Conditions: Rheumatoid Arthritis
Keywords: RA Tilmanocept
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 169
Healthy volunteers: no

Brief summary:
This study will confirm the ability of Tc 99m tilmanocept imaging to predict clinical response in individuals with RA who are beginning anti-TNFα therapy.

Detailed description:
This is a prospective, open-label, multicenter study designed to evaluate the early predictive capacity of Tc 99m tilmanocept planar imaging for downstream clinical response(s) in individuals with moderate to severe RA who are candidates for change in anti-TNFα therapy. Temporal (Baseline to 5 week) differences in quantitative imaging will be correlated with longitudinal (Baseline to 12- and 24-week) assessments of clinical RA outcomes to evaluate the clinical utility of Tc 99m tilmanocept for the expedited evaluation of antirheumatic treatment efficacy when compared with longitudinal assessments in clinical practice.

Arms:
arm 1: All subjects will be candidates for initiation of, or change to, a new anti-TNFα bDMARD for RA treatment.

Interventions: intervention 1: TC99m-tilmanocept
Intervention descriptions: intervention 1: Tilmanocept is a radiotracer that accumulates in macrophages by binding to a mannose binding receptor that resides on the surface.

Protocol document:
SAP_002.pdf: 
Statistical Analysis Plan (SAP) 
Evaluation of Tc 99m Tilmanocept Imaging for the Early 
Prediction of Anti-TNFα Therapy Response in Patients 
with Moderate to Severe Active Rheumatoid Arthritis 
(RA) 
Study No: NAV3-33 
Version 4.0 
October 6, 2023 
Prepared for 
Navidea Biopharmaceuticals, Inc. 
4995 Bradenton Avenue, Suite 240 
Dublin, OH  43017 
Prepared by 
STATKING Clinical Services 
3570 Pleasant Ave 
Hamilton, OH  45015 
513-858-2989
www.statkingclinical.com 

STATKING Clinical Services


Statistical Analysis Plan 
Study No. NAV3-33 
Approval Page 
By entering into this Statistical Analysis Plan (SAP), the parties acknowledge 
and agree that this SAP shall be incorporated into and subject to the terms of 
the Master Services Agreement (MSA). Any changes requested by Client to this 
SAP shall be subject to Section l.C of the MSA requiring a mutually agreed upon 
"Change Order" prior to any modification of the procedures set forth herein. 
I agree to the format and content of this document. 
Approved by: 
4 
___ L 
Michael S. Blue, 
,,(,., 
Chief Medical Officer 
Navidea Biopharmaceuticals 
4995 Bradenton Avenue, Suite 240 
Dublin, Ohio 43017 
mblue@navidea.com 
Authored by: 
Zactl'ary SteckleY, MS 
Statistician 
STATKING Clinical Services 
3570 Pleasant Ave 
Hamilton, OH 45015 
zachary@gd3services.com 
Approved by (internal review): 
Ian Lees, MS 
Statistician 
STATKING Clinical Services 
3570 Pleasant Ave 
Hamilton, OH 45015 
ilees@gd3services.com 
STATKING Clinical Services 
Version 4.0 
Page 2 of94 
Date 
' 
Date 
Navldea Biopharmaceutlcals, Inc. 
October 6, 2023 


Statistical Analysis Plan 
Approved by: 
Clare Geiger, RN 
Project Manager 
STATKING Clinical Services 
3570 Pleasant Ave 
Hamilton, OH 45015 
cgeiger@gd3services.com 
STATKING Clinical Services 
Version 4.0 
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Study No. NAV3-33 
/rJ .- j<) 
l....02 3 
Date 
Navidea Biopharmaceuticals, Inc. 
October 6, 2023 


Statistical Analysis Plan 
 
Study No. NAV3-33 
 
 
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Version 4.0                                                                                                        October 6, 2023                                  
Revision History 
 
Version 3.0 to 4.0 
• Updated signature page to reflect changes in staff and contacts 
• Removed non-bucketing algorithms, so that all subjects with TUVglobal[b] < 
5 will be predicted non-responders 
• Clarified secondary objective in section 1.0 for qualitative assessment of 
Tc 99m tilmanocept imaging by removing language pertaining to change 
from baseline 
• Added description of tipping point analyses for mean imputation of 
clinical status at week 24 and TUV prediction to section 2.3 
• Modified section 4.1.4 to indicate that the secondary efficacy variables 
will be based on bucketing algorithms 
• Removed table and listing shells for non-bucketing algorithms 
• Removed columns, footnotes, and annotations in TLF shells for non-
bucketing algorithms 
• Added figures to summarize tipping point analyses using 95% 
confidence intervals to TLF shells 
 
Version 2.0 to 3.0 
• Added description of analysis of qualitative assessments to section 4.2.3 
• Added description of analysis of the additive effect of either quantitative 
or qualitative assessment of Tc 99m tilmanocept imaging to section 4.2.3 
• Modified description of concordance of improvement classification of 
each algorithm with clinical improvement criteria to indicate that p-values 
for sensitivity and specificity will be included 
• Added tables for concordance of qualitative assessment of Tc 99m 
tilmanocept imaging with clinical improvement criteria 
• Added tables for concordance of qualitative plus quantitative 
assessment of Tc 99m tilmanocept imaging with clinical improvement 
criteria 
• Added tables for summary of generalized linear mixed model to asses 
the additive effect of either quantitative or qualitative assessment of Tc 
99m tilmanocept imaging on patient response status 
• Added p-values for all clinical assessments in addition to those for 
ACR50 to tables 15-22 
• Added data listing for qualitative imaging assessments  
• Added data listing for qualitative plus quantitative assessments which 
differ from original quantitative assessment 
• Updated TLF table of contents to remove redundant tables 
• Added new tables and listings to TLF table of contents 
• Renumbered TLFs to include new additions 
 
 


Statistical Analysis Plan 
 
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Version 1.0 to 2.0 
• Changed intent-to-diagnose population in section 2.2 to include all 
subjects who were injected with Tc 99m tilmanocept at visit 2 and 
received planar imaging of the hands at visit 2, regardless of if they 
received any other assessments. 
• Changed wording in section 1.3 to specify that at least the same two of 
three readers must reject both null hypotheses for the two co-primary 
endpoints to be achieved. 
• Added detail in section 2.3 regarding imputation strategies, and 
proposed secondary imputation strategy for some missing data 
scenarios if primary imputation strategy does not work. 
• Added detail in section 4.1.1.1 regarding the possibility for a patient’s 
TUV prediction from bucketing vs. non-bucketing to differ, and how these 
findings will be summarized. 
• Added tables 27-28 to summarize the number of patients who TUV 
predictions from bucketing vs. non-bucketing differ. 
• Added data listing 28 to provide detail on patients who TUV predictions 
from bucketing vs. non-bucketing differ. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
Study No. NAV3-33 
 
 
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Table of Contents 
 
APPROVAL PAGE ............................................................................................ 2 
REVISION HISTORY ......................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................... 8 
INTRODUCTION .............................................................................................. 10 
1.0  SYNOPSIS OF STUDY DESIGN/PROCEDURES .................................... 10 
1.1 Design and Treatment ........................................................................................................ 12 
1.2 Study Procedures ............................................................................................................... 12 
1.3 Sample Size ........................................................................................................................ 13 
2.0  DATA ANALYSIS CONSIDERATIONS .................................................... 15 
2.1 Types of Analyses .............................................................................................................. 15 
2.2 Analysis Populations ......................................................................................................... 15 
2.2.1 Subgroup Definitions and Considerations ................................................................... 16 
2.3 Missing Data Conventions ................................................................................................ 16 
2.4 Interim Analyses ................................................................................................................. 17 
2.5 Calculation of TUV ............................................................................................................. 17 
2.6 Study Center Considerations in the Data Analysis ........................................................ 19 
2.7 Documentation and Other Considerations ...................................................................... 19 
3.0  ANALYSIS OF BASELINE PATIENT CHARACTERISTICS .................... 19 
4.0  ANALYSIS OF EFFICACY ....................................................................... 19 
4.1 DESCRIPTION OF EFFICACY VARIABLES ............................................ 19 
4.1.1 Definition of Responder/Non-Responder Status ......................................................... 19 
4.1.1.1 Prediction Algorithms .................................................................................................. 19 


Statistical Analysis Plan 
 
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4.1.1.2 Clinical Assessments .................................................................................................. 20 
4.1.2 Description of Primary Efficacy Variables .................................................................... 21 
4.1.3 Description of Key Secondary Efficacy Variables ....................................................... 21 
4.1.4 Description of Secondary Efficacy Variables ............................................................... 22 
4.2 Analysis of Efficacy Variables .......................................................................................... 23 
4.2.1 Analysis of Primary Efficacy Variables ......................................................................... 23 
4.2.2 Analysis of Key Secondary Efficacy Variables ............................................................ 24 
4.2.3 Analysis of Secondary Efficacy Variables .................................................................... 24 
5.0  ANALYSIS OF SAFETY ........................................................................... 26 
6.0  OTHER RELEVANT DATA ANALYSES/SUMMARIES ........................... 27 
6.1 Patient Completion ............................................................................................................. 27 
6.2 Physical Exam .................................................................................................................... 27 
6.3 Study Drug Administration................................................................................................ 28 
6.4 RA Evaluation and Screening Physical Exam ................................................................. 28 
6.5 Concomitant Medications.................................................................................................. 28 
7.0  LIST OF ANALYSIS TABLES, FIGURES AND LISTINGS ...................... 29 
8.0  REFERENCES .......................................................................................... 33 
APPENDIX A – TABLES, FIGURES AND LISTING SPECIFICATIONS ........ 34 
APPENDIX B – TABLE, FIGURE, AND LISTING SHELLS ............................ 36 
 
 
 


Statistical Analysis Plan 
 
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Version 4.0                                                                                                        October 6, 2023                                  
List of Abbreviations and Definitions of Terms  
 
Term 
Definition 
Δ 
Greek letter delta, used to represent the change in a particular 
variable 
g 
microgram 
ACPA 
anti-citrullinated protein/peptide antibody 
ACR/EULAR American College of Rheumatology/ European League 
Against Rheumatism 
AE 
adverse event 
Anti-TNF- 
bDMARD 
Anti-Tumor Necrosis Factor  biological Disease Modifying 
Anti-Rheumatic Drug 
CDAI 
Clinical Disease Activity Index 
CFB 
change from baseline 
CI 
confidence interval 
CRF 
case report form 
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(s) 
healthy control(s)  
ICH 
International Conference on Harmonization 
ITD 
intent-to-diagnose  
IV 
intravenous 
mCi 
milliCurie (37x106 becquerels; 37megabecquerels) 
MCP 
metacarpophalangeal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
macrophage-involved contribution 
NPV 
Negative Predictive Value 
OA 
Overall Accuracy 
PIP 
proximal interphalangeal 
PP 
per protocol 
PPV 
Positive Predictive Value 
PR 
the time from the onset of the P wave to the start of the QRS 
complex 
QRS 
time from the start of the Q wave to the end of the S wave, 
representing ventricular depolarization 
QT 
time from the start of the Q wave to the end of the T wave 
QTcF 
QT interval with Fridericia’s correction formula 
RA 
rheumatoid arthritis 
ROI 
region of interest 
SAE 
serious adverse event 


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Term 
Definition 
SAP 
statistical analysis plan 
SJC 
swollen joint count 
SOC 
system organ class 
SPECT 
single photon emission computed tomography 
Tc 99m 
technetium-99m metastable isotope; -emitting (half-life  6.02 
h) 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
tilmanocept 
DTPA Mannosyl Dextran (the US Adopted Name for the drug 
substance of Lymphoseek) 
TJC 
tender joint count 
TUV 
Tilmanocept uptake value 
US 
United States 
WPI 
Widespread Pain Index 
 
 
 


Statistical Analysis Plan 
 
Study No. NAV3-33 
 
 
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STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 4.0                                                                                                        October 6, 2023                                  
INTRODUCTION 
 
Description 
 
This statistical analysis plan (SAP) is consistent with Amendment #3 of the study 
protocol (dated 29 September 2023) and includes details of efficacy and safety 
summaries for use in support of the planned trial, as outlined in ICH E3 (Structure 
and Content of Clinical Study Reports) and ICH E9 (Statistical Principles for 
Clinical Trials). Considerations were also given to the FDA Guidance for industry 
on Developing Medical Imaging Drug and Biological Products Part 3: Design, 
Analysis, and Interpretation of Clinical Studies (June 2004), FDA Guidance for 
Industry on Clinical Trial Imaging Endpoint Process Standards (April 2018) and 
Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic 
Tests - Guidance for Industry and FDA Staff (March 2007).  The study design 
and analysis plans align with recommendations received from the US FDA at the 
End of Phase 2 meeting on 01 September 2021 (IND 132943). 
 
1.0  Synopsis of Study Design/Procedures 
 
This is a prospective, multicenter, open-label study designed to evaluate the 
early predictive capacity of quantitative Tc 99m tilmanocept planar imaging for 
downstream clinical response(s) in individuals with moderate to severe 
rheumatoid arthritis (RA) who are candidates for change in anti-TNF therapy. 
Temporal changes (from baseline to 5-weeks) in quantitative imaging will be 
correlated with longitudinal changes (from baseline to 12 weeks and baseline to 
24 weeks) in RA clinical assessments, with the intent of evaluating the clinical 
utility of Tc 99m tilmanocept for the expedited evaluation of antirheumatic 
treatment efficacy when compared with longitudinal assessments in clinical 
practice. 
 
The study objectives are as follows: 
 
Primary: 
 
• To demonstrate that global tilmanocept uptake values (TUVglobal) 
obtained before initiation of anti-TNFa therapy (TUVglobal[b]) and at 5 
weeks ± 1 week following change in therapy (TUVglobal[5w]) has a 
specificity of greater than 80% to correctly specify a clinical non-
response to therapy at 24 weeks. 
• To demonstrate that TUVglobal obtained before initiation of anti-TNF 
therapy and at 5 weeks ± 1 week following change in therapy has a 
sensitivity of greater than 65% to correctly classify a positive clinical 
response to therapy at 24 weeks. 
 


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Key Secondary 
 
• To evaluate the negative predictive value (NPV) of TUVglobal obtained 
before initiation of anti-TNFα therapy (TUVglobal[b]) relative to a clinical 
non-response to therapy at 24 weeks. 
 
Secondary  
• To evaluate the sensitivity and specificity of TUVglobal obtained before 
initiation of anti-TNF therapy and at 5 weeks ± 1 week following change 
in therapy relative to a positive clinical response or a non-response to 
therapy at 12 weeks. 
• To evaluate the NPV of TUVglobal[b] relative to a clinical non-response to 
therapy at 12 weeks. 
• To evaluate the positive predictive value (PPV), NPV, and overall 
accuracy (OA) of TUVglobal obtained before initiation of anti-TNF 
therapy and at 5 weeks ± 1 week (ΔTUVglobal[5w]) following change in 
therapy relative to a positive clinical response or a non-response to 
therapy at 12 and/or 24 weeks. 
• To evaluate the qualitative assessment of Tc 99m tilmanocept imaging 
to predict clinical response or non-response following a change in anti-
TNF therapy. 
• To evaluate the additive effect of either quantitative or qualitative 
assessment of Tc 99m tilmanocept imaging to the other at baseline and 
change from baseline to 5 weeks ± 1 week to predict clinical response or 
non-response following a change in anti-TNF therapy. 
• To evaluate the correlation of changes in TUVglobal obtained before 
initiation of anti-TNFα therapy and at 5 weeks ± 1 week following a 
change in therapy with changes in composite clinical assessments and 
their constituent parameters at 12 and/or 24 weeks. 
• To evaluate the correlation of changes in TUVglobal obtained before 
initiation of anti-TNFα therapy and at 5 weeks ± 1 week following a 
change in therapy with changes in clinical assessments at 12 and/or 24 
weeks for specific anti-TNFα bDMARD agents.  
• To evaluate the ability of changes in TUVglobal obtained before initiation 
of anti-TNFα therapy and at 12 weeks ± 1 week following change in 
therapy to accurately predict a clinical response or non-response at 24 
weeks. 
• To evaluate the correlation of changes with TUVglobal and changes in 
clinical RA assessments as a means to monitor therapy. 
• To evaluate sensitivity and specificity in patient subgroups. 


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• To evaluate the safety of IV-administered tilmanocept radiolabeled with 
Tc 99m. 
 
The statistical endpoints that address these objectives are defined in Section 4 
(efficacy) and Section 5 (safety). Refer to Section 2.2.1 for subgroup definitions 
and considerations.  
 
1.1 Design and Treatment 
 
This is a prospective, open-label, multicenter study designed to evaluate the 
early predictive capacity of quantitative Tc 99m tilmanocept planar imaging for 
downstream clinical response(s) in individuals with moderate to severe RA who 
are candidates for change in anti-TNF therapy.   
 
All patients will receive an IV dose of 150 mcg tilmanocept radiolabeled with 10 
mCi of Tc 99m prior to imaging. 
 
1.2 Study Procedures 
 
Prior to the initiation of a new anti-TNF therapy, patients will undergo baseline 
rheumatological evaluations of ACR/EULAR 2010, Clinical Disease Activity 
Index (CDAI), DAS28, and Health Assessment Questionnaire Disability Index 
(HAQ-DI) for the characterization of disease activity. After these evaluations, 
patients will receive an IV dose of 150 mcg tilmanocept radiolabeled with 10 mCi 
of Tc 99m and undergo baseline planar imaging of the bilateral hands and wrists. 
Upon completion of baseline imaging procedures, patients will commence a new 
anti-TNF bDMARD treatment regimen and return to the clinic 5 +/- 1 weeks,  12 
+/- 1 weeks, and  24 +/- 1 weeks later for a series of rheumatological evaluations 
(including CDAI, DAS28, ACR Response Criteria, and HAQ-DI), drug 
administration, and bilateral hand/wrist imaging.   
 
Images will undergo centralized quantification for the derivation of joint-specific 
and global TUV. At the joint level, TUV is defined as the intrapatient ratio of the 
average pixel intensity of a joint to the average pixel intensity of the reference 
region. TUVglobal is a per patient summary of TUVjoint values greater than the 
normative database representing RA-specific inflammation. 
 
All images will be read by three nuclear medicine specialists trained in the 
reading of these images. Each reader will work independently of the other 
readers. Each reader will provide both a qualitative read and map regions of 
interest for calculation of TUV. 
 
Temporal differences in TUVglobal from baseline to 5 +/- 1 weeks of therapy 
(ΔTUVglobal[5w]) will be compared with longitudinal clinical outcomes at 12 +/- 1 


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and 24 +/- 1 weeks of therapy defined by changes in CDAI (ΔCDAI[12/24w]), 
changes in ACR Response Criteria (ΔACR[12/24w]), and changes in DAS28 
(ΔDAS28[12/24w]) to evaluate the efficacy of TUVglobal for the accelerated prediction 
of clinical response to antirheumatic drugs. 
 
Refer to the clinical study protocol for further details on the study procedures and 
for the schedule of events table. 
 
1.3 Sample Size 
 
NAV3-33 is sized with respect to achieving specified goals in the co-primary 
endpoints of sensitivity and specificity of ΔTUVglobal[5w] with bucketing. Sensitivity 
and specificity require knowledge of the patient’s clinical status at Week 24, and 
so hypothesis testing will be performed after classification. The value of 
ΔTUVglobal[5w] necessary to predict response vs. non-response and the value of 
TUVglobal[b] at baseline necessary to predict non-response will be determined in 
advance. The classification procedure occurs in two stages, following the 
baseline image acquisition and (possibly) following the 5 week image acquisition 
and calculation of ΔTUVglobal[5w]. After the baseline imaging, patients whose 
TUVglobal[b] is < 5 are predicted to be non-responders. After ΔTUVglobal[5w] is 
available, patients whose TUVglobal[b] is ≥ 5 and D% is ≤ -10% are predicted to be 
responders. All other patients are predicted to be non-responders. The Week 24 
ACR50 will be used as the primary determination of clinical response for the 
reference standard 
 
The hypotheses for the co-primary endpoints to be tested are: 
 
𝐻𝑂1: 𝜋Sp ≤0.8
𝐻𝐴1: 𝜋Sp > 0.8; 
 
And 
𝐻𝑂2: 𝜋Se ≤0.65
𝐻𝐴2: 𝜋Se > 0.65. 
 
In the above πSp represents the true specificity of the classification procedure 
and πSe represents the true sensitivity of the classification procedure when used 
to predict the outcome of the anti-TNFα bDMARD inhibitor therapy at 24 weeks. 
An overall two-tailed Type I error rate of 0.05 (one-tailed 0.025) was used without 
adjusting for multiple endpoints, as both co-primary endpoints must be achieved 
in order to have a successful study. If the actual specificity is 0.92 and the actual 
sensitivity is 0.8, and if an exact binomial test is used to test the above 
hypotheses, a total of 98 clinical non-responders and 100 clinical responders are 


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needed for 90% power of the individual tests. That is, a minimum of 198 total 
patients is needed. This applies to a single reader.  
 
To evaluate the power characteristics of this process with 3 correlated readers 
where at least the same two of the three readers must reject both null hypotheses 
above, a simulation study was performed. Correlated binomial random variables 
were generated using a copula. The hypotheses were tested for each simulated 
reader using an exact binomial test, and the number of iterations where at least 
the same two of the three readers rejected both hypotheses was counted. Under 
the conditions above this procedure has power 0.93 when   = 0.7 and 0.89 when 
  = 0.9. 
 
In Arm 3 of the NAV3-31 study a ratio of 5 non-responders to 1 responder was 
observed. If this ratio is maintained in NAV3-33 for the ΔTUVglobal[5w] with 
bucketing predictions, a total of 600 patients is needed to achieve the desired 
power. That is, a total of 500 clinical non-responder patients is expected to be 
enrolled before reaching the required 100 clinical responders.  
 
Taking into account a 10% dropout rate, the anticipated total sample size for the 
study is approximately 672 patients (560 clinical non-responders and 112 clinical 
responders).  That is:  
 
• Clinical Non-Responders: 90% completion rate relative to 560 enrolled 
patients will result in 500 completed patients   
• Clinical Responders: 90% completion rate relative to 112 enrolled 
patients will result in 100 completed patients    
 
Because there is uncertainty about how responding and non-responding patients 
will enroll, enrollment may continue until at least 560 clinical non-responders and 
112 clinical responders are participating in the study. The cumulative enrollment 
of clinical non-responders and responders will be tracked throughout the study 
in order to stop enrollment once the required number has been reached for each 
clinical category. This tracking of clinical response and non-response status will 
be performed by individuals without knowledge of the TUV data.  At the 
Sponsor’s discretion, the week 12 clinical response outcomes may be used to 
help track enrollment.  
If the two co-primary endpoints are achieved (i.e., both null hypotheses are 
rejected for at least the same 2 out of 3 readers), then the following hypotheses 
will be tested at one-tailed 0.025 for the key secondary endpoint of NPV of 
TUVglobal[b] with respect to ACR50 at week 24: 
 


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𝐻𝑂3: 𝜋NPV ≤0.7
𝐻𝐴3: 𝜋NPV > 0.7; 
 
If the actual NPV is 0.85, and if an exact binomial test is used to test the above 
hypotheses, a total of 89 predicted non-responders using TUVglobal[b] are needed 
for 90% power and a total of 71 non-responders using TUVglobal[b] are needed for 
80% power. Enrollment of predicted non-responders at baseline will be tracked 
in order to ensure enough subjects are enrolled to achieve at least 80% power 
for this endpoint.   
 
All enrollment tracking will be done in aggregate by individuals without 
knowledge of the subject-level data.  Enrollment tracking will include the total 
number of predicted non-responders at baseline, the total number of clinical 
responders at or beyond week 12, and the total number of clinical non-
responders at or beyond week 12.   
 
2.0  Data Analysis Considerations 
 
2.1 Types of Analyses 
 
Efficacy, safety, and descriptive analyses will be performed on the data collected 
in this trial. 
  
2.2 Analysis Populations 
 
The following analysis populations will be defined.   
 
Safety population – The safety population includes all patients that have been 
enrolled in the study and injected with at least one dose of Tc 99m tilmanocept. 
Intent-to-diagnose (ITD) population – Patients in the safety population meeting 
the following criteria are members of the ITD population: 
• were injected with Tc 99m tilmanocept at Visit 2 (Day 0) 
• received planar imaging of the hands at Visit 2 (Day 0) 
This population will include all patients for whom a prediction might be made, 
although some patients may be excluded from analysis under this definition if a 
prediction cannot be made due to missing imaging or clinical data. 
Per-protocol (PP) population – The PP population will include all ITD patients 
without major protocol violations. All protocol deviations will be classified as 
major or minor prior to database lock. 


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All efficacy analyses will be carried out on the ITD and PP populations with the 
ITD population being the primary analysis set. All analyses of safety data and 
baseline patient characteristics will be carried out on the safety population. A 
data listing displaying the patients excluded from each population will be created, 
as shown in Appendix B.  
  
2.2.1 Subgroup Definitions and Considerations 
 
Summaries of the agreement between the primary TUV prediction algorithm and 
all clinical outcomes will be performed in the following subgroups: 
 
• Age (< 60 years, 60 years and older) 
• Sex 
• Race (white, non-white) 
• Time from RA diagnosis (< 5 years, 5 years and longer) 
• Disease severity at baseline (moderate, severe) 
• Previous use of biologics (yes, no) 
• Previous and current use of DMARDs (background methotrexate only, 
other conventional DMARDs only, combination of methotrexate and other 
conventional DMARDs) 
• Specific anti-TNF therapy taken during trial  
• Prednisone use on-study (on a stable dose, no prednisone use)    
• ACPA level at baseline (high/low: 85 and above / < 85) 
 
The study will make every effort to enroll enough patients in each of these 
subgroups so that half-widths of the 95% confidence intervals of sensitivity and 
specificity are less than 20%. P-values on parameter estimates will not be 
included. 
 
2.3 Missing Data Conventions 
 
In the statistical analysis of the primary efficacy endpoints of the study, missing 
data will be handled according to the following table of missing data scenarios: 
 
Variable 
Scenario   
Primary Imputation 
Rule 
Secondary 
Imputation Rule 
Clinical 
Status at 
Week 24 
Patient 
discontinued 
anti-TNF 
therapy prior to 
Week 24 due 
to non-
response to 
therapy 
Patient classified as 
a clinical non-
responder 
N/A 


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Clinical 
Status at 
Week 24 
Patient 
discontinued 
study for 
reasons not 
attributable to 
non-response 
to therapy 
Clinical status set to 
missing 
Impute mean clinical 
response* 
TUV 
Prediction  
Patient has 
TUVglobal[b] that 
is ≥ 5 but is 
missing week 
5 imaging data 
Impute mean 
prediction** 
Prediction is Y (patient 
has improved) 
TUV 
Prediction  
Patient is 
missing 
TUVglobal[b]  
Prediction set to 
missing 
N/A 
*Mean clinical response will be calculated as follows:  calculate the proportion of 
unique patients whose clinical status is Y (patient is a clinical responder), 
randomly allocate this proportion of “Y” to the missing clinical status at week 24 
values.  Assign all other missing clinical status values “N” (patient is clinical non-
responder). 
 
**Mean prediction will be calculated as follows:  using the patients for whom 
TUVglobal[b] ≥ 5, calculate the proportion whose TUV prediction is Y (patient has 
improved), randomly allocate this proportion of “Y” to the missing TUV 
predictions.  Assign all other missing TUV predictions “N” (patient has not 
improved). 
 
To assess the appropriateness of the missing data conventions for clinical status 
at week 24 and TUV prediction using mean imputation, tipping point analyses 
will be performed.  Specifically, 95% confidence intervals for sensitivity and 
specificity will be plotted against increasing proportions of missing values 
imputed as “Y” to see at what point the conclusion of the study is reversed. 
 
2.4 Interim Analyses 
     
There are no interim analyses planned for this study.      
2.5 Calculation of TUV  
 
TUVjoint is defined to be the mean pixel intensity of the region of interest (ROI) 
defined by the reader divided by the mean pixel intensity of the hand reference 
region. Each of the three blinded readers will have determined the TUV 
distribution for both anterior and posterior views of the wrists and hands (wrists, 
MCPs,  and PIPs) for the healthy patient normative data set. For all of the 
following calculations, the reader-specific TUVjoint limits will be used. The upper 


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limit of normal is defined to be the upper limit of the 95% prediction interval of the 
joint-and-view-specific TUV in the normative data set. 
For each RA patient do the following. 
Step 1: Calculate TUVjoint for each of the 22 DAS28 joints for which data are 
collected. 
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
. 
The change in TUVglobal (TUVglobal[5w]) is the % from baseline: 
ΔTUVglobal[5w] = 100 ⋅
TUVglobal[5w] −TUVglobal[b]
TUVglobal[b]
. 
 


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2.6 Study Center Considerations in the Data Analysis 
 
A study center is defined as a treatment administration site or group of treatment 
administration sites under the control and supervision of the same Principal 
Investigator (PI). There will be no selective pooling of study centers. 
 
2.7 Documentation and Other Considerations 
 
The data analyses will be conducted using SAS© Software, version 9.4 or later. 
 
3.0  Analysis of Baseline Patient Characteristics 
 
Baseline and demographic characteristics of the safety population (i.e., those 
injected with tilmanocept) will be summarized for all patients in the safety 
population.  Continuous variables will be displayed via summary statistics (mean, 
median, sample size, standard deviation, minimum and maximum). Categorical 
variables will be summarized via counts and percentages. 
Detailed listings of all baseline and demographic data for each patient will also 
be provided as shown in Section 7 below. 
 
4.0  Analysis of Efficacy 
 
4.1 Description of Efficacy Variables 
 
4.1.1 Definition of Responder/Non-Responder Status 
 
4.1.1.1 Prediction Algorithms  
 
The following two prediction algorithms will be defined for use in evaluating 
primary and secondary efficacy. Each algorithm will be used to predict a clinical 
response, and the subsequent prediction will be compared to the actual observed 
clinical response as described in Sections 4.1.2 and 4.1.3.  In addition to these 
two prediction algorithms, the use of TUVglobal[b] alone for the prediction of non-
response will be analyzed as the key secondary efficacy variable. If TUVglobal[b] is 
< 5 then the prediction is N (no improvement), otherwise, prediction is Y 
(improvement). 
 
The TUVglobal[5w] values will be used to predict improvement at 12 and 24 weeks 
according to algorithm 1. The TUVglobal[12w] values will be used to predict 
improvement at 24 weeks according to algorithm 2. Both algorithms will be 
applied after the change in TUV calculations have been rounded to the nearest 
integer percentage (i.e., nearest hundredths place for a proportion).  
 


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1. TUVglobal[5w] bucketing 
 
In the below, TUVglobal represents the global TUV at the current time point 
and TUVglobal[b] represents the global TUV at baseline: 
• If TUVglobal[b] is < 5 then the prediction is N (No improvement) 
• Else if  
ΔTUVglobal[5w] =
TUVglobal[5w] −TUVglobal[b]
TUVglobal[b]
≤−0.10 
the prediction is Y (patient has improved). That is, a patient will be 
predicted as improved if TUVglobal goes down by greater than or 
equal to 10%.   
• Otherwise, the prediction is N. 
 
2. TUVglobal[12w] bucketing 
 
In the below, TUVglobal represents the global TUV at the current time point 
and TUVglobal[b] represents the global TUV at baseline: 
• If TUVglobal[b] is < 5 then the prediction is N (No improvement) 
• Else if  
ΔTUVglobal[12w] =
TUVglobal[12w] −TUVglobal[b]
TUVglobal[b]
≤−0.10 
the prediction is Y (patient has improved). That is, a patient will be 
predicted as improved if TUVglobal goes down by greater than or 
equal to 10%.   
• Otherwise, the prediction is N. 
 
Tables which display the concordance between the predictions from each 
algorithm vs. clinical assessment will be provided.  A listing showing which 
algorithms provide a prediction of improvement vs. no improvement, by patient, 
will also be provided.   
 
4.1.1.2 Clinical Assessments 
 
ACR Response is derived through a combination of reductions from baseline in 
swollen or tender joint counts as well as improvement from baseline in at least 3 
of the other parameters (patient assessment, physician assessment, pain scale, 
disability/functionality questionnaire, and acute phase reactant [ESR]).  This 
study will evaluate the following three levels of ACR Response: 
 
• ACR20: An ACR20 indicates that 20% improvement is observed in tender 
and swollen joint counts as well as 20% improvement in at least 3 of the 
other 5 criteria.  


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• ACR50: An ACR50 indicates that 50% improvement is observed in tender 
and swollen joint counts as well as 50% improvement in at least 3 of the 
other 5 criteria.  
• ACR70: An ACR70 indicates that 70% improvement is observed in tender 
and swollen joint counts as well as 70% improvement in at least 3 of the 
other 5 criteria.  
 
Each patient will be classified as a yes or a no for whether they meet each of the 
above ACR Response Criteria at each of the applicable post-baseline time 
points. Note that the above criteria are nested, such that if a patient is a yes for 
ACR70 at a given time point, then the patient is also a yes for ACR50 and ACR20 
for that same time point. 
 
A patient will be classified as improved on the CDAI depending on the baseline 
score as follows: 
 
• If the baseline value is greater than 22, a reduction of more than 12 will 
be classified as improved. Otherwise, the patient is not improved. 
• If the baseline value is between 10 and 22 (inclusive) a decrease of more 
than 6 will classified as improved. Otherwise, the patient is not improved. 
• If the baseline value is less than 10, a decrease of more than 1 will be 
classified as improved. Otherwise the patient is not improved. 
 
A patient will be classified as improved on the DAS28 with a score change of 
greater than 1.2. 
 
A decrease of at least 0.22 in the HAQ-DI will be classified as improved. 
Otherwise, the patient is not improved on the HAQ-DI.  
 
4.1.2 Description of Primary Efficacy Variables 
     
The primary efficacy variables for determining clinical response are the 
response/non-response status at 24 weeks to new or changed anti-TNF 
bDMARD therapy for rheumatoid arthritis based on the ACR50 criterion. The 
primary efficacy variables for determining the predicted response and non-
response are ΔTUVglobal[5w] bucketing.   
The co-primary efficacy endpoints of the study are:  
• Specificity of ΔTUVglobal[5w] bucketing with respect to ACR50 at week 24.  
• Sensitivity of ΔTUVglobal[5w] bucketing with respect to ACR50 at week 24. 
 
4.1.3 Description of Key Secondary Efficacy Variables 
  
The key secondary efficacy endpoint is: 


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• NPV of TUVglobal[b] with respect to ACR50 at week 24. 
 
4.1.4 Description of Secondary Efficacy Variables 
  
The secondary efficacy predictor variables are the findings based on prediction 
algorithms 1 and 2, as described in Section 4.1.1. 
 
The secondary efficacy response variables are: 
 
• CDAI score at baseline (CDAIb), 12 (CDAI12w) and 24 weeks (CDAI24w)  
• ACR Response Criteria (ACR20, ACR50, ACR70) at 12 and 24 weeks 
• DAS28 Score at baseline, 12 weeks, and 24 weeks  
• Constituent scores of the ACR Response Criteria at baseline, 12 weeks, 
and 24 weeks, including: 
o TJC 
o SJC 
o Patient assessment of global disease activity 
o Rheumatologist assessment of global disease activity 
o Patient assessment of pain 
o Patient assessment of physical function 
o Acute-phase reactant value 
 
• Constituent scores of the CDAI score at baseline, 12 weeks, and 24 
weeks, including: 
o TJC 
o SJC 
o Patient Global Assessment 
o Physician Global Assessment 
 
The secondary efficacy endpoints are as follows: 
 
• Sensitivity and specificity of ΔTUVglobal[5w] bucketing with respect to 
ACR50 at week 12. 
• NPV, PPV, and OA of ΔTUVglobal[5w] bucketing with respect to ACR50 at 
weeks 12 and 24.  
• NPV of TUVglobal[b] with respect to ACR50 at week 12  
• TUVglobal[b] and response to new anti-TNFα bDMARD therapy defined by 
the change from baseline (CFB) of CDAI to 12 ± 1 weeks and 24 ± 1 
weeks (ΔCDAI12w and ΔCDAI24w, respectively), by the CFB of DAS28 to 
12 ± 1 weeks and 24 ± 1 weeks (ΔDAS2812w and ΔDAS2824w, 


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respectively) and by the CFB in each of the ACR Response Criteria 
components at 12 ± 1 weeks and at 24 ± 1 weeks. 
• ΔTUVglobal[5w] bucketing and response to new anti-TNFα bDMARD therapy 
defined by the CFB of CDAI to 12 ± 1 weeks and 24 ± 1 weeks (ΔCDAI12w 
and ΔCDAI24w, respectively). 
• Concordance of ΔTUVglobal[5w] bucketing with clinical criteria, including 
ACR Response Criteria, CDAI, DAS28, and HAQ-DI©. Concordance 
between the predicted response or non-response status and the clinical 
criteria will be evaluated using NPV, PPV, sensitivity, specificity, and OA.   
• Concordance of ΔTUVglobal[12w] bucketing with clinical criteria, including 
ACR Response Criteria, CDAI, DAS28, and HAQ-DI©. Concordance 
between the improvement classifications and the clinical criteria will be 
evaluated using NPV, PPV, sensitivity, specificity, and OA. 
• Response to new anti-TNFα bDMARD therapy defined by the CFB of 
CDAI to 12 ± 1 weeks and 24 ± 1 weeks (ΔCDAI12w and ΔCDAI24w, 
respectively). 
• The correlation of ΔTUVglobal[5w] bucketing and response to new anti-TNFα 
bDMARD therapy from baseline to 24 ± 1 weeks defined by the changes 
from baseline in each of the ACR Response Criteria components.  
• Constituent parameters of CDAI12w, CDAI24w, ΔCDAI12w, ΔCDAI24w, ACR 
Response Criteria at 12 and 24 weeks, including:  
o TJC  
o SJC  
o Patient assessment of global disease activity  
o Rheumatologist assessment of global disease activity  
o Patient assessment of pain  
o Patient assessment of physical function  
o Acute-phase reactant value 
 
4.2 Analysis of Efficacy Variables 
 
Efficacy analyses will be conducted on the ITD and PP populations, with the ITD 
population serving as the primary analysis population. 
 
4.2.1 Analysis of Primary Efficacy Variables 
 
The co-primary efficacy variables will be summarized by reader in a 2 by 2 
contingency table displaying the cell frequencies and marginal totals at 24 
weeks. The specificity of ΔTUVglobal[5w] bucketing and the sensitivity of 
ΔTUVglobal[5w] bucketing will be calculated for each reader. The 95% exact 
(Clopper-Pearson) confidence intervals will be provided for each of these 
parameters. Observed significance levels (p-values) for the exact binomial tests 
of specificity of ΔTUVglobal[5w] bucketing greater than 0.8 and sensitivity of 


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ΔTUVglobal[5w] bucketing greater than 0.65 (see hypotheses specified in Section 
1.3 above) will be provided. 
 
Sensitivity and specificity are defined according to the following cross-tabulation: 
 
 
Clinical Response 
 
Predicted Response 
Responder 
Non-Responder 
Total 
Responder 
A 
B 
T1 
Non-Responder 
C 
D 
T2 
Total 
T3 
T4 
N 
 
Sensitivity = A/T3. 
Specificity = D/T4. 
 
The above 2 by 2 contingency table will also be used to calculate the secondary 
efficacy endpoints of NPV, PPV, and OA as follows: 
 
NPV = D/T2. 
PPV = A/T1. 
OA = (A + D)/N. 
 
4.2.2 Analysis of Key Secondary Efficacy Variables 
 
NPV of TUVglobal[b] will be calculated for each reader. The 95% exact (Clopper-
Pearson) confidence intervals will be provided. Observed significance levels (p-
values) for the exact binomial tests of NPV of TUVglobal[b] greater than 0.7 will be 
provided. 
 
4.2.3 Analysis of Secondary Efficacy Variables 
 
All RA quantitative assessment variables (CDAI, ACR Response Criteria 
component scores, DAS28 score, and HAQ-DI) will be summarized by 
computing the mean, standard deviation, number of observations, minimum, 
median, and maximum for the observed values at each time point and for the 
change from baseline for values collected after Day 0. The ACR Response 
Criteria will be summarized with a frequency table of the highest ACR Response 
level (None, ACR20, ACR50, ACR70) attained by that patient at that time point. 
That is, a patient who satisfies ACR50 also satisfies ACR20 but will not appear 
in the frequency count for ACR20. 
 
The qualitative assessments will be summarized in a 2 by 2 contingency table 
displaying the cell frequencies and marginal totals by reader as shown in section 


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4.2.1 above. The PPV and NPV of the predicted response will be calculated for 
each reader, as will the OA. In addition, 95% exact confidence intervals will be 
provided for each of these parameters. Observed significance levels (p-values) 
for the exact binomial (Clopper-Pearson) tests of PPV and NPV (see sections 
1.3 and 4.2.1 above) will be provided for each reader. These tests will be based 
on PPV of the predicted response greater than 0.65, and NPV of the predicted 
response greater than 0.7. 
 
Concordance of improvement classification for: 1) TUVglobal[5w] bucketing and 2) 
TUVglobal[12w] bucketing with clinical criteria (ACR Response, CDAI, DAS28, and 
HAQ-DI) will be analyzed as follows. Note that the concordance of TUVglobal[5w] 
bucketing with ACR50 at 24 weeks is evaluated as co-primaries (sensitivity and 
specificity). For each of the RA improvement criteria, a cross-classification table 
will be provided. The PPV, NPV, sensitivity, specificity, and OA will be calculated 
and 95% exact (Clopper-Pearson) confidence intervals will be provided. 
Observed significance levels (p-values) for the exact binomial (Clopper-Pearson) 
tests for sensitivity and specificity will be provided for each reader. 
 
Figures displaying the TUVglobal by time point (5, 12, and 24 weeks) will be 
created to display the relationship between TUVglobal over time with the 
corresponding clinical response assessment (ACR20/50/70, DAS28, and CDAI) 
at the given time point. 
 
The Kendall rank correlation between ΔTUVglobal[5w] with ΔCDAI12w and ΔCDAI24w 
will be computed and a 95% confidence interval for its value will be computed 
using Fisher’s Z-transformation. Similarly, the Kendall rank correlation between 
ΔTUVglobal[5w] with changes from baseline in DAS28 and in each of the ACR 
Response Criteria components at weeks 12 and 24 will be computed and a 95% 
confidence interval for its value will be computed using Fisher’s Z-transformation. 
The marginal distributions of the variables will be characterized with the mean, 
standard deviation, and the number of data pairs. 
 
The additive effect of either quantitative or qualitative assessment of Tc 99m 
tilmanocept imaging will be assessed with a generalized linear mixed model with 
the logit link function. The patient’s response status will be used as the response 
variable. Fixed model terms for the quantitative and qualitative plus quantitative 
assessments will be used. The quantitative assessment will be based on 
TUVglobal[5w] bucketing. Random terms will be fit for the subject and reader within 
subject using the variance component model. A table displaying the partial 
hypothesis tests (Type 3 test) for the fixed effects will be displayed. 
 


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5.0  Analysis of Safety  
 
All safety analyses will be performed on the Safety Population. 
 
The safety analysis variables are defined as follows: 
 
• Adverse Events (AEs) 
• Clinical Laboratory Tests (hematology, serum chemistry, urinalysis, RA 
panel) 
• ECG Parameters 
• Vital Signs 
 
Adverse Events  
Adverse events will be observed for each patient from signing of informed 
consent until termination from the study. AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA®). A treatment-emergent AE 
(TEAE) is defined as an AE whose start date is on or after the initial procedure 
date. Based on the coded terms, frequencies of each TEAE will be summarized 
by MedDRA® preferred term within system organ class (SOC), by severity grade, 
and by relationship to Tc 99m tilmanocept. 
 
A summary of TEAEs will be constructed showing the following: 
 
• Number of patients with at least one TEAE 
• TEAEs by severity grade 
• TEAE by relationship to Tc 99m tilmanocept 
• TEAEs by relationship of TEAE to study procedure 
• Number of patients with at least one treatment emergent serious adverse 
event 
 
Treatment-emergent serious adverse events (TESAEs) will be tabulated by 
MedDRA® preferred term within SOC. 
 
A by-patient AE data listing of all AEs including verbatim term, coded term, grade, 
and relation to study drug will be provided.   
 
Clinical Laboratory Tests  
Clinical laboratory tests will be performed at screening (baseline) and after the 
image acquisition on each imaging day (Visits 2, 4, 6, and 8). Only RA panel lab 
values and abnormal clinical laboratory values will be assessed for clinical 
significance as applicable. For each quantitative laboratory test, summary 
statistics (mean, standard deviation, median, range, n) on the raw as well as their 
changes from baseline will be presented by timepoint. A shift table will also be 
produced to show the changes in lab values over time relative to the normal 
ranges.   


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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 
ECGs will be performed within 30-minutes before and after injection. For each 
ECG parameter (heart rate, QRS, QT, PR, and QTcF), summary statistics (mean, 
standard deviation, median, range, n) on the raw as well as their changes from 
baseline will be presented by timepoint. A shift table will be provided to show 
changes in the qualitative assessment (abnormal or normal) from baseline (pre-
injection) to post-injection. The baseline value for each of the post-injection ECG 
parameters will be the corresponding pre-injection time point. All ECG data will 
be listed.   
 
Vital Signs 
Vital signs will be performed at screening and within 30-minutes before and after 
injection. Height and weight will be measured only at screening and will be 
summarized as part of the baseline and demographic information. For each vital 
sign (respiration rate, systolic blood pressure, diastolic blood pressure, heart rate 
and temperature), summary statistics (mean, standard deviation, minimum, 
maximum, n) on the raw as well as their changes from baseline will be presented 
by timepoint. 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 patients.  
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 patients that withdraw before completion of the study, counts and 
percentages of the reasons for withdrawal will be tabulated. A data listing of all 
patient 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. 
 


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6.3 Study Drug Administration 
 
The volume, the calculated mass dose, and radioactivity of Tc 99m tilmanocept 
injected will be summarized. All study drug administration data will be listed. 
 
6.4 RA Evaluation and Screening Physical Exam 
 
Each RA patient will undergo a DAS28 evaluation during screening and at weeks 
5, 12, and 24. 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.


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7.0  List of Analysis Tables, Figures and Listings 
 
 
 
Table 
No. 
 
 
Table Title 
Included 
in Final 
Tables 
Shown in 
Appendix 
B 
 
 
 
 
1 
Patient Disposition  
X 
X 
2 
Demographics and Baseline Data Summary Statistics - 
Continuous Variables (Safety Population) 
X 
X 
3 
Demographics and Baseline Data Summary Statistics– 
Categorical Variables (Safety Population) 
X 
X 
4 
Summary of Study Drug Administration (Safety Population) 
X 
X 
5 
Summary of TUV by Study Day and DAS28 Joint (ITD 
population) 
X 
X 
6 
Summary of TUV by Study Day and DAS28 Joint (PP 
Population) 
X 
 
7 
RA Status Summaries (ITD Population) 
X 
X 
8 
RA Status Summaries (PP Population) 
X 
 
9 
ACR Response Classification by Time Point (ITD Population) 
X 
X 
10 
ACR Response Classification by Time Point (PP Population) 
X 
 
11 
Concordance of TUVglobal[b] Alone and of TUVglobal[5w] 
Bucketing and Week 12 Clinical Improvement Criteria (ITD 
Population) 
X 
X 
12 
Concordance of TUVglobal[b] Alone and of TUVglobal[5w] 
Bucketing and Week 12 Clinical Improvement Criteria (PP 
Population) 
X 
 
13 
Concordance of TUVglobal[b] Alone and of TUVglobal[5w] 
Bucketing and Week 24 Clinical Improvement Criteria (ITD 
Population) 
X 
 
14 
Concordance of TUVglobal[b] Alone and of TUVglobal[5w] 
Bucketing and Week 24 Clinical Improvement Criteria (PP 
Population) 
X 
 
15 
Concordance of TUVglobal[12w] Bucketing and Week 24 Clinical 
Improvement Criteria (ITD Population) 
X 
X 
16 
Concordance of TUVglobal[12w] Bucketing and Week 24 Clinical 
Improvement Criteria (PP Population) 
X 
 
17 
Concordance of TUVglobal[5w] Bucketing and Week 12 Clinical 
Improvement Criteria in Subgroups (ITD Population) 
X 
X 
18 
Concordance of TUVglobal[5w] Bucketing and Week 12 Clinical 
Improvement Criteria in Subgroups (PP Population) 
X 
 
19 
Concordance of TUVglobal[5w] Bucketing and Week 24 Clinical 
Improvement Criteria in Subgroups (ITD Population) 
X 
 
20 
Concordance of TUVglobal[5w] Bucketing and Week 24 Clinical 
Improvement Criteria in Subgroups (PP Population) 
X 
 
21 
Concordance of Qualitative Assessment of Tc 99m 
Tilmanocept Imaging and Week 12 Clinical Improvement 
Criteria (ITD Population) 
X 
X 


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Table 
No. 
 
 
Table Title 
Included 
in Final 
Tables 
Shown in 
Appendix 
B 
22 
Concordance of Qualitative Assessment of Tc 99m 
Tilmanocept Imaging and Week 12 Clinical Improvement 
Criteria (PP Population) 
X 
 
23 
Concordance of Qualitative Assessment of Tc 99m 
Tilmanocept Imaging and Week 24 Clinical Improvement 
Criteria (ITD Population) 
X 
 
24 
Concordance of Qualitative Assessment of Tc 99m 
Tilmanocept Imaging and Week 24 Clinical Improvement 
Criteria (PP Population) 
X 
 
25 
Concordance of Qualitative plus Quantitative Assessment of 
Tc 99m Tilmanocept Imaging and Week 12 Clinical 
Improvement Criteria (ITD Population) 
X 
 
26 
Concordance of Qualitative plus Quantitative Assessment of 
Tc 99m Tilmanocept Imaging and Week 12 Clinical 
Improvement Criteria (PP Population) 
X 
 
27 
Concordance of Qualitative plus Quantitative Assessment of 
Tc 99m Tilmanocept Imaging and Week 24 Clinical 
Improvement Criteria (ITD Population) 
X 
 
28 
Concordance of Qualitative plus Quantitative Assessment of 
Tc 99m Tilmanocept Imaging and Week 24 Clinical 
Improvement Criteria (PP Population) 
X 
 
29 
Kendall Rank Correlation of TUV, CDAI, ACR Response 
Criteria Components, and DAS28 with TUV at 5 weeks  
(ITD Population) 
X 
X 
30 
Kendall Rank Correlation of TUV, CDAI, ACR Response 
Criteria Components, and DAS28 with TUV at 5 weeks (PP 
Population) 
X 
 
31 
Kendall Rank Correlation of TUV, CDAI, ACR Response 
Criteria Components, and DAS28 with TUV at 12 weeks  
(ITD Population) 
X 
X 
32 
Kendall Rank Correlation of TUV, CDAI, ACR Response 
Criteria Components, and DAS28 with TUV at 12 weeks 
(PP Population) 
X 
 
33 
Kendall Rank Correlation of CDAI, ACR Response Criteria 
Components, and DAS28 with TUV at 24 weeks (ITD 
Population) 
X 
X 
34 
Kendall Rank Correlation of CDAI, ACR Response Criteria 
Components, and DAS28 with TUV at 24 weeks (PP 
Population) 
X 
 
35 
Summary of Generalized Linear Mixed Model to Asses the 
Additive Effect of either Quantitative or Qualitative assessment 
of Tc 99m Tilmanocept Imaging on Patient Response Status at 
Week 12 (ITD Population) 
X 
X 
36 
Summary of Generalized Linear Mixed Model to Asses the 
Additive Effect of either Quantitative or Qualitative assessment 
of Tc 99m Tilmanocept Imaging on Patient Response Status at 
Week 12 (PP Population) 
X 
 
37 
Summary of Generalized Linear Mixed Model to Asses the 
Additive Effect of either Quantitative or Qualitative assessment 
X 
 


Statistical Analysis Plan 
 
Study No. NAV3-33 
 
 
Page 31 of 94 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 4.0                                                                                                        October 6, 2023                                  
 
Table 
No. 
 
 
Table Title 
Included 
in Final 
Tables 
Shown in 
Appendix 
B 
of Tc 99m Tilmanocept Imaging on Patient Response Status at 
Week 24 (ITD Population) 
38 
Summary of Generalized Linear Mixed Model to Asses the 
Additive Effect of either Quantitative or Qualitative assessment 
of Tc 99m Tilmanocept Imaging on Patient Response Status at 
Week 24 (PP Population) 
X 
 
39 
Number and Percentage of Patients with TEAEs (Safety 
Population) 
X 
X 
40 
Summary of TEAEs (Safety Population) 
X 
X 
41 
Number and Percentage of Patients with TESAEs (Safety 
Population) 
X 
X 
42 
Number and Percentage of Patients with TEAEs by Severity 
Grade (Safety Population) 
X 
X 
43 
Number and Percentage of Patients with TEAEs by Level of 
Relationship to Tc 99m Tilmanocept  (Safety Population) 
X 
X 
44 
Serum Chemistry Clinical Laboratory Parameters Summary 
Statistics (Safety Population) 
X 
X 
45 
Hematology Clinical Laboratory Parameters Summary 
Statistics (Safety Population) 
X 
 
46 
Urinalysis Clinical Laboratory Parameters Summary Statistics 
(Safety Population) 
X 
 
47 
Serum Chemistry Clinical Laboratory Parameters Shift Table 
(Safety Population) 
X 
X 
48 
Hematology Clinical Laboratory Parameters Shift Table 
(Safety Population) 
X 
 
49 
Urinalysis Clinical Laboratory Parameters Shift Table (Safety 
Population) 
X 
 
50 
ECG Parameters Summary Statistics (Safety Population) 
X 
X 
51 
ECG Shift Table (Safety Population) 
X 
X 
52 
Vital Signs Summary Statistics (Safety Population) 
X 
X 
 
 
Figure 
No. 
 
 
Figure Title 
Included 
in Final 
Figures 
Shown in 
Appendix 
B 
 
 
 
 
Fig1 
Plot of TUVglobal by Imaging Time Point and ACR20 (ITD 
Population) 
X 
X 
Fig2 
Plot of TUVglobal by Imaging Time Point and ACR50 (ITD 
Population) 
X 
 
Fig3 
Plot of TUVglobal by Imaging Time Point and ACR70 (ITD 
Population) 
X 
 
Fig4 
Plot of TUVglobal by Imaging Time Point and CDAI (ITD 
Population) 
X 
 
Fig5 
Plot of TUVglobal by Imaging Time Point and DAS28 (ITD 
Population) 
X 
 
Fig6 
Sensitivity Analysis #1 – Tipping Point Analysis to Assess 
the Appropriateness of Imputation of Clinical Status at Week 
24 (ITD Population) 
X 
X 


Statistical Analysis Plan 
 
Study No. NAV3-33 
 
 
Page 32 of 94 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 4.0                                                                                                        October 6, 2023                                  
 
Figure 
No. 
 
 
Figure Title 
Included 
in Final 
Figures 
Shown in 
Appendix 
B 
Fig7 
Sensitivity Analysis #2 – Tipping Point Analysis to Assess 
the Appropriateness of Imputation of TUV Prediction (ITD 
Population) 
X 
 
 
 
 
Listing 
No. 
 
 
Data Listing Title 
Included 
in Final 
Listings 
 
Shown in 
Appendix 
B 
 
 
 
 
DL1 
Patient 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 
Patients Excluded from ITD Population Data Listing 
X 
X 
DL6 
Patients Excluded from PP Population Data Listing 
X 
X 
DL7 
Patients 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 
Patient Laboratory Profiles – Hematology Data Listing 
X 
X 
DL13 
Patient Laboratory Profiles – Serum Chemistry Data Listing 
X 
 
DL14 
Patient Laboratory Profiles – Urinalysis Data Listing 
X 
 
DL15 
Patient Laboratory Profiles – Rheumatology Panel Data 
Listing 
X 
 
DL16 
Physical Exam Data Listing 
X 
X 
DL17 
ACR/EULAR 2010 Classification Data Listing 
X 
X 
DL18 
ACR Data Listing 
X 
X 
DL19 
CDAI, DAS28, HAQ-DI, and WPI Scores Data Listing 
X 
X 
DL20 
DAS28 by Joint Data Listing 
X 
X 
DL21 
DAS28 by Patient Data Listing 
X 
X 
DL22 
Vital Signs Data Listing 
X 
X 
DL23 
ECG Parameters Data Listing 
X 
X 
DL24 
Study Drug Administration Data Listing 
X 
X 
DL25 
Post-Injection Imaging Data Listing 
X 
X 
DL26 
SPECT/CT Reader Results Data Listing – Hands and Wrists 
X 
X 
DL27 
TUV Data Listing 
X 
X 
DL28 
Qualitative Assessment Data Listing 
X 
X 
DL29 
Qualitative plus Quantitative Assessments which differ from 
Original Quantitative Assessment 
X 
X 
DL30 
ACR Response Criteria Data Listing 
X 
X 
 


Statistical Analysis Plan 
 
Study No. NAV3-33 
 
 
Page 33 of 94 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 4.0                                                                                                        October 6, 2023                                  
8.0  References 
 
N/A 


Statistical Analysis Plan 
 
Study No. NAV3-33 
 
 
Page 34 of 94 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 4.0                                                                                                        October 6, 2023                                  
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 (Date)” 
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. NAV3-33 
 
 
Page 35 of 94 
STATKING Clinical Services                                               Navidea Biopharmaceuticals, Inc. 
Version 4.0                                                                                                        October 6, 2023                                  
Missing Values 
 
All missing values will be displayed on the output tables/listings as blanks. 
 
Display of Study Dates 
 
The date format to be used is dd-mmm-yyyy.  Missing parts of dates are not 
shown (i.e., for a missing day value, the value displayed is in yyyy-mm format).  


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 36 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
Appendix B – Table, Figure, and Listing Shells 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 37 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Table 1. Patient Disposition  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Overall 
(N = xx) 
Screen Failures 
 
xx 
 
 
 
Enrolled 
 
xx 
 
 
 
Completed 
 
xx (xxx%) 
 
 
 
Withdrawn  
 
xx (xxx%) 
 
 
 
Withdrawal Reason 
Adverse Event 
xx (xxx%) 
 
Protocol Violation 
 
 
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%) 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
The denominator for all percentages in the table is the number of enrolled patients. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 38 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
 
Page x of y 
 
Table 2. Demographics and Baseline Data Summary Statistics – Continuous Variables 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
             
 
Variable 
 
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 
 
 
 
 
 
 
 
Time from Diagnosis of RA (months)a 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Calculated as the difference between date of enrollment and date of RA diagnosis. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 39 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 3. Demographics and Baseline Data Summary Statistics – Categorical Variables 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
Variable 
 
Category 
Overall 
 (N=xxx) 
 
 
 
Gender 
Male 
xxx (xxx%) 
 
Female 
xxx (xxx%) 
 
 
 
Race 
American Indian or Alaska Native 
xxx (xxx%) 
 
Asian 
xxx (xxx%) 
 
Black or African American 
xxx (xxx%) 
 
Native Hawaiian or Other Pacific Islander 
xxx (xxx%) 
 
White 
xxx (xxx%) 
 
Other 
 
 
 
 
Ethnicity 
Hispanic or Latino 
xxx (xxx%) 
 
Not Hispanic or Latino 
xxx (xxx%) 
 
 
 
 
 
 
Severity of Disease 
Mild 
xxx (xxx%) 
 
Moderate 
xxx (xxx%) 
 
Severe 
xxx (xxx%) 
 
 
 
Age Group 
< 60 Years 
xxx (xxx%) 
 
60 Years and Older 
xxx (xxx%) 
 
 
 
Previous Use of Biologics 
Yes 
xxx (xxx%) 
 
No 
xxx (xxx%) 
 
 
 
Baseline ACPA Level 
Low (< 85) 
xxx (xxx%) 
 
High (85 and Above) 
xxx (xxx%) 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 40 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 4. Summary of Study Drug Administration 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
Mean 
Std Dev 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
Tc 99m Dose (mCi) 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
Mass Dose (µg) 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
Total Volume of Tc 99m Tilmanocept Injected (mL) 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 41 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 5. Summary of TUV by Study Day and DAS28 Joint 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
DAS28 Joint 
Study Day 
View 
Number 
of Patients 
Mean 
Std Dev 
n 
Min 
Max 
 
Median 
 
%CV 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxx  
xxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx.x 
 
xxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx.x 
xxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx.x 
 
xxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx.x 
xxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx.x 
 
xxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for the PP population (table 6).   
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 42 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 7. RA Status Summaries 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
 
RA Status 
Measure 
 
Study 
Visit 
 
Data 
Type 
Mean 
Standard 
Deviation 
 
 
n 
Min 
Max 
 
 
Median 
 
 
 
 
 
 
 
 
 
xxxxxxxxxxx 
xxx 
Baseline 
xxxx.x 
xxx.xx 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxx 
RAW 
xxxx.x 
xxx.xx 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
CFB 
xxxx.x 
xxx.xx 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
 
 
 
 
 
 
xxxxxxxxxxx 
xxx 
Baseline 
xxxx.x 
xxx.xx 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxx 
RAW 
xxxx.x 
xxx.xx 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
CFB 
xxxx.x 
xxx.xx 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
 
 
 
 
 
xxxxxxxxxxx 
xxx 
Baseline 
xxxx.x 
xxx.xx 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
xxx 
RAW 
xxxx.x 
xxx.xx 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
CFB 
xxxx.x 
xxx.xx 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for the PP population (table 8).  
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 43 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 9. ACR Response Classification by Time Point 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table Format Repeats for PP Population (table 10). 
 
 
 
Assessment 
Time Point 
None 
ACR20 
ACR50 
ACR70 
 
 
 
 
 
Week 5 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
Week 12 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
Week 24 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 44 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Table 11. Concordance of TUVglobal[b] Alone and of TUVglobal[5w] Bucketing and Week 12 Clinical Improvement 
Criteria  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
Part 1 of 6: ACR20 
 
______________________________________________________________________________________________________________________________________  
a p-values of TUV Alone for NPV testing Ho:  = 0.7 and of TUV Bucketing for sensitivity testing Ho:  = 0.65 and specificity testing 
Ho:  = 0.8.  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Within each part, the above two TUV prediction algorithm results will be displayed for each reader and sorting will be done by reader 
then prediction algorithm. For TUV Alone, the only reported outcome measure is NPV.  For TUV Bucketing, outcome measures will 
include sensitivity, specificity, PPV, NPV, and OA, as shown above. 
 
This format repeats for Part 2 (ACR50), Part 3 (ACR70), Part 4 (CDAI), Part 5 (DAS28), and Part 6 (HAQ-DI).  
Full table format repeats for PP population (table 12) and for tables 13 – 14. 
 
 
 
Clinical Assessment 
 
 
 
TUV Prediction 
Algorithm 
Reader 
Algorithm 
Classification 
Improved 
Not 
Improved 
Total 
Measure 
Valuea 
 
 
 
 
 
 
 
 
TUVglobal[b] Alone 
x 
Not Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
NPV 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
p-value 
x.xxxx 
 
 
 
 
 
 
 
 
TUVglobal[5w] Bucketing 
x 
Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
Sensitivity 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
p-value 
x.xxxx 
 
 
Not Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
Specificity 
xxxx 
 
 
Total 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
p-value 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NPV 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
PPV 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
OA 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 45 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Table 15. Concordance of TUVglobal[12w] Bucketing and Week 24 Clinical Improvement Criteria 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
 
Part 1 of 6: ACR20 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Within each part, the above will be displayed for each reader. This format repeats for Part 2 (ACR50), Part 3 (ACR70), Part 4 (CDAI), Part 
5 (DAS28), and Part 6 (HAQ-DI).  Full table format repeats for PP population (table 16). 
 
 
Clinical Assessment 
 
 
 
Reader 
TUVglobal[12w] 
Bucketing 
Classification 
Improved 
Not 
Improved 
Total 
Measure 
Value 
 
 
 
 
 
 
 
x 
Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
PPV  
xxxx 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
Not Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
NPV 
xxxx 
 
Total 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
 
 
 
 
 
 
Sensitivity 
xxxx 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
 
 
 
 
 
 
Specificity 
xxxx 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
 
 
 
 
 
 
OA 
xxxx 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 46 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Table 17. Concordance of TUVglobal[5w] Bucketing and Week 12 Clinical Improvement Criteria in Subgroups 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
Part 1 of 6: ACR20 
 
 
 
_____________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Within each part, the above will be displayed for each reader and subgroup, sorted by reader then subgroup. This format repeats for 
Part 2 (ACR50), Part 3 (ACR70), Part 4 (CDAI), Part 5 (DAS28), and Part 6 (HAQ-DI).  Full table format repeats for PP population (table 18) 
and for tables 19 - 20. 
 
 
 
Clinical Assessment 
 
 
 
 
Subgroup 
Reader 
TUVglobal[5w] 
Bucketing 
Classification 
Improved 
Not 
Improved 
Total 
Measure 
Value 
 
 
 
 
 
 
 
 
Female (N=xx) 
x 
Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
PPV  
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
Not Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
NPV 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
Total 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
Sensitivity 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
Specificity 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
OA 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
 
 
xxxxxxxxxx (N=xx) 
x 
Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
PPV  
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
Not Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
NPV 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
Total 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
Sensitivity 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
Specificity 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
OA 
xxxx 
 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 47 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Table 21. Concordance of Qualitative Assessment of Tc 99m Tilmanocept Imaging and Week 12 Clinical 
Improvement Criteria 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
 
Part 1 of 6: ACR20 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________  
a p-values for PPV testing Ho:  = 0.65 and for NPV testing Ho:  = 0.7.  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Within each part, the above will be displayed for each reader. This format repeats for Part 2 (ACR50), Part 3 (ACR70), Part 4 (CDAI), Part 
5 (DAS28), and Part 6 (HAQ-DI).  Full table format repeats for PP population (table 22) and for tables 23 – 28. 
 
 
Clinical Assessment 
 
 
 
Reader 
Qualitative 
Assessment 
Improved 
Not 
Improved 
Total 
Measure 
Valuea 
 
 
 
 
 
 
 
x 
Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
PPV  
xxxx 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
p-value 
x.xxxx 
 
Not Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
NPV 
xxxx 
 
Total 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
p-value 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
OA 
xxxx 
 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 48 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Table 29. Kendall Rank Correlation of TUV, CDAI, ACR Response Criteria Components, and DAS28 with 
TUV at 5 Weeks  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
Part 1 of 3: Reader x 
 
 
Measurea 
Component 
Parameter 
Time Point 
Kendall 
Correlationb 
95% Confidence 
Limitsc 
n 
Mean 
Standard 
Deviation 
 
 
 
 
 
 
 
 
TUV 
 
5 Weeks 
-- 
-- 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
TUV 
 
12 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
CDAI 
Overall 
 5 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
12 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
CDAI 
xxxxxxxx 
 5 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
12 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
ACR 
xxxxxxxx 
 5 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
12 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
DAS28 
 
 5 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
12 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Change in ACR will be evaluated through the following components of the ACR Response Criteria: swollen joint count, tender joint 
count, patient assessment, physician assessment, pain scale, disability/functionality questionnaire, and acute phase reactant (ESR).  
b Kendall rank correlation between TUV at 5 weeks and the indicated measurement and time point. 
c Confidence limits calculated using Fisher’s Z-transformation. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for each reader. Entire table (all parts) is repeated for the PP population (table 30). 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 49 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 31. Kendall Rank Correlation of TUV, CDAI, ACR Response Criteria Components, and DAS28 with 
TUV at 12 Weeks  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
Part 1 of 3: Reader x 
 
 
Measurea 
Component 
Parameter 
Time Point 
Kendall 
Correlationb 
95% Confidence 
Limitsc 
n 
Mean 
Standard 
Deviation 
 
 
 
 
 
 
 
 
TUV 
 
12 Weeks 
-- 
-- 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
TUV 
 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
CDAI 
Overall 
12 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
CDAI 
xxxxxxxx 
12 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
ACR 
xxxxxxxx 
12 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
DAS28 
 
12 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Change in ACR will be evaluated through the following components of the ACR Response Criteria: swollen joint count, tender joint 
count, patient assessment, physician assessment, pain scale, disability/functionality questionnaire, and acute phase reactant (ESR).  
b Kendall rank correlation between TUV at 12 weeks and the indicated measurement and time point. 
c Confidence limits calculated using Fisher’s Z-transformation. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for each reader. Entire table (all parts) is repeated for the PP population (table 32). 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 50 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 33. Kendall Rank Correlation of CDAI, ACR Response Criteria Components, and DAS28 with TUV at 
24 Weeks  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
Part 1 of 3: Reader x 
 
 
Measurea 
Component 
Parameter 
Time Point 
Kendall 
Correlationb 
95% Confidence 
Limitsc 
n 
Mean 
Standard 
Deviation 
 
 
 
 
 
 
 
 
TUV 
 
24 Weeks 
-- 
-- 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
CDAI 
Overall 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
CDAI 
xxxxxxxx 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
ACR 
xxxxxxxx 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
DAS28 
 
24 Weeks 
x.xxx 
(x.xxx, x.xxx) 
xxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Change in ACR will be evaluated through the following components of the ACR Response Criteria: swollen joint count, tender joint 
count, patient assessment, physician assessment, pain scale, disability/functionality questionnaire, and acute phase reactant (ESR).  
b Kendall rank correlation between TUV at 24 weeks and the indicated measurement and time point. 
c Confidence limits calculated using Fisher’s Z-transformation. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for each reader. Entire table (all parts) is repeated for the PP population (table 34). 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 51 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
Table 35. Summary of Generalized Linear Mixed Model to Asses the Additive Effect of either Quantitative 
or Qualitative Assessment of Tc 99m Tilmanocept Imaging on Patient Response Status at Week 12 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
Model Terma 
Parameter 
Estimateb 
Standard Error 
95% Confidence 
Limits 
p-valuec 
 
 
 
 
 
Quantitative Imaging 
Assessment 
xxx.xxx 
xxx.xxx 
(xxx.xxx, xxx.xxx) 
x.xxxx 
 
 
 
 
 
Qualitative plus 
Quantitative Imaging 
Assessment 
xxx.xxx 
xxx.xxx 
(xxx.xxx, xxx.xxx) 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Indicator variable for prediction of “Improved” compared to the reference category of “Not Improved.” 
b Estimate calculated from a generalized linear mixed model with the logit link function with patient response status as the response 
variable, fixed terms for quantitative and qualitative plus quantitative imaging assessment, and random terms for subject and reader 
within subject using a variance component model. 
c Based on a two-sided t-test. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table is repeated for the PP population (table 36) and for tables 37 – 38. 
 
 
Page x of y 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 52 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
Table 39. Number and Percentage of Patients with TEAEs 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Adverse Event Categorya: 
Overall 
(N=xxx) 
 
 
Total Number of TEAEs 
xxx 
 
 
Patients 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. NAV3-33 
 
Page 53 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 40. Summary of TEAEs  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
Overall 
(N=xxx) 
 
 
Patients With at Least One TEAE 
xxx 
 
 
Maximum TEAE Severity Grade 
 
    Mild 
xxx (xxx%) 
    Moderate 
xxx (xxx%) 
    Severe 
xxx (xxx%) 
 
 
Highest Relationship of TEAE to Tc 99m tilmanocept 
 
    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%) 
 
 
Patients with at Least One TESAE 
xxx (xxx%) 
 
 
____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 54 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 41. Number and Percentage of Patients with TESAEs  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Categorya: 
Overall 
(N=xxx) 
 
 
Total Number of TESAEs 
xxx 
 
 
Patients with at Least One TESAE 
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. NAV3-33 
 
Page 55 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 42. Number and Percentage of Patients with TEAEs by Severity Grade 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
Severity Grade 
Adverse Event Categorya: 
Mild 
Moderate 
Severe 
 
 
 
 
Total Number of TEAEs 
xxx 
xxx 
xxx 
 
 
 
 
Patients with at Least One TEAE 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
  System Organ Class 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
  System Organ Class 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a Adverse events coded with MedDRA Coding Dictionary Version XXX. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 56 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 43. Number and Percentage of Patients with TEAEs by Level of Relationship  
to Tc 99m Tilmanocept  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
Level of Relationship 
Adverse Event Categorya: 
Definitely 
Not 
Probably 
Not 
Possibly 
Related 
Probably 
Related 
Definitely 
Related 
 
 
 
 
 
 
Total Number of TEAEs 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Patients with at Least One TEAE 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
  System Organ Class 1 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
  System Organ Class 2 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a Adverse events coded with MedDRA Coding Dictionary Version XXX. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 57 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 44.  Serum Chemistry Clinical Laboratory Parameters Summary Statistics  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
                                  
 
Parameter(units) 
Visit  
Data Typea 
Mean 
Std 
Dev 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
 
xxxxxxxx(xxx) 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Day 0 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Day 8 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx(xxx) 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Day 0 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Day 8 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
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 
Table format repeats for tables 45 and 46. 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 58 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 47. Serum Chemistry Clinical Laboratory Parameters Shift Table  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 1 of 4: Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for Tables 48 (Hematology) and 49 (Urinalysis) 
 
 
 
 
Baseline Result/ 
Post-Injection Result 
 
Panel/Parameter 
(units) 
Low/ 
Low 
Low/ 
Normal 
Low/ 
High 
Normal/ 
Low 
Normal/ 
Normal 
Normal/ 
High 
High/ 
Low 
High/ 
Normal 
High/ 
High 
 
 
 
 
 
 
 
 
 
 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 59 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Table 47. Serum Chemistry Clinical Laboratory Parameters Shift Table  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 2 of 4: Week 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for Tables 48 (Hematology) and 49 (Urinalysis) 
 
 
 
 
 
Baseline Result/ 
Post-Injection Result 
 
Panel/Parameter 
(Units) 
 
Low/ 
Low 
Low/ 
Normal 
Low/ 
High 
Normal/ 
Low 
Normal/ 
Normal 
Normal/ 
High 
High/ 
Low 
High/ 
Normal 
High/ 
High 
 
 
 
 
 
 
 
 
 
 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 60 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 47. Serum Chemistry Clinical Laboratory Parameters Shift Table 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 3 of 4: Week 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
Table format is repeated for Tables 48 (Hematology) and 49 (Urinalysis) 
 
 
 
 
Baseline Result/ 
Post-Injection Result 
 
Panel/Parameter 
(Units) 
 
Low/ 
Low 
Low/ 
Normal 
Low/ 
High 
Normal/ 
Low 
Normal/ 
Normal 
Normal/ 
High 
High/ 
Low 
High/ 
Normal 
High/ 
High 
 
 
 
 
 
 
 
 
 
 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 61 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 47. Serum Chemistry Clinical Laboratory Parameters Shift Table  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 4 of 4: Week 24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for Tables 48 (Hematology) and 49 (Urinalysis) 
 
 
 
 
 
Baseline Result/ 
Post-Injection Result 
 
Panel/Parameter 
(Units) 
 
Low/ 
Low 
Low/ 
Normal 
Low/ 
High 
Normal/ 
Low 
Normal/ 
Normal 
Normal/ 
High 
High/ 
Low 
High/ 
Normal 
High/ 
High 
 
 
 
 
 
 
 
 
 
 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxxxx/ 
xxxxxxxx(xxx) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 62 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Table 50.  ECG Parameters Summary Statistics  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
                                  
ECG 
Parameter(units) 
Visit 
Data 
Typea 
Mean 
Std Dev 
n 
Min 
Max 
Median 
xxxxxxxxx (xxx) 
Day 0 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Day 0 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Week 5 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Week 5 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Week 12 Pre-Injection 
(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Week 12 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Week 24 Pre-Injection 
(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Week 24 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
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  
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 63 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Table 51. ECG Shift Table  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
 
Baseline Result/ 
Post-Injection Result 
Visit 
 
Abnormal/ 
Abnormal 
Abnormal/ 
Normal 
Normal/ 
Abnormal 
Normal/ 
Normal 
 
 
 
 
 
xxxxx 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxx 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxx 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
xxxxx 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxx 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxx 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
xxxxx 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxx 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxxxx 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 64 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
 
Page x of y 
 
Table 52.  Vital Signs Summary Statistics 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
                                 
Vital Sign 
Parameter (units) 
Visit 
Data 
Typea 
Mean 
Std Dev 
n 
Min 
Max 
Median 
xxxxxxxxx (xxx) 
Day 0 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Day 0 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Week 5 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Week 5 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Week 12 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Week 12 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Week 24 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Week 24 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
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 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 65 of 94 
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Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Figure 1.  Plot of ΔTUVglobal by Imaging Time Point and ACR20  
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
 
 
 
Part 1 of 3: Reader x 
                                  
 
 
 
______________________________________________________________________________________________________________________________________  
Responder status based on ACR20 at each week. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Figure format repeats for each part and for Figures 2-5.  Footnote text will be updated in each figure to correspond to the  
clinical assessment noted in the title (ACR50, ACR70, CDAI, or DAS28).  


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 66 of 94 
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Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
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Figure 6.  Sensitivity Analysis #1 – Tipping Point Analysis to Assess the Appropriateness of Imputation of 
Clinical Status at Week 24  
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
 
 
 
Part 1 or 2: Sensitivity 
                                  
 
 
 
 
______________________________________________________________________________________________________________________________________  
Remaining missing week 24 clinical status outcomes imputed as non-responders. Solid horizontal line represents 65% sensitivity. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 67 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
 
 
Page x of y 
 
Figure 6.  Sensitivity Analysis #1 – Tipping Point Analysis to Assess the Appropriateness of Imputation of 
Clinical Status at Week 24  
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
ITD Population (N=xxx) 
 
 
 
 
Part 2 of 2: Specificity 
                                  
 
 
 
 
______________________________________________________________________________________________________________________________________  
Remaining missing week 24 clinical status outcomes imputed as non-responders. Solid horizontal line represents 80% specificity. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Figure format repeats for Figure 7.  


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 68 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
 
Page x of y 
 
Data Listing 1. Patient Disposition Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
Patient 
No. 
 
 
Disposition Status 
 
Date of 
Completion or 
Withdrawal 
 
 
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. NAV3-33 
 
Page 69 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Data Listing 2. Inclusion/Exclusion Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Patient 
No. 
 
Did Patient 
Meet All 
Eligibility 
Criteria? 
Criterion Category 
 
 
Criterion 
Was a 
Waiver 
Granted? 
Is Patient 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. NAV3-33 
 
Page 70 of 94 
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Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
 
Page x of y 
 
Data Listing 3. Protocol Deviations Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Patient 
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. NAV3-33 
 
Page 71 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
 
Page x of y 
 
Data Listing 4. Demographics Data Listing  
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
                        
 
                                                                                                                             
 
 
 
Patient 
No. 
 
Informed 
Consent 
Date/Time 
Time from 
Diagnosis 
of RA 
(months)a 
Disease 
Severity 
 
Date 
of 
Birth 
Height 
(inches) 
Weight 
(pounds) 
 
 
Age 
(years) 
 
 
 
Gender 
 
 
 
Race 
 
 
 
Ethnicity 
Previous 
Use of 
Biologics 
(Y/N) 
Baseline 
ACPA Level 
(Low/High)b 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxx 
xxx 
xxxxxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
x 
xxx 
xxxx 
xxxxxx 
xxx 
xxxxxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
x 
xxx 
xxxx 
xxxxxx 
xxx 
xxxxxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
x 
xxx 
xxxx 
xxxxxx 
xxx 
xxxxxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
x 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________  
a Calculated as the difference between date of enrollment and date of RA diagnosis. 
b Low is < 85, and High is 85 and above. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 72 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Data Listing 5. Patients Excluded from ITD Population Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
All Enrolled Patients (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Patient 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. NAV3-33 
 
Page 73 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Data Listing 6. Patients Excluded from PP Population Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
All Enrolled Patients (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Patient 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. NAV3-33 
 
Page 74 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Data Listing 7. Patients Excluded from Safety Population Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
All Enrolled Patients (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Patient 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. NAV3-33 
 
Page 75 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Data Listing 8. Medical History Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
Patient 
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. NAV3-33 
 
Page 76 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Data Listing 9. Prior and Concomitant Medications Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
Patient 
No. 
Drug Preferred Terma/ 
Verbatim/ 
ATC Level 1 Text/ 
ATC Level 4 Text 
Prior 
Medication? Indication Frequency 
Start 
Date 
Stop 
Date 
Route Ongoing? 
 
 
 
 
 
 
 
 
 
Xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
x 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
x 
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. NAV3-33 
 
Page 77 of 94 
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Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Data Listing 10. Prior and Concomitant RA Medications Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
Patient 
No. 
 
 
Drug Preferred Terma/ 
Verbatim/ 
ATC Level 1 Text/ 
ATC Level 4 Text 
Prior 
Medication? Indication Frequency 
 
 
 
 
 
Start 
Date 
 
 
 
 
 
 
Stop 
Date 
 
 
 
 
 
 
Route 
 
 
 
 
 
 
Ongoing? 
 
 
 
 
 
 
 
 
 
Xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
x 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
x 
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. NAV3-33 
 
Page 78 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Data Listing 11. Adverse Events Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
Patient 
No. 
Start 
Date and 
Time/ 
End Date 
and Time 
Start Date 
and Time of 
Nearest 
Previous 
tilmanocept 
Injection 
Treatment 
Emergent? 
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 
xxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxx 
xxxxxxxx/ 
xxxxxxxx 
 
xxx 
 
xxxxxxxx 
 
 
 
 
 
 
 
 
 
xxxxxxxxx 
xxxxxxx 
xxxxxxx/ 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
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. NAV3-33 
 
Page 79 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Data Listing 12. Patient Laboratory Profiles – Hematology Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Normal Range 
 
Patient 
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 13, 14, 15). 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 80 of 94 
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Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Data Listing 16. Physical Exam Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
Patient 
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 
 
 
 
 
Page x of y 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 81 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
Data Listing 17. ACR/EULAR 2010 Classification Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
   
 
 
 
ACR/EULAR 2010 
 
 
Patient 
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. NAV3-33 
 
Page 82 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Data Listing 18. ACR Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACR Components 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient 
No. 
 
 
 
Visit 
 
 
 
Date 
Tender 
Joint 
Count 
Swollen 
Joint 
Count 
Patient’s 
Global 
Disease 
Activity 
Physician’s 
Global 
Disease 
Activity 
Patient 
Assessment 
of Pain 
Patient 
Assessment  
Physical 
Function 
Acute 
Phase 
Reactant 
Value 
ACR20 
ACR50 ACR70 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxxx 
xxxxxxx xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 83 of 94 
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Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Data Listing 19. CDAI, DAS28, HAQ-DI, and WPI Scores Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
 
CDAI Component 
 
 
 
 
 
 
 
 
Patient 
No. 
 
 
 
Visit 
 
 
 
Date 
Tender 
Joint 
Score 
Swollen 
Joint 
Score 
Patient’s 
Global 
Disease 
Activity 
Physician’s 
Global 
Disease 
Activity 
CDAI 
Total 
Score 
CDAI 
Improved 
DAS28 
Total 
Score 
DAS28 
Improved 
HAQ-
DI 
Total 
Score 
WPI 
Total 
Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x 
xx.x 
x 
xx.x 
xx.x 
xxxx 
xxxxxxx xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x 
xx.x 
x 
xx.x 
xx.x 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 84 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
 
Page x of y 
 
Data Listing 20. DAS28 by Joint Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
 
 
DAS28 Joint Classification 
 
 
Patient 
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. NAV3-33 
 
Page 85 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
Page x of y 
 
Data Listing 21. DAS28 by Patient Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
 
DAS28 
 
 
Patient 
No. 
 
Visit 
 
 
Date 
Tender 
Joint 
Count 
Swollen 
Joint 
Count 
Patient 
VAS 
Global 
(mm) 
Erythrocyte 
Sedimentation 
Rate (ESR; 
mm/hr) 
DAS28 
Score 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 86 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
 
 
Page x of y 
 
Data Listing 22. Vital Signs Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
Patient 
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. NAV3-33 
 
Page 87 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
 
Page x of y 
 
Data Listing 23. ECG Parameters Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
Patient 
No. 
 
 
 
Visit 
 
 
 
Date 
 
 
 
Time 
Heart Rate 
(bpm)  
 
 
PR Interval 
(msec) 
QRS 
Interval 
(msec) 
QT Interval 
(msec)  
 
QTcF 
Interval 
(msec) 
 
 
Overall 
Interpretation 
 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxx 
xxxxx 
xxxxxx 
xxxxxx 
xxxxxxxx 
xxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
       
 
 
 
 
 
 
 
 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page x of y 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 88 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
 
Data Listing 24. Study Drug Administration Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
 
Patient 
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. NAV3-33 
 
Page 89 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
                                                                                                                                                          October 6, 2023 
    
 
Page x of y 
 
Data Listing 25. Post-Injection Imaging Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
 
Patient 
No. 
 
Visit 
Date of 
Imaging  
Start Time 
of Imaging 
SPECT/CT Image 
Finding 
 
 
 
 
 
xxxx 
xxxxxxxx 
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STATKING Clinical Services (DD-MMM-YYYY) 
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Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
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STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
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Data Listing 26. SPECT/CT Reader Results Data Listing – Hands and Wrists 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
Patient 
No. 
Post-Injection 
Imaging Time Point 
Joint 
SPECT/CT 
Image Finding 
 
 
 
 
xxxx 
xxxxxxx 
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xxxx 
 
 
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STATKING Clinical Services (DD-MMM-YYYY) 
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Statistical Analysis Plan 
 
 
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STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
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Data Listing 27. TUV Data Listing 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
 
 
TUV Classification of Improvement 
 
 
 
 
Patient No. 
Reader No. 
 
Algorithms 
Predicting 
Improvementa 
Algorithms 
Predicting No 
Improvementa 
 
Visit 
Date/Time 
Region of 
Interestb 
TUV 
 
 
 
 
 
 
 
 
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xxxxxxx 
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_____________________________________________________________________________________________________________________________________ 
a 1 = Change in Global TUV[5w] Bucketing, 2 = Change in Global TUV[12w] Bucketing 
b Region of Interest is joint or Global. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
Page 92 of 94 
STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
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Data Listing 28. Qualitative Assessment Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
  
Patient No. 
Reader No. 
 
Qualitative 
Assessmenta 
Date/Time 
 
 
 
 
xxxx 
 
xxxx 
 
 
x 
 
x 
 
 
xxxxxxx 
 
xxxxxxx 
 
 
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a Qualitative Assessment is either “Improved” or “Not Improved.” 
STATKING Clinical Services (DD-MMM-YYYY) 
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Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
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STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
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Data Listing 29. Qualitative plus Quantitative Assessments which differ from Original Quantitative 
Assessment 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
Patient No. 
Reader No. 
 
Qualitative 
plus 
Quantitative 
Assessmenta 
Date/Time of 
Qualitative plus 
Quantitative 
Assessment 
 
 
Original 
Quantitative 
Assessmenta 
 
Date/Time of 
Original 
Quantitative 
Assessment 
 
 
 
 
 
 
xxxx 
 
xxxx 
 
 
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a Assessment is either "Improved” or “Not Improved.” 
STATKING Clinical Services (DD-MMM-YYYY) 
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Statistical Analysis Plan 
 
 
                            Study No. NAV3-33 
 
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STATKING Clinical Services                                                                                                                                Navidea Biopharmaceuticals, Inc. 
Version 4.0 
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Data Listing 30. ACR Response Criteria Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-33 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
Patient 
No. 
 
Visit 
Highest ACR 
Response 
Assessmenta 
Number of 
Tender 
Joints 
Number of 
Swollen 
Joints 
Patient 
Global 
Assessment 
Physician 
Global 
Assessment 
HAQ Total 
VAS Pain 
Score 
ESR 
 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxx 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a Options are None, ACR20, ACR50, or ACR70.  Response assessment will be blank for baseline measurements. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 

ICF_001.pdf: 
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RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
 
TITLE: 
Evaluation of Tc 99m Tilmanocept Imaging for the Early 
Prediction of Anti-TNFα Therapy Response in Patients with 
Moderate to Severe Active Rheumatoid Arthritis (RA) 
 
PROTOCOL NO.: 
NAV3-33  
 
WCG IRB Protocol #20216706 
 
SPONSOR: 
Navidea Biopharmaceuticals, Inc. 
 
INVESTIGATOR: 
Charles Talakkottur, MD 
 
5106 N Armenia Ave. 
 
Suite 1 
 
Tampa, Florida 33603 
 
United States 
 
STUDY-RELATED  
PHONE NUMBER(S): 
813-874-1852 (24 hours) 
 
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. It explains 
how your health information will be used for this study and may be used for research in the 
future and requests your authorization (permission) to use your health information. 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 is a study to see how well a drug called technetium Tc 99m tilmanocept (Lymphoseek®) 
helps us find inflammation in your joints. You are being asked to be in this study because you 
are currently undergoing evaluation and treatment for rheumatoid arthritis (RA) and your doctor 
wants to change your RA medication. 
 
Description of the study 
The purpose of this study is to find out how well imaging can predict response to your RA 
medication. Patients participating in this study will receive 150 mcg of tilmanocept radiolabeled 
with 10 mCi (370 MBq) of technetium Tc 99m per injection. You will receive 2 injections over 
the 31-week study, one at each of 2 imaging visits. You will receive a single injection of the 
study drug by intravenous (IV) injection in your arm on each imaging day. Tilmanocept (study 
drug) will travel through your blood stream to the sites in your body where you have 
inflammation. 
 
The study drug is a radioactive mapping drug that sticks to swelling and can be seen with a 
gamma camera (scan). The camera (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. 
 


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Participant Selection 
In total, up to 672 subjects will take part in this study at up to 50 centers in the United States. 
You are being asked to participate because your current medication for RA is not working as 
well as your doctor would like, and your doctor will be starting you on a new medication in 
about 1 month. Your doctor will explain this change to you in detail. 
 
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, all the medical care you would normally receive will continue 
and nothing will change. Refusing to take part will not result in any penalty or loss of benefits to 
which you are otherwise entitled. 
 
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 affect the medical care that you would 
receive. Withdrawing will not result in any penalty or loss of benefits to which you are otherwise 
entitled. If you decide to withdraw from participation, no additional follow up will be required 
for the study.  
 
The research site management does not urge, influence, or encourage anyone who works for the 
company to take part in a research study. Your participation in this study is completely 
voluntary.  You may withdraw from the study at any time and for any reason.  Your decision to 
not participate in the study, or a decision on your part to withdraw from the study, will have no 
effect whatsoever on your student/employment status at the research site.  You may refuse to 
participate, or you may withdraw from the study at any time without penalty or prejudice. 
 
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 rheumatoid arthritis. The study drug has been 
tested in 18 clinical trials. The study drug is also called Lymphoseek® and is approved by the 
Food and Drug Administration (FDA) for use in mapping lymph nodes. The study drug is 
investigational (being used for research) in this study because it is being used for a different 
purpose, different route of administration and at a different dose amount.  
 
If I agree to join the study, what will I need to do? 
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 if you are an appropriate candidate for the study. 
• You will be asked questions about your medical history, medications, and 
demographic information (such as age, sex, and race). 
• You will have a physical examination (routine examination of your body 
including assessing your height and weight). 


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• You will have an evaluation of your joints, including your shoulders, elbows, 
hands, wrists, and knees. 
• Vital signs, which include assessing your body temperature, blood pressure, heart 
rate, and breathing rate, will be taken. 
• Your blood will be taken (about 2.5 teaspoons) for routine testing and for 
rheumatoid arthritis testing. 
• Your urine will be collected for routine urinalysis.  
• If you can become pregnant, you will have a urine pregnancy test before the study 
drug injection. If you are pregnant, you will not be able to participate. 
• You will answer some questionnaires about your health. 
 
Visit 2: Injection of Study Drug and Imaging  
This visit will take about 2 hours. 
• Before injection 
• If you can become pregnant, you will have a urine pregnancy test before 
the study drug injection. If you are pregnant, you will not be able to 
participate. 
• You will be asked about any changes in your health and medications since 
your last visit. 
• Your vital signs, which include your body temperature, blood pressure, 
heart rate and breathing rate, will be taken. 
• Injection of the study drug  
• You will receive the injection of the study drug through an IV placed in 
your arm. The amount of the study drug injection is small, less than a 
teaspoon. This injection will take less than one minute. 
• After study drug injection (within 30 minutes) 
• Your vital signs, which include your body temperature, blood pressure, 
heart rate and breathing rate, will be taken. 
• Imaging (Scanning) 
• You will have scanning at about 60 minutes after injection. You will be 
positioned with both hands and wrists lying flat on the scanner while you 
stand or rest on a chair. The scanner detects the radiation in the study drug 
to create a picture of the study drug in your hands and wrists. This scan 
will take up to 15 minutes.  
• After scanning is finished 
• Your blood will be taken (about 1.8 teaspoons) for routine testing. 
• Your urine will be collected for routine urinalysis. 
• You will start your new RA medication. Your doctor will explain this 
change to you in detail.  
 
Visit 3: Safety Follow-Up Telephone Call (5 ± 3 days after Visit 2) 
• You will be asked about changes in your health and medication. 
 


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Visit 4: RA Clinical Assessments and Injection of Study Drug and Imaging (Week 5 ± 1) 
This visit will take about 3 hours. 
• At a separate appointment (within 7 days) before you arrive for imaging, you will 
visit the Rheumatologist’s office to complete the following: 
• You will be asked to complete some questionnaires about your health.  
• You will have an evaluation of your joints, including your shoulders, 
elbows, hands, wrists, and knees. 
• Before injection 
• If you can become pregnant, you will have a urine pregnancy test before 
the study drug injection. If you are pregnant, you will not be able to 
participate. 
• You will be asked about any changes in your health and medications since 
your last visit. 
• Your vital signs, which include your body temperature, blood pressure, 
heart rate and breathing rate, will be taken. 
• Injection of the study drug  
• You will receive the injection of the study drug through an IV placed in 
your arm. The amount of the study drug injection is small, less than a 
teaspoon. This injection will take less than one minute. 
• After study drug injection (within 30 minutes) 
• Your vital signs, which include your body temperature, blood pressure, 
heart rate and breathing rate, will be taken. 
• Imaging (Scanning) 
• You will have scanning at about 60 minutes after injection. You will be 
positioned with both hands and wrists lying flat on the scanner while you 
stand or rest on a chair. The scanner detects the radiation in the study drug 
to create a picture of the study drug in your hands and wrists. This scan 
will take up to 15 minutes.  
• After scanning is finished 
• Your blood will be taken (about 2.5 teaspoons) for routine testing and RA 
testing. 
• Your urine will be collected for routine urinalysis.  
 
Visit 5: Safety Follow-Up Telephone Call (5±3 days after Visit 4) 
• You will be asked about changes in your health and medication. 
 
Visit 6: RA Clinical Assessments (Week 12 ±1) 
This visit will take about 1 hour. 
• At this visit you will visit the Rheumatologist’s office to complete the following: 
• You will be asked about any changes in your health and medications since 
your last visit. 
• You will be asked to complete some questionnaires about your health.  
• You will have an evaluation of your joints, including your shoulders, 
elbows, hands, wrists, and knees. 
• Your blood will be taken (less than 1 teaspoons) for RA testing. 


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Visit 8: RA Clinical Assessments (Week 24 ±1) 
This visit will take about 1 hour. 
• At this visit you will visit the Rheumatologist’s office to complete the following: 
• You will be asked about any changes in your health and medications since 
your last visit. 
• You will be asked to complete some questionnaires about your health.  
• You will have an evaluation of your joints, including your shoulders, 
elbows, hands, wrists, and knees. 
• Your blood will be taken (less than 1 teaspoons) for RA testing. 
 
How long will I be in the study? 
The screening period begins after you have signed this consent form. Total participation may last 
up to 31 weeks for a total of 7 visits: 1 screening visit, 2 injection and imaging visits, 4 clinic 
visits including an assessment of swollen and tender joints, and 2 safety follow-up telephone 
calls. 
 
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 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 (less than 1%). The study drug has been available 
commercially for other medical uses since May 2013, and since that time, over 800,000 patients 
have received this drug.  The most commonly reported adverse reactions have been injection site 
pain (less than 0.02%) and rash (less than 0.02%). 
 
To date, there have been more than 300 IV injections with the study drug with no adverse drug 
reactions. 
 
You will receive the study drug through an IV needle 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. 
 
Your blood will be collected for routine testing and RA 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. 
 


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The study drug used in this study will expose you to ionizing radiation. Radiation occurs 
naturally in the environment and is 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. In comparison, the equivalent for this 
study is approximately 3.6 years of exposure to natural background radiation. The total amount 
of radiation exposure you will receive from the study drug is about 10.8 msv or 1080 mrem. 
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. 
 
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 (urine test) and before each injection at no cost. 
 
Tell one of the study doctors right away if: 
• You are pregnant 
• You become 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 the last dose of the study drug during visit 4. 
  


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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 sponsor.  
 
Will I be paid for taking part in this study? 
You will receive the amounts below for each completed visit: 
Visit 1 Screening $150 
Visit 2 after imaging $250 
Visit 3 telephone $25 
Visit 4 after imaging $250 
Visit 5 telephone $25 
Visit 6 after imaging $250 
Visit 7 telephone $25 
Visit 8 after imaging $250 
Visit 9 telephone $25 
 
You will be paid at each visit. 
 
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 
“Health 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. 
Believe Clinical Trials 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 Believe Clinical Trials will 
be able to link the assigned number to your name.   
 
To do this study, we will use the following kinds of health information: 
• Results of the tests and procedures done as part of the study 
• Things you tell the researchers about your health and the health of your family who have 
similar conditions 
• Information currently in your medical records as well as information added to your 
medical records during the course of the study 


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Your health information will be stored so that researchers can continue to use the data in the 
future and may be combined with information from other studies to explore and better 
understand the study drug and rheumatoid arthritis.  
 
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 
 
WCG IRB, 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 Believe Clinical Trials 
 
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. 
 
Can I see all my health information collected in the study? 
You can see all the health information collected for the study. However, the scan results of your 
hands and wrists are experimental and will not be used for clinical decision making. Thus, the 
results of these scans will not be shared with you.  
 
What if I change my mind about sharing my health information? 
Your authorization for researchers to use your health information does not have an end date.  
However: 
• You can choose to take back your authorization for researchers to use your health 
information.  You can do this at any time before or during your participation in the 
research.  
• If you take back your authorization, information that was already collected may still be 
used and shared with others, but the researchers will no longer be able to collect NEW 
information about you.   


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• If you take back your authorization, you will not be able to take part in the remainder of 
the research study. 
• To take back your authorization, you will need to tell the research staff in writing at 
Believe Clinical Trials 5106 N Armenia Ave, Suite 1, Tampa, Florida 33603 
 
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 Believe Clinical Trials. 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 Believe Clinical Trials. If you need to leave early from the study between 
Week 12 and Week 24, we will try to schedule a final visit to complete clinical assessments. 
 
What other choices do I have if I do not participate in this study? 
The alternative to participating is to not participate. You can have your joints evaluated using 
other standard imaging methods outside the study. 
 
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? 
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. 


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• 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, or complaints about this study or your participation in this 
study, contact your study doctor: 
 
Dr. Charles Talakkottur 813-874-1852 (24 Hours) 
 
If you have questions about your rights as a research subject or have other questions, complaints, 
or concerns about the research, you can contact WCG IRB at 855-818-2289 or 
clientcare@wcgclinical.com.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site 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. 
 
In the event of an emergency, dial 911 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. Charles Talakkottur if I have any more 
questions about taking part in this study.  I understand that Dr. Charles Talakkottur 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. 
 
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Prot_000.pdf: 
Clinical Study Protocol: NAV3-33 
Study Title: 
Evaluation of Tc 99m Tilmanocept Imaging for the Early Prediction 
of Anti-TNFα Therapy Response in Patients with Moderate to Severe 
Active Rheumatoid Arthritis (RA)  
Study Number: 
NAV3-33 
Study Phase: 
3 
Product Name: 
Technetium Tc 99m tilmanocept 
IND Number: 
132943 
Investigator(s): 
Multicenter 
Sponsor: 
Navidea Biopharmaceuticals, Inc 
4100 Horizons Dr., Suite 205 
Columbus, OH 43220 
Sponsor Contacts: Simon Blackburn 
Director, Clinical Development 
614-323-7034 
Joanna Shuping 
Director, Clinical Operations 
937-926-5252   
Medical Monitor: 
Michael Blue, MD 
Chief Medical Officer 
614-571-4313 
 
 
Date 
Original Protocol: 
11 November 2021 
Amendment #1: 
18 January 2022 
Amendment #2: 
01 November 2022 
Amendment #3 
29 September 2023 
Amendment #4 
30 January 2024 
 
 
Confidentiality Statement 
This document and its contents are the property of and confidential to Navidea 
Biopharmaceuticals. Any unauthorized copying or use of this document is prohibited. 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................19 
STUDY ADMINISTRATIVE STRUCTURE .........................................................................23 
1 
INTRODUCTION ...........................................................................................................24 
1.1 
Background ............................................................................................................24 
1.2 
Previous Nonclinical Research and Clinical Trial Experience With Tc 99m 
Tilmanocept ...........................................................................................................29 
1.2.1 
Nonclinical Evaluations – Subcutaneous Administration ............................29 
1.2.2 
Nonclinical Evaluations – IV Administration ..............................................29 
1.2.3 
Clinical Pharmacokinetics (IV) ....................................................................31 
1.2.4 
Clinical Efficacy ..........................................................................................32 
1.2.4.1 
NAV3-23 (SC) ...................................................................................32 
1.2.4.2 
NAV3-21 (IV) ....................................................................................33 
1.2.4.3 
NAV3-31 (IV) ....................................................................................33 
1.2.5 
Clinical Safety ..............................................................................................34 
1.2.5.1 
NAV3-23 (SC) ...................................................................................34 
1.2.5.2 
NAV3-21 (IV) ....................................................................................34 
1.2.5.3 
NAV3-31 (IV) ....................................................................................34 
2 
STUDY OBJECTIVES ....................................................................................................35 
2.1 
Primary Objectives .................................................................................................35 
2.2 
Key Secondary Objective ......................................................................................35 
2.3 
Secondary Objectives .............................................................................................35 
3 
INVESTIGATIONAL PLAN ..........................................................................................37 
3.1 
Overall Study Design and Plan ..............................................................................37 
3.2 
Protocol Adherence ................................................................................................38 
3.3 
Study Duration .......................................................................................................38 
4 
STUDY POPULATION ..................................................................................................39 
4.1 
Eligibility ...............................................................................................................39 
4.1.1 
Inclusion Criteria .........................................................................................39 
4.1.2 
Exclusion Criteria ........................................................................................40 
4.2 
Recruitment ............................................................................................................40 
4.3 
Withdrawal .............................................................................................................40 
4.4 
Replacement ...........................................................................................................41 
4.5 
Subject Identification .............................................................................................41 
5 
INVESTIGATIONAL PRODUCT ..................................................................................42 
5.1 
Identification of Investigational Product ...............................................................42 
5.2 
Investigational Product Dosage and Administration .............................................42 


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5.3 
Treatment Assignment ...........................................................................................43 
5.4 
Packaging and Labeling .........................................................................................43 
5.5 
Drug Logistics and Investigational Product Accountability ..................................43 
6 
THERAPIES OTHER THAN INVESTIGATIONAL PRODUCT .................................44 
6.1 
Prior and Concomitant Therapy .............................................................................44 
6.2 
Post-Study Therapy ................................................................................................44 
7 
STUDY PROCEDURES .................................................................................................45 
7.1 
Schedule of Evaluations .........................................................................................45 
7.2 
Visit Description ....................................................................................................45 
7.2.1 
Visit 1, Screening (Day -30 to Day -1) ........................................................45 
7.2.2 
Visit 2, Baseline (Day 0; Drug administration/Imaging) .............................46 
7.2.2.1 
Before Administration of Tc 99m Tilmanocept .................................46 
7.2.2.2 
Administration of Tc 99m Tilmanocept ............................................46 
7.2.2.3 
0 to 30 Minutes After Tc 99m Tilmanocept Administration .............46 
7.2.2.4 
60 to 75 Minutes After Tc 99m Tilmanocept Administration ...........47 
7.2.3 
Visit 3 (Day 5 ± 3; Follow-up Telephone Safety Assessment) ...................47 
7.2.4 
Visit 4 (Week 5 ± 1; Tc 99m Tilmanocept Administration, Imaging, and 
Clinical Assessments) ..................................................................................47 
7.2.4.1 
Before Tc 99m Tilmanocept Administration (0-7 days pre-
injection) ............................................................................................47 
7.2.4.2 
Before Tc 99m Tilmanocept Administration (day of injection) ........48 
7.2.4.3 
Tc 99m Tilmanocept Administration .................................................48 
7.2.4.4 
0 to 30 Minutes After Tc 99m Tilmanocept Administration .............48 
7.2.4.5 
60 to 75 Minutes After Tc 99m Tilmanocept Administration ...........48 
7.2.5 
Visit 5 (5 ± 3 Days After Visit 4; Follow-up Telephone Safety 
Assessment) .................................................................................................49 
7.2.6 
Visit 6 (Week 12 ± 1; Clinical Assessments) ..............................................49 
7.2.7 
Visit 8 (Week 24 ± 1; Clinical Assessments; note that Visit 7 will not be 
conducted per this amendment) ...................................................................49 
7.2.7.1 
Before Tc 99m Tilmanocept Administration (0-7 days pre-
injection) ............................................................................................49 
8 
PROCEDURES AND VARIABLES ..............................................................................50 
8.1 
Population Characteristics .....................................................................................50 
8.1.1 
Demographic and Other Baseline Characteristics .......................................50 
8.1.2 
Medical and Surgical History ......................................................................50 
8.2 
Tc 99m Tilmanocept Administration .....................................................................50 
8.3 
Rheumatological Assessments ...............................................................................50 
8.3.1 
2010 ACR/EULAR Classification Criteria ..................................................50 
8.3.2 
DAS28 Evaluation .......................................................................................50 
8.3.3 
CDAI ............................................................................................................51 


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8.3.4 
ACR Response Criteria ................................................................................51 
8.3.5 
Other ............................................................................................................52 
8.3.5.1 
28-joint Count (SJC and TJC)............................................................52 
8.3.5.2 
Patient Assessment of Pain (VAS) ....................................................52 
8.3.5.3 
Patient Assessment of Physical Function (HAQ-DI©).......................52 
8.3.5.4 
Acute-phase Reactant .........................................................................53 
8.3.5.5 
Widespread Pain Index ......................................................................53 
8.4 
Image Acquisition ..................................................................................................53 
8.4.1 
Planar Scintigraphy ......................................................................................53 
8.4.2 
Tilmanocept Uptake Value (TUV) ..............................................................53 
8.5 
Adverse Events ......................................................................................................53 
8.5.1 
Definition of Adverse Event ........................................................................53 
8.5.2 
Categories for Adverse Event Assessment ..................................................54 
8.5.3 
Assessments and Documentation of Adverse Events ..................................55 
8.5.4 
Expected Adverse Events ............................................................................56 
8.5.5 
Serious Adverse Events ...............................................................................57 
8.6 
Physical Examination.............................................................................................58 
8.7 
Vital Signs ..............................................................................................................59 
8.8 
Clinical Laboratory Parameters for Screening and Safety .....................................59 
9 
STATISTICAL METHODS ............................................................................................61 
9.1 
Randomization Methods ........................................................................................61 
9.2 
Safety Variables .....................................................................................................61 
9.3 
Efficacy Variables ..................................................................................................61 
9.3.1 
Primary Efficacy Variables ..........................................................................61 
9.3.2 
Key Secondary Efficacy Variable ................................................................61 
9.3.3 
Secondary Efficacy Variables ......................................................................61 
9.4 
Sample Size Justification .......................................................................................63 
9.5 
Statistical Analyses ................................................................................................65 
9.5.1 
Analysis Populations ....................................................................................65 
9.5.2 
Analysis of Baseline and Demographic Characteristics ..............................65 
9.5.3 
Analysis of Efficacy Variables ....................................................................66 
9.5.3.1 
Analysis of Primary Efficacy Variables ............................................66 
9.5.3.2 
Analysis of Key Secondary Efficacy Variables .................................67 
9.5.3.3 
Analysis of Secondary Efficacy Variables ........................................67 
9.5.4 
Analysis of Safety Variables ........................................................................68 
9.5.5 
Handling of Missing Values ........................................................................68 
9.5.6 
Interim Analyses ..........................................................................................68 
10 DATA HANDLING AND QUALITY ASSURANCE ...................................................69 
10.1 
Data Recording ......................................................................................................69 


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10.1.1 
CRF Design ..................................................................................................69 
10.2 
Monitoring .............................................................................................................69 
10.3 
Data Processing ......................................................................................................69 
10.4 
Auditing .................................................................................................................69 
10.5 
Archiving ...............................................................................................................70 
10.6 
Premature Termination of the Study ......................................................................70 
10.6.1 
Termination by the Sponsor .........................................................................70 
10.6.2 
Termination by the Investigator ...................................................................70 
10.6.3 
Study as a Whole .........................................................................................71 
10.6.4 
Center ...........................................................................................................71 
10.6.5 
Study Participant ..........................................................................................71 
11 ETHICAL AND LEGAL ASPECTS ...............................................................................72 
11.1 
Ethical and Legal Conduct of the Study ................................................................72 
11.2 
Subject Information and Consent...........................................................................72 
11.3 
Financing/Financial Disclosure .............................................................................73 
11.4 
Publication Policy ..................................................................................................73 
11.5 
Subject Injury .........................................................................................................73 
12 REFERENCE LIST .........................................................................................................74 
 


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LIST OF IN-TEXT TABLES 
Table 1 
Preclinical Tests .........................................................................................30 
Table 2 
Whole Blood PK Parameter Summaries by Group....................................31 
Table 3 
Urine PK Parameter Summaries by Group ................................................32 
Table 4 
Clinical Laboratory Parameters .................................................................59 
Table 5 
Approximate Amount of Blood Drawn per Subject ..................................60 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Tc 99m tilmanocept and the Mannose Receptor........................................42 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .....................................................................................78 
Appendix 2 
2010 ACR/ EULAR Classification Criteria ...............................................80 
Appendix 3 
DAS28 Scale ..............................................................................................82 
Appendix 4 
CDAI Scoring ............................................................................................83 
Appendix 5 
ACR Response Criteria ..............................................................................84 
Appendix 6 
HAQ-DI© Questionnaire ...........................................................................85 
Appendix 7 
Sponsor Signatures.....................................................................................88 
Appendix 8 
Investigator’s Signature .............................................................................89 
 


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SYNOPSIS 
Study title 
Evaluation of Tc 99m Tilmanocept Imaging for the Early 
Prediction of Anti-TNFα Therapy Response in Subjects with 
Active Moderate to Severe Rheumatoid Arthritis (RA) 
Study phase 
Phase 3 
Study objective(s) 
Primary  
• To demonstrate that global tilmanocept uptake values 
(TUVglobal) obtained before initiation of anti-TNFα 
therapy (TUVglobal[b]) and at 5 weeks ± 1 week following 
change in therapy (TUVglobal[5w]) has a specificity of 
greater than 80% to correctly specify a clinical non-
response to therapy at 24 weeks. 
• To demonstrate that TUVglobal obtained before initiation 
of anti-TNFα therapy and at 5 weeks ± 1 week following 
change in therapy has a sensitivity of greater than 65% to 
correctly classify a positive clinical response to therapy at 
24 weeks. 
 
Key Secondary 
• To evaluate the negative predictive value (NPV) of 
TUVglobal obtained before initiation of anti-TNFα therapy 
(TUVglobal[b]) relative to a clinical non-response to therapy 
at 24 weeks. 
 
Secondary  
• To evaluate the sensitivity and specificity of TUVglobal 
obtained before initiation of anti-TNFa therapy and at 
5 weeks ± 1 week following change in therapy relative to 
a positive clinical response or a non-response to therapy 
at 12 weeks. 
• To evaluate the NPV of TUVglobal[b] relative to a clinical 
non-response to therapy at 12 weeks. 
• To evaluate the positive predictive value (PPV), negative 
predictive value (NPV), and overall accuracy (OA) of 
TUVglobal obtained before initiation of anti-TNFα therapy 
and at 5 weeks ± 1 week (ΔTUVglobal[5w]) following 
change in therapy relative to a positive clinical response 
or a non-response to therapy at 12 and/or 24 weeks. 


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• To evaluate the qualitative assessment of Tc 99m 
tilmanocept imaging to predict clinical response or non-
response following a change in anti-TNFα therapy. 
• To evaluate the additive effect of either quantitative or 
qualitative assessment of Tc 99m tilmanocept imaging to 
the other at baseline and change from baseline to 
5 weeks ± 1 week to predict clinical response or non-
response following a change in anti-TNFα therapy. 
• To evaluate the correlation of changes in TUVglobal 
obtained before initiation of anti-TNFα therapy and at 
5 weeks ± 1 week following a change in therapy with 
changes in composite clinical assessments and their 
constituent parameters at 12 and/or 24 weeks. 
• To evaluate the correlation of changes in TUVglobal 
obtained before initiation of anti-TNFα therapy and at 
5 weeks ± 1 week following a change in therapy with 
changes in clinical assessments at 12 and/or 24 weeks for 
specific anti-TNFα bDMARD agents.  
• To evaluate the correlation of changes with TUVglobal and 
changes in clinical RA assessments as a means to monitor 
therapy. 
• To evaluate sensitivity and specificity in patient 
subgroups. 
• To evaluate the safety of IV-administered tilmanocept 
radiolabeled with Tc 99m. 
Duration of treatment 
24 ± 1 weeks; Tc 99m tilmanocept will be administered at 
baseline and at Week 5. Tilmanocept will also be administered 
to a subset of subjects at weeks 12 and 24 (those enrolled and 
completing Weeks 12 and 24 prior to activation of 
Amendment 4). 
Study drug 
Technetium Tc 99m tilmanocept 
Dose(s) and Route of 
administration 
Dose: Tilmanocept will be administered at a mass dose of 
150 mcg radiolabeled with 10 mCi Tc 99m. 
Route of Administration: Tc 99m tilmanocept will be 
administered through an intravenous (IV) route of 
administration using a single syringe injected as a slow IV 
push. 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. 


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Inclusion criteria 
1. The subject has provided written informed consent with 
HIPAA 
(Health 
Information 
Portability 
and 
Accountability Act) authorization before the initiation of 
any study-related procedures. 
2. The subject is at least 18 years of age and was ≥ 18 years 
of age at the time of RA diagnosis. 
3. The subject is a candidate for initiation of, or change to, a 
new anti-TNFα bDMARD therapy. 
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).  
5. The subject has moderate to severe RA as determined by a 
28-joint disease activity score (DAS28) of ≥ 3.2 (includes 
the Erythrocyte Sedimentation Rate [ESR] test and Visual 
Analog Scale [VAS]). 
6. Subjects receiving traditional DMARDs must have been 
on therapy for ≥ 90 days and at a stable dose for ≥ 30 days 
prior to the first imaging visit (Day 0). 
7. Subjects receiving bDMARD or janus kinase (JAK) 
inhibitor therapy must have been at a stable dose > 60 days 
prior to the first imaging visit (Day 0). 
8. If the subject is receiving NSAIDS (nonsteroidal anti-
inflammatory drug) or oral corticosteroids, the dose must 
have been stable for > 28 days prior to the first imaging 
visit (Day 0). The corticosteroid dose must be ≤ 10 mg/day 
of prednisone or an equivalent steroid dose. 
Exclusion criteria 
1. The subject is pregnant or lactating. 
2. The subject size or weight is not compatible with imaging 
per the investigator 
3. The subject is currently receiving radiation therapy or 
chemotherapy or has received radiation 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 


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aminotransferase [SGOT]) greater than 2 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 history of hypersensitivity reactions to 
TNF-inhibitors. 
10. The subject has a known allergy to or has had an adverse 
reaction to dextran exposure. 
11. The subject has received an investigational product within 
30 days prior to the Tc 99m tilmanocept administration at 
the first imaging visit (Day 0). 
12. The subject has received intra-articular corticosteroid 
injections ≤ 8 weeks prior to the first imaging visit (Day 0). 
13. The subject has received any radiopharmaceutical within 
7 days or 10 half-lives prior to the administration of 
Tc 99m tilmanocept at the first imaging visit (Day 0). 
14. 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 prospective, open-label, multicenter study designed 
to evaluate the early predictive capacity of Tc 99m 
tilmanocept planar imaging for downstream clinical 
response(s) in individuals with moderate to severe RA who are 
candidates for change in anti-TNFα therapy. Temporal 
(Baseline to 5-week) differences in quantitative imaging will 
be correlated with longitudinal (Baseline to 12- and 24-week) 
assessments of clinical RA outcomes to evaluate the clinical 
utility of Tc 99m tilmanocept for the expedited evaluation of 
antirheumatic treatment efficacy when compared with 
longitudinal assessments in clinical practice.   
Prior to the initiation of a new anti-TNFα therapy, subjects will 
undergo 
baseline 
rheumatological 
evaluations 
of 
ACR/EULAR 2010 Classification Criteria, Clinical Disease 
Activity Index (CDAI), DAS28, and Health Assessment 
Questionnaire 
Disability 
Index 
(HAQ-DI©) 
for 
the 
characterization of disease activity. Following these 
evaluations, subjects will receive an IV dose of 150 mcg 


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tilmanocept radiolabeled with 10 mCi of Tc 99m and undergo 
baseline planar imaging of the bilateral hands and wrists 
beginning 60-75 minutes following Tc 99m tilmanocept 
administration. Upon completion of baseline imaging 
procedures, subjects will commence a new anti-TNFα 
bDMARD treatment regimen and return to the clinic 5 ± 1 
weeks later for a series of rheumatological evaluations 
(including CDAI, DAS28, ACR Response Criteria, and 
HAQ-DI©), drug administration, and bilateral hand/wrist 
imaging. The rheumatological evaluations will be repeated at 
12 ± 1 weeks and 24 ± 1 weeks after commencement of the 
new therapy. 
Images will undergo centralized quantification for the 
derivation of joint-specific and global tilmanocept uptake 
values (TUV). At the joint level, TUVjoint is defined as the 
intra-patient ratio of the average pixel intensity of a joint to the 
average pixel intensity of the reference region. TUVglobal is a 
per patient summary of TUVjoint values greater than the upper 
limit of the 95% prediction interval of the joint-and-view-
specific TUV in the normative database representing 
RA-specific inflammation. TUV calculations are additionally 
described in the Statistical Analysis Plan.  
All images will be read by three nuclear medicine specialists 
trained in the reading of these images. Each reader will work 
independently of the other readers and will be blinded to 
clinical assessments. Each reader will provide both a 
qualitative read and map regions of interest for calculation of 
TUVs. 
Temporal differences in TUVglobal from baseline to 5 ± 1 
weeks of therapy (ΔTUVglobal[5w]) will be compared with 
longitudinal clinical outcomes at 12 ± 1 and 24 ± 1 weeks of 
therapy defined by changes in CDAI (ΔCDAI12/24w), changes 
in DAS28 (ΔDAS28[12/24w]), and assessment of ACR Response 
Criteria (ACR12/24w) to evaluate the efficacy of TUVglobal for 
the accelerated prediction of clinical response to antirheumatic 
drugs. 
Planned study dates 
Start of study 
recruitment/February 
2022 
End of Recruitment/October 
2024 
End of Study/May 2025 
Planned number of 
study centers 
Up to 50 centers in the United States  


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Number of subjects 
198 to 672 evaluable subjects may be enrolled. Details of 
sample size calculations are further described in Statistical 
Methods below. 
Efficacy Assessments 
Primary endpoints: 
• Specificity of ΔTUVglobal[5w] bucketing with respect to 
ACR50 at week 24.  
• Sensitivity of ΔTUVglobal[5w] bucketing with respect to 
ACR50 at week 24. 
Key secondary endpoint: 
• NPV of TUVglobal[b] with respect to ACR50 at week 24. 
Secondary endpoints: 
• Sensitivity and specificity of ΔTUVglobal[5w] bucketing with 
respect to ACR50 at week 12. 
• NPV, PPV, and OA of ΔTUVglobal[5w] bucketing with 
respect to ACR50 at weeks 12 and 24.  
• NPV of TUVglobal[b] with respect to ACR50 at week 12  
• TUVglobal[b] and response to new anti-TNFα bDMARD 
therapy defined by the change from baseline (CFB) of 
CDAI to 12 ± 1 weeks and 24 ± 1 weeks (∆CDAI12w and 
∆CDAI24w, respectively), by the CFB of DAS28 to 12 ± 1 
weeks and 24 ± 1 weeks (∆DAS2812w and ∆DAS2824w, 
respectively) and by the CFB in each of the ACR Response 
Criteria components at 12 ± 1 weeks and at 24 ± 1 weeks. 
• ΔTUVglobal[5w] and response to new anti-TNFα bDMARD 
therapy defined by the CFB of CDAI to 12 ± 1 weeks and 
24 ± 1 weeks (ΔCDAI12w and ΔCDAI24w, respectively). 
• Concordance of ΔTUVglobal[5w] bucketing with clinical 
criteria, including ACR Response Criteria, CDAI, DAS28, 
and HAQ-DI©. Concordance between the predicted 
response or non-response status and the clinical criteria 
will be evaluated using NPV, PPV, sensitivity, specificity, 
and overall accuracy.   
• Concordance of ΔTUVglobal[12w] bucketing with clinical 
criteria, including ACR Response Criteria, CDAI, DAS28, 
and HAQ-DI©. Concordance between the improvement 
classifications and the clinical criteria will be evaluated 
using NPV, PPV, sensitivity, specificity, and overall 
accuracy. 


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• Response to new anti-TNFα bDMARD therapy defined by 
the CFB of CDAI to 12 ± 1 weeks and 24 ± 1 weeks 
(ΔCDAI12w and ΔCDAI24w, respectively). 
• The correlation of ΔTUVglobal[5w] and response to new anti-
TNFα bDMARD therapy from baseline to 24 ± 1 weeks 
defined by the changes from baseline in each of the ACR 
Response Criteria components.  
• Constituent parameters of CDAI12w, CDAI24w, ΔCDAI12w, 
ΔCDAI24w, ACR Response Criteria at 12 and 24 weeks, 
including:  
• Tender joint count (TJC)  
• Swollen joint count (SJC)  
• Patient assessment of global disease activity  
• Rheumatologist assessment of global disease activity  
• Patient assessment of pain  
• Patient assessment of physical function  
• Acute-phase reactant value 
Safety Assessments 
Incidence of AEs and assessment of changes over time in 
clinical laboratory tests (hematology, serum chemistry, 
urinalysis, and RA panel), ECG parameters, and vital signs. 
Statistical Methods  
Sample size 
NAV3-33 is sized with respect to achieving specified goals in 
the co-primary endpoints of sensitivity and specificity of 
ΔTUVglobal[5w] bucketing. Sensitivity and specificity require 
knowledge of the patient’s clinical status at Week 24, and so 
hypothesis testing will be performed after classification. The 
value of ΔTUVglobal[5w] necessary to predict response vs. non-
response and the value of TUVglobal[b] at baseline necessary to 
predict non-response will be determined in advance. The 
classification procedure occurs in two stages, following the 
baseline image acquisition and (possibly) following the 
5-week image acquisition and calculation of ΔTUVglobal[5w]. 
After the baseline imaging, patients whose TUVglobal[b] is < 5 
are predicted to be non-responders. After ΔTUVglobal[5w] is 
available, patients whose TUVglobal[b] is ≥ 5 and D% is ≤ -10% 
are predicted to be responders. All other patients are predicted 
to be non-responders. The Week-24 ACR50 will be used as 
the primary determination of clinical response for the 
reference standard. 


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The hypotheses for the co-primary endpoints to be tested are: 
𝐻𝐻𝑂𝑂1: 𝜋𝜋Sp ≤0.8
𝐻𝐻𝐴𝐴1: 𝜋𝜋Sp > 0.8; 
 
And 
𝐻𝐻𝑂𝑂2: 𝜋𝜋Se ≤0.65
𝐻𝐻𝐴𝐴2: 𝜋𝜋Se > 0.65. 
 
In the above πSp represents the true specificity of the 
classification procedure and πSe represents the true sensitivity 
of the classification procedure when used to predict the 
outcome of the anti-TNFα bDMARD inhibitor therapy at 24 
weeks. An overall two-tailed Type I error rate of 0.05 (one-
tailed 0.025) was used without adjusting for multiple 
endpoints, as both co-primary endpoints must be achieved 
(i.e., at least the same two of three readers reject both null 
hypotheses) in order to have a successful study. If the actual 
specificity is 0.92 and the actual sensitivity is 0.8, and if an 
exact binomial test is used to test the above hypotheses, a total 
of 98 clinical non-responders and 100 clinical responders are 
needed for 90% power of the individual tests. That is, a 
minimum of 198 total patients is needed. This applies to a 
single reader.  
To evaluate the power characteristics of this process with 
3 correlated readers where at least the same two of the three 
readers must reject both null hypotheses above, a simulation 
study was performed. Correlated binomial random variables 
were generated using a copula. The hypotheses were tested for 
each simulated reader using an exact binomial test, and the 
number of iterations where at least the same two of the three 
readers rejected both hypotheses was counted. Under the 
conditions above this procedure has power 0.93 when ρ = 0.7 
and 0.89 when ρ = 0.9. 
In Arm 3 of the NAV3-31 study a ratio of 5 non-responders to 
1 responder was observed. If this ratio is maintained in 
NAV3-33 for the ΔTUVglobal[5w] bucketing predictions, a total 
of 600 patients is needed to achieve the desired power. That is, 
a total of 500 clinical non-responder patients is expected to be 
enrolled before reaching the required 100 clinical responders.  
Taking into account a 10% dropout rate, the anticipated total 
sample size for the study is approximately 672 patients (560 
clinical non-responders and 112 clinical responders).  That is:  


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• Clinical Non-Responders: 90% completion rate 
relative to 560 enrolled patients will result in 500 
completed patients   
• Clinical Responders: 90% completion rate relative 
to 112 enrolled patients will result in 100 
completed patients    
Because there is uncertainty about how responding and non-
responding patients will enroll, enrollment will continue until 
at least 560 clinical non-responders and 112 clinical 
responders are participating in the study. The cumulative 
enrollment of clinical non-responders and responders will be 
tracked throughout the study in order to stop enrollment once 
the required number has been reached for each clinical 
category. This tracking of clinical response and non-response 
status will be performed by individuals without knowledge of 
the TUV data.  
If the two co-primary endpoints are achieved (i.e., both null 
hypotheses are rejected for at least the same 2 out of 3 readers), 
then the following hypotheses will be tested at one-tailed 
0.025 for the key secondary endpoint of NPV of TUVglobal[b] 
with respect to ACR50 at week 24: 
 
𝐻𝐻𝑂𝑂3: 𝜋𝜋NPV ≤0.7
𝐻𝐻𝐴𝐴3: 𝜋𝜋NPV > 0.7; 
 
If the actual NPV is 0.85, and if an exact binomial test is used 
to test the above hypotheses, a total of 89 predicted non-
responders using TUVglobal[b] are needed for 90% power and a 
total of 71 non-responders using TUVglobal[b] are needed for 
80% power. 
Analysis of Primary Efficacy Variables  
The co-primary efficacy variables will be summarized by 
reader in a 2 by 2 contingency table displaying the cell 
frequencies and marginal totals at 24 weeks. The specificity of 
ΔTUVglobal[5w] bucketing and the sensitivity of ΔTUVglobal[5w] 
bucketing will be calculated for each reader. The 95% exact 
(Clopper-Pearson) confidence intervals will be provided for 
each of these parameters. Observed significance levels 
(p-values) for the exact binomial tests of specificity of 
ΔTUVglobal[5w] bucketing greater than 0.8 and sensitivity of 
ΔTUVglobal[5w] bucketing greater than 0.65 will be provided. 
Sensitivity and specificity are defined according to the 
following cross-tabulation: 


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Clinical Response 
 
Predicted 
Response 
Responder 
Non-
Responder 
Total 
Responder 
A 
B 
T1 
Non-Responder 
C 
D 
T2 
Total 
T3 
T4 
N 
 
Sensitivity = A/T3. 
Specificity = D/T4. 
The above 2 by 2 contingency table will also be used to 
calculate the secondary efficacy endpoints of NPV, PPV, and 
overall accuracy (OA) as follows: 
NPV = D/T2. 
PPV = A/T1. 
Overall Accuracy = (A + D)/N. 
 
Analysis of Key Secondary Efficacy Variables  
NPV of TUVglobal[b] will be calculated for each reader. The 
95% exact (Clopper-Pearson) confidence intervals will be 
provided. Observed significance levels (p-values) for the exact 
binomial tests of NPV of TUVglobal[b] greater than 0.7 will be 
provided. 
 
Analysis of Secondary Efficacy Variables  
All RA quantitative assessment variables (CDAI, ACR 
Response Criteria component scores, DAS28 score, and HAQ-
DI©) will be summarized by computing the mean, standard 
deviation, number of observations, minimum, median, and 
maximum for the observed values at each time point and for 
the change from baseline for values collected after Day 0. The 
ACR Response Criteria will be summarized with a frequency 
table of the highest ACR Response level (None, ACR20, 
ACR50, ACR70) attained by that patient at that time point. 
That is, a patient who satisfies ACR50 also satisfies ACR20 
but will not appear in the frequency count for ACR20. 
Concordance of improvement classification for  ΔTUVglobal[5w] 
bucketing with clinical criteria (ACR Response, CDAI, 
DAS28, and HAQ-DI©) will be analyzed as follows.  Note that 
the concordance of ΔTUVglobal[5w] bucketing with ACR50 is 


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evaluated as co-primaries (sensitivity and specificity).  For 
each of the RA improvement criteria, a cross-classification 
table will be provided. The PPV, NPV, sensitivity, specificity, 
NPV, PPV, and OA will be calculated, and 95% exact 
(Clopper-Pearson) confidence intervals will be provided. 
The Kendall rank correlation between ΔTUVglobal[5w] with 
ΔCDAI12w and ΔCDAI24w will be computed and a 95% 
confidence interval for its value will be computed using 
Fisher’s Z-transformation. Similarly, the Kendall rank 
correlation between ΔTUVglobal[5w] with changes from baseline 
in DAS28 and in each of the ACR Response Criteria 
components at weeks 12 and 24 will be computed and a 95% 
confidence interval for its value will be computed using 
Fisher’s Z-transformation. The marginal distributions of the 
variables will be characterized with the mean, standard 
deviation, and the number of data pairs. 
Additional efficacy analyses may be described in the study 
Statistical Analysis Plan (SAP). 
 
Analysis of Safety 
All safety analyses will be performed on the Safety 
Population. 
The safety analysis variables are defined as follows: 
• Adverse Events (AEs) 
• Clinical 
Laboratory 
Tests 
(hematology, 
serum 
chemistry, urinalysis, RA panel) 
• ECG Parameters 
• Vital Signs 
 
Adverse Events  
Adverse events will be observed for each patient from signing 
of informed consent until termination from the study. AEs will 
be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA®). A treatment-emergent AE (TEAE) is 
defined as an AE whose start date is on or after the initial 
procedure date. Based on the coded terms, frequencies of each 
TEAE will be summarized by MedDRA® preferred term 
within system organ class (SOC), by severity grade, and by 
relationship to Tc 99m tilmanocept. 
A summary of TEAEs will be constructed showing the 
following: 


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• Number of patients with at least one TEAE 
• TEAEs by severity grade 
• TEAE by relationship to Tc 99m tilmanocept 
• TEAEs by relationship of TEAE to study procedure 
• Number of patients with at least one treatment 
emergent serious adverse event (TESAE) 
 
TESAEs will be tabulated by MedDRA® preferred term within 
SOC. 
A by-patient AE data listing of all AEs including verbatim 
term, coded term, grade, and relation to study drug will be 
provided.   
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. 
Additional safety analyses may be described in the study 
Statistical Analysis Plan (SAP). 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACR/EULAR 
American College of Rheumatology/ European League Against 
Rheumatism 
ACPA 
anti-citrullinated peptide antibody (which may also appear as cyclic 
citrullinated peptide (CCP) 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the concentration-time curve 
AUC0-t 
AUC from hour 0 to last measurable concentration 
AUC0-∞ 
AUC extrapolated to infinity 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Cmax 
maximum observed concentration 
CD206 
Mannose-binding receptor (Ca2+-binding lectin) 
 
CO2 
carbon dioxide 
CRF 
case report form 
CRA 
clinical research associate 
CRO 
contract research organization 
CRP 
C-reactive protein 
CT 
X-ray computed tomography 
Cy3 
Cy3 cyanine dyes fluoresce orange (~550 nm excitation, ~570 nm 
emission) 


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DAS28 
disease activity score used with the ACR/EULAR 2010 RA guidelines 
DICOM 
Digital Imaging Communications in Medicine 
DMARD(s) 
disease-modifying antirheumatic drug(s)  
DTPA 
diethylene triamine pentaacetic acid  
ECG 
electrocardiogram 
eCRFs 
electronic case report forms 
ESR 
erythrocyte sedimentation rate 
EU 
European Union 
FDA 
Food and Drug Administration 
FNR 
false negative rate 
GCP 
Good Clinical Practice 
HC 
healthy controls  
HCT 
hematocrit 
Hgb 
hemoglobin 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonization  
ILM 
intraoperative lymphatic mapping 
IRB 
Institutional Review Board 
ISF 
investigator site file 
ITD 
intent-to-diagnose population 
IV 
intravenous 
kDa 
kiloDalton (molecular weight designation) 
mCi 
milliCurie (37x106 becquerels; 37megabecquerels) 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MTD 
maximum tolerated dose 
NOAEL 
no-observed adverse-effect level 
NSAIDS 
nonsteroidal anti-inflammatory drug 
OA 
overall accuracy 
OLINDA/EXM® Organ Level INternal Dose Assessment/EXponential Modeling 
PI 
principal investigator 
PK 
pharmacokinetics  
PP 
per protocol 
RA 
rheumatoid arthritis 
RBC 
red blood cells 
RF 
rheumatoid factor 
RPK 
radiopharmacokinetic  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
study day 
SJC 
swollen joint count 
SPECT 
single photon emission computed tomography 
SUSARs 
suspected, unexpected, serious adverse reactions 
t1/2 
apparent terminal elimination half life 
Tc 99m 
technetium-99m metastable isotope; γ-emitting (t½ = 6.02 h) 
TcSC 
Tc 99m sulfur colloid 
Tilmanocept 
DTPA Mannosyl Dextran (the US Adopted Name for the drug 
substance of Lymphoseek) 
TJC 
tender joint count 
TMF 
trial master file 
TNFα 
tumor necrosis factor alpha 
TUV 
tilmanocept uptake value 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 


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WBC  
white blood cell 
λz 
apparent terminal elimination rate constant 


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STUDY ADMINISTRATIVE STRUCTURE 
The principal investigator (PI) must sign and date the protocol signature sheet before study 
participant recruitment may start.  Likewise, all protocol amendments must be signed and dated 
by the PI before coming into effect. 
The name and address of the participating center, the investigators, and all required signature 
documents will be maintained in the trial master file (TMF). 
In addition to the PI, there are additional onsite roles that may be performed by other sub-
investigators:   
• Subject referral to the study 
• Review of subject eligibility and medical records  
• Clinical evaluations 
• Safety assessments 
• Injection and imaging  
• On-site image analysis 
 
Study personnel not listed in this section are identified in a separate personnel list.  This list 
will be updated as needed.  The list of personnel will be available in the center’s investigator 
site file (ISF). 


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1 
INTRODUCTION 
1.1 
Background 
Worldwide, approximately 1 in 200 adults suffer from RA. In the US, 1.3 million adults are 
living with RA. Each year, about 130,000 Americans are newly diagnosed with RA. Persons 
with inadequately controlled RA have significantly shorter life expectancies and frequently 
become disabled, leading to reduced quality of life and severe adverse economic consequences 
(Lassere 2013, Michelsen 2018, Uhlig 2014, Verstappen 2015). 
It has been realized for many years that RA patients who are placed on DMARDs soon after 
they develop arthritis symptoms respond much more favorably to these therapies than do 
patients whose initiation of DMARD therapy is delayed (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 has a 73% 
sensitivity and a 74% specificity for correctly identifying early RA. If the ACR/EULAR 2010 
criteria are used to decide who should receive DMARD therapy, this meta-analysis indicates 
that over a quarter of true early RA patients would not be provided with appropriate DMARD 
therapy during the critical window of opportunity for an optimal response. Furthermore, a 
significant portion of arthritis patients who do not have RA would be prescribed DMARD 
therapies for which they would not receive benefit and would be exposed to possible adverse 
side effects of the drugs. Clearly there remains an unmet need for a more accurate means to 
identify early RA patients, to improve aggregate outcomes for early RA patients, and to reduce 
adverse drug effects and healthcare costs associated with unproductive delivery of RA 
therapies to individuals who do not have RA.  
Basic research on the pathobiology of RA has revealed that the inflammation observed in RA 
is the consequence of a self-perpetuating pathological alteration in the expression and 
downstream signaling of a network of cytokines (Meyer 2010, Olszewski 2001). Frequently, 


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at the center of this cytokine network is the overexpression of tumor necrosis factor alpha 
(TNFα) (Choy 2001, Keffer 1991, Leizer 1990, 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 (Chen 2006, Kalden 2002, 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 
(Firestein 1990, Ishikawa 1976, 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, Kennedy 2011, Kraan 2002). 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 (Mulherin 1996, Orr 2017, 
Vieira-Sousa 2011, Yanni 1994). Not surprisingly, activated synovial macrophage numbers—
but not the numbers of other immune cell types—correlate with radiographically determined 
joint destruction in RA (Mulherin 1996, Yanni 1994). Thus, CD206 positivity of inflamed 
synovia in RA patients is expected to provide clinically significant prognostic information for 
RA patients. Another important finding is that activated macrophage numbers are reduced by 
effective RA therapy (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, 


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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 
(Bresnihan 2009, Smith 2001).  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 (Bresnihan 2009, van de Sande 2012, 
Wijbrandts 2007). Therefore, there is a possibility that future clinical studies may show that 
quantitative assessment of CD206 positivity of inflamed synovia in RA patients could be used 
to monitor the efficacy of RA therapies, providing physicians and patients with earlier and 
more objective criteria to abandon ineffective therapies and adopt alternative therapies that 
may be more effective.  
In recent years, synovial biopsy-enabled studies have greatly increased our understanding of 
the pathological processes occurring within the inflamed joints of RA patients (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 (Astorri 2015, Dennis 2014). Myeloid pathotype variants 
have the highest density of macrophages, whereas the fibroid pathotype is largely devoid of 
both macrophages and lymphoid cells. These pathotypes are not fully discreet with some 
overlap occurring. However, they provide a strong basis for temporal or cytological 
compartmentalization in RA disease natural history.  
Current studies utilizing IHC analyses of synovial biopsies are insufficient to determine the 
distribution of the various pathotypes in RA patients but suggest that the diffuse myeloid and 
lympho-myeloid pathotypes are about equally frequent in RA patients with the fibroid 
pathotype being less common. There is growing evidence that patients with different RA 
pathotypes respond differently to various therapies, holding out the possibility that determining 
the RA pathotype of an individual patient’s RA can direct choice of the most effective therapy 
for that patient (i.e., personalized RA therapy) (Dennis 2014). This is an area of ongoing active 
investigation in RA therapy research (Donlin 2018, Mandelin 2018, Pitzalis 2013). However, 
already there is significant evidence indicating that patients with a myeloid-driven RA 
pathotype and/or with high densities of macrophages in their inflamed synovium respond best 
to anti-TNFα biologic therapy (Dennis 2014, Wijbrandts 2008), 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-


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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.  
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 
membrane may not yet have expanded (i.e. thickened) sufficiently to permit biopsy sampling. 
As discussed below, there is an urgent need to more accurately identify RA patients as early in 
the disease process as possible and place them on DMARD therapy immediately to provide 
these patients with their best possible therapy responses.  
The third reason why Tc 99m tilmanocept imaging may be preferred to synovial biopsies for 
evaluations of RA patients is that, although synovial biopsy procedures typically extract 6 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 1 biopsy procedure can be performed on an 
individual joint, there are likely to be limitations on the number of times or how often a single 
joint can be biopsied. Furthermore, while not discussed in the literature, repeated biopsies may 


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alter the inflammatory microenvironment in an inflamed synovial membrane and/or induce its 
own inflammation or wound healing response to trauma. In any event, Tc 99m tilmanocept 
imaging, being non-invasive and non-traumatic, is likely to be more amenable to repeat 
examination and would not affect synovial inflammation through repeated biopsy related 
trauma. These issues may be most significant when considering evaluations of the small joints 
of the hands where there is a limited quantity of inflammatory tissue.  
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.  
Indeed, Tc 99m tilmanocept quantitative imaging reliably assesses all joints, is not dependent 
on synovial swelling, is non-invasive and non-traumatic, and does not require extensive 
practitioner training. Thus, for all these reasons, Tc 99m tilmanocept imaging is expected to 
provide clinically predictive information about the inflammatory status of inflamed joints in 
RA patients that is not obtainable from synovial biopsies or will be preferred over invasive and 
potentially risky synovial biopsies as a means to evaluate RA patients. 
In diagnostic radiology, quantitative imaging provides a layer of clinically meaningful 
information beyond that of qualitative interrogation. The Radiological Society of North 
America (RSNA) defines quantitative imaging as “the extraction of quantifiable features from 
medical images for the assessment of normal or the severity, degree of change, or status of a 
disease, injury, or chronic condition relative to normal. Quantitative imaging includes the 
development, standardization, and optimization of anatomical, functional, and molecular 
imaging acquisition protocols, data analyses, display methods, and reporting structures. These 
features permit the validation of accurately and precisely obtained image-derived metrics with 
anatomically and physiologically relevant parameters, including treatment response and 
outcome, and the use of such metrics in research and patient care.” (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 SUV = 
r
(a′/w). (Kinahan 2010)   
Based on the clinical utility of SUV in 18F-FDG PET imaging, Navidea pursued the 
development of the TUV to quantify CD206 activity on planar gamma camera imaging. TUV 
considers the fundamental principles of SUV and introduces modifications to account for inter- 
and intra-patient variability and disease pathobiology. After the evaluation of several formula 


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Clinical Study Protocol: NAV3-33 
 
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permutations, Navidea has established TUV as a metric for the measurement of joint-specific 
CD206 activity in RA through the quantification of Tc 99m tilmanocept uptake using the 
following parameters: 𝑥𝑥̅, the average pixel intensity of an ROI, and B, the average pixel 
intensity of the whole hand and part of the forearm on the same view and side as the joint ROI 
(serving as an intra-patient reference region), such that TUV =
xത
B. The overall purpose of this 
study will be to establish the mean and variance of healthy control joint uptake values for 
reference to be used to assess RA-inflamed joints in patients with RA. 
1.2 
Previous Nonclinical Research and Clinical Trial Experience With 
Tc 99m Tilmanocept  
A detailed evaluation of the nonclinical evaluations from subcutaneous (SC) and IV routes of 
administration, clinical pharmacokinetics (PK), clinical efficacy, and clinical safety of Tc 99m 
tilmanocept can be found in the accompanying Investigator’s Brochure supplied by Navidea 
Biopharmaceuticals, Inc.   
1.2.1 
Nonclinical Evaluations – Subcutaneous Administration 
Nonclinical studies of Tc 99m tilmanocept demonstrated that the drug selectively binds to its 
intended receptor (the CD206 mannose binding receptor), and is well tolerated by rats, rabbits, 
guinea pigs, and dogs. 
PK data obtained from nonclinical studies demonstrated rapid absorption into the plasma. 
Urinary excretion was a major pathway of elimination. Tc 99m tilmanocept exhibited rapid 
clearance from the injection site, rapid uptake by the local lymph node, and low uptake by the 
remaining lymph nodes. Tilmanocept was well tolerated at all doses tested in nonclinical safety 
pharmacology studies and in single and repeated dose toxicology studies in rats, rabbits, and 
dogs. In some studies in rabbits and dogs, tilmanocept acted as a local irritant of the subcutis 
or skeletal muscle, and induced mild inflammation and tissue degeneration. The no-observed 
adverse-effect level (NOAEL) was 42μg/kg/day. Tilmanocept was not mutagenic or genotoxic 
in vitro or in vivo. No signs or symptoms of hypersensitivity were observed in a study in guinea 
pigs.  
1.2.2 
Nonclinical Evaluations – IV Administration 
In preparation to initiate the IV route of administration, 11 preclinical tests were conducted to 
assess safety, toxicity, and interaction potential at doses hundreds to thousands of times the 
expected maximum human dose, as summarized in Table 1. The nonclinical evaluations 
yielded safety and pharmacokinetics profiles that were appropriate for initiation of IV dosing 
in clinical trials. Nonclinical study results can be found in the accompanying Investigator’s 
Brochure. 


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


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


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


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•
Tc 99m tilmanocept demonstrates a greater frequency of localization to swollen/tender
joints at 200 mcg/2.0 mCi than 50 mcg/2.0 mCi.
•
There is an overall lack of concordance between qualitative observation of Tc 99m
tilmanocept localization to swollen/tender joints identified in DAS28 joint count
assessment. Swollen/tender joints did not appear to be reliable predictors of presumed
abnormal activated macrophage infiltration and overall disease progression when used
as an isolated diagnostic system.
•
Increased tilmanocept mass dosing, increased Tc 99m specific activity, and other routes
of administration may enhance localization and anatomic delineation in
tilmanocept-positive joints of RA patients.
•
The potential for using Tc 99m tilmanocept to delineate macrophage infiltration in
RA-affected joints may allow for earlier RA-specific treatment beyond the current
standard of care ACR/EULAR criteria.
1.2.4.2 
NAV3-21 (IV) 
This was an open-label, multicenter, dose-escalation safety with PK and dosimetry study of 
Tc 99m tilmanocept by IV injection in HCs and subjects with active RA. Thirty-nine subjects 
were enrolled. A total of 27 subjects with active RA were enrolled to Groups 1 to 9 in the dose 
escalation phase. Group 10 consisted of 6 HCs (3 female and 3 male) and Group 11 consisted 
of 6 subjects with active RA (3 female and 3 male). Tilmanocept was administered IV at 1 of 
3 mass doses: 50 mcg, 200 mcg, or 400 mcg.  Within each mass dose group, tilmanocept was 
radiolabeled with 1 of 3 Tc 99m doses: 1 mCi, 5 mCi, or 10 mCi.  Subjects in Groups 10 and 
11 received the maximum dose of 400 mcg/10 mCi. Imaging was performed 60 ± 15 minutes 
after injection. The following clinical efficacy conclusions were drawn upon study completion: 
•
The TUVbrain(average) readout provides an objective means of quantification of Tc 99m
tilmanocept localization when administered at the calculated optimal dose of 150
mcg/10 mCi and planar images are acquired 60 to 180 minutes after drug
administration.
•
Joint-specific localization of activity and joint-specific clinical symptomology were not
fully concordant. Within the spectrum of RA disease involvement, there may be a
decoupling of the causal active immune process and subsequent clinical sequelae. We
surmise that imaging and quantification of Tc 99m tilmanocept uptake may provide a
fuller and more accurate, responsive, and objective measure of RA disease activity than
can be obtained from clinical assessments alone. Future studies will examine whether
the approach to image acquisition and calculation of TUV can be further refined.
1.2.4.3 
NAV3-31 (IV) 
This was an open-label, multi-center, single and repeat-dose study designed to evaluate the 
reliability and sensitivity of TUV assessments in HCs and subjects with active RA. 
One hundred and sixteen evaluable subjects were enrolled. Tilmanocept was administered IV 


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at a dose of 150 mcg tilmanocept radiolabeled with 10 mCi Tc 99m. Clinical efficacy 
conclusions for this study are still in progress.  
1.2.5 
 Clinical Safety 
1.2.5.1 
NAV3-23 (SC) 
The NAV3-23 (NCT02683421) safety evaluation included all trial subjects injected with 
Tc 99m tilmanocept (N = 18). The AE monitoring was performed from the time of dose 
administration until completion of onsite safety assessment. There was 1 AE that was possibly 
related to and 1 AE that was probably related to Tc 99m tilmanocept. However, there were no 
AEs that led to trial discontinuation, and no SAEs were observed. There were no deaths on 
trial. 
1.2.5.2 
NAV3-21 (IV) 
The primary safety endpoint of the NAV3-21 study was evaluated by examining the incidence 
of AEs, changes over time in clinical laboratory tests, physical exams, electrocardiogram 
(ECG) parameters, and vital signs. The safety evaluation included all subjects who were 
enrolled in the study and administered Tc 99m tilmanocept (n = 39). There were no Tc 99m 
tilmanocept related AEs. There were no deaths during the trial; no SAEs; and no AEs that led 
to discontinuation from the trial. In addition, radiation exposure was within regulatory and 
safety limits at the doses evaluated. Radiation exposure and pharmacokinetics do not appear 
to differ in subjects with RA and healthy control subjects. 
1.2.5.3 
NAV3-31 (IV) 
The primary safety endpoint of the NAV3-31 study was evaluated by examining the incidence 
of AEs, changes over time in clinical laboratory tests, electrocardiogram (ECG) parameters, 
and vital signs. The safety evaluation included all subjects who were enrolled in the study and 
administered Tc 99m tilmanocept (n = 116). There were no Tc 99m tilmanocept related AEs. 
There were no deaths during the trial; there were three SAEs that were not related to study 
drug or study procedures; and one AE that led to discontinuation from the trial. There were no 
Adverse Drug Reactions reported. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objectives  
•
To demonstrate that global tilmanocept uptake values (TUVglobal) obtained before initiation
of anti-TNFα therapy (TUVglobal[b]) and at 5 weeks ± 1 week following change in therapy
(TUVglobal[5w]) has a specificity of greater than 80% to correctly specify a clinical non-
response to therapy at 24 weeks.
•
To demonstrate that TUVglobal obtained before initiation of anti-TNFα therapy and at
5 weeks ± 1 week following change in therapy has a sensitivity of greater than 65% to
correctly classify a positive clinical response to therapy at 24 weeks.
2.2 
Key Secondary Objective 
•
To evaluate the negative predictive value (NPV) of TUVglobal obtained before initiation of
anti-TNFα therapy (TUVglobal[b]) relative to a clinical non-response to therapy at 24 weeks.
2.3 
Secondary Objectives 
•
To evaluate the sensitivity and specificity of TUVglobal obtained before initiation of
anti-TNFa therapy and at 5 weeks ± 1 week following change in therapy relative to a
positive clinical response or a non-response to therapy at 12 weeks.
•
To evaluate the NPV of TUVglobal[b] relative to a clinical a non-response to therapy at
12 weeks.
•
To evaluate the positive predictive value (PPV), negative predictive value (NPV), and
overall accuracy (OA) of TUVglobal obtained before initiation of anti-TNFα therapy and at
5 weeks ± 1 week (ΔTUVglobal[5w]) following change in therapy relative to a positive
clinical response or a non-response to therapy at 12 and/or 24 weeks.
•
To evaluate the qualitative assessment of Tc 99m tilmanocept imaging to predict clinical
response or non-response following a change in anti-TNFα therapy.
•
To evaluate the additive effect of either quantitative or qualitative assessment of Tc 99m
tilmanocept imaging to the other at baseline and change from baseline to 5 weeks ± 1 week
to predict clinical response or non-response following a change in anti-TNFα therapy.
•
To evaluate the correlation of changes in TUVglobal obtained before initiation of anti-TNFα
therapy and at 5 weeks ± 1 week following a change in therapy with changes in composite
clinical assessments and their constituent parameters at 12 and/or 24 weeks.
•
To evaluate the correlation of changes in TUVglobal obtained before initiation of anti-TNFα
therapy and at 5 weeks ± 1 week following a change in therapy with changes in clinical
assessments at 12 and/or 24 weeks for specific anti-TNFα bDMARD agents.
•
To evaluate the correlation of changes in TUVglobal and changes in clinical RA assessments
as a means to monitor therapy.


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•
To evaluate sensitivity and specificity in patient subgroups.
•
To evaluate safety of IV-administered tilmanocept radiolabeled with Tc 99m.


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a prospective, open-label, multicenter study designed to evaluate the predictive capacity 
of Tc 99m tilmanocept planar imaging for downstream clinical response(s) in individuals with 
moderate to severe RA who are candidates for change in anti-TNFα therapy. Temporal 
(Baseline to 5-week) changes in quantitative imaging will be correlated with longitudinal 
(Baseline to 12- and 24-week) assessments of clinical RA outcomes to evaluate the clinical 
utility of Tc 99m tilmanocept for the expedited evaluation of antirheumatic treatment efficacy 
when compared with longitudinal assessments in clinical practice.   
Prior to the initiation of a new therapy, subjects will undergo baseline rheumatological 
evaluations of ACR/EULAR 2010 Classification Criteria, CDAI, DAS28, HAQ-DI©, and a 
serological RA panel for the characterization of disease activity. Following these evaluations, 
subjects will receive an IV dose of 150 mcg tilmanocept radiolabeled with 10 mCi of Tc 99m 
and undergo baseline planar imaging of the bilateral hands and wrists beginning 60-75 minutes 
following Tc 99m tilmanocept administration. Upon completion of baseline imaging 
procedures, subjects will commence a new anti-TNFα bDMARD treatment regimen and return 
to the clinic 5 ± 1 weeks later for a series of rheumatological evaluations (including CDAI, 
DAS28, ACR Response Criteria, and HAQ-DI©), drug administration, and bilateral hand/wrist 
imaging.  The rheumatological evaluations will be repeated at 12 ± 1 weeks and 24 ± 1 weeks 
after commencement of the new therapy. 
Images will undergo centralized quantification for the derivation of joint-specific and global 
tilmanocept uptake values (TUV). At the joint level, TUV is defined as the intrasubject ratio 
of the average pixel intensity of a joint to the average pixel intensity of the reference region. 
TUVglobal is a per subject summary of TUVjoint values greater than the upper 95th percent 
(2 standard deviations) of the normative database representing RA-specific inflammation. 
TUV calculations are additionally described in the Statistical Analysis Plan.  
All images will be read by three nuclear medicine specialists trained in the reading of these 
images. Each reader will work independently of the other readers and will be blinded to clinical 
assessments. Each reader will provide both a qualitative read and map regions of interest for 
calculation of TUVs. 
Temporal differences in TUVglobal from baseline to 5 ± 1 weeks of therapy (ΔTUVglobal[5w]) will 
be compared with longitudinal clinical outcomes at 12 ± 1 and 24 ± 1 weeks of therapy defined 
by changes in CDAI (ΔCDAI12/24w), changes in DAS28 (ΔDAS28[12/24w]), and assessment of 
ACR Response Criteria (ACR12/24w) to evaluate the efficacy of TUVglobal for the accelerated 
prediction of clinical response to antirheumatic drugs. 
Tc99 tilmanocept images with low levels of localization in the joints- and thus presumptively 
low numbers of synovial lining macrophages are thought to be less likely to respond to 
anti-TNFα therapies, and these cases will be classified as predicted non-responders using their 
baseline scan alone. The determination of low level of localization is done quantitatively by 


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applying a threshold TUVglobal of 5 as the cutoff value. Patients whose baseline scans are 
determined to have TUVglobal below this are predicted to be non-responders. This value was 
determined in the completed Phase 2B trial NAV3-31. Patients whose TUVglobal scores are 5 
or above then have their baseline scans compared to their Week 5 scans to determine if they 
will be classified as predicted responders or non-responders. A quantitative analysis of their 
change in TUVglobal score from baseline to Week 5 is performed to see if their levels of 
localization have changed significantly. All subjects in this trial will undergo baseline and 
Week 5 scans, including those whose baseline scans demonstrate TUVglobal below 5, as an 
objective is to assess if any longitudinal changes in TUVglobal from baseline to Week 5 can be 
predictive of clinical response or non-response. The process of dichotomizing subjects based 
on their baseline TUVglobal scores is referred to as bucketing. Statistical analyses will be 
performed on bucketed data. In the bucketed analyses, subjects with baseline TUVglobal below 
5 are classified as predicted non-responders while those with baseline TUVglobal above 5 are 
classified as either predicted responders or non-responders based on the change in TUVglobal 
between baseline and Week 5.  
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 
Protocol Adherence 
Strict adherence to all specifications outlined in this protocol is required for all aspects of the 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol. If protocol modifications are necessary, all alterations that are not solely of an 
administrative nature require a formal protocol amendment for the involvement of Institutional 
Review Board(s) (IRB(s)). 
If an investigator has deviated from the protocol in order to eliminate an immediate hazard to 
subjects or for other inevitable medical reasons, the investigator shall document all such 
deviations, including the reasons thereof, and submit the document to the sponsor and the IRB 
as applicable. 
3.3 
Study Duration 
Subjects will be “on study” for up to 213 days depending on the duration of the screening 
window (up to 30 days). 


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4 
STUDY POPULATION 
The study population will comprise subjects with clinically diagnosed active RA who are 
candidates for initiation of, or change to, a new anti-TNFα bDMARD regimen.  Subjects who 
meet the eligibility criteria listed below will be eligible for enrollment without regard to other 
aspects of their disease, such as chronicity of their RA.  That is, subjects with newly diagnosed 
disease, those with chronic disease, and those who have failed multiple therapies will all be 
eligible for enrollment if they meet the enumerated eligibility criteria. 
4.1 
Eligibility 
Subjects who fulfill all respective inclusion and none of the exclusion criteria will be eligible 
for enrollment into the study.  All inclusion/exclusion criteria must be verified before a subject 
may be considered eligible for administration of Tc 99m tilmanocept and imaging (Day 0 
procedures).  A subject will be considered enrolled in the study on the morning of study Day 0 
when they arrive at the study site.  Written, dated (with time noted) informed consent will be 
obtained from all subjects. A subject who withdraws consent prior to arrival at the study site 
on Day 0 will be considered a screen failure. 
4.1.1 
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) authorization before the initiation of any study-
related procedures.
2. The subject is at least 18 years of age and was ≥ 18 years of age at the time of RA
diagnosis.
3. The subject is a candidate for initiation of, or change to, a new anti-TNFα bDMARD
therapy.
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).
5. The subject has moderate to severe RA as determined by a 28-joint disease activity
score (DAS28) of ≥ 3.2 (includes the Erythrocyte Sedimentation Rate [ESR] test and
Visual Analog Scale [VAS]).
6. Subjects receiving traditional DMARDs must have been on therapy for ≥ 90 days and
at a stable dose for ≥ 30 days prior to the first imaging visit (Day 0).
7. Subjects receiving bDMARD or janus kinase (JAK) inhibitor therapy must have been
at a stable dose > 60 days prior to the first imaging visit (Day 0).
8. If the subject is receiving NSAIDS (nonsteroidal anti-inflammatory drug) or oral
corticosteroids, the dose has been stable for > 28 days prior to the first imaging visit
(Day 0). The corticosteroid dose must be ≤ 10 mg/day of prednisone or an equivalent
steroid dose.


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4.1.2 
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.
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
2 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 history of hypersensitivity reactions to TNF-inhibitors.
10. The subject has a known allergy to or has had an adverse reaction to dextran exposure.
11. The subject has received an investigational product within 30 days prior to the Tc 99m
tilmanocept administration at the first imaging visit (Day 0).
12. The subject has received intra-articular corticosteroid injections ≤ 8 weeks prior to the
first imaging visit (Day 0).
13. The subject has received any radiopharmaceutical within 7 days or 10 half-lives prior
to the administration of Tc 99m tilmanocept at the first imaging visit (Day 0).
14. The subject has heart failure (NYHA Class III-IV), a demyelinating disorder, or a
chronic/latent infection (e.g., +PPD, HIV, Hepatitis B).
4.2 
Recruitment 
Subjects will be recruited from rheumatology practices in accordance with the inclusion and 
exclusion criteria listed above.  Potentially suitable subjects will be asked by their treating 
physician about their willingness to participate in this study.  Subjects may also be identified 
through social media campaigns or advertising.     
4.3 
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. 


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A subject who withdraws consent prior to arrival at the study site on Day 0 will be 
considered a screen failure. 
Should a subject withdraw after administration of the investigational product, all efforts will 
be made to complete and report the observations up to the time of withdrawal as thoroughly as 
possible. An explanation should be given of why the subject is withdrawing or being 
withdrawn from the study.  
The investigator may withdraw a subject from the study at any time at the discretion of the 
investigator for any of the following reasons:  
•
A protocol violation occurs
•
A serious or intolerable AE occurs
•
A clinically significant change in a laboratory parameter occurs
•
At the investigator’s/sponsor’s discretion as long as it is in the best interest of the
subject
•
The sponsor or investigator terminates the study
•
The subject requests to be discontinued from the study
4.4 
Replacement 
Subjects will be replaced under the following conditions: 
•
Subjects who did not receive study drug administration or did not proceed to imaging
4.5 
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 “33”  
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 “33-01-001.”  
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 
Identification of Investigational Product 
Technetium Tc 99m tilmanocept was approved under the brand name Lymphoseek in the USA 
by the FDA in year 2013 NDA number 202207 as radio-inaging agent. Technetium Tc 99m 
tilmanocept is a scintigraphic imaging radiotracer that binds to CD206 (mannose receptor) on 
the surface of macrophages and other inflammatory cells. It is comprised of multiple units of 
DTPA (diethylenetriaminepentaacetic acid) and mannose, each synthetically attached to 
a 10 kDa dextran backbone (Figure 1). The mannose acts as a substrate for the receptor and 
the DTPA serves as a chelating agent for labeling with Tc 99m. Tilmanocept has a 
diameter of about 7 nm, which permits enhanced diffusion into lymph nodes and blood 
capillaries.  
Figure 1 
Tc 99m tilmanocept and the Mannose Receptor 
5.2 
Investigational Product Dosage and Administration 
Tc 99m tilmanocept will be administered through an IV route of injection. A 150-mcg dose 
containing 10 mCi of Tc 99m in 3 mL will be delivered using 1 syringe. The dose will be 
injected as a slow push into the IV catheter. At the completion of the injection, a 10-mL sterile 
normal saline flush will be administered. The preferred site of IV placement will be the left or 
right antecubital vein. 
The administered dose will be ± 20% of the tilmanocept mass dose and radiolabel mCi dose. 


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5.3 
Treatment Assignment 
Subjects will receive the study-defined dose of 150 mcg tilmanocept radiolabeled with 10 mCi 
of Tc99m. Subjects will undergo drug administration and imaging at the following 
4 timepoints: 
1. Day 0 (Visit 2)
2. 5 ± 1 weeks after the initiation of new anti-TNFα bDMARD therapeutic regimen
(Visit 4)
5.4 
Packaging and Labeling 
Tilmanocept cartons ready for radiolabeling will be shipped and stored at the study-assigned 
radiopharmacy. Tilmanocept is provided in a vial. Vials are packaged as a kit. A carton (kit) 
contains 5 vials of tilmanocept.  
A detailed radiolabeling protocol will be provided to each radiopharmacy with instructions on 
how to radiolabel the vials and prepare the final tilmanocept product for injection. Quality 
Control worksheets will also be completed. 
5.5 
Drug Logistics and Investigational Product Accountability 
The investigator (or designated personnel) will confirm receipt of the investigational product 
in writing and will use the investigational product only within the framework of this clinical 
study and in accordance with this study protocol. For each subject, he/she will keep a record 
of the investigational product dispensed and store all other forms that accompanied the delivery 
of the radiolabeled product to the clinical site. These documents are to be filed in the 
investigator site file. Overall drug accountability and reconciliation will be completed by the 
sponsor or its representative. A list of investigational product vials and other materials that 
were returned, or destroyed, must be recorded and signed by the PI or an appropriately 
qualified designee. 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 Therapy 
All medications taken 30 days prior to Tc 99m tilmanocept injection through the post-injection 
safety follow-up must be documented and maintained at a stable dose according to the 
inclusion criteria. The subject’s complete history of RA treatments will also be collected. 
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 Study Events (see Appendix 1). Visits 
7 and 9 have been eliminated per Protocol Amendment 4. For continuity, visits have not been 
renumbered (i.e., Visit 6 is followed by Visit 8). 
7.2 
Visit Description 
7.2.1 
Visit 1, Screening (Day -30 to Day -1) 
•
Preliminary review of inclusion and exclusion criteria
•
Obtain signed informed consent for study participation
•
Allocation of unique subject number; this number will be used to document the subject
data in the case report forms (CRFs) and enrollment log
•
Demography – date of birth, biological sex, race
•
Medical and surgical history – all relevant prior medical and surgical conditions, which
may include RA family history, and RA treatment history, will be recorded in the CRF.
Documented medical conditions will also note the month and year of onset if the
condition is still active.
•
Concomitant medications (within 30 days before injection).
•
Vital signs (body temperature, heart rate, blood pressure, and respiratory rate after at
least 1 minute in a resting position)
•
Physical examination will include an assessment of height, weight, and an examination
of general appearance, skin, eyes, ears, nose, throat, head and neck (including thyroid),
lungs, heart, abdomen, lymph nodes, musculoskeletal, and nervous system. Any
clinically relevant finding is to be documented as a baseline finding. Physical exams
that are conducted as standard of care prior to signing informed consent may be used if
they are performed within 30 days of injection.
•
Clinical laboratory tests – study subjects will have blood obtained for hematology,
chemistry, and an RA panel (Table 4)
•
Urine collection for routine analysis
•
Urine pregnancy test for women of childbearing potential. Females of childbearing
potential are defined as women that are not surgically sterile (hysterectomy or bilateral
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who
are not of childbearing potential will not require a pregnancy test.
•
RA Evaluations: Swollen and tender joints will be identified and documented during
physical examination as established by the 2010 ACR/EULAR Classification Criteria
and DAS28. A HAQDI© assessment will be completed to assess quality of life related
to health. A CDAI assessment will be used to quantify and track disease activity. A
review of the subject’s RA history including previous treatments, date of symptom
onset, and date of diagnosis will also be performed.


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•
Widespread Pain Index (WPI) Assessment
Changes in health occurring after consent and prior to the day of injection will be added to the 
subject’s medical history unless related to a study procedure. 
7.2.2 
Visit 2, Baseline (Day 0; Drug administration/Imaging) 
All subjects will be assessed for adverse events in an ongoing manner from the day of injection 
through the end of participation.  
7.2.2.1 
Before Administration of Tc 99m Tilmanocept 
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 childbearing potential. Females of childbearing
potential are defined as women that are not surgically sterile (hysterectomy or
bilateral oophorectomy) nor postmenopausal for at least 1 year prior to screening.
Women who are not of childbearing potential will not require a pregnancy test.
•
Assessment of adverse events
•
Concomitant medication review
•
Vital signs after at least 1 minute in a resting position (body temperature, heart rate,
blood pressure, and respiratory rate) within 30 minutes prior to administration of
Tc 99m tilmanocept
7.2.2.2 
Administration of Tc 99m Tilmanocept 
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 pre-filled syringe will be connected to a 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 adverse events.  
7.2.2.3 
0 to 30 Minutes After Tc 99m Tilmanocept Administration 
•
Assessment of adverse events
•
Vital signs after at least 1 minute in a resting position (body temperature, heart rate,
blood pressure, and respiratory rate)


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7.2.2.4 
60 to 75 Minutes After Tc 99m Tilmanocept Administration 
•
Assessment of adverse events
•
Image acquisition: planar scan of bilateral hands and wrists
•
Clinical labs (within 60 minutes after the completion of imaging)
•
Urinalysis (within 60 minutes after the completion of imaging)
Upon the completion of all Visit 2 procedures, subjects will initiate their new anti-TNFα 
bDMARD treatment regimen. The exact agent, dose, start date, and planned dosing frequency 
will be documented. For each subsequent administration, the following details will be 
documented:   
1. Administration start time
2. Administration end time
3. Total volume injected
4. Total dose administered
7.2.3 
Visit 3 (Day 5 ± 3; Follow-up Telephone Safety Assessment) 
•
Review of concomitant medications
•
Assessment of adverse events
7.2.4 
Visit 4 (Week 5 ± 1; Tc 99m Tilmanocept Administration, Imaging, and 
Clinical Assessments) 
7.2.4.1 
Before Tc 99m Tilmanocept Administration (0-7 days pre-injection) 
The following procedures will be completed for all subjects within 7 days prior to the 
administration of Tc 99m tilmanocept: 
•
CDAI
•
DAS28 (note: associated labs occur after imaging)
•
HAQ-DI©
•
WPI


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7.2.4.2 
 Before Tc 99m Tilmanocept Administration (day of injection) 
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 childbearing potential. Females of childbearing
potential are defined as women that are not surgically sterile (hysterectomy or bilateral
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who
are not of childbearing potential will not require a pregnancy test.
•
Assessment of adverse events
•
Concomitant medication review
•
Vital signs after at least 1 minute in a resting position (body temperature, heart rate,
blood pressure, and respiratory rate) within 30 minutes prior to administration of
Tc 99m tilmanocept
7.2.4.3 
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 a 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 adverse events. 
7.2.4.4 
0 to 30 Minutes After Tc 99m Tilmanocept Administration 
•
Assessment of adverse events
•
Vital signs after at least 1 minute in a resting position (body temperature, heart rate,
blood pressure, and respiratory rate)
7.2.4.5 
60 to 75 Minutes After Tc 99m Tilmanocept Administration 
•
Assessment of adverse events
•
Image acquisition: planar scan of bilateral hands and wrists
•
Clinical labs (within 60 minutes after the completion of imaging)
•
Urinalysis (within 60 minutes after the completion of imaging)
•
RA labs (within 60 minutes after the completion of imaging)


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7.2.5 
Visit 5 (5 ± 3 Days After Visit 4; Follow-up Telephone Safety Assessment) 
•
Review of concomitant medications
•
Assessment of adverse events
7.2.6 
Visit 6 (Week 12 ± 1; Clinical Assessments) 
The following procedures will be completed for all subjects at Week 12 ± 1: 
•
CDAI
•
DAS28
•
HAQ-DI©
•
WPI
•
RA labs
•
Assessment of adverse events
•
Concomitant medication review
7.2.7 
Visit 8 (Week 24 ± 1; Clinical Assessments; note that Visit 7 will not be 
conducted per this amendment) 
7.2.7.1 
 Before Tc 99m Tilmanocept Administration (0-7 days pre-injection) 
The following procedures will be completed for all subjects at Week 24 ± 1: 
•
CDAI
•
DAS28
•
HAQ-DI©
•
WPI
•
RA labs
•
Assessment of adverse events
•
Concomitant medication review


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8 
PROCEDURES AND VARIABLES 
8.1 
Population Characteristics 
8.1.1 
Demographic and Other Baseline Characteristics 
Based on response to anti-TNFα bDMARD therapy, 198 to 672 evaluable subjects may be 
enrolled. Subjects will be men and women ≥ 18 years of age with evidence of active RA.  A 
subject is considered evaluable if he/she meets the criteria for the analysis population and has 
the data necessary for computing the primary endpoint. There will be no exclusions based on 
specific subgroups (e.g., subjects with various demographic characteristics; disease severity, 
duration, or response to prior therapies; co-existing conditions; genetic variants; concomitant 
medications; or prior treatment with non-TNF biologic therapies). 
8.1.2 
Medical 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. 
8.2 
Tc 99m Tilmanocept Administration 
Tc 99m tilmanocept must be ordered from the study-assigned radiopharmacy once the subject 
has been scheduled for IV administration and imaging. The preferred site of IV placement will 
be the left or right antecubital vein. The filled syringe will be connected to a catheter for a slow 
push injection. Immediately after the completion of the injection, a 10 mL sterile normal saline 
flush will be administered. Injection of Tc 99m tilmanocept will be at study time 0:00. 
8.3 
Rheumatological Assessments 
8.3.1 
2010 ACR/EULAR Classification Criteria 
All subjects will be evaluated at screening using the 2010 ACR/EULAR Classification Criteria 
as part of eligibility and inclusion (Aletaha 2010). The 2010 ACR/EULAR Classification 
Criteria includes 4 components: number and site of involved joints, serologic abnormality, 
elevated acute-phase response and symptom duration. See Appendix 2 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.” 
8.3.2 
DAS28 Evaluation 
Subjects will be evaluated for the DAS28 (Prevoo 1995) at the following timepoints: screening 
(Day -30 to -1), Visit 4 (5 ± 1 weeks post-initiation of new anti-TNFα bDMARD), Visit 6 
(12 ± 1 weeks post-initiation of new anti-TNFα bDMARD), and Visit 8 (24 ± 1 weeks post-


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initiation of new anti-TNFα bDMARD). DAS28 evaluations may be completed up to 30 days 
before imaging Visit 2 and up to 7 days before imaging Visits 4, 6, and 8.  
DAS28 is calculated from 4 components: Tender Joint Count (TJC), Swollen Joint Count 
(SJC), visual analogue scale (VAS) of the subject’s global health, and the laboratory parameter 
erythrocyte sedimentation rate (ESR), such that: 
𝐷𝐷𝐷𝐷𝐷𝐷28 = 0.56ඥ𝑇𝑇𝑇𝑇𝑇𝑇+ 0.28ඥ𝑆𝑆𝑆𝑆𝑆𝑆+ 0.7 ln(𝐸𝐸𝐸𝐸𝐸𝐸) + 0.014(𝑉𝑉𝑉𝑉𝑉𝑉) 
A DAS28 score of higher than 5.1 is indicative of high disease activity whereas a DAS28 
below 3.2 indicates low disease activity. A subject with a DAS28 lower than 2.6 is considered 
to be in remission. For consistent scoring, the following calculator should be utilized: 
https://qxmd.com/calculate/.  See Appendix 3 for details. 
8.3.3 
CDAI 
Subjects will be evaluated for disease activity using the Clinical Disease Activity Index 
(Aletaha 2009). CDAI will be collected a total of 4 times per subject (screening, Visit 4, Visit 
6, and Visit 8). The CDAI evaluation may be completed up to 30 days before imaging Visit 2 
and up to 7 days before imaging Visits 4, 6, and 8. This metric is calculated as the sum of 4 
components: TJC, SJC, patient global assessment of disease activity, and provider global 
assessment of disease activity. A CDAI score of 0.0 to 2.8 is indicative of disease remission; 
2.9 to 10.0 of low activity, 10.1 to 22.0 of moderate activity, and 22.1 to 76.0 of high activity. 
See Appendix 4 for details. 
8.3.4 
ACR Response Criteria 
Subjects will be evaluated using the ACR Response Criteria (Felson 1995). ACR Response is 
derived from 6 possible parameters: swollen/tender joint count, patient assessment, physician 
assessment, pain scale, disability/functionality questionnaire, and acute phase reactant 
(ESR/CRP). Response is reported as percent (%) improvement from baseline to a later 
timepoint. In this case, a total of 2 timepoints will be evaluated per subject (Visits 6 and 8).  
Percent improvement is defined as a combination of reductions in swollen and tender joint 
counts as well as improvement in at least at least 3 of the other parameters (patient assessment, 
physician assessment, pain scale, disability/functionality questionnaire, and acute phase 
reactant [ESR]). An ACR20 indicates that 20% improvement is observed in tender and swollen 
joint counts as well as 20% improvement in at least 3 of the other 5 criteria. An ACR50 
indicates that 50% improvement is observed in tender and swollen joint counts as well as 50% 
improvement in at least 3 of the other 5 criteria. An ACR70 indicates that 70% improvement 
is observed in tender and swollen joint counts as well as 20% improvement in at least 3 of the 
other 5 criteria. See Appendix 5 for details. 


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8.3.5 
Other 
8.3.5.1 
28-joint Count (SJC and TJC) 
The 28-joint count will be performed for swollen and/or tender joints in the following: 
shoulder, elbow, wrist, MCP and PIP, and knee. Joint swelling is defined as soft tissue swelling 
that is detectable along the joint margins. Joint tenderness is defined as the presence of pain in 
a joint at rest with pressure or on movement of the joint (Scott 1996). This assessment will 
be used as an input parameter for 2010 ACR/EULAR Classification Criteria (Section 
8.3.1), DAS28 score (Section 8.3.2), and CDAI score (Section 8.3.3). 
Patient Global Assessment of Disease Activity 
Patient global assessment of disease activity will be evaluated using a 10-point scale wherein 
a score of 0 is considered ‘very well’ and score of 10 is considered ‘very poor’. Score intervals 
are 0.5 apart (yielding 20 possible options – 0, 0.5, 1.0, 1.5…20). This assessment will be 
used as an input parameter for CDAI score (Section 8.3.3) and ACR Response 
Criteria (Section 8.3.4). 
Provider Global Assessment of Disease Activity 
Provider global assessment of disease activity will be evaluated using a 10-point scale wherein 
a score of 0 is considered ‘very well’ and score of 10 is considered ‘very poor’. Score intervals 
are 0.5 apart (yielding 20 possible options – 0, 0.5, 1.0, 1.5…20). This assessment will be 
used as an input parameter for CDAI score (Section 8.3.3) and ACR Response 
Criteria (Section 8.3.4). 
8.3.5.2 
Patient Assessment of Pain (VAS) 
Patient assessment of pain will be evaluated using the visual analog scale (VAS). Using a ruler, 
the score will be determined by measuring the distance (mm) on the 10-cm line between the 
‘no pain’ anchor and the patient’s mark, providing a range of scores from 0 to 100. This 
assessment will be used as an input parameter for DAS28 score (Section 8.3.2) and 
ACR Response Criteria (Section 8.3.4). 
8.3.5.3 
Patient Assessment of Physical Function (HAQ-DI©) 
Patient assessment of physical function will be evaluated using the Health Assessment 
Questionnaire Disability Index (HAQ-DI©) at screening (up to 30 days before imaging Visit 
2) and Visits 4, 6, and 8 (up to 7 days before imaging visits 4, 6, and 8). This evaluation
includes questions about functional ability, fine movements of the upper extremity, locomotor 
activities of the lower extremity, and compound activities requiring both extremities. It also 
includes assessments of various functional activities such as dressing, rising, eating, walking, 
etc. Responses are scored on a 0 (no disability) to 3 (completely disabled) scale (Bruce 2003). 
See Appendix 6 for more information. 


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8.3.5.4 
Acute-phase Reactant 
ESR and CRP will be obtained in the RA-specific laboratory panel (see Table 4) at 
screening and Visits 4, 6, and 8.  ESR is used in the calculation of the ACR response level. 
8.3.5.5 
Widespread Pain Index 
Assessment of widespread pain will be evaluated using the widespread pain index (WPI) at 
screening (up to 30 days before imaging Visit 2) and Visits 4, 6, and 8 (up to 7 days before 
imaging visits 4, 6, and 8). Providers will assess 19 areas of widespread pain over the last 7 
days and will add the total number of areas in pain for the WPI score (score range 0 to 19). 
This assessment will be used as an additional pain assessment tool to evaluate central pain. 
8.4 
 Image Acquisition 
8.4.1 
Planar Scintigraphy 
Planar spot views of the hands and wrists will be acquired beginning 60 to 75 minutes post 
injection at Visits 2 and 4. Images and results derived from the images are investigational and 
should not be used for clinical decision making or shared with the participant. 
8.4.2 
Tilmanocept Uptake Value (TUV) 
TUV is a quantitative imaging metric used to characterize the amount of CD206 activity on 
planar imaging. Results from prior Phase 1 and 2 studies have demonstrated that TUV is a 
sensitive and specific predictor of visually interrogated Tc 99m tilmanocept localization in 
joint regions with presumed inflammatory macrophage activity. A per-joint TUV (TUVjoint) 
relative ratio will be calculated for the each of the 22 DAS-28 joints located in the hands and 
wrists. A subject-level global TUV (TUVglobal) assessed across the 22 joints will be used as an 
indication of overall disease burden.  
For all subjects, delegated trained imaging scientists blinded to all clinical subject information 
will perform semi-automated ROI drawing on planar images of the bilateral hands and wrists 
to derive relevant count statistics, which are input parameters for TUVjoint and TUVglobal. TUV 
metrics are further described in the NAV3-33 Statistical Analysis Plan. 
8.5 
Adverse Events 
8.5.1 
Definition of Adverse Event 
The definitions below follow International Conference on Harmonization (ICH) – Good 
Clinical Practice (GCP) (see also ICH E2A Guideline for Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting). 
Adverse Event (AE) 
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 


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treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product.  
Any clinically significant change in a condition (worsening) from screening that results in a 
change in subject management will be considered an AE and will be recorded on the AE page 
of the CRF. 
By definition for this study, all untoward medical occurrences beginning on the day of Visit 2 
Baseline (Day 0) through the final visit (Visit 8) are to be reported as AEs.  AEs continuing 
after study completion will be followed to normalization or stabilization. Additionally, 
untoward medical events occurring prior to the day of Tc 99m tilmanocept administration will 
be collected and added to the subject’s medical history unless they are related to a study 
procedure in which case the event will be recorded as an AE. SAEs will be reported from the 
time of consent through the end of participation. 
8.5.2 
Categories for Adverse Event Assessment 
All AEs will be assessed and documented by the investigator according to the categories 
detailed below. 
Seriousness 
For each AE, the seriousness must be determined according to the criteria given in 
Section 8.5.5. 
Severity 
The severity of an AE is classified according to the following categories, taking into account 
the possible range of the intensity of the event: 
•
Mild -
The adverse event is transient and easily tolerated by the subject. 
•
Moderate -  The adverse event causes the subject discomfort and interrupts the
subject’s usual activities. 
•
Severe -  
The adverse event causes considerable interference with the subject’s
usual activities and may be incapacitating or life-threatening. 
Specific drug treatment 
Any specific drug treatment will be documented. 
Causal relationship to investigational product 
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of investigational product:  


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Definitely related: 
Event can be fully explained by administration of the investigational 
product. 
Probably related: 
Event is most likely to be explained by administration of the 
investigational product rather than the subject’s clinical state or 
other agents/therapies. 
Possibly related: 
Event may be explained by administration of the investigational 
product or by the subject’s clinical state or other agents/therapies. 
Probably not related: 
Event is most likely to be explained by the subject’s clinical state or 
other agents/therapies, rather than the investigational product. 
Definitely not related: 
Event can be fully explained by the subject’s clinical state or other 
agents/therapies. 
For causality assessments, events meeting the categories of definitely, probably, or possibly 
related will be considered to be related to investigational product. 
Causal relationship to study procedure 
The investigator will use the following definitions to assess the relationship of the adverse 
event to study procedure:  
Definitely related: 
Event can be fully explained by the study procedure. 
Probably related: 
Event is most likely to be explained by the study rather than the 
subject’s clinical state or other agents/therapies. 
Possibly related: 
Event may be explained by the study procedure or by the subject’s 
clinical state or other agents/therapies. 
Probably not related: 
Event is most likely to be explained by the subject’s clinical state or 
other agents/therapies, rather than the study procedure. 
Definitely not related: 
Event can be fully explained by the subject’s clinical state or other 
agents/therapies. 
For causality assessments, events meeting the categories of definitely, probably, or possibly 
related will be considered to be related to study. 
8.5.3 
Assessments and Documentation of Adverse Events 
Attention shall be paid to the occurrence of AEs for the duration of subject participation. Events 
occurring prior to Visit 2 (day of Tc 99m tilmanocept administration) will be recorded in the 
subject’s medical history. Untoward medical events beginning on Visit 2 (day of Tc 99m 
tilmanocept administration) through the completion of Visit 8 will be reported as adverse 


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events.  Thus, subjects should be closely observed by the investigator both during and after the 
evaluation.   
Any AE (observed, volunteered, or elicited) should be recorded in detail in the source 
documentation. 
The following information is required: 
•
The date and time of onset of any AE.
•
The duration (the entire duration of an event or symptom, calculated from date of onset
to date of end, if not recorded directly).
•
The seriousness of the AE will be assessed by the investigator.  If the investigator
deems that an AE qualifies as an SAE, a special form provided by the sponsor should
be completed and the event must immediately, and within one day (i.e., within 24
hours) of becoming aware of the SAE, be reported to the sponsor.  A definition of
serious adverse events is provided in Section 8.5.5.
•
The maximum intensity (mild, moderate, or severe).
•
Whether drug treatment was administered for the event, any specific drug treatment
must be documented.
•
The relationship of the AE to the investigational product and to study conduct (for
definitions, see above).
•
The outcome of the AE (resolved, resolved with sequelae, not resolved, unknown,
death).
AEs will be coded according to an internationally recognized dictionary (Medical Dictionary 
for Regulatory Activities [MedDRA]). 
8.5.4 
Expected Adverse Events 
Investigational Product-Related Risks 
In all completed studies of Lymphoseek, 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 500,000 patients.  Routes of 
administration included: subcutaneous, intradermal, and peritumoral. The intended route of 
administration in this study is intravenous.   


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Precautionary Measures 
Special precautionary measures are not considered necessary for this study.  In case of 
emergency, standard emergency procedures will be employed. 
Unexpected Adverse Events 
An unexpected adverse event is defined as an adverse reaction that in nature and severity is 
not consistent with the applicable product information (e.g., Investigator’s Brochure).  Any 
adverse experience that is not listed in the current Investigator’s Brochure or which is, with 
regard to the specificity or severity, not consistent with the risk information shall be regarded 
as unexpected.  
Examples would be (a) acute renal failure listed in the Investigator’s Brochure with a 
subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant 
hepatitis.  “Unexpected” as used in this definition refers to an adverse drug experience that has 
not been previously observed and included in the Investigator’s Brochure, rather than from the 
perspective of such experience not being anticipated from the pharmacological properties of 
the investigational product. 
8.5.5 
Serious Adverse Events 
Definition of Serious Adverse Events 
Definition 
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 on Expedited Safety Reporting 
Requirements for Human Drug and Biological Products. 
An SAE is classified as any untoward medical occurrence that at any dose: 
•
results in death, or
•
is life threatening, or
•
requires inpatient hospitalization or prolongation of existing hospitalization, or
•
results in persistent or significant disability/incapacity, or
•
is a congenital anomaly/birth defect, or
•
is an important medical event (see paragraphs below).
The term ‘life threatening’ in the definition refers to an event in which the subject was at risk 
of death at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe. 


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


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•
General Appearance
•
Skin/dermatological
•
Eyes, ears, nose, throat
•
Head and neck (including thyroid)
•
Lungs
•
Heart
•
Abdomen (liver, kidney, spleen, gastrointestinal)
•
Lymph nodes
•
Musculoskeletal
•
Nervous system
8.7 
Vital Signs 
Vital signs comprise the measurement of body temperature, heart rate, respiration, systolic and 
diastolic blood pressure. All measurements will be taken after the subject has been in a resting 
position for at least 1 minute. Vital signs will be measured at screening, within 30 minutes 
before investigational product injection, and within 30 minutes after injection. Any clinically 
significant change from screening (worsening) that results in a change in subject management 
will be considered an AE and will be recorded on the AE page of the CRF. 
8.8 
Clinical Laboratory Parameters for Screening and Safety 
Clinical laboratory tests to be evaluated in this study include hematology, serum 
chemistry, and urinalysis.  Clinical laboratory tests will include the following as defined in 
Table 4. 
Table 4 
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; this assay may also appear as cyclic citrullinated peptide 
[CCP]) 


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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. 
Any change in a laboratory value, which results in a change in subject management (additional 
controls or treatment required), will be reported as a clinically significant change. Clinically 
significant changes in laboratory parameters, which are not the result of laboratory error, are 
to be recorded as AEs. 
Any clinically significant changes in laboratory values are to be followed up with repeated 
tests at appropriate intervals (as determined by the investigator) until the values return to 
baseline level or until the abnormality is explained by the investigator. The expected 
amount of blood to be drawn is shown in Table 5. 
Table 5 
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 (3 teaspoons) 
Visit 2 (Day 0) 
Chemistry (5 mL) 
Hematology (4 mL) 
9 mL (1.8 teaspoons) 
Visit 4 (5 ± 1 weeks after 
initiation of new anti-TNFα 
bDMARD therapy) 
Chemistry (5 mL) 
Hematology (4 mL) 
RA panel (4 mL) 
13 mL (2.6 teaspoons) 
Visit 6 (12 ± 1 weeks after 
initiation of new anti-TNFα 
bDMARD therapy 
RA panel (4 mL) 
4 mL (0.8 teaspoons) 
Visit 8 (24 ± 1 weeks after 
initiation of new anti-TNFα 
bDMARD therapy) 
RA panel (4 mL) 
4 mL (0.8 teaspoons) 
Total: 43 mL (8.7 teaspoons) 


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9 
STATISTICAL METHODS 
This is a prospective, open-label, multicenter study designed to evaluate the early predictive 
capacity of quantitative Tc 99m tilmanocept planar imaging for downstream clinical 
response(s) in individuals who are candidates for change in anti-TNFα therapy. Temporal 
(Baseline to 5-week) differences in quantitative imaging will be correlated with longitudinal 
(Baseline to 12- and 24-week) assessments of clinical RA outcomes to evaluate the clinical 
utility of Tc 99m tilmanocept for the expedited evaluation of antirheumatic treatment efficacy 
when compared with longitudinal assessments in clinical practice. 
9.1 
Randomization Methods 
This study is not randomized.  
9.2 
Safety Variables 
The safety analysis variables are defined as follows: 
• Adverse events (AEs) 
• Clinical laboratory tests (hematology, serum chemistry, urinalysis, and RA panel) 
• Vital signs 
 
9.3 
Efficacy Variables 
9.3.1 
Primary Efficacy Variables 
The co-primary efficacy predictor variables are the response/non-response status at 24 weeks 
to new or changed anti-TNFa bDMARD therapy for rheumatoid arthritis based on the ACR50 
criterion, and the predicted response/non-response based on ΔTUVglobal[5w] bucketing.   
The co-primary endpoints of the study are sensitivity and specificity of ΔTUVglobal[5w] 
bucketing with respect to ACR50 at week 24. 
9.3.2 
Key Secondary Efficacy Variable 
The key secondary efficacy predictor variable is the response/non-response status at 24 weeks 
to new or changed anti-TNFa bDMARD therapy for rheumatoid arthritis based on the ACR50 
criterion, and the TUVglobal[b] value.   
The key secondary endpoint of the study is the NPV of TUVglobal[b] with respect to ACR50 at 
Week 24. 
9.3.3 
Secondary Efficacy Variables  
The secondary efficacy response variables are: 
• CDAI score at baseline (CDAIb), 12 (CDAI12w) and 24 weeks (CDAI24w)  


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• ACR Response Criteria (ACR20, ACR50, ACR70) at 12 and 24 weeks 
• DAS28 Score at baseline, 12 weeks, and 24 weeks  
• Constituent scores of the ACR Response Criteria at baseline, 12 weeks, and 24 weeks, 
including: 
• TJC 
• SJC 
• Patient assessment of global disease activity 
• Rheumatologist assessment of global disease activity 
• Patient assessment of pain 
• Patient assessment of physical function 
• Acute-phase reactant value. 
 
• Constituent scores of the CDAI score at baseline, 12 weeks, and 24 weeks, including: 
• TJC 
• SJC 
• Patient Global Assessment 
• Physician Global Assessment 
 
The secondary efficacy endpoints are as follows: 
• Sensitivity and specificity of ΔTUVglobal[5w] bucketing with respect to ACR50 at week 
12. 
• NPV, PPV, and OA of ΔTUVglobal[5w] bucketing with respect to ACR50 at weeks 12 
and 24.  
• NPV of TUVglobal[b] with respect to ACR50 at week 12. 
• TUVglobal[b] and response to new anti-TNFα bDMARD therapy defined by the change 
from baseline (CFB) of CDAI to 12 ± 1 weeks and 24 ± 1 weeks (∆CDAI12w and 
∆CDAI24w, respectively), by the CFB of DAS28 to 12 ± 1 weeks and 24 ± 1 weeks 
(∆DAS2812w and ∆DAS2824w, respectively) and by the CFB in each of the ACR 
Response Criteria components at 12 ± 1) weeks and at 24 ± 1 weeks. 
• ΔTUVglobal[5w] and response to new anti-TNFα bDMARD therapy defined by the CFB 
of CDAI to 12 ± 1 weeks and 24 ± 1 weeks (ΔCDAI12w and ΔCDAI24w, respectively). 
• Concordance of ΔTUVglobal[5w] bucketing with clinical criteria, including ACR 
Response Criteria, CDAI, DAS28, and HAQ-DI. Concordance between the predicted 
response or non-response status and the clinical criteria will be evaluated using NPV, 
PPV, sensitivity, specificity, and OA.  Note that sensitivity and specificity of 


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ΔTUVglobal[5w] with bucketing with respect to ACR50 at weeks 12 and 24 are excluded 
from this set of secondary endpoints, as they are the co-primary. 
• Concordance ΔTUVglobal[12w] bucketing with clinical criteria, including ACR Response 
Criteria, CDAI, DAS28, and HAQ-DI. 
• Response to new anti-TNFα bDMARD therapy defined by the CFB of CDAI to 
12 ± 1 weeks and 24 ± 1 weeks (ΔCDAI12w and ΔCDAI24w, respectively). 
• The correlation of ΔTUVglobal[5w] and response to new anti-TNFα bDMARD therapy 
from baseline to 24 ± 1 weeks defined by the changes from baseline in each of the ACR 
Response Criteria components.  
• Constituent parameters of CDAI12w, CDAI24w, ΔCDAI12w, ΔCDAI24w, ACR Response 
Criteria at 12 and 24 weeks, including:  
• Tender joint count (TJC)  
• Swollen joint count (SJC)  
• Patient assessment of global disease activity  
• Rheumatologist assessment of global disease activity  
• Patient assessment of pain  
• Patient assessment of physical function  
• Acute-phase reactant value 
 
9.4 
Sample Size Justification 
The study is sized with respect to achieving specified goals in the co-primary endpoints of 
sensitivity and specificity of ΔTUVglobal[5w] bucketing. Sensitivity and specificity require 
knowledge of the patient’s clinical status at Week 24, and so hypothesis testing will be 
performed after classification. The value of ΔTUVglobal[5w] necessary to predict response vs. 
non-response and the value of TUVglobal[b] at baseline necessary to predict non-response will 
be determined in advance. The classification procedure occurs in two stages, following the 
baseline image acquisition and (possibly) following the 5-week image acquisition and 
calculation of ΔTUVglobal[5w]. After the baseline imaging, patients whose TUVglobal[b] is < 5 are 
predicted to be non-responders. After ΔTUVglobal[5w] is available, patients whose TUVglobal[b] is 
≥ 5 and ∆ % is ≤ -10% are predicted to be responders. All other patients are predicted to be 
non-responders. See the ΔTUVglobal[5w] bucketing algorithm specified in the Statistical Analysis 
Plan for details on this algorithm and for additional algorithms specified for the secondary 
analysis. The Week 24 ACR50 will be used as the primary determination of clinical response 
for the reference standard. The hypotheses for the co-primary endpoints to be tested are: 
𝐻𝐻𝑂𝑂2: 𝜋𝜋Sp ≤0.8
𝐻𝐻𝐴𝐴2: 𝜋𝜋Sp > 0.8; 
 


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And 
𝐻𝐻𝑂𝑂1: 𝜋𝜋Se ≤0.65
𝐻𝐻𝐴𝐴1: 𝜋𝜋Se > 0.65. 
 
In the above πSp represents the true specificity of the classification procedure and πSe represents 
the true sensitivity of the classification procedure when used to predict the outcome of the anti-
TNFa bDMARD inhibitor therapy at 24 weeks. An overall two-tailed Type I error rate of 0.05 
(one-tailed 0.025) was used without adjusting for multiple endpoints, as both co-primary 
endpoints must be achieved (i.e., at least the same two of three readers reject both null 
hypotheses) in order to have a successful study.  
If the actual specificity is 0.92 and the actual sensitivity is 0.8, and if an exact binomial test is 
used to test the above hypotheses, a total of 98 clinical non-responders and 100 clinical 
responders are needed for 90% power of the individual tests. That is, a minimum of 198 total 
patients is needed. This applies to single reader.  
To evaluate the power characteristics of this process with 3 correlated readers where at least 
the same two of the three readers must reject both null hypotheses above, a simulation study 
was performed. Correlated binomial random variables were generated using a copula. The 
hypotheses were tested for each simulated reader using an exact binomial test, and the number 
of iterations where at least the same two of the three readers rejected both hypotheses was 
counted. Under the conditions above this procedure has power 0.93 when ρ = 0.7 and 0.89 
when ρ = 0.9. 
In Arm 3 of the NAV3-31 study a ratio of 5 non-responders to 1 responder was observed. If 
this ratio is maintained in NAV3-33 for the ΔTUVglobal[5w] bucketing predictions, a total of 654 
patients is needed to achieve the desired power. That is, a total of 500 clinical non-responder 
patients is expected to be enrolled before reaching the required 100 clinical responders. Taking 
into account a 10% dropout rate, the anticipated total sample size for the study is approximately 
672 patients (560 clinical non-responders and 112 clinical responders).  That is:  
• Clinical Non-Responders: 90% completion rate relative to 560 enrolled patients 
will result in 500 completed patients   
• Clinical Responders: 90% completion rate relative to 112 enrolled patients will 
result in 100 completed patients    
Because there is uncertainty about how responding and non-responding patients will enroll, 
enrollment will continue until at least 560 clinical non-responders and 112 clinical responders 
are participating in the study. The cumulative enrollment of clinical non-responders and 
responders will be tracked throughout the study in order to stop enrollment once the required 
number has been reached for each clinical category. This tracking of clinical response and non-
response status will be performed by individuals without knowledge of the clinical response 
data. 


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If the two co-primary endpoints are achieved (i.e., both null hypotheses are rejected for at least 
the same 2 out of 3 readers), then the following hypotheses will be tested at one-tailed 0.025 
for the key secondary endpoint of NPV of TUVglobal[b] with respect to ACR50 at week 24: 
 
𝐻𝐻𝑂𝑂3: 𝜋𝜋NPV ≤0.7
𝐻𝐻𝐴𝐴3: 𝜋𝜋NPV > 0.7; 
 
If the actual NPV is 0.85, and if an exact binomial test is used to test the above hypotheses, a 
total of 89 predicted non-responders using TUVglobal[b] are needed for 90% power and a total 
of 71 non-responders using TUVglobal[b] are needed for 80% power. 
  
9.5 
Statistical Analyses 
9.5.1 
Analysis Populations 
The following populations are defined for this study: 
Intent-to-Diagnose (ITD) Population – Patients in the safety population meeting the 
following criteria are members of the ITD population: 
• Were injected with Tc 99m tilmanocept at Visit 2 (Day 0) 
• Received planar imaging of the hands at Visit 2 (Day 0) 
This population will include all patients for whom a prediction might be made, although some 
patients may be excluded from analysis under this definition if a prediction cannot be made 
due to missing Day 0 imaging data. 
Per-Protocol (PP) Population – The PP population consists of all ITD subjects without major 
protocol violations. 
Safety Population – The safety population includes all subjects who have been enrolled in the 
study and injected with at least one dose of Tc 99m tilmanocept. 
9.5.2 
Analysis of Baseline and Demographic Characteristics 
Baseline and demographic characteristics of the safety population will be summarized by 
subject status and overall.  Continuous variables (age, height, and weight) will be summarized 
via mean, standard deviation, minimum, maximum, and number of non-missing responses. 
Categorical variables (biological sex, race and ethnicity) will be summarized via counts and 
percentages. 
Additionally, summaries of the agreement between the primary TUV prediction algorithm 
and all clinical outcomes will be performed in the following subgroups: 
• Age (< 60 years, 60 years and older) 


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• Sex 
• Race (white, non-white) 
• Time from RA diagnosis (< 5 years, 5 years and longer) 
• Disease severity at baseline (moderate, severe) 
• Previous use of biologics (yes, no) 
• Previous and current use of DMARDs (background methotrexate only, other 
conventional DMARDs only, combination of methotrexate and other conventional 
DMARDs) 
• Specific anti-TNFα therapy taken during trial 
• Prednisone use on-study (on a stable dose, no prednisone use) 
• ACPA (or CCP) level at baseline (high/low: 85 and above / < 85) 
The study will make every effort to enroll enough patients in each of these subgroups so that 
half-widths of the 95% confidence intervals of NPV and PPV are less than 20%. P-values on 
parameter estimates will not be included. 
9.5.3 
Analysis of Efficacy Variables 
All efficacy analyses will be conducted on both the ITD and PP populations. The ITD 
population will be the primary analysis set. 
9.5.3.1 
Analysis of Primary Efficacy Variables 
The co-primary efficacy variables will be summarized by reader in a 2 by 2 contingency table 
displaying the cell frequencies and marginal totals at 24 weeks. The specificity of 
ΔTUVglobal[5w] bucketing and the sensitivity of ΔTUVglobal[5w] bucketing will be calculated for 
each reader. The 95% exact (Clopper-Pearson) confidence intervals will be provided for each 
of these parameters. Observed significance levels (p-values) for the exact binomial tests of 
specificity of ΔTUVglobal[5w] bucketing greater than 0.8 and sensitivity of ΔTUVglobal[5w] 
bucketing greater than 0.65 will be provided. 
Specificity and sensitivity are defined according to the following cross-tabulation: 
 


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Clinical Response 
 
Predicted Reponse 
Responder 
Non-
Responder 
Total 
Responder 
A 
B 
T1 
Non-Responder 
C 
D 
T2 
Total 
T3 
T4 
N 
Sensitivity = A/T3 
Specificity = D/T4 
The above 2 by 2 contingency table will also be used to calculate the secondary efficacy 
endpoints of NPV, PPV, and OA as follows: 
NPV = D/T2 
PPV = A/T1 
Overall Accuracy = (A + D)/N. 
9.5.3.2 
Analysis of Key Secondary Efficacy Variables 
NPV of TUVglobal[b] will be calculated for each reader. The 95% exact (Clopper-Pearson) 
confidence intervals will be provided. Observed significance levels (p-values) for the exact 
binomial tests of NPV of TUVglobal[b] greater than 0.7 will be provided. 
9.5.3.3 
Analysis of Secondary Efficacy Variables 
All RA quantitative assessment variables (CDAI, ACR Response Criteria component scores, 
DAS28 score, and HAQ-DI) will be summarized by computing the mean, standard deviation, 
number of observations, minimum, median, and maximum for the observed values at each time 
point and for the change from baseline for values collected after Day 0. The ACR Response 
Criteria will be summarized with a frequency table of the highest ACR Response level (None, 
ACR20, ACR50, ACR70) attained by that patient at that time point. That is, a patient who 
satisfies ACR50 also satisfies ACR20 but will not appear in the frequency count for ACR20. 
Concordance of improvement classification for ΔTUVglobal[5w] bucketing with clinical criteria 
(ACR Response, CDAI, DAS28, and HAQ-DI) will be analyzed as follows. Note that the 
concordance of ΔTUVglobal[5w] bucketing with ACR50 is evaluated as co-primaries (sensitivity 
and specificity). For each of the RA improvement criteria, a cross-classification table will be 
provided. The sensitivity, specificity, PPV, NPV, and OA will be calculated and 95% exact 
(Clopper-Pearson) confidence intervals will be provided. 
The Kendall rank correlation between ΔTUVglobal[5w] with ΔCDAI12w and ΔCDAI24w will be 
computed and a 95% confidence interval for its value will be computed using Fisher’s 
Z transformation. Similarly, the Kendall rank correlation between ΔTUVglobal[5w] with changes 
from baseline in DAS28 and in each of the ACR Response Criteria components at weeks 12 
and 24 will be computed and a 95% confidence interval for its value will be computed using 


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Fisher’s Z-transformation. The marginal distributions of the variables will be characterized 
with the mean, standard deviation, and the number of data pairs.  
Additional efficacy analyses may be described in the NAV3-33 Statistical Analysis Plan 
(SAP).  
9.5.4 
Analysis of Safety Variables 
All safety analyses will be conducted on the safety population. 
All AEs will be observed for each subject from the time of signing of informed consent until 
study completion. A treatment-emergent AE (TEAE) is defined as an AE whose start date is 
on or after the initial procedure date. If the procedure date or the AE start date is missing, the 
AE will be considered treatment emergent. 
Prior to analysis all AEs will be coded using the MedDRA coding dictionary. Based on the 
coded terms, TEAEs will summarized by cohort and overall as follows: 
• By system organ class (SOC) and preferred term (PT); 
• By SOC and PT and relation to the study drug; 
• By SOC and PT and severity. 
 
Observed and change from baseline vital sign parameters, ECG parameters, and hematology, 
clinical chemistry and urinalysis parameters will be summarized using descriptive statistics 
(mean, standard deviation, median, and range) at each time point. 
Other safety analyses may be described in the SAP for the study. 
9.5.5 
Handling of Missing Values 
The data required for the statistical analysis of the primary efficacy endpoints are the 
predictions of responder status (i.e., based on TUV) and the 24-week determination of clinical 
response using ACR50. Handling of potential missing TUV and/or clinical data and imputation 
rules are discussed in the SAP.  
9.5.6 
Interim Analyses 
No interim analyses will be performed for this study. 


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10 DATA HANDLING AND QUALITY ASSURANCE 
10.1 Data Recording 
Data required according to this protocol is captured in the subject’s source documentation and 
are to be entered onto the electronic CRFs (provided by the sponsor) as soon as possible. 
10.1.1 
CRF Design 
Electronic CRFs (eCRFs) will be used for collecting all data generated during the trial. CRF 
completion details will be documented in a separate document that will be provided by the 
sponsor and maintained in the TMF. 
10.2 Monitoring 
This study will be monitored regularly by a clinical research associate (CRA) from the sponsor 
or a contract research organization (CRO).  Monitoring procedures include one 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 imaging facility prior to a favorable opinion from the IRB and the 
regulatory authority and, if appropriate, from the radiation protection authorities. In 
addition, the CRA will determine whether all AEs and SAEs have been appropriately reported 
(including adherence to the time periods required for SAEs). 
10.3 Data Processing 
Study data documentation will be maintained specifying all relevant aspects of data processing 
for the study (including data validation, cleaning, correcting, releasing).  This documentation 
will be stored in the TMF. 
For data coding (e.g., AEs, medication, medical/surgical history), internationally recognized 
and accepted dictionaries will be used.  These and the processes used for coding will be 
specified in the data management plan. 
10.4 Auditing 
A member of the sponsor’s (or a designated CRO) quality assurance unit may arrange to visit 
the investigator in order to audit the performance of the study at the study site and the study 
documents originating there.  The auditor(s) will usually be accompanied by a CRA or the 
study team leader.  The investigator will be informed about the outcome of the audit. 


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


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10.6.3 
Study as a Whole 
The sponsor retains the right to prematurely terminate the study as a whole at any time.  
At the discretion of the sponsor, the entire study may be canceled for medical reasons.  In 
addition, the sponsor retains the right to end the study at any time if the study cannot be carried 
out as agreed upon in the protocol. In case of early termination or suspension of the study, the 
principal investigator/sponsor will promptly inform the investigator/institutions, regulatory 
authorities, and IRB of the termination or suspension and the reason for that. 
10.6.4 
Center 
At any time, the study may be terminated at an individual center if: 
•
The center cannot comply with the requirements of the protocol.
•
It is not possible for the center to comply with GCP standards.
10.6.5 
Study Participant 
Individual subjects may be withdrawn from the study according to the criteria specified in 
Section 4.3. 


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11 ETHICAL AND LEGAL ASPECTS 
11.1 Ethical and Legal Conduct of the Study 
The planning and conduct of this clinical study are subject to national laws. Only when all of 
the requirements of the appropriate regulatory authority have been fulfilled will the study 
begin. The study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki and the ICH-GCP Guidelines of 17 Jan 1997 including 
Integrated Addendum to ICH E6(R1) as well as the Guideline For Good Clinical Practice 
E6(R2) of 24 August 2018. At the discretion of the investigator, the entire study may be 
canceled for medical reasons. In addition, the sponsor retains the right to end the study for 
medical-scientific or GCP-relevant reasons. In case of premature termination, the 
investigators, IRB(s) and Regulatory Authorities will be informed by the Study Manager. As 
required by local law, current safety-relevant information will be provided to the IRB(s) and 
the regulatory authorities by the sponsor. The sponsor will also inform all investigators about 
relevant safety events according to the applicable regulations. 
11.2 Subject Information and Consent 
All relevant information on the study will be summarized in the subject consent form and 
additionally as required by the investigator’s institution in an integrated subject information 
and consent sheet. A sample informed consent form (ICF) is provided as a document separate 
to this protocol. 
Based on this subject ICF, the investigator will explain all relevant aspects of the study to each 
subject, before entry into the study (i.e., before examinations and procedures associated with 
selection for the study are performed).  
The investigator will also mention that written approval of the IRB has been obtained.  Each 
subject will have ample time and opportunity to ask questions and will be informed about the 
right to withdraw from the study at any time without any disadvantage and without having to 
provide reasons for this decision.  Following this informative discussion, the subject will be 
asked if he/she is willing to sign and personally date a statement of informed consent.  Only if 
the subject voluntarily agrees to sign the ICF and has done so, may he/she enter the study. 
Additionally, the investigator or his/her designee will personally sign and date the form.  The 
subject will receive a duplicate of the signed and dated form.  
The investigator will record in the source documentation the consent process including the 
time and date of obtaining informed consent. In the event that informed consent is obtained on 
the date that baseline study procedures are performed, the study record or subject's clinical 
record must clearly show that informed consent was obtained prior to these procedures.  
The ICF and any other written information provided to subjects will be revised whenever 
important new information becomes available that may be relevant to the subject’s consent, or 
there is an amendment to the protocol which necessitates a change to the content of the subject 
information and/or the written ICF. The investigator will inform the subject of changes in a 


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


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Appendix 1 
Schedule of Events 
a Initiation of anti-TNFα bDMARD therapy change will occur following Day 0 procedures; b May be completed up to 30 days prior to imaging Visit 2 and up to 
7 days prior to imaging Visit 4;  
Evaluation 
Visit #1 
Screening 
(Day -30 to -1) 
Visit #2 
(Day 0) 
Visit #3 
Telephone 
(Day 5 ± 3) 
Visit 4 
(5 ± 1 Week Post-Treatment Change) 
- 00:30 
to 
- 00:01 
00:00 
00:01 
to 
 00:30 
60 to 75 
min 
After 
Imaginga 
- 00:30 
to 
- 00:01 
00:00 
00:01 
to 
00:30 
60 to 75 
min 
After 
Imaging 
Informed consent 
x 
Entry criteria 
x 
Medical History, RA 
History, Demography 
x 
2010 ACR/EULAR 
x 
Vital signs 
x 
x 
x 
x 
x 
Physical Examination 
x 
DAS28 
x 
x 
CDAIb 
x 
x 
HAQ-DI©b 
x 
x 
WPIb 
x 
x 
Clinical laboratory 
evaluation: chemistry, 
hematology, UA 
x 
x 
x 
RA panel 
x 
x 
Urine pregnancy test WCBP 
x 
x 
x 
Tc 99m tilmanocept 
administration  
x 
x 
Planar Imaging: bilateral 
hands and wrists  
x 
x 
Concomitant medications 
x 
x 
x 
x 
AE monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


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Evaluation 
Visit #5 
Telephone 
(5 ± 3 days 
after 
Visit 4) 
Visit #6  
(12 ± 1 Week Post-Treatment Change) 
Visit #8 
(24 ± 1 Week Post Treatment Change) 
Informed consent 
Entry criteria 
Medical History, RA 
History, Demography 
2010 ACR/EULAR 
Vital signs 
Physical Examination 
DAS28b 
x 
x 
CDAIb 
x 
x 
HAQ-DI© b 
x 
x 
WPIb 
x 
x 
Clinical laboratory 
evaluation: chemistry, 
hematology, UA 
RA panel 
x 
x 
Urine pregnancy test 
WCBP 
Tc 99m tilmanocept 
administration  
Planar Imaging: bilateral 
hands and wrists  
Concomitant medications 
x 
AE monitoring 
x 
x 
x 
Note: Visits 7 and 9 will not be conducted per this protocol amendment 


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Appendix 2 
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 


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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.  
** 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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Clinical Study Protocol: NAV3-33 
Navidea Biopharmaceuticals, Inc 
30 January 2024 
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Appendix 3 
DAS28 Scale 
Courtesy of http://www.iche.edu/newsletter/DAS28.pdf 


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30 January 2024   
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Appendix 4 
CDAI Scoring 


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Clinical Study Protocol: NAV3-33 
Navidea Biopharmaceuticals, Inc 
30 January 2024  
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Appendix 5 
ACR Response Criteria 
ACR Response Criteria 
The ACR (American College of Rheumatology) Criteria is a standard criteria to measure the effectiveness of various arthritis medications or treatments in clinical trials for Rheumatoid Arthritis. 
The ACR is used to maximally discrimate effective treatment for placebo treatment in clincal trials. The ACR criteria is indicated as ACR 20, ACR 50, or ACR 70. The ACR is reported as % 
improvement, comparing disease activity at two discrete time points (usually baseline and post-baseline comparison).  
•
ACR20 is ≥ 20% improvement
•
ACR50 is ≥ 50% improvement
o
ACR50 reponders include ACR20 responders
•
ACR70 is ≥ 70% improvement
o
ACR70 reponders include ACR20 & ACR50 responders 
Definition 
The ACR Criteria is a dichotomous variable with a positive (=responder) or negative (=non-reponder) outcome.  
The ACR Criteria measures improvement in tender and swollen joint counts in improvement in at least three or the following parameters: 
1.
Patient assessment 
2.
Physician assessment
3.
Pain scale 
4.
Disability/functional questionnaire 
5.
Acute phase reactant (ESR or CRP)
ACR 20 has a positive outcome if 20% improvement in tender and swollen joint counts were achieved as well as 20% improvement in at least three of the other five criteria.  
ACR 50 has a positive outcome if 50% improvement in tender and swollen joint counts were achieved as well as 50% improvement in at least three of the other five criteria. 
ACR 70 has a positive outcome if 70% improvement in tender and swollen joint counts were achieved as well as 70% improvement in at least three of the other five criteria. 


Technetium Tc 99m tilmanocept 
Clinical Study Protocol: NAV3-33 
Navidea Biopharmaceuticals, Inc 
30 January 2024   
Confidential 
Page 85 of 89 
Appendix 6 
HAQ-DI© Questionnaire 


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30 January 2024   
Confidential 
Page 86 of 89 


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Clinical Study Protocol: NAV3-33 
Navidea Biopharmaceuticals, Inc 
30 January 2024   
Confidential 
Page 87 of 89 
Courtesy of https://integrationacademy.ahrq.gov/center/default/files/-DI_0.pdf 


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Clinical Study Protocol: NAV3-33
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Confidential
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Appendix 7
Sponsor Signatures
Study Title:
Evaluation of Tc 99m Tilmanocept Imaging for the Early 
Prediction of Anti-TNF  Therapy Response in Subjects with 
Moderate to Severe Active Rheumatoid Arthritis (RA)
Study Number:
NAV3-33 
Original Protocol 
Date:
11 November 2021
Amendment 1 Date:
18 January 2022 
Amendment 2 Date:
01 November 2022 
Amendment 3 Date:
29 September 2023 
Amendment 4 Date:
30 January 2024 
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: 
Date:
Simon Blackburn 
Director, Clinical Development 
Navidea Biopharmaceuticals
Signed: 
Date:
Joanna Shuping 
Director, Clinical Operations 
Navidea Biopharmaceuticals
Signed: 
Date:
Michael S. Blue, MD 
Chief Medical Officer
Navidea Biopharmaceuticals
Signed: 
Date:
Rich McFerron
Sr. Director, Regulatory Affairs
Navidea Biopharmaceuticals


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Clinical Study Protocol: NAV3-33 
Navidea Biopharmaceuticals, Inc
30 January 2024    
Confidential 
Page 89 of 89 
Appendix 8 
Investigator’s Signature 
Study Title: 
Evaluation of Tc 99m Tilmanocept Imaging for the Early 
Prediction of Anti-TNFα Therapy Response in Subjects with 
Moderate to Severe Active Rheumatoid Arthritis (RA) 
Study Number: 
NAV3-33 
Original Protocol 
Date: 
11 November 2021 
Amendment 1 Date: 
18 January 2022 
Amendment #2: 
01 November 2022 
Amendment #3 
29 September 2023 
Amendment # 4: 
30 January 2024 
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: