLES 
8.1 
Population Characteristics 
8.1.1 
Demographics and Other Baseline Characteristics 
Twelve (12) to 24 evaluable subjects may be enrolled. Subjects will be men and women aged 
≥ 18 years with clinically diagnosed RA who are on stable therapy.  
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 last follow-up telephone safety assessment (Visit 5) will be documented. All 
concomitant treatments for RA and RA-specific drugs taken within the last 6 months should 
be documented.  
8.2 
Tc 99m Tilmanocept Administration 
The site representative will complete an investigational product order form to order Tc 99m 
tilmanocept from the local radiopharmacy once the subject has been scheduled for IV Tc 99m 
tilmanocept administration and imaging. The preferred site of IV placement will be the left or 
right antecubital vein. The filled syringe will be connected to a catheter for a slow push 
injection. Immediately after the Tc 99m tilmanocept administration, a 10-mL sterile normal 
saline flush will be injected. Tc 99m tilmanocept administration 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 
(Aletaha 2010) as part of eligibility and inclusion. The 2010 ACR/EULAR classification 
criteria include 4 components: number and site of involved joints, serologic abnormality, 
elevated acute-phase response and symptom duration. See Appendix 3 for details. A total score 
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.”  Eligibility for this trial requires that 
the subject has had a 2010 ACR/EULAR Classification Criteria score of ≥ 6 prior to or at 
screening. 


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8.3.2 
DAS28 
All subjects will be evaluated for the DAS28 (Prevoo 1995) at screening. DAS28 is calculated 
from 4 components: tender joint count (TJC), swollen joint count (SJC), VAS of the subject’s 
global health, and the laboratory parameter CRP, such that: 
𝐷𝐷𝐷𝐷𝐷𝐷28 = 0.56ඥ𝑇𝑇𝑇𝑇𝑇𝑇+ 0.28ඥ𝑆𝑆𝑆𝑆𝑆𝑆+ 0.36 ln(𝐶𝐶𝐶𝐶𝐶𝐶+ 1) + 0.014(𝑉𝑉𝑉𝑉𝑉𝑉) + 0.96 
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 4 for details on classifying and calculating DAS28. 
8.3.3 
Other 
8.3.3.1 
28-joint Count (Swollen Joint Count [SJC] and Tender Joint Count [TJC]) 
The 28-joint count will be performed for swollen and/or tender joints in the following: 
shoulder, elbow, wrist, metacarpophalangeal (MCP), proximal interphalangeal (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 (Scott 1996). This assessment will be used as an input parameter for 
2010 ACR/EULAR score (Section 8.3.1) and DAS28 score (Section 8.3.2). 
8.3.3.2 
Visual Analog Scale (VAS) 
Patient assessment of global health will be evaluated using the VAS to self-assess disease 
activity on a 0-100 scale, where 100 represents maximal disease activity. Using a validated 
ruler, the score will be determined by measuring the distance (mm) on the 10-cm line between 
0 and the subject’s mark, providing a range of scores from 0 to 100. This assessment will be 
used as an input parameter for DAS28 score (Section 8.3.2). 
8.3.3.3 
Acute-phase Reactant 
CRP and ESR will be obtained in the RA-specific laboratory panel (see Table 5).  CRP will 
be used in the calculation of the DAS28 score. 
8.4 
Imaging 
8.4.1 
Planar Image Acquisition 
All subjects will receive anterior and posterior static gamma camera views of the hands and 
wrists at 60 to 75 minutes post-Tc 99m tilmanocept administration.  


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Refer to the Imaging Manual for all required imaging technical specifications and acquisitions. 
8.4.2 
Image Evaluation 
All images obtained for this study will be evaluated by a central image core lab. The image 
core lab will be responsible for image intake; processing, including overall assessment of the 
scan and QC; region of interest (ROI) drawings; and TUV calculations. All images will be de-
identified and provided directly to the Image Core Lab by the site personnel via electronic or 
CD transfer. Refer to the Imaging Manual for details relating to image intake and analysis. 
8.4.2.1 
Tilmanocept Uptake Value (TUV) 
TUV is a quantitative imaging metric used to characterize the amount of CD206 activity on 
planar imaging. Standardized TUV calculations are performed at a centralized core image lab 
in accordance with established image processing guidelines.  
For all subjects, a delegated imaging scientist blinded to all subject information (including any 
clinical data and/or image acquisition data) will perform semi-automated ROI drawing on 
static images of the bilateral hands and wrists to derive relevant count statistics, which are 
input parameters for joint-specific (TUVjoint) TUVs. 
TUVjoint is defined as the intrasubject ratio of the average pixel intensity of a joint to the 
average pixel intensity of the reference region, such that TUVjoint =
xതJoint ROI
xതRR
. 
Timelines and further details on image intake, ROI drawing, and TUV calculations can be 
found in the NAV3-32 Imaging Manual and NAV3-32 Statistical Analysis Plan.  
8.5 
Synovial Biopsy 
8.5.1 
Joint Selection 
All subjects will undergo a synovial biopsy of a selected hand or wrist joint. All joints selected 
for biopsy will be required to have an ultrasound gray-scale synovitis score of ≥ 2 (range 0 to 
3). In instances where more than 1 joint is qualified for biopsy, the candidate joint will be 
selected based on TUVjoint (as described in Table 4). 


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Table 4  
Biopsy Selection Options 
Option 
Description 
1 
The subject has only 1 MCP joint or wrist joint with an ultrasound gray-
scale synovitis score of ≥ 2. This joint will be selected for biopsy. 
2 
The subject has 2 or more MCP and/or wrist joints with an ultrasound gray-
scale synovitis score of ≥ 2. The joint for biopsy will be selected based on 
evaluation of corresponding TUVjoint. In the first subject with multiple 
qualifying joints, the joint with the highest TUVjoint will be selected; in the 
second subject with multiple qualifying joints, the joint with the lowest 
TUVjoint will be selected. Selection will proceed in this fashion, alternating 
between highest and lowest TUVjoint. 
The ultrasound assessment for synovitis score should take place at screening and prior to 
biopsy at Visit 4 (Day 3 to 7 post-Tc 99m tilmanocept administration) in accordance with 
institutional standard operating procedures (SOPs).  
8.5.2 
Biopsy Procedure 
Subjects will undergo a synovial biopsy of a single joint in the hand or wrist. The synovial 
biopsy will be performed by a trained member of the clinical study team. Biopsy samples 
(approximately 12) will be obtained via an 18- or 19-gauge ultrasound-guided quick core 
biopsy needle and immediately prepared for pathology assessment. Biopsy procedures 
including subject preparation, tissue harvest, and post-procedure care will be completed in 
accordance with institutional SOPs. 
8.6 
Pathology Evaluation of Synovial Tissue 
Following the synovial biopsy, tissue will be collected following local SOPs, processed, and 
shipped to the central pathology lab in accordance with the NAV3-32 Pathology Manual. If 
fewer than 4 biopsy samples can be obtained for a given subject, all samples will be used for 
IHC analyses, but that subject’s pathology data will be considered non-evaluable and will be 
excluded from the PP population.  If 4 to 6 biopsy samples are obtained, all samples will be 
used for IHC analyses, and the subject’s pathology data will be included in the PP 
population.  When > 6 biopsy samples are obtained, 4 to 6 of the samples will be used for 
IHC and the remaining samples will be split approximately evenly to be used for RNA-seq 
and flow cytometry analyses, when applicable. 
8.6.1 
Preparation and Shipping of Synovial Tissue Samples to Central Laboratory 
All viable tissue collected for IHC will be placed in formalin for processing at the central 
laboratory. Synovial tissue collected for RNA-seq will be placed into a tissue storage solution, 
such as RNAlater, for transfer and processing at the central pathology laboratory. All samples 
will be maintained by the central pathology laboratory until trial completion. Contact 


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information and additional preparation and shipping instructions can be found in the NAV3-32 
Pathology Manual. 
Shipments as well as questions regarding logistics, quality assurance, or documentation can be 
directed to the central pathology laboratory.   
8.6.2 
Central Pathology Laboratory Processing of Samples – IHC and RNA-seq 
IHC 
The central pathology laboratory will process approximately 4 to 6 samples with hematoxylin 
and eosin (H&E) and IHC stains for IHC analysis.  Processing and semi-quantitative scoring 
of histological tissue samples will be followed in accordance with the detailed guidelines 
specified in the NAV3-32 Pathology Manual.  
Central pathology laboratory results will be entered into the electronic CRFs (eCRFs) by 
designated central pathology laboratory staff. 
The joint-level pathobiology of each synovial tissue will be classified as follows in 
accordance with the SOP of the central pathology laboratory: 
A – diffuse myeloid 
B - lympho-myeloid 
C – pauci-immune fibroid 
RNA-seq 
The central pathology laboratory will process approximately 4 samples in a tissue storage 
solution (i.e., RNAlater) for RNA sequencing. Whole tissue processing for preparation of the 
RNA library and RNA-seq analysis will be performed in accordance with the guidelines 
specified in the NAV3-32 Pathology Manual. 
8.6.3 
Local Laboratory Processing of Samples – Flow Cytometry 
Optional flow-cytometry analysis of tissues will be conducted on a selected subset of subjects 
enrolled and biopsied. Approximately 4 fresh samples will be placed into a MACS-buffered 
solution for tissue dissociation. Additional specifications for tissue preparation and cell sorting 
for flow cytometric analysis can be found in the NAV3-32 Pathology Manual. 
8.7 
Safety 
8.7.1 
Adverse Events 
8.7.1.1 
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). 


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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 drug related.  
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. 
For this study, all untoward medical occurrences beginning on the Visit 2 (Day 0) until the 
final Follow-up Telephone Safety Assessment (Visit 5) 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. 
8.7.1.2 
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 administered for an AE 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. 


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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. 
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. 
8.7.1.3 
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 they 
are related to a study procedure in which case the event will be recorded as an AE. Untoward 
medical events beginning on Visit 2 (Day 0) through the completion of the Visit 5 Follow-up 
Telephone Safety Assessment will be reported as adverse events.  SAEs will be reported from 
the time of consent through the end of participation.  
Any AE (observed, volunteered, or elicited) should be recorded in detail in the source 
documentation. 
The following information is required: 


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• 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 8.7.1.5.   
• The maximum severity (mild, moderate, or severe). 
• If drug treatment was administered for the event, specific concomitant medication 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]). 
8.7.1.4 
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.  
In addition to the Lymphoseek pre-approval clinical studies, post-marketing surveillance 
shows that Lymphoseek has been administered to more than 300,000 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 
over 135IV administrations of Tc 99m tilmanocept and no SAEs or adverse drug reactions 
(ADRs) have been reported to date.  
Risks of Imaging Procedures 
Radiation dose considerations from Tc 99m Tilmanocept planar scans – Subjects enrolled in 
this trial will have a hand/wrist planar gamma camera scan following Tc 99m tilmanocept 
injection.  


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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 this study will receive one injection, equal to 2.7 mSv total. This 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 computed tomography (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. 
8.7.1.5 
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 


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• 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. 
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)/IEC(s) 
The sponsor and/or the investigator will notify the IRB(s)/IEC(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. 


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8.7.2 
Vital Signs 
Vital signs comprise the measurement of body temperature, heart rate, respiration, and 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 administration, and within 30 minutes after 
investigational product administration (after the ECG assessment during this 30-minute post-
Tc 99m tilmanocept interval). 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.  
8.7.3 
Electrocardiogram 
A standard 12-lead ECG will be obtained up to 30 minutes before investigational product 
administration and within 30 minutes after investigational product administration. The ECG 
will be measured with the subject in a resting position for at least 1 minute. Continuous ECG 
monitoring is not required.  At a minimum, the heart rate, QRS, PR, and QT intervals will be 
collected.  QTc will be calculated using the Fridericia formula. 
On-site investigator’s responsibilities 
The immediate cardiac safety of the subject will be ensured by the on-site qualified physician.  
Any 12-lead ECG intervals, waveform abnormalities, and rhythm changes that are clinically 
significant in that they result in a change in subject management will be considered an AE.  In 
the case of an SAE, once SAE notification is decided upon, investigators are required to follow 
the procedure described for SAE notification and document abnormal ECG findings (intervals 
and waveforms).  Any interval data or abnormal waveform finding that resulted in an AE 
(i.e., change of patient management) must be followed to normalization or stabilization. Each 
12-lead ECG tracing must be signed and dated and stored in the subject’s source 
documentation.   
8.7.4 
Clinical Laboratory Parameters 
Table 5  
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) 


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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. 
Only abnormal laboratory values 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 that 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 6. 
Table 6 
Approximate Amount of Blood Drawn per Subject 
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 
PLANNED STATISTICAL METHODS 
This study is a Phase 2b, prospective, open-label, multicenter study of the patterns of 
association between quantitative Tc 99m tilmanocept planar imaging and synovial 
histopathology in subjects clinically diagnosed with RA.  
Subjects will undergo an imaging assessment followed by an ultrasound-guided synovial 
biopsy of a selected joint in a subsequent visit. Tissue samples from the synovial biopsy 
procedure will be used for 2 mandatory anatomic pathology evaluations: 
•
IHC and immunofluorescence imaging targeting various immune markers associated
with inflammatory disease; and,
•
RNA-sequencing to provide transcriptional profiling of pathotype-specific gene
expression profiles.
Optional flow cytometry will be performed by a local pathology laboratory with a subset of 
subjects for the exploratory analysis of TUVjoint and the number and size of CD68, CD163, and 
CD206.  
Results from each of the 3 anatomic pathology evaluations will be correlated with TUVs on 
planar imaging to mechanistically assess the relationship between synovial anatomic pathology 
and TUV. These evaluations will provide quantitative and semi-quantitative information 
regarding joint-specific disease activity.  
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
•
ECG Parameters
•
Vital Signs
9.3 
Efficacy Variables 
The primary efficacy variables for this study are defined below: 
•
Tc 99m tilmanocept uptake values (TUVjoint) for the biopsied joints;
•
IHC assessment of macrophage expression of the CD206 receptor.


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The secondary variables for this study are defined below: 
•
IHC and immunofluorescence assessment of macrophage expression and co-
expression of the CD68 and CD163 receptors;
•
Pathotype classification of RA disease as lympho-myeloid, diffuse myeloid, or pauci-
immune fibroid, based on TUVjoint.
The exploratory efficacy variables for this study are defined below: 
•
IHC assessment of macrophage expression of the CD3, CD20, CD55, and TE7
biomarkers;
•
mRNA levels in synovial tissue for the CD206, CD163, and CD68 biomarkers;
•
Flow cytometry measurements of CD206, CD163, and CD68 biomarker expression
and co-expression.
•
IHC assessment of the expression of a biomarker (e.g., CD206, TE7) is determined
from immunofluorescent microscopy, specifically:
•
The ratio of the total fluorescent stained area to the total field area under 4x and
10x power magnification.
All IHC assessments will be done at a single laboratory in accordance with the laboratory 
SOPs. 
•
Classification of synovial anatomic pathology into lympho-myeloid, diffuse myeloid,
and pauci-immune fibroid types using a multinomial logistic regression model with
TUVglobal as a covariate.
•
Tc 99m tilmanocept global uptake values (TUVglobal) per subject.
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. 
TUV is defined as: 
TUVROI = 
Xഥjoint
XഥRR
; 
where 
◦
Xഥjoint is the average pixel intensity of a region of interest (ROI) of a subject at the
time of imaging (nominally 60 minutes); 
◦
XഥRR is the average pixel intensity of the reference region (RR) of a subject at the
time of imaging (nominally 60 minutes). 
Calculation of TUVjoint and TUVglobal are further described in the study statistical analysis 
plan (SAP).  


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9.4 
Sample Size and Justification 
The sample size is expected to be approximately 12 to 24 joints. The final sample size will be 
determined after the completion of an interim analysis including at least 4 subjects in each 
pathotype (diffuse myeloid, lympho-myeloid and pauci-immune fibroid). The final sample size 
will be chosen on the basis of the sponsor’s business requirements regarding precision for the 
estimated correlation between CD206 expressing macrophage density and TUVjoint. The final 
sample size will be at least N = 12. If the rarest pathotype has 25% prevalence in the study 
patient pool, the expected number of subjects at the interim analysis is N = 16. These needs 
may be further increased because synovial biopsy fails to recover enough tissue for histological 
analysis in about 15% of cases (Wechalekar 2014). 
9.5 
Statistical Analyses 
9.5.1 
Analysis Populations 
The following populations are defined for this study: 
Safety Population – The safety population includes all subjects who have been enrolled in the 
study and injected with Tc 99m tilmanocept regardless of imaging or biopsy status. 
Intent-to-Assay (ITA) Population – the ITA population includes all subjects who have been 
enrolled in the study, injected with Tc 99m tilmanocept, received all imaging procedures, and 
have been biopsied. 
Per-Protocol (PP) Population – the PP population consists of all ITA subjects without major 
protocol violations. At least 4 evaluable synovial biopsy samples must be available for a 
subject to be included in the PP population. 
9.5.2 
Analysis of Baseline and Demographic Characteristics 
Baseline and demographic characteristics of the safety population will be summarized. 
Continuous variables (age, height, 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.   
9.5.3 
Analysis of Efficacy Variables 
All efficacy analyses will be conducted on both the ITA and PP populations. The ITA 
population will be the primary analysis set. Additional efficacy analyses may be described in 
the study SAP. 


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9.5.3.1 
Primary Endpoint 
The primary endpoint will be analyzed by computing the Pearson (product-moment) and 
Spearman (rank) correlation coefficient between the TUV for the biopsied joint and the final 
CD206 expressing macrophage count. The CD206 expressing macrophage count is derived 
from IHC histopathology and ultrasound imaging: 
•
The fraction of CD206 expressing macrophages under 4x and 10x power
magnification, defined as the ratio of the total fluorescent stained area to total field
area. Specifically, area fraction (AF) is defined as
𝐴𝐴𝐴𝐴 = 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐴𝐴𝐴𝐴𝑒𝑒𝑎𝑎
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴
× 100%. 
•
The volume of synovial tissue in the biopsied joint, defined as the ultrasound synovial
thickness score (Vol). The CD206 macrophage count will be the product of these
2 variables (that is, CD206 = AF*Vol).
CD206 expressing macrophage fraction and TUVjoint will be summarized with descriptive 
statistics (number of data pairs, means, standard deviations, minima, medians, and maxima as 
well as the Pearson correlation between the variables). The ultrasound synovitis score will be 
summarized with a frequency table. A 95% confidence interval for the population correlation 
coefficient (ρ) based on the Fisher Z-transformation (the inverse hyperbolic tangent) and its 
normal approximation will be provided. The joint distribution of the CD206 macrophage count 
and TUVjoint will be summarized graphically with a scatter diagram of the data pairs with the 
least-squares regression line superimposed on the graph. The joint distribution of the 
component variables of CD206 macrophage count will be graphically summarized with box 
plots showing the conditional distribution of TUVjoint for each category of synovitis score. 
9.5.3.2 
Secondary Endpoints 
Co-expression of the CD68, CD163, and CD206 markers will be analyzed by 2 methods. First, 
by providing the product-moment and Spearman rank correlation matrices of the IHC field 
measurements (that is, the fraction of macrophages expressing the markers will not be 
multiplied by the synovitis score). Summary statistics of the data triplets used to calculate the 
correlation matrices will be provided (number of data triplets, means, standard deviations, 
minima, medians, and maxima). In the second method, histological sections will undergo 
immunofluorescent staining for the 3 markers and DAPI. For each section evaluated, up to 
50 cells from the synovial sublining will be identified for each of the 3 markers. For each 
identified cell (up to 150/section), the rate of co-expression of the 3 markers will be 
determined. For sections with sparse marker expressing cells, four microscope fields will be 
randomly selected. Co-expression of the markers will be quantified for any cell observed 
expressing any marker.   
The ability of TUVjoint to discriminate among lympho-myeloid, diffuse myeloid, and pauci-
immune fibroid RA disease types will be evaluated with a multinomial logistic regression 


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model with TUVjoint as a covariate. RA type will be the response variable and TUVjoint will be 
the explanatory variable. ROC curves will be generated using the lympho-myeloid type as the 
base class. The marginal distribution of disease type will be summarized with a frequency 
table, while the marginal distribution of TUVjoint will be summarized with descriptive statistics 
(number of data pairs, mean, standard deviation, minimum, median and maximum). The joint 
distribution will be graphically summarized with box plots showing the conditional 
distribution of TUVjoint for each disease type. 
9.5.3.3 
Exploratory Endpoints 
Expression of CD3, CD20, CD55, CD68, CD163, CD206, and TE7 biomarkers and their 
association with TUVjoint will be assessed with the Pearson (product-moment) and Spearman 
(rank) correlation matrices calculated for each measurement of expression (IHC, RNAseq, and 
[optional] flow cytometry). The marginal distributions will be summarized with descriptive 
statistics (number of complete data points, means, standard deviations, minima, medians, and 
maxima). The joint distribution will be presented graphically in a windowpane plot of the 
scatter diagrams. 
Expression of CD206, CD163, and CD68 genes in mRNA will be measured with cDNA 
probes. The TUVjoint values concentrations will be regressed on the mRNA abundance as 
determined by RNA-seq values. The marginal distributions will be summarized with 
descriptive statistics (number of complete data points, means, standard deviations, minima, 
medians, and maxima). The joint distribution will be presented in a windowpane plot of the 
scatter diagrams. The regression coefficients will be presented with the estimated residual 
covariance matrix. 
The number, size, and co-expression of CD68, CD163, and CD206 expressing macrophages 
measured by flow cytometry and their relationship with TUVjoint will be assessed with the 
Pearson (product-moment) and Spearman (rank) correlation matrices. The marginal 
distributions of all variables will be summarized by descriptive statistics (number of complete 
data points, means, standard deviations, minima, medians, and maxima). The joint distributions 
will be presented graphically in a windowpane plot of the scatter diagrams. 
The ability of TUVglobal to discriminate among lympho-myeloid, diffuse myeloid, and pauci-
immune fibroid RA disease types will be evaluated with a multinomial logistic regression 
model with TUVglobal as a covariate. RA type will be the response variable and TUVglobal will 
be the explanatory variable. ROC curves will be generated using the lympho-myeloid type as 
the base class. The marginal distribution of disease type will be summarized with a frequency 
table, while the marginal distribution of TUVglobal will be summarized with descriptive 
statistics (number of data pairs, mean, standard deviation, minimum, median and maximum). 
The distribution will be graphically summarized with box plots showing the conditional 
distribution of TUVglobal for each disease type. 
9.5.4 
Analysis of Safety Variables 
All safety analyses will be conducted on the safety population. 


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All adverse events (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 date of the first tilmanocept injection. If the first injection 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 be summarized as follows: 
•
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 for vital sign parameters, ECG parameters, hematology, 
clinical chemistry, and urinalysis parameters will be summarized using descriptive statistics 
(n, mean, standard deviation, minima, median, and maximum) at each time point. 
A data listing will be prepared that reflects the occurrence of TEAEs associated with each 
concomitant medication or class of medications to examine whether a drug interaction signal 
is detectable. 
Other safety analyses may be described in the SAP for the study. 
9.5.5 
Handling of Missing Values 
The analysis of the efficacy and safety variables will be carried out on the observed data, i.e., 
a complete case analysis. For the regression and correlation analyses, a subject must have valid 
values for all variables to be used in the analysis. 
9.5.6 
Interim Analysis 
 An interim analysis will be performed after 4 subjects in each of the 3 pathotypes (diffuse 
myeloid, lympho-myeloid, and pauci-immune fibroid) have been imaged. Specific analyses 
will be described in the study SAP (or interim analysis plan [IAP]) and will include 
computation of the product-moment and rank correlations between TUVjoint and CD206 
expressing macrophage count (defined in Section 9.5.3.1). Additional analyses may be 
described in the study IAP (if written) or SAP (if no IAP is written). The final sample size will 
be recalculated after completion of the interim analysis. 


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10 DATA HANDLING AND QUALITY ASSURANCE 
10.1 Data Recording 
Data required according to this protocol are captured in the subject’s source documentation 
and are to be entered onto the eCRFs (provided by the sponsor) as soon as possible. 
10.1.1 
CRF Design 
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 trial master file (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/IEC 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)/IEC(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. 
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)/IEC(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/IEC 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 4.5 


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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 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)/IEC(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)/IEC(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/IEC 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/IEC’s 
approval/favorable opinion in advance of use. 
11.3 Financing/Financial Disclosure 
Each investigator (including principal and/or any sub-investigators; as well as their spouses 
and dependent children) who is directly involved in the treatment or evaluation of research 
subjects must 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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Wijbrandts CA, Vergunst CE, Haringman JJ, Gerlag DM, Smeets TJ, Tak PP. 
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Appendix 1 
Schedule of Events 
 
Evaluation 
Visit #1 
(Screening) 
Visit #2 
(Tc 99m tilmanocept administration 
and Imaging Day 0) 
Visit #3 
Follow-up Safety 
Telephone Call 
Visit #4 
Synovial Tissue 
Biopsy 
Visit #5 
Follow-up Safety 
Telephone Call 
Days -30 
to -1 
-00:30 to 
00:00 
 
00:00  
 
00:01 to 
00:30 
60 to 75 
minutes 
24 to 72 hours 
post-
administration 
Day 3-7 post- 
administration 
5 ± 2 days post-
biopsy 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility Review 
X 
 
 
 
 
 
 
 
Medical /Surgical /RA History, 
Demographics 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
Clinical Labs: Chemistry, 
Hematology, Urinalysis 
X 
 
 
 
Xc 
 
 
 
RA Panel (ESR, CRP, RF, ACPA) 
X 
 
 
 
 
 
 
 
ACR/EULAR 2010 Classification 
X 
 
 
 
 
 
 
 
DAS28 Assessment  
X 
 
 
 
 
 
 
 
28 joint count assessment for DAS28 
X 
 
 
 
 
 
 
 
VAS questionnaire for DAS28 
X 
 
 
 
 
 
 
 
Ultrasound Assessment of Synovitis 
X 
 
 
 
 
 
X 
 
Vital Sign Assessmentb 
X 
X 
 
X 
 
 
 
 
Urine Pregnancy Test  
X 
Xa 
 
 
 
 
 
 
Tc 99m tilmanocept Administration 
 
 
X 
 
 
 
 
 
Imaging: Static Hands/Wrists 
 
 
 
 
X 
 
 
 
ECG 
 
X 
 
X 
 
 
 
 
Adverse Event Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications Review 
X 
X 
 
 
 
X 
X 
X 
Synovial Tissue Biopsy 
 
 
 
 
 
 
X 
 
aUrine Pregnancy test must be completed and determined to be negative in women of childbearing potential within 48 hours of Tc 99m tilmanocept 
administration. 
bObtained post-ECG at Visit 2 
cLabs will be completed at the end of the 60 to 75 minutes imaging session 


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Appendix 2 
NAV3-32 Study Workflow 
 


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Appendix 3 
2010 ACR/EULAR Classification 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. 
 


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Appendix 4 
DAS28 Scoring 
 
Courtesy of http://www.iche.edu/newsletter/DAS28.pdf 


Tc 99m tilmanocept 
IRAS Project ID: 269022 
Clinical Trial Protocol: NA V3-32 
Appendix 5 
Sponsor Signatures 
Navidea Biopharmaceuticals, Inc. 
v8.D 25 October 2022 
Study Title: 
A Comparison of Tc 99m Tilmanocept Quantitative Imaging with 
Immunohistochemical (IHC) Analysis of CD206 Expression in 
Synovial Tissue from Subjects Clinically Diagnosed with 
Rheumatoid Atthritis (RA) 
Study Number: 
NAV3-32 
Original Date: 
12 June 2019 
Amendment 1 Date 
Amendment 2 Date 
Amendment 3 Date 
Amendment 4 Date 
Amendment 5 Date 
Amendment 6 Date 
Amendment 7 Date 
28 October 2019 
11 February 2020 
29 April 2020 
17 September 2020 
07 April 2021 
24 June 2021 
25 October 2022 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor. The following personnel contributed to writing and/or approving this protocol: 
Signed <WhA 
Michael Rosol, PhD 
Chief Medical Officer 
Navidea Biopharmaceuticals, Inc. 
Signed: ~ 
/.J j~ 
Date: 3\ Ol-\o\111r ?IJ'Z't-
Michael Blue, MD, F ACEP 
Senior Medical Director 
Navidea Biopharmaceuticals, Inc. 
Confidential 
Page 74 of75 
(_


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Appendix 6 
Investigator’s Signature 
Study Title: 
A Comparison of Tc 99m Tilmanocept Quantitative Imaging with 
Immunohistochemical (IHC) Analysis of CD206 Expression in 
Synovial Tissue from Subjects Clinically Diagnosed with 
Rheumatoid Arthritis (RA) 
Study Number: 
NAV3-32 
Original Date: 
12 June 2019 
Amendment 1 Date 
Amendment 2 Date 
Amendment 3 Date 
Amendment 4 Date 
28 October 2019 
11 February 2020 
29 April 2020 
17 September 2020 
Amendment 5 Date 
07 April 2021 
Amendment 6 Date 
24 June 2021 
Amendment 7 Date 
25 October 2022 
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: