Clinical trial NCT03938636
Conditions: Rheumatoid Arthritis
Keywords: RA healthy control tilmanocept diagnostic imaging
Sponsor: Navidea Biopharmaceuticals
Start date: 2019-04-08; Completion date: 2021-06-30
Enrollment: 116 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This clinical trial will look at scans of the hands and wrists taken from healthy control subjects (HCs) and from subjects with rheumatoid arthritis (RA). Before each scan, subjects will be given an injection of Tc 99m tilmanocept to help the scan identify inflammation in the hand and wrist joints, which can be a part of the RA disease. Data from the scans will be used to calculate a number referred to as tilmanocept uptake value (or TUV) that is a measure of how much Tc 99m tilmanocept has located in the joints. The questions this trial aims to answer are:

* How consistent are the scan results (TUVs) when the scans are repeated over time?
* What are normal TUVs in healthy people? This will help define abnormally high values in people with RA.
* Are TUVs calculated early after a person starts a new drug to treat RA able to predict whether that person will have a good response to the drug later on (after it has had time to take full effect several weeks later)?

Detailed description:
This trial is a prospective, open-label, multicenter, single and repeated-dose study designed to evaluate the reliability and sensitivity of TUV assessments in healthy control subjects and subjects with active RA.

This study is stratified into 3 arms. The first 2 arms, consisting of \[1\] disease-free HCs and \[2\] clinically diagnosed RA subjects on stable treatment, respectively, are designed to evaluate the image re-image and/or test re-test (i.e., repeated dose) consistency of joint-specific and global TUVs across a variety of image acquisition intervals.

The third arm consists of clinically-diagnosed subjects with active RA who are candidates for initiation of, or change to, a new anti-TNFα bDMARD therapy. This arm is designed to assess the efficacy of TUVglobal as an early predictor of response to the new anti-TNFα bDMARD therapy.

Arms: arm 1: Arm 1 includes inflammatory-disease-free HCs. Arm 1 was designed to evaluate image/re-image consistency (repeatability and stability) of joint-specific and global TUVs across a variety of image acquisition intervals and to collect normative HC data. arm 2: Arm 2 includes clinically-diagnosed RA subjects on stable treatment. Arm 2 was designed to evaluate image/re-image and test re-test (i.e., repeated dose) consistency of joint-specific and global TUVs across a variety of image acquisition intervals. arm 3: Arm 3 includes clinically-diagnosed RA subjects on stable treatment who are candidates for initiation of, or change to, new anti-TNFα therapy. Arm 3 was designed to assess the efficacy of global TUVs, obtained before and after initiation of a new anti-TNFα therapy, to predict future clinical responsiveness to the new therapy.
Interventions: intervention 1: Tc 99m tilmanocept
Intervention descriptions: intervention 1: Tilmanocept is a radiotracer that accumulates in macrophages by binding to a mannose binding receptor that resides on the surface.

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol: NAV3-31 
Study Title: 
Evaluation of the Precision and Sensitivity of Tilmanocept Uptake 
Value (TUV) on Tc 99m Tilmanocept Planar Imaging 
Study Number: 
NAV3-31 
Study Phase: 
Phase 2b 
Product Name: 
Technetium Tc 99m tilmanocept 
IND Number: 
132943 
Investigators: 
Multicenter 
Sponsor: 
Navidea Biopharmaceuticals, Inc. 
4995 Bradenton Ave., Suite 240 
Dublin, OH 43017 
Sponsor 
Contact: 
Bonnie Abbruzzese, MS, CCRA 
Senior Director, Clinical Research & Development 
(614) 946-8077
Medical 
Monitor: 
Michael Blue, MD, FACEP 
Senior Medical Director 
(614) 571-4313
Date 
Original Protocol: 
16 November 2018 
Amendment #1: 
28 February 2019 
Amendment #2 
19 April 2019 
Amendment #3 
24 April 2019 
Amendment #4 
02 February 2021 
Confidentiality Statement 
This document and its contents are the property of and confidential to Navidea 
Biopharmaceuticals. Any unauthorized copying or use of this document is prohibited. 
NCT03938636


Technetium Tc 99m tilmanocept 
 
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Clinical Trial Protocol: NAV3-31 
 
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SYNOPSIS 
Study Title: 
Evaluation of the Precision and Sensitivity of Tilmanocept Uptake Value (TUV) on Tc 
99m Tilmanocept Planar Imaging  
Study Number: 
NAV3-31 
Study Phase: Phase 2b 
Primary Objective(s):  
• To assess the longitudinal precision of joint-specific (TUVjoint) and global 
(TUVglobal) TUVs on planar imaging in subjects with clinically diagnosed active 
rheumatoid arthritis (RA) on stable anti-rheumatic therapy. 
• To evaluate the camera-specific precision of TUVjoint and TUVglobal on planar 
imaging in healthy controls (HCs) and in subjects with clinically diagnosed active 
RA using centralized and standardized imaging parameters. 
• To assess the correlation of TUV and changes in TUV with changes in clinical 
assessments at multiple time points after initiation of a new anti-tumor necrosis 
factor alpha (TNFα) biologic disease-modifying antirheumatic drug (bDMARD) 
therapy. 
Secondary Objective(s): 
• To assess the temporal post-injection stability of TUVjoint and TUVglobal at a dose of 
150 mcg tilmanocept radiolabeled with 10 mCi of Tc 99m. 
• To establish normal ranges for TUVjoint in HCs.  
• To assess Tc 99m tilmanocept anatomic localization based on single photon 
emission computed tomography/ computed tomography (SPECT/CT) imaging of 
the synovial space in hands and wrists.   
Safety Objective:  
• To evaluate safety through the examination of adverse event (AE) incidence and 
changes over time in laboratory tests, vital signs, and physical examination 
findings. 


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Clinical Trial Protocol: NAV3-31 
 
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Inclusion Criteria:   
ALL SUBJECTS 
1. The subject has provided written informed consent with HIPAA (Health 
Information Portability and Accountability Act) authorization before the 
initiation of any study-related procedures. 
2. ARMS 1 and 2 (only): The subject has agreed to not engage in any diet, 
lifestyle, or medication changes until study completion.  
 
HEALTHY CONTROL SUBJECTS  
3. The subject is between 18 and 80 years of age at the time of consent. 
4. The subject is deemed to be clinically free of any inflammatory disease(s) and 
has not experienced joint pain for at least 28 days prior to the consent date. 
5. The subject is not currently on anti-inflammatory drugs (including non-steroidal 
anti-inflammatory drugs [NSAIDs]) and has not taken any anti-inflammatories 
for at least 28 days prior to the consent date.  
6. For all ongoing concomitant medications, the subject has maintained a stable 
dose for at least 28 days prior to the consent date. 
 
RA SUBJECTS 
3. The subject is at least 18 years of age and was ≥ 18 years of age at the time of 
RA diagnosis. 
4. The subject has moderate to severe RA as determined by the 2010 American 
College of Rheumatology/European League Against Rheumatism 
(ACR/EULAR) Classification Criteria (score of ≥ 6/10). 
5. The subject has a 28-joint disease activity score (DAS28) of ≥ 3.2 (includes the 
Erythrocyte Sedimentation Rate [ESR] test and Visual Analog Scale [VAS]). 
6. Subjects receiving traditional DMARDs must have been on therapy for 
≥ 90 days and at a stable dose for ≥ 30 days prior to the first imaging visit 
(Day 0). 
7. If the subject is receiving bDMARD or janus kinase (JAK) inhibitor therapy, 
they have been at a stable dose > 180 days prior to the first imaging visit 
(Day 0).  
8. If the subject is receiving NSAIDs or oral corticosteroids, the dose has been 
stable for > 28 days prior to first imaging visit (Day 0). The corticosteroid dose 
must be ≤ 10 mg/day of prednisone or an equivalent steroid dose. 
9. ARM 3 (only): The subject is receiving anti-rheumatic treatment and is a 
candidate for initiation of, or change to, a new anti-TNFα bDMARD treatment. 
 
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 has had or is currently receiving radiation therapy or chemotherapy. 
4. The subject has renal insufficiency as demonstrated by a glomerular filtration 
rate of < 60 mL/min. 


Technetium Tc 99m tilmanocept 
 
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Clinical Trial Protocol: NAV3-31 
 
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5. The subject has hepatic insufficiency as demonstrated by ALT (alanine 
aminotransferase [SGPT]) or AST (aspartate aminotransferase [SGOT]) greater 
than 3 times the upper limit of normal. 
6. 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. 
7. The subject has a known allergy to or has had an adverse reaction to dextran 
exposure. 
8. The subject has received an investigational product within 30 days prior to the 
Tc 99m tilmanocept administration (Day 0). 
9. The subject has received intra-articular corticosteroid injections ≤ 8 weeks prior 
to the first imaging visit (Day 0). 
10. 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). 
 
Study Design: 
This is a prospective, open-label, multicenter, single and repeat-dose study designed to 
evaluate the reliability and sensitivity of TUV assessments in HCs and subjects with 
active RA.  
TUV is a quantitative imaging metric used to characterize Tc 99m tilmanocept uptake 
on planar imaging. Results from a prior Phase 1 and 2 study have demonstrated that 
TUV is a sensitive and specific predictor of visually interrogated Tc 99m tilmanocept 
localization in joint regions with presumed inflammatory macrophage activity. A per-
joint TUV (TUVjoint) relative ratio will be calculated for the each of the 22 DAS-28 
joints located in the hands and wrists. A subject-level global TUV (TUVglobal) assessed 
across the 22 joints will be used as an indication of overall disease burden. TUV 
metrics are further described in the NAV3-31 Statistical Analysis Plan. 
This study is stratified into 3 arms. The first 2 arms, comprised of [1] disease-free HCs 
and [2] clinically diagnosed RA subjects on stable treatment, respectively, are designed 
to apprise the image re-image and/or test re-test (i.e., repeat dose) consistency of joint-
specific and global TUVs across a variety of image acquisition intervals including: 
• Consecutive (15-minute) acquisitions—for the assessment of TUV precision in 
relation to camera settings and standardization (Study Arms 1 and 2); 
• Temporal (1-hour and 3-hour) acquisitions—for the assessment of TUV 
stability across a 2-hour time window that is conducive to variable patient 
workflow in clinical practice (Study Arms 1 and 2), and; 
• Longitudinal (8 ± 1-day) acquisitions—for the assessment of TUV precision in 
the context of disease-specific Tc 99m tilmanocept pharmacodynamics (Study 
Arm 2 only). 
 


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Clinical Trial Protocol: NAV3-31 
 
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The third arm is designed to assess the efficacy of TUVglobal in clinically diagnosed 
subjects with active RA who are candidates for initiation of, or change to, a new anti-
TNFα bDMARD therapy. Specific evaluations will include:  
• Sensitivity—the capacity for TUVglobal to detect changes in disease activity from 
baseline to 5 ± 1 weeks of new anti-TNFα bDMARD treatment 
(ΔTUVglobal[5w]), and; 
• Clinical concordance—the correlation between the change in TUVglobal from 
baseline to 5 ± 1 weeks post-therapy and change in established rheumatological 
measures of disease response from baseline to 12 ± 1 and 24 ± 1 weeks post-
therapy including Clinical Disease Activity Index (ΔCDAI12/24w) and ACR 
Response (ACR12/24w). 
 
Methodology: 
Study Arm 1: HC Subjects Free of Inflammatory Disease 
Visit 1 (Screening; Day -30 to Day -1) 
• Informed consent 
• Review of study eligibility 
• Collection of medical history (including medications)  
• Vital sign assessment 
• Physical examination (including height and weight)  
• Clinical labs 
• RA-specific labs  
• Urinalysis 
• Urine pregnancy test for subjects of childbearing potential 
• 2010 ACR/ EULAR score 
 
Visit 2 (Tc 99m Tilmanocept Administration and Imaging; Day 0) 
Pre-Tc 99m Tilmanocept Administration 
• Urine pregnancy test for women of child-bearing potential  
• Electrocardiogram (ECG) up to 30 minutes prior to drug administration 
• Post-ECG vital sign assessment 
• Review of concomitant medications 
• AE assessment 
 
Tc 99m Tilmanocept Administration: Subjects will receive a single intravenous (IV) 
dose of 150 mcg tilmanocept radiolabeled with 10 mCi (370 MBq) of Tc 99m. 
0-30 Minutes Post-Tc 99m Tilmanocept Administration 
• ECG 
• Post-ECG vital sign assessment 


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Clinical Trial Protocol: NAV3-31 
 
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• AE assessment 
 
60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration 
• AE assessment  
• Image acquisition (in the following order) 
1. Planar scan of the whole body followed by up to a 15-minute pause 
(includes patient preparation for the subsequent acquisition); 
2. Planar scan of the bilateral hands and wrists followed by immediate 
preparation (up to 10 minutes) for the subsequent scan; 
3. Consecutive planar scan of the whole body followed by up to a 15-
minute pause (includes patient preparation for the subsequent 
acquisition); 
4. Consecutive planar scan of the bilateral hands and wrists followed by a 
pause until the 180 ± 15-minute imaging timepoint. 
 
180 ± 15 Minutes Post-Tc 99m Tilmanocept Administration 
• AE assessment 
• Image acquisition (in the following order) 
1. 
Planar scan of the whole body followed by up to a 15-minute pause 
(includes patient preparation for the subsequent acquisition); 
2. 
Planar scan of the bilateral hands and wrists followed by immediate 
preparation (up to 10 minutes) for the subsequent scan; 
3. 
Consecutive planar scan of the whole body followed by up to a 15-
minute pause (includes patient preparation for the subsequent 
acquisition); 
4. 
Consecutive planar scan of the bilateral hands and wrists  
• Clinical labs (after imaging) 
• Urinalysis (after imaging) 
 
Visit 3 (Follow-up Telephone Safety Assessment; Day 5 ± 3) 
• Review of concomitant medications 
• AE assessment 


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Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-31 
 
02 February 2021 
 
 
 
 
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Study Arm 2: RA Subjects on Stable Therapy 
Visit 1 (Screening; Day -30 to Day -1) 
• Informed consent 
• Review of study eligibility 
• Collection of medical history (including medications)  
• Vital sign assessment 
• Physical examination (including height and weight)  
• Clinical labs 
• RA-specific labs  
• Urinalysis 
• Urine pregnancy test for subjects of childbearing potential 
• 2010 ACR/EULAR score 
• DAS28 evaluation 
 
Visit 2 (Tc 99m Tilmanocept Administration and Imaging; Day 0) 
Pre-Tc 99m Tilmanocept Administration  
• Urine pregnancy test for women of child-bearing potential  
• ECG up to 30 minutes prior to drug administration 
• Post-ECG vital sign assessment 
• Review of concomitant medications 
• Adverse event (AE) assessment  
 
Tc 99m Tilmanocept Administration: Subjects will receive a single IV dose of 150 mcg 
tilmanocept radiolabeled with 10 mCi (370 MBq) of Tc 99m. 
0-30 Minutes Post-Tc 99m Tilmanocept Administration 
• ECG 
• Post-ECG vital sign assessment 
• AE assessment 
 
60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration:  
• AE Assessment 
• Image acquisition (in the following order): 
1. Planar scan of the whole body followed by up to a 15-minute pause 
(includes patient preparation for the subsequent acquisition); 
2. Planar scan of the bilateral hands and wrists followed by immediate 
preparation (up to 10 minutes) for the subsequent scan; 


Technetium Tc 99m tilmanocept 
 
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Clinical Trial Protocol: NAV3-31 
 
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3. Consecutive planar scan of the whole body followed by up to a 15-
minute pause (includes patient preparation for the subsequent 
acquisition); 
4. Consecutive planar scan of the bilateral hands and wrists followed by a 
pause until the 180 ± 15-minute imaging timepoint. 
 
180 ± 15 Minutes Post-Tc 99m Tilmanocept Administration 
• AE assessment 
• Image acquisition (in the following order): 
1. Planar scan of the whole body followed by up to a 15-minute pause 
(includes patient preparation for the subsequent acquisition); 
2. Planar scan of the bilateral hands and wrists followed by immediate 
preparation (up to 10 minutes) for the subsequent scan; 
3. Consecutive planar scan of the whole body followed by up to a 15-
minute pause (includes patient preparation for the subsequent 
acquisition); 
4. Consecutive planar scan of the bilateral hands and wrists. 
• Clinical labs (after imaging) 
• Urinalysis (after imaging) 
 
Visit 3 (Follow-up Telephone Safety Assessment; Day 5 ± 3) 
• Review of concomitant medications 
• AE assessment 
 
Visit 4 (Tc 99m Tilmanocept Administration and Imaging; Day 8 ± 1) 
Pre-Tc 99m Tilmanocept Administration 
• Urine pregnancy test for women of child-bearing potential  
• ECG up to 30 minutes prior to drug administration 
• Post-ECG vital sign assessment 
• Review of concomitant medications 
• AE assessment 
 
Tc 99m Tilmanocept Administration: Subjects will receive a single IV dose of 150 mcg 
tilmanocept radiolabeled with 10 mCi (370 MBq) of Tc 99m. 
0-30 Minutes Post-Tc 99m Tilmanocept Administration 
• ECG 
• Post-ECG vital sign assessment 
• AE assessment 
 


Technetium Tc 99m tilmanocept 
 
Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-31 
 
02 February 2021 
 
 
 
 
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60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration: 
• AE assessment 
• Image acquisition (in the following order): 
1. Planar scan of the whole body followed by up to a 15-minute pause 
(includes patient preparation for the subsequent acquisition) 
2. Planar scan of the bilateral hands and wrists followed by a pause until 
the 180 ± 15-minute imaging timepoint 
 
180 ± 15 Minutes Post-Tc 99m Tilmanocept Administration 
• AE assessment 
• Image acquisition (in the following order): 
1. Planar scan of the whole body followed by up to a 15-minute pause 
(includes patient preparation for the subsequent acquisition); 
2. Planar scan of the bilateral hands and wrists followed by immediate 
preparation (up to 15 minutes) for the subsequent SPECT/CT scan 
3. SPECT/CT scan of the bilateral hands and wrists. 
•  Clinical labs (after imaging) 
• Urinalysis (after imaging) 
 
Visit 5 (Follow-up Telephone Safety Assessment; 1-3 days following Visit 4 ) 
• Review of concomitant medications 
• AE assessment 
 
Study Arm 3: RA Subjects who are Candidates for Initiation of, or Change to, a 
New Anti-TNFα bDMARD Therapy* 
Visit 1 (Screening; Day -30 to Day -1): 
• Informed consent 
• Review of study eligibility 
• Collection of medical history (including medications) 
• Vital sign assessment  
• Physical examination (including height and weight) 
• Clinical labs 
• RA-specific labs 
• Urinalysis 
• Urine pregnancy test for women of childbearing potential 
• 2010 ACR/EULAR score 
• DAS28 evaluation 
• Health Assessment Questionnaire Disability Index (HAQ-DI©) 
• CDAI 


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Clinical Trial Protocol: NAV3-31 
 
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• Widespread Pain Index (WPI) 
Visit 2 (Baseline Tc 99m Tilmanocept Administration and Imaging; Day 0)  
Pre-Tc 99m Tilmanocept Administration 
• Urine pregnancy test for women of child-bearing potential  
• ECG up to 30 minutes prior to drug administration 
• Post-ECG vital sign assessment 
• Review of concomitant medications 
• AE assessment 
 
Tc 99m Tilmanocept Administration: Subjects will receive a single IV dose of 150 mcg 
tilmanocept radiolabeled with 10 mCi (370 MBq) of Tc 99m. 
0-30 Minutes Post-Tc 99m Tilmanocept Administration 
• ECG 
• Post-ECG vital sign assessment 
• AE assessment 
 
60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration  
• AE assessment 
• Image acquisition (in the following order): 
1. Planar scan of whole body 
2. Planar scan of bilateral hands and wrists 
• Clinical labs (after imaging) 
• Urinalysis (after imaging) 
 
Upon the completion of all Visit 2 procedures, subjects will initiate their new anti-
TNFα bDMARD treatment regimen.  
Visit 3 (Follow-up Telephone Safety Assessment; Day 5 ± 3) 
• Review of concomitant medications 
• AE assessment 
 
Visit 4 (Week 5 ± 1 Tc 99m Tilmanocept Administration, Imaging, and Clinical 
Assessments) 
Pre-Tc 99m Tilmanocept Administration (0-7 days pre-injection)   
• CDAI 
• DAS28 
• HAQ-DI© 
• WPI 
 


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Clinical Trial Protocol: NAV3-31 
 
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Pre-Tc 99m Tilmanocept Administration (day of injection) 
• Urine pregnancy test for women of child-bearing potential 
• ECG up to 30 minutes prior to tilmanocept administration 
• Post-ECG vital sign assessment 
• Review of concomitant medications 
• AE assessment 
 
Tc 99m Tilmanocept Administration: Subjects will receive a single IV dose of 150 mcg 
tilmanocept radiolabeled with 10 mCi (370 MBq) of Tc 99m. 
0-30 Minutes Post-Tc 99m Tilmanocept Administration 
• ECG 
• Post-ECG vital sign assessment 
• AE assessment 
 
60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration  
• AE assessment 
• Image acquisition (in the following order): 
1. Planar scan of whole body 
2. Planar scan of bilateral hands and wrists 
• Clinical labs (after imaging) 
• RA-specific labs (after imaging) 
• Urinalysis (after imaging) 
 
Visit 5 (Follow-up Telephone Safety Assessment; 5 ± 3 Days After Visit 4) 
• Review of concomitant medications 
• AE assessment 
 
Visit 6 (Week 12 ± 1 Tc 99m Tilmanocept Administration, Imaging, and Clinical 
Assessments*) 
Pre-Tc 99m Tilmanocept Administration (0-7 days pre-injection)  
• CDAI 
• DAS28 
• HAQ-DI© 
• WPI 
 
Pre-Tc 99m Tilmanocept Administration (day of injection) 
• Urine pregnancy test for women of child-bearing potential 
• ECG up to 30 minutes prior to tilmanocept administration 


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Clinical Trial Protocol: NAV3-31 
 
02 February 2021 
 
 
 
 
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• Post-ECG vital sign assessment 
• Review of concomitant medications 
• AE assessment 
 
Tc 99m Tilmanocept Administration: Subjects will receive a single IV dose of 150 mcg 
tilmanocept radiolabeled with 10 mCi (370 MBq) of Tc 99m. 
0-30 Minutes Post-Tc 99m Tilmanocept Administration 
• ECG 
• Post-ECG vital sign assessment 
• AE assessment 
 
60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration  
• AE assessment 
• Image acquisition (in the following order): 
1. Planar scan of whole body 
2. Planar scan of bilateral hands and wrists 
• Clinical labs (after imaging) 
• RA-specific labs (after imaging) 
• Urinalysis (after imaging) 
 
Visit 7 (Follow-up Telephone Safety Assessment; 5 ± 3 Days After Visit 6) 
• Review of concomitant medications 
• AE assessment 
 
Visit 8 (Week 24 ± 1 Tc 99m Tilmanocept Administration, Imaging, and Clinical 
Assessments*) 
Pre-Tc 99m Tilmanocept Administration (0-7 days pre-injection) 
• CDAI 
• DAS28 
• HAQ-DI© 
• WPI 
 
Pre-Tc 99m Tilmanocept Administration (day of injection) 
• Urine pregnancy test for women of child-bearing potential  
• ECG up to 30 minutes prior to tilmanocept administration 
• Post-ECG vital sign assessment 
• Review of concomitant medications 
• AE assessment 


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Clinical Trial Protocol: NAV3-31 
 
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Tc 99m Tilmanocept Administration: Subjects will receive a single IV dose of 150 mcg 
tilmanocept radiolabeled with 10 mCi (370 MBq) of Tc 99m. 
0-30 Minutes Post-Tc 99m Tilmanocept Administration 
• ECG 
• Post-ECG vital sign assessment 
• AE assessment 
 
60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration  
• AE assessment 
• Image acquisition (in the following order): 
1. Planar scan of whole body 
2. Planar scan of bilateral hands and wrists 
• Clinical labs (after imaging) 
• RA-specific labs (after imaging) 
• Urinalysis (after imaging) 
 
Visit 9 (Follow-up Telephone Safety Assessment; 5 ± 3 Days After Visit 8) 
• Review of concomitant medications 
• AE assessment 
 
*If a subject in Arm 3 requires early exit from the study between Week 16 and Week 
24, an attempt should be made to complete a final imaging visit and all clinical 
assessments.  
Test Product, Dose, and Mode of Administration:  
Tc 99m tilmanocept will be administered through an IV route of injection. A 150-mcg 
dose containing 10 mCi of Tc 99m will be injected as a slow push into the IV catheter. 
At the completion of the injection, a 10-mL sterile normal saline flush will be 
administered. The preferred site of IV placement will be between the elbow and the 
wrist. 
Planned Number of Study Centers: 
Up to 10 centers in the United States 
Sample Size: 
105 evaluable subjects in Arms 1, 2, and 3 as allocated below. Arms 1 and 2 will have 
N = 38 evaluable subjects per Arm, and Arm 3 will have N = 29 evaluable subjects. A 
subject is considered evaluable if he/she meets the criteria for the analysis population 
and has the data necessary for computing the primary endpoint. 


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Rationale for Sample Size: 
The sample size for Arm 1 was determined to provide sufficient data to quantify the 
precision of TUV in HCs. The sample size of Arm 2 was determined to power a 
hypothesis test of   
H𝑂𝑂: 𝜋𝜋≤0.80 
H𝐴𝐴: 𝜋𝜋> 0.80 
at 80%. Here, π represents the fraction of the absolute differences less than 7.5%. The 
sample size for Arm 3 was determined to set the length of the lower 97.5% confidence 
limit for Spearman’s rank correlation to be no more than 0.15. 
After the injection, imaging, and quantitation of a total of 4 subjects in Arms 1 and 2, 
an interim analysis (interim analysis 1) will be held for the review of quantitative TUV 
results and assessment of imaging parameters and logistics. A second interim analysis 
(interim analysis 2) will be held after a total of 30 subjects (≥ 15 RA) in Arms 1 and 2 
are injected, imaged, and quantified for the review of intra-and inter-subject TUV 
variation to contribute to the power analysis of a future Phase 3 study and/or to 
terminate the study on grounds of data sufficiency.  
After 15 subjects in Arm 3 have completed Visit 4, an interim analysis (interim 
analysis 3) will be performed to estimate the distribution of treatment effects on TUV 
and to optimize the TUV metric based on the interim data from all three Arms. 
Efficacy Assessments: 
Primary Endpoint(s) 
ARMS 1-2 
• The camera-specific precision of TUVjoint and TUVglobal in HCs and subjects 
with active RA, which is defined as the Root Mean Square Difference (RMSD) 
between the consecutive 15-minute planar images. 
• The stability of the mean/variance relationship, which is assessed by comparing 
the Coefficient of Variation (CV) of TUVjoint and TUVglobal in HCs and subjects 
with active RA. 
 
ARM 2  
• The longitudinal (8-day) precision of TUVjoint and TUVglobal in subjects with 
active RA, which is defined as the RMSD of images at the same time point. 
 
ARM 3  
• The correlation of ΔTUVglobal[5w] 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). The correlation of 
ΔTUVglobal[5w] and response to new anti-TNFα bDMARD therapy from baseline 


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Clinical Trial Protocol: NAV3-31 
 
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to 12 ± 1 weeks and 24 ± 1 weeks defined by ACR Response Criteria (ACR12w 
and ACR24w, respectively). 
 
Secondary Endpoint(s) 
ARMS 1-2 
• The temporal stability of the 150 mcg tilmanocept mass dose/10 mCi 
radiolabeling dose 
 
ARM 1  
• The normal ranges of TUVjoint  in HC subjects, which is defined as the 5 and 95 
percentiles of:  
- 
TUVjoint of bilateral joints (i.e., bilateral wrists, metacarpophalangeal 
joint [MCPs], proximal interphalangeal [PIPs], knees, elbows, 
shoulders)  
 
ARM 2 
• The qualitative evaluations of SPECT/CT in detecting localization within 
synovial spaces of the bilateral hands and wrists 
 
ARM 3 
• The correlation of the TUVglobal[0week] 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) and by 
ACR Response Criteria (ACR12w and ACR24w, respectively). 
• The correlation of ΔTUVglobal[12w] and ΔTUVglobal[24w] 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) and 
by ACR Response Criteria (ACR12w and ACR24w, respectively).   
• The correlation of ΔTUVglobal[5w] and constituent parameters of ΔCDAI12/24w 
and ACR12/24w including: 
1. Tender Joint Count (TJC) 
2. Swollen Joint Count (SJC) 
3. Patient assessment of global disease activity 
4. Rheumatologist assessment of global disease activity 
5. Patient assessment of pain 
6. Patient assessment of physical function 
7. Acute-phase reactant value 
Statistical Methods: 
ARMS 1-2 
Longitudinal precision and camera-specific precision will be analyzed with confidence 
intervals for Root Mean Square Difference (RMSD) and the mean difference (i.e., the 
bias) between the relevant time points. Confidence intervals (95% confidence level) 


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will be calculated using Normal theory results (Lin 2002). As a sensitivity measure, the 
80th and 90th percentiles of the distribution of the absolute differences will computed 
using quantile methods. 
Stability of the mean/variance relationship will be assessed with a 95% confidence 
interval for the difference between the CV for RA and HC subjects at each time point. 
If the CV for both groups at an imaging time point is less than 0.30, a 95% confidence 
interval based on the methods outlined in (Forkman 2009) will be provided. Because 
Forkman’s methods are based on Normal theory, a 95% bootstrap confidence interval 
will also be provided for all time points.  
Temporal stability of the 150 mcg dose will be assessed with a 95% Student’s T 
interval for the difference between the TUV at 60 minutes and at 180 minutes. As a 
sensitivity check, a signed-rank test of the hypotheses: 
H0: 𝜇𝜇180 −𝜇𝜇60 = 0 
H1: 𝜇𝜇180 −𝜇𝜇60 ≠0 
where 𝜇𝜇180 represents the median TUV at 180 minutes and 𝜇𝜇60 represents the median 
TUV at 60 minutes, will be provided. 
ARM 1 
Normal ranges in HC subjects will be estimated by pooling similar joints and 
computing the average TUV per joint per subject. The 5 and 95 percentiles will be 
estimated using quantile regression methods. Joints to be pooled include the following: 
• Shoulders (bilateral, 2 per subject) 
• Knees (bilateral, 2 per subject) 
• Wrists (bilateral, 2 per subject) 
• MCP (bilateral, 5 per hand, 10 per subject) 
• PIP (bilateral, 5 per hand, 10 per subject) 
 
ARM 2 
The qualitative evaluations of SPECT/CT in detecting localization within synovial 
spaces of the bilateral hands and wrists.  
ARM 3 
The utility of ΔTUVglobal[5w] to predict the subject’s response to changed therapy will 
be assessed by computing the Kendall rank correlation between ΔTUVglobal[5w] and 
∆CDAI12w,∆CDAI24w, ΔACR12w, and ΔACR24w. All times are relative to Study Day 0, 
and it is assumed that the new bDMARD therapy will begin after imaging on Day 0. A 
95% confidence interval on the value of the rank correlation will be computed. 
Date of Original Approved Protocol: 16 November 2018 
 
 
 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF IN-TEXT TABLES ..................................................................................................20 
LIST OF IN-TEXT FIGURES.................................................................................................20 
LIST OF APPENDICES ..........................................................................................................21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................22 
1 
INTRODUCTION ...........................................................................................................25 
1.1 
Background ............................................................................................................25 
1.2 
Previous Nonclinical Research and Clinical Trial Experience in Tc 99m 
Tilmanocept ...........................................................................................................30 
1.2.1 
Nonclinical Evaluations –Subcutaneous Administration.............................30 
1.2.2 
Nonclinical Evaluations – IV Administration..............................................30 
1.2.3 
Clinical Pharmacokinetics (IV)....................................................................32 
1.2.4 
Clinical Efficacy ..........................................................................................33 
1.2.4.1 
NAV3-23 (SC) ...................................................................................33 
1.2.4.2 
NAV3-21 (IV) ....................................................................................34 
1.2.5 
Clinical Safety ..............................................................................................34 
1.2.5.1 
NAV3-23 (SC) ...................................................................................34 
1.2.5.2 
NAV3-21 (IV) ....................................................................................34 
2 
STUDY OBJECTIVES ....................................................................................................35 
2.1 
Primary Objective(s) ..............................................................................................35 
2.2 
Secondary Objective(s) ..........................................................................................35 
2.3 
Safety Objective(s).................................................................................................35 
3 
INVESTIGATIONAL PLAN ..........................................................................................36 
3.1 
Overall Study Design and Plan ..............................................................................36 
3.1.1 
Arm 1: No Inflammatory and/or Joint Disease (HC Subjects) ....................36 
3.1.1.1 
Description of Patient Population ......................................................36 
3.1.1.2 
Overview of Study Procedures ..........................................................36 
3.1.1.3 
Justification for Population ................................................................36 
3.1.2 
Arm 2: Stable Anti-Rheumatic Therapy (RA Subjects) ..............................37 
3.1.2.1 
Description of Patient Population ......................................................37 
3.1.2.2 
Overview of Study Procedures ..........................................................37 
3.1.3 
Arm 3: Change in anti-TNFα bDMARD Therapy (RA Subjects) ...............38 
3.1.3.1 
Description of Patient Population ......................................................38 
3.1.3.2 
Overview of Study Procedures ..........................................................38 
3.1.3.3 
Justification for Population ................................................................38 
3.2 
Protocol Adherence ................................................................................................38 
3.3 
Study Duration(s) ...................................................................................................39 
4 
STUDY POPULATION ..................................................................................................40 


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4.1 
Study Arms ............................................................................................................40 
4.2 
Eligibility ...............................................................................................................40 
4.2.1 
Inclusion Criteria .........................................................................................40 
4.2.2 
Exclusion Criteria ........................................................................................41 
4.3 
Recruitment ............................................................................................................41 
4.4 
Withdrawal .............................................................................................................42 
4.5 
Replacement ...........................................................................................................42 
4.6 
Screen Failures .......................................................................................................42 
4.7 
Subject Identification .............................................................................................42 
5 
INVESTIGATIONAL PRODUCT ..................................................................................44 
5.1 
Description of Investigational Product ..................................................................44 
5.2 
Investigational Product Dosage and Administration .............................................44 
5.3 
Timing and Frequency of Drug Administration ....................................................45 
5.4 
Packaging and Labeling .........................................................................................46 
5.5 
Drug Logistics and Investigational Product Accountability ..................................46 
6 
THERAPIES OTHER THAN INVESTIGATIONAL PRODUCT .................................47 
6.1 
Prior and Concomitant Therapies ..........................................................................47 
6.2 
Post-Study Therapy ................................................................................................47 
7 
STUDY PROCEDURES .................................................................................................48 
7.1 
Schedule of Evaluations .........................................................................................48 
7.1.1 
Arm 1 (HC Subjects) ...................................................................................48 
7.1.2 
Arm 2 (RA Subjects on Stable Therapy) .....................................................50 
7.1.3 
Arm 3 (RA Patients Initiating Change in Anti-TNFα bDMARD 
Therapy)* .....................................................................................................54 
8 
PROCEDURES AND VARIABLES ..............................................................................61 
8.1 
Population Characteristics .....................................................................................61 
8.1.1 
Demographics and Other Baseline Characteristics ......................................61 
8.1.2 
Medical, Rheumatological, and Surgical History ........................................61 
8.1.3 
Prior and Concomitant Medication ..............................................................61 
8.2 
Tc 99m Tilmanocept Administration .....................................................................61 
8.3 
Rheumatological Assessments ...............................................................................62 
8.3.1 
2010 ACR/EULAR Classification Criteria ..................................................62 
8.3.2 
DAS28..........................................................................................................62 
8.3.3 
CDAI ............................................................................................................62 
8.3.4 
ACR Response Criteria ................................................................................63 
8.3.5 
Other ............................................................................................................64 
8.3.5.1 
28-joint Count (SJC and TJC)............................................................64 
8.3.5.2 
Global Assessment of Disease Activity .............................................64 


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8.3.5.3 
Patient Assessment of Pain (VAS) ....................................................64 
8.3.5.4 
Patient Assessment of Physical Function (HAQ-DI©).......................64 
8.3.5.5 
Acute-phase Reactant.........................................................................64 
8.3.5.6 
Widespread Pain Index ......................................................................65 
8.4 
Imaging ..................................................................................................................65 
8.4.1 
Image Acquisition ........................................................................................65 
8.4.1.1 
Planar Scintigraphy ............................................................................65 
8.4.1.2 
SPECT/CT .........................................................................................66 
8.4.1.3 
Tilmanocept Uptake Value (TUV) ....................................................66 
8.5 
Adverse Events ......................................................................................................67 
8.5.1 
Definition of Adverse Event ........................................................................67 
8.5.2 
Categories for Adverse Event Assessment ..................................................67 
8.5.3 
Assessments and Documentation of Adverse Events ..................................68 
8.5.4 
Expected Adverse Events ............................................................................69 
8.5.5 
Serious Adverse Events ...............................................................................70 
8.6 
Physical Examination.............................................................................................72 
8.7 
Vital Signs ..............................................................................................................72 
8.8 
Electrocardiogram ..................................................................................................72 
8.9 
Clinical Laboratory Parameters .............................................................................73 
9 
STATISTICAL METHODS ............................................................................................75 
9.1 
Randomization Methods ........................................................................................75 
9.2 
Safety Variables .....................................................................................................75 
9.3 
Efficacy Variables ..................................................................................................75 
9.4 
Sample Size Justification .......................................................................................77 
9.5 
Statistical Analyses ................................................................................................77 
9.5.1 
Analysis Populations ....................................................................................77 
9.5.2 
Analysis of Baseline and Demographic Characteristics ..............................77 
9.5.3 
Analysis of Efficacy Variables ....................................................................78 
9.5.3.1 
Primary Endpoints Arms 1- 2 ............................................................78 
9.5.3.2 
Secondary Endpoints Arms 1- 2 ........................................................78 
9.5.3.3 
Primary endpoint Arm 3 ....................................................................78 
9.5.3.4 
Secondary endpoint Arm 3 ................................................................78 
9.5.4 
Analysis of Safety Variables ........................................................................79 
9.5.5 
Handling of Missing Values ........................................................................79 
9.5.6 
Interim Analyses ..........................................................................................79 
10 DATA HANDLING AND QUALITY ASSURANCE ...................................................80 
10.1 
Data Recording ......................................................................................................80 
10.1.1 
CRF Design ..................................................................................................80 
10.2 
Monitoring .............................................................................................................80 


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10.3 
Data Processing ......................................................................................................80 
10.4 
Auditing .................................................................................................................80 
10.5 
Archiving ...............................................................................................................81 
10.6 
Premature Termination of the Study ......................................................................81 
10.6.1 
Termination by the Sponsor .........................................................................81 
10.6.2 
Termination by the Investigator ...................................................................81 
10.6.3 
Study as a Whole .........................................................................................81 
10.6.4 
Center ...........................................................................................................82 
10.6.5 
Study Participant ..........................................................................................82 
11 ETHICAL AND LEGAL ASPECTS...............................................................................83 
11.1 
Ethical and Legal Conduct of the Study ................................................................83 
11.2 
Subject Information and Consent...........................................................................83 
11.3 
Financing/Financial Disclosure .............................................................................84 
11.4 
Publication Policy ..................................................................................................84 
11.5 
Subject Injury .........................................................................................................84 
12 REFERENCES ................................................................................................................85 
 
LIST OF IN-TEXT TABLES 
Table 1  
Preclinical Tests .........................................................................................31 
Table 2  
Whole Blood PK Parameter Summaries by Group....................................32 
Table 3  
Urine PK Parameter Summaries by Group ................................................33 
Table 4  
Study Arms ................................................................................................36 
Table 5  
Study Duration for Arms 1-3 .....................................................................39 
Table 6  
Summary of Tc 99m Tilmanocept Administration Timepoints by 
Study Arm ..................................................................................................45 
Table 7  
Documentation Window for Recent or Concomitant RA-specific 
Treatments..................................................................................................61 
Table 8  
Timing of DAS28 Evaluations by Study Arm ...........................................62 
Table 9  
Timing of CDAI Evaluations by Study Arm .............................................63 
Table 10  
Timing of ACR Response Evaluations by Study Arm ..............................63 
Table 11  
Planar Image Acquisition by Study Arm ...................................................65 
Table 12  
Clinical Laboratory Parameters .................................................................73 
Table 13  
Approximate Amount of Blood Drawn per Subject by Study Arm...........74 
 
LIST OF IN-TEXT FIGURES 
Figure 1  
Tc 99m tilmanocept and the Mannose Receptor........................................44 
 


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LIST OF APPENDICES 
Appendix 1 
Schedule of Events (Arms 1-2) ..................................................................89 
Appendix 2 
Workflow Diagram (Arms 1-2) .................................................................90 
Appendix 3 
Schedule of Events (Arm 3) .......................................................................91 
Appendix 4 
Workflow Diagram (Arms 3).....................................................................93 
Appendix 5 
2010 ACR/EULAR Criteria .......................................................................94 
Appendix 6 
DAS28 Scoring ..........................................................................................96 
Appendix 7 
CDAI Scoring ............................................................................................97 
Appendix 8 
ACR Response Criteria ..............................................................................98 
Appendix 9 
HAQ-DI© Questionnaire ............................................................................99 
Appendix 10 Sponsor Signatures...................................................................................102 
Appendix 11 Investigator’s Signature ...........................................................................103 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ΔCDAI12/24w 
Change in Clinical Disease Activity Index from 12 ± 1 weeks / 24 ± 1 
weeks of newly initiated bDMARD therapy and baseline 
ΔTUVglobal[5w] 
Difference (change) of TUVglobal from 5 ± 1 weeks of newly initiated 
bDMARD therapy and baseline 
ΔTUVglobal[12w] 
Difference (change) of TUVglobal from 12 ± 1 weeks of newly initiated 
bDMARD therapy and baseline 
ΔTUVglobal[24w] 
Difference (change) of TUVglobal from 24 ± 1 weeks of newly initiated 
bDMARD therapy and baseline 
ACPA 
Anti-Citrullinated Peptide Antibody 
ACR 
American College of Rheumatology 
ACR12/24w 
American College of Rheumatology response criteria at 12 ± 1 weeks / 
24 ± 1 weeks of newly initiated bDMARD therapy and baseline 
ACR20/50/70 
American College of Rheumatology response criteria 
ACR/EULAR 
American College of Rheumatology/European League Against 
Rheumatism 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
bDMARD 
Biological disease-modifying antirheumatic drug 
BMI 
Body mass index 
CD206 
Mannose-binding receptor (Ca2+-binding lectin) 
CDAI 
Clinical disease activity index 
CFB 
Change from baseline 
CRF 
Case report form 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CV 
Coefficient of variation 
DAS28 
Disease activity score -28 for RA describing the severity of RA using 
clinical and laboratory data. 
DMARD 
Disease-modifying antirheumatic drug 
DTPA 
Diethylenetriaminepentaacetic Acid 


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ECG 
Electrocardiogram  
eCRF 
Electronic case report form 
ESR 
Erythrocyte sedimentation rate 
GCP 
Good Clinical Practice 
HAQ-DI© 
Health Assessment Questionnaire - Disability Index 
HC 
Healthy control 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
ITD 
Intent to diagnose 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
MCP 
Metacarpophalangeal joint  
NSAID 
Non-steroidal anti-inflammatory drug 
p.i. 
Post injection 
PIP 
Proximal interphalangeal 
PK 
Pharmacokinetics 
PP 
Per Protocol 
QT 
Interval from the Q wave to the end of the T wave 
QTc 
Corrected QT interval 
RA 
Rheumatoid arthritis 
RF 
Rheumatoid factor 
RMSD 
Root mean square difference 
ROC 
Receiver operating characteristic 
ROI 
Region of interest 
RR 
Reference region 
RSNA 
Radiological Society of North America 
SAP 
Statistical analysis plan 


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SJC 
Swollen joint count 
SC 
Sulfur colloid 
SOC 
System organ class 
SPECT 
Single-photon emission computerized tomography 
SPECT/CT 
Combined single-photon emission computerized tomography and 
computed tomography 
TJC 
Tender joint count 
TMF 
Trial master file 
TNFα 
Tumor necrosis factor alpha 
TUV 
Tilmanocept uptake value 
TUVglobal 
Global tilmanocept uptake value 
TUVjoint 
Joint-specific tilmanocept uptake value 
UC 
Uncertainty coefficient 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
WB  
Whole body 
WPI 
Widespread pain index 


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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 2017a, 
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, 
reductions in activated synovial macrophages associated with effective RA therapy typically 


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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 2017a).  
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 2017b). 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-
myeloid and/or fibroid RA pathotypes. Such results, if attained, would provide a great benefit 
to RA patients by enabling personalized delivery of an optimal treatments to all RA patients.  


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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 6-14 
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 
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 


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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 
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 decay-corrected average pixel intensity of a ROI, and B, the 


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decay-corrected pixel intensity of an anatomically defined area of the cerebral vasculature 
(serving as an intra-patient reference region), such that TUV =
xത
B × 100. Thus, the overall 
purpose of this study will be to test the reliability and clinical utility of TUV. 
1.2 
Previous Nonclinical Research and Clinical Trial Experience in Tc 
99m Tilmanocept  
A detailed evaluation of the nonclinical evaluations from subcutaneous (SC) and IV routes of 
administration, clinical pharmacokinetics (PK), clinical efficacy, and clinical safety of Tc 99m 
tilmanocept can be found in the accompanying Investigator’s Brochure supplied by Navidea 
Biopharmaceuticals, Inc.   
1.2.1 
Nonclinical Evaluations –Subcutaneous Administration 
Nonclinical studies of Tc 99m tilmanocept demonstrated that the drug selectively binds to its 
intended receptor (the CD206 mannose binding receptor), and is well tolerated by rats, rabbits, 
guinea pigs, and dogs. 
PK data obtained from nonclinical studies demonstrated rapid absorption into the plasma. 
Urinary excretion was a major pathway of elimination. Tc 99m tilmanocept exhibited rapid 
clearance from the injection site, rapid uptake by the local lymph node, and low uptake by the 
remaining lymph nodes. Tilmanocept was well tolerated at all doses tested in nonclinical safety 
pharmacology studies and in single and repeated dose toxicology studies in rats, rabbits, and 
dogs. In some studies in rabbits and dogs, tilmanocept acted as a local irritant of the subcutis 
or skeletal muscle, and induced mild inflammation and tissue degeneration. The no-observed 
adverse-effect level (NOAEL) was 42μg/kg/day. Tilmanocept was not mutagenic or genotoxic 
in vitro or in vivo. No signs or symptoms of hypersensitivity were observed in a study in guinea 
pigs.  
1.2.2 
Nonclinical Evaluations – IV Administration 
In preparation to initiate the IV route of administration, 11 preclinical tests were conducted to 
assess safety, toxicity, and interaction potential at doses hundreds to thousands of times the 
expected maximum human dose, as summarized in Table 1. The nonclinical evaluations 
yielded safety and pharmacokinetics profiles that were appropriate for initiation of IV dosing 
in clinical trials. Nonclinical study results can be found in the accompanying Investigator’s 
Brochure. 


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


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


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Table 3  
Urine PK Parameter Summaries by Group 
Group 
Statistic 
Percent 
Recovered a 
AUC(0-t) 
(h*nCi) 
Max Rate 
(nCi/h) b 
HC 
n 
6 
6 
6 
Mean 
7.6 
1468788.9 
949280.7 
Std Dev 
2.07 
432723.27 
236916.28 
CV% 
27.2 
29.5 
25.0 
Geometric Mean 
7.4 
1411786.8 
924858.6 
Lower 90% CI 
5.84 
1088888.09 
752742.08 
Upper 90% CI 
 9.28 
1830437.75 
1136329.94 
RA 
n 
6 
6 
6 
Mean 
6.9 
1384642.0 
841331.0 
Std Dev 
1.74 
313600.65 
227308.94 
CV% 
25.2 
22.6 
27.0 
Geometric Mean 
6.7 
1355137.9 
817282.6 
Lower 90% CI 
5.46 
1123310.11 
659111.71 
Upper 90% CI 
8.33 
1634810.07 
1013410.74 
a Percent recovered is the cumulative amount of radioactivity divided by the dose and multiplied by 100.  
b Maximum observed excretion rate, calculated as (radioactivity*volume)/ (end time – start time). 
 
A comparison of the PK parameters in subjects with active RA and HC subjects does not reveal 
any apparent differences in the elimination of radioactivity from the body. 
1.2.4 
Clinical Efficacy 
1.2.4.1 
NAV3-23 (SC) 
This was an open-label, multicenter study of Tc 99m tilmanocept by subcutaneous injection in 
patients with active RA and healthy controls.  Tilmanocept was administered SC at 1 of 2 mass 
doses: [1] 50 mcg (Cohorts 1 & 3), or [2] 200 mcg (Cohorts 2 & 4). Both mass doses were 
radiolabeled with 2 mCi of Tc 99m. A total of 18 subjects were enrolled and evaluated (9 active 
RA, 9 HC). Imaging was performed 60 ± 15 minutes and 180 ± 15 minutes post injection. The 
following performance conclusions were drawn upon study completion:  
• Based on data from this study and parallel pathology studies, Tc 99m tilmanocept 
localizes to activated macrophage-infiltrated joints at doses of 50 µg and 200 µg 
radiolabeled with 2.0 mCi (74.0 MBq) by SC administration.  
• Across all combined RA subjects, swollen/tender joints demonstrating the highest 
proportions of localization include the wrists and knees.  
• Based on qualitative image evaluation, Tc 99m tilmanocept does not show differences 
in localization between 2 to 3 and 4  to 6-hour planar imaging within dosing groups.  
• Tc 99m tilmanocept demonstrates a greater frequency of localization to swollen/tender 
joints at 200 mcg/2.0 mCi than 50 mcg/2.0 mCi.  
• There is an overall lack of concordance between qualitative observation of Tc 99m 
tilmanocept localization to swollen/tender joints identified in DAS28 joint count 


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assessment. Swollen/tender joints did not appear to be reliable predictors of presumed 
abnormal activated macrophage infiltration and overall disease progression when used 
as an isolated diagnostic system.  
• Increased tilmanocept mass dosing, increased Tc 99m specific activity, and other routes 
of administration may enhance localization and anatomic delineation in tilmanocept-
positive joints of RA patients.  
• The potential for using Tc 99m tilmanocept to delineate macrophage infiltration in RA-
affected joints may allow for earlier RA-specific treatment beyond the current standard 
of care ACR/EULAR criteria. 
 
1.2.4.2 
NAV3-21 (IV) 
This was an open-label, multicenter, dose-escalation safety with PK and dosimetry study of 
Tc 99m tilmanocept by IV injection in HCs and subjects with active RA. Thirty-nine subjects 
were enrolled. A total of 27 subjects with active RA were enrolled to Groups 1 to 9 in the dose 
escalation phase. Group 10 consisted of 6 HCs (3 female and 3 male) and Group 11 consisted 
of 6 subjects with active RA (3 female and 3 male). Tilmanocept was administered IV at 1 of 
3 mass doses: 50 mcg, 200 mcg, or 400 mcg.  Within each mass dose group, tilmanocept was 
radiolabeled with 1 of 3 Tc 99m doses: 1 mCi, 5 mCi, or 10 mCi.  Subjects in Groups 10 and 
11 received the maximum dose of 400 mcg/10 mCi. Imaging was performed 60 ± 15 minutes 
and 180 ± 15 minutes p.i. Clinical efficacy conclusions for this study are still under review.  
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, ECG parameters, and 
vital signs. The safety evaluation included all subjects who were enrolled in the study and 
administered Tc 99m tilmanocept (n = 39). There were no Tc 99m tilmanocept related AEs. 
There were no deaths during the trial; no SAEs; and no AEs that led to discontinuation from 
the trial. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective(s)  
• To assess the longitudinal precision of TUVjoint and global TUVglobal on planar imaging 
in subjects with clinically diagnosed active RA on stable anti-rheumatic therapy. 
• To evaluate the camera-specific precision of TUVjoint and TUVglobal on planar imaging 
in HCs and in subjects with clinically diagnosed active RA using centralized and 
standardized imaging parameters. 
• To assess the correlation of TUV and changes in TUV with changes in clinical 
assessments at multiple time points after initiation of a new anti-tumor necrosis factor 
alpha (TNFα) biologic disease-modifying antirheumatic drug (bDMARD) therapy. 
 
2.2 
Secondary Objective(s)  
• To assess the temporal post-injection stability of TUVjoint and TUVglobal at a dose of 
150 mcg tilmanocept radiolabeled with 10 mCi of Tc 99m. 
• To establish normal ranges for TUVjoint in HCs.  
• To assess Tc 99m tilmanocept anatomic localization based on SPECT/CT imaging of 
the synovial space in hands and wrists  
 
2.3 
Safety Objective(s) 
• To evaluate safety through the examination of AE incidence and changes over time in 
laboratory tests, vital signs, and physical examination findings. 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a prospective, open-label, multicenter, single and repeat-dose study designed to 
evaluate the reliability and sensitivity of TUV assessments in HCs and subjects with active 
RA. Subjects will be enrolled in 1 of 3 study arms (Table 4) with distinct timelines, study 
procedures, and study durations in accordance with Arm-specific eligibility requirements.  
Table 4  
Study Arms  
Arm 
Subjects 
Evaluation(s) 
1 
HC subjects clinically free of any inflammatory 
disease and/or joint pain 
Image Re-image 
2 
Subjects with clinically diagnosed active RA who 
have been on stable anti-rheumatic therapy  
Image Re-image 
Test Re-test 
3 
Subjects with clinically diagnosed active RA who are 
candidates for initiation of, or change to, a new anti-
TNFα bDMARD treatment. 
Sensitivity  
Clinical Concordance 
 
3.1.1 
Arm 1: No Inflammatory and/or Joint Disease (HC Subjects) 
3.1.1.1 
Description of Patient Population 
This arm will be comprised of HC subjects who are deemed to be clinically free of 
inflammatory disease(s) and/or joint pain for at least 28 days prior to the consent date. These 
subjects will not receive any anti-inflammatory treatment(s) (including NSAIDs) during study 
participation and will not have taken any such drugs at least 28 days prior to the consent date. 
All other concomitant medications (for non-inflammatory conditions) will have been 
maintained at a stable dose for at least 28 days prior to consent. 
3.1.1.2 
Overview of Study Procedures 
Refer to Section 7.1 for a detailed description of all study procedures. Refer to Appendix 2 for 
a schedule of events and Appendix 4 for a sequential diagram of study procedures. 
3.1.1.3 
Justification for Population 
There are 2 reasons for the inclusion of this study population. The first is to evaluate the image 
re-image precision of TUVjoint. Identical image acquisitions performed up to 15 minutes apart 
(e.g., planar WB scan and planar bilateral hand/wrist scan followed by planar WB scan and 
planar bilateral hand/wrist scan 15 minutes later) will provide important information about 
potential differences in TUVs in the context of standardized imaging protocols. Identical image 
acquisitions performed 2 hours apart (e.g., planar WB scan at 60 ± 15 minutes post-drug 
administration and planar WB scan at 180 ± 15 minutes post-drug administration) will provide 
important information about any potential time-dependent pharmacokinetic effects of Tc 99m 


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tilmanocept on resultant TUVs. Both image re-image evaluations are ultimately designed to 
summarize the overall stability of TUV. 
The second reason is to establish normal ranges for TUVjoint.. By determining the upper limit 
of normal (ULN) for average TUVjoint across pooled joints (e.g., MCPs 1-5) across patients, 
these assessments can be further investigated for their utility in providing clinically meaningful 
reference data for symptomatic individuals presenting to the clinic.  
3.1.2 
Arm 2: Stable Anti-Rheumatic Therapy (RA Subjects) 
3.1.2.1 
Description of Patient Population 
This arm will be comprised of subjects with clinically diagnosed active RA on stable anti-
inflammatory and/or anti-rheumatic therapy. All subjects’ RA diagnoses will be moderate to 
severe in accordance with a 2010 ACR/EULAR score of 6 or higher.  All subjects receiving 
traditional DMARDs must have been on therapy for ≥ 90 days and at a stable dose for ≥ 30 days 
prior to the first imaging visit; all subjects receiving bDMARDs or JAK inhibitors must have 
been on stable therapy for at least 180 days prior to the first imaging visit; and all subjects 
receiving NSAIDs and/or oral corticosteroids must have been on therapy for at least 28 days 
prior to the first imaging visit.  
3.1.2.2 
Overview of Study Procedures 
Subjects in this arm will have a total of 3 on-site visits and 2 telephone safety assessments. The 
maximum possible study duration for these subjects will be 42 days.  
Refer to Section 7.1 for a detailed description of all study procedures. Refer to Appendix 2 for 
a schedule of events and Appendix 4 for a sequential diagram of study procedures. 
Justification for Population 
There are 2 reasons for the inclusion of this study population. The first is to evaluate the image 
re-image precision of TUVjoint and TUVglobal. Identical image acquisitions performed up to 15 
minutes apart (e.g., planar WB scan and planar bilateral hand/wrist scan followed by planar 
WB scan and planar bilateral hand/wrist scan 15 minutes later) will provide important 
information about potential differences in TUVs in the context of standardized imaging 
protocols. Identical image acquisitions performed 2 hours apart (e.g., planar WB scan at 60 ± 
15 minutes post-drug administration and planar WB scan at 180 ± 15 minutes post-drug 
administration) will provide important information about any potential time-dependent 
pharmacokinetic effects of Tc 99m tilmanocept on resultant TUVs.  
The second reason is to determine the longitudinal test re-test precision of TUVjoint and 
TUVglobal. Identical image acquisitions performed 8 ± 1 days apart (e.g., planar WB scan at 
60 ± 15 minutes compared with planar WB scan at 60 ± 15 minutes 8 ± 1 days after the first 
planar WB scan) will provide important information about the pharmacodynamic stability of 
Tc 99m tilmanocept as it relates to standardized TUV derivations. The overall purpose of these 
evaluations will be to determine if longitudinally repeated injection and imaging can provide 


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reliable quantitative data with minimal variation (assuming stable disease and treatment). The 
results from these assessments will have significant translational importance for the clinical 
utility of TUVs in the stable monitoring of changes in disease activity over time.  
3.1.3 
Arm 3: Change in anti-TNFα bDMARD Therapy (RA Subjects) 
3.1.3.1 
Description of Patient Population 
This arm will be comprised of subjects with clinically diagnosed active RA who are candidates 
for initiation of, or change to, a new anti-TNFα bDMARD treatment. All subjects’ RA 
diagnoses will be moderate to severe in accordance with a 2010 ACR/EULAR score of 6or 
higher. All subjects receiving traditional DMARDs must have been on therapy for ≥ 90 days 
and at a stable dose for ≥ 30 days prior to the first imaging visit; all subjects receiving 
bDMARDs or JAK inhibitors must have been on stable therapy for at least 180 days prior to 
the first imaging visit; and all subjects receiving NSAIDs and/or oral corticosteroids must have 
been on therapy for at least 28 days prior to the first imaging visit. Upon completion of the first 
set of imaging assessments, all subjects will begin their new anti-TNFα bDMARD therapeutic 
regimen. 
3.1.3.2 
Overview of Study Procedures 
Subjects in this arm will have a total of 5 on-site visits and 4 telephone safety assessments. The 
maximum possible study duration for these subjects will be 213 days.  
Refer to Section 7.1 for a detailed description of all study procedures. Refer to Appendix 2 for 
a schedule of events and Appendix 4 for a sequential diagram of study procedures. 
3.1.3.3 
Justification for Population 
There are 2 reasons for the inclusion of this study population. The first is to determine the 
sensitivity of TUVglobal towards the detection of anti-TNFα bDMARD therapy-driven changes 
in CD206 macrophage activity after 5 ± 1 weeks of treatment. By establishing that TUVglobal 
has sufficient sensitivity to detect such changes, the predictive utility of this metric for 
downstream clinical outcomes can be further investigated.  
The second reason, which is strongly predicated on the results of the first reason, is to establish 
a preliminary understanding of how changes from baseline of TUVglobal to 5 ± 1 weeks of a 
new anti-TNFα bDMARD treatment correlate with changes in clinical response parameters. 
Refer to Section 8.3 for an overview of all clinical parameters under investigation. 
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)). 


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If an investigator has deviated from the protocol in order to eliminate an immediate hazard to 
subjects or for other inevitable medical reasons, the investigator shall document all such 
deviations, including the reasons thereof, and submit the document to the sponsor and the IRB 
as applicable. 
3.3 
Study Duration(s) 
Study duration will be contingent upon study arm. The maximum possible study durations for 
Arms 1, 2, and 3 are 38 days, 42 days, and 213 days, respectively. 
Table 5  
Study Duration for Arms 1-3 
Study Arm 
Maximum Possible Study Duration 
1 
38 days 
2 
42 days 
3 
213 days 
 


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4 
STUDY POPULATION  
4.1 
Study Arms 
The study population will be comprised of HC subjects, subjects with clinically diagnosed 
active RA on stable anti-rheumatic therapy, and subjects with clinically diagnosed active RA 
who are candidates for initiation of, or change to, a new anti-TNFα bDMARD regimen (see 
Table 4). 
4.2 
Eligibility 
All inclusion/exclusion criteria must be verified before any subject is considered eligible for 
enrollment and for administration of Tc 99m tilmanocept and imaging (Day 0 procedures). 
Subjects will be considered enrolled once injected with Tc 99m tilmanocept (Day 0). Written 
and dated (with time-noted) informed consent will be obtained from all subjects. A subject 
who withdraws consent prior to receiving Tc 99m tilmanocept injection on Day 0 will be 
considered a screen failure.   
4.2.1 
Inclusion Criteria 
ALL SUBJECTS 
1. The subject has provided written informed consent with HIPAA (Health Information 
Portability and Accountability Act) authorization before the initiation of any study-
related procedures. 
2. ARMS 1 and 2 (only): The subject has agreed to not engage in any diet, lifestyle, or 
medication changes until study completion.  
 
HEALTHY CONTROL SUBJECTS  
3. The subject is between 18 and 80 years of age at the time of consent. 
4. The subject is deemed to be clinically free of any inflammatory disease(s) and has not 
experienced joint pain for at least 28 days prior to the consent date. 
5. The subject is not currently on anti-inflammatory drugs (including NSAIDs) and has 
not taken anti-inflammatories for at least 28 days prior to the consent date.  
6. For all ongoing concomitant medications, the subject has maintained a stable dose for 
at least 28 days prior to the consent date. 
 
CLINICALLY DIAGNOSED ACTIVE RA SUBJECTS 
3. The subject is at least 18 years of age and was ≥ 18 years of age at the time of RA 
diagnosis. 
4. The subject has moderate to severe RA as determined by the 2010 ACR/EULAR (score 
of ≥ 6/10) classification criteria. 


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5. The subject has a 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. If the subject is receiving bDMARD or JAK inhibitor therapy, they have been at a 
stable dose > 180 days prior to the first imaging visit (Day 0).  
8. If the subject is receiving NSAIDs (nonsteroidal anti-inflammatory drugs) or oral 
corticosteroids, the dose has been stable for > 28 days prior to first imaging visit 
(Day 1). The corticosteroid dose must be ≤ 10mg/day of prednisone or an equivalent 
steroid dose. 
9. ARM 3 (only): The subject is receiving anti-rheumatic treatment and is a candidate for 
initiation of, or change to, a new anti-TNFα bDMARD therapy. 
 
4.2.2 
Exclusion Criteria 
1. The subject is pregnant or lactating.  
2. The subject size or weight is not compatible with imaging per the investigator. 
3. The subject has had or is currently receiving radiation therapy or chemotherapy. 
4. The subject has renal insufficiency as demonstrated by a glomerular filtration rate of 
< 60 mL/min. 
5. The subject has hepatic insufficiency as demonstrated by ALT (alanine 
aminotransferase [SGPT]) or AST (aspartate aminotransferase [SGOT]) greater than 
3 times the upper limit of normal. 
6. 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. 
7. The subject has a known allergy to or has had an adverse reaction to dextran exposure. 
8. The subject has received an investigational product within 30 days prior to the Tc 99m 
tilmanocept administration. 
9. The subject has received intra-articular corticosteroid injections ≤ 8 weeks prior to the 
first imaging visit (Day 0). 
10. The subject has received any radiopharmaceutical within 7 days or 10 half-lives prior 
to the administration of Tc 99m tilmanocept. 
 
4.3 
Recruitment 
Subjects will be recruited from rheumatology practices in accordance with the inclusion and 
exclusion criteria listed above. Candidate subjects will be asked by their treating physician 
about their willingness to participate in the study. Healthy control subjects will be recruited 
via IRB-approved advertisements and clinically assessed for the “absence” of painful and/or 
swollen joints. 


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4.4 
Withdrawal 
In accordance with the Declaration of Helsinki, each subject is free to withdraw from the study 
at any time and without providing a reason.  
A subject who withdraws consent prior to receiving Tc 99m tilmanocept injection on Day 0 
will be considered a screen failure.  
Should a subject withdraw after administration of the investigational product, all efforts will 
be made to complete and report the observations up to the time of withdrawal as thoroughly as 
possible. An explanation should be given of why the subject is withdrawing or being 
withdrawn from the study. 
The investigator may withdraw a subject from the study at any time at the discretion of the 
investigator for any of the following reasons:  
• A protocol violation occurs  
• A serious or intolerable AE occurs  
• A clinically significant change in a laboratory parameter occurs  
• At the investigator’s/sponsor’s discretion as long as it is in the best interest of the 
subject  
• The sponsor or investigator terminates the study  
• The subject requests to be discontinued from the study  
 
4.5 
Replacement 
Subjects will be replaced only under the condition that they have not been administered the 
study drug or did not proceed to imaging.  
4.6 
Screen Failures 
Subjects who sign an informed consent form (ICF) but are ultimately not injected will be 
considered a screen failure. Subjects will be assigned a study identification number at the time 
the ICF is signed. eCRFs for Inclusion, Exclusion, Demographics, Adverse Events, and final 
disposition should be completed for all screen failure subjects. 
4.7 
Subject Identification 
After the subject provides written informed consent, the site will assign the subject a 7-digit 
subject number. Subject numbers are to be assigned in a sequential manner using the following 
format:  
Digits 1 to 2: Study number “31”  
 
Digits 3 to 4: Site number (e.g., “01”)  
 


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Digits 5 to 7: Sequential subject number (e.g., “001”, “002”, “003”)  
For example, the first subject consented at Site 01 is subject number “31-01-001.”  
 
Subjects will maintain the same number given at screening for the entire study. If a subject is 
a screen failure, the number will not be used for any other subject. 


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


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5.3 
Timing and Frequency of Drug Administration 
Subjects in all 3 arms will receive the study-defined dose of 150 mcg tilmanocept radiolabeled 
with 10 mCi of Tc 99m. The timing and frequency (i.e., repetition) of drug administration will 
be contingent upon arm assignment as described below and summarized in Table 6. 
• Subjects enrolled in Arm 1, defined as those who are healthy controls clinically free 
of inflammatory disease and/or joint pain, will undergo drug administration at the 
Day 0 (Visit 1) only.  
• Subjects enrolled in Arm 2, defined as those who are clinically diagnosed with active 
RA and are on a stable anti-rheumatic therapy, will undergo drug administration at 
the following two timepoints:  
1. Day 0 (Visit 2)  
2. Day 8 ± 1 (Visit 4) 
• Subjects enrolled in Arm 3, defined as those who are clinically diagnosed with active 
RA and are candidates for initiation of, or change to, a new anti-TNFα bDMARD 
treatment, 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) 
3. 12 ± 1 weeks after the initiation of new anti-TNFα bDMARD therapeutic 
regimen (Visit 6) 
4. 24 ± 1 weeks after the initiation of new anti-TNFα bDMARD therapeutic 
regimen (Visit 8) 
 
Table 6  
Summary of Tc 99m Tilmanocept Administration Timepoints by 
Study Arm 
Arm Subjects 
Administrations Day(s)/Visit  
1 
HCs 
1 
[1] Day 0 (Visit 1) 
2 
Active RA on stable anti-
rheumatic treatment 
2 
[1] Day 0 (Visit 1) 
[2] Day 8 ± 1 (Visit 4) 
3 
Active RA with initiation of, 
or change to, a new anti-
TNFα bDMARD therapy 
4 
[1] Day 0 (Visit 2) 
[2] 5 ± 1 weeks after new  anti-
 
TNFα bDMARD 
[3] 12 ± 1 weeks after new 
 
anti-TNFα bDMARD 
[4] 24 ± 1 weeks after new 
 
anti-TNFα bDMARD 
 


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


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


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7 
STUDY PROCEDURES 
A schedule of evaluations is provided in the schedule of events (Appendices 1 and 3) and study 
workflow diagram (Appendices 2 and 4). 
7.1 
Schedule of Evaluations 
7.1.1 
Arm 1 (HC Subjects) 
Visit 1 (Screening; Day -30 to Day -1) 
• Preliminary review of inclusion and exclusion criteria 
• Obtain signed informed consent for study participation 
• Allocation of unique subject number; this number will be used to document the subject 
data in the case report forms (CRFs) and enrollment log 
• Demography – date of birth, gender, race 
• Medical surgical history – all relevant prior medical and surgical conditions will be 
recorded in the CRF. Documented medical conditions will also note the month and year 
of onset if the condition is still active. 
• Concomitant medications (within 30 days before injection). 
• Vital signs (body temperature, heart rate, blood pressure, and respiratory rate after at 
least 1 minute in a resting position) 
• Physical examination will include an assessment of height, weight, and examination of 
general appearance, skin, eyes, ears, nose, throat, head and neck (including thyroid), 
lungs, heart, abdomen, lymph nodes, musculoskeletal, and nervous system. Any 
clinically relevant finding is to be documented as a baseline finding. Physical exams 
that are conducted as standard of care prior to signing informed consent may be used if 
they are performed within 30 days of injection. 
• Clinical laboratory tests – study subjects will have blood obtained for hematology, 
chemistry, and an RA panel (see Table 12)  
• Urine collection for routine analysis 
• Urine pregnancy test for women of child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who 
are not of childbearing potential will not require a pregnancy test. 
• 2010 ACR/EULAR: to confirm that the subject is clinically free of inflammatory 
disease and joint pain Swollen and tender joints will be identified and documented 
during physical examination as established by the 2010 ACR/EULAR.  
 


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Visit 2 (Tc 99m Tilmanocept Administration and Imaging; Day 0) 
All subjects will be assessed for adverse events in an ongoing manner from the day of injection 
through the end of participation.  
Pre-Tc 99m Tilmanocept Administration 
 
The following procedures will be completed for all subjects on the day of injection prior to the 
administration of Tc 99m tilmanocept: 
• A urine pregnancy test for women of child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who 
are not of childbearing potential will not require a pregnancy test. 
• Assessment of adverse events 
• Concomitant medication review 
• ECG (see Section 8.8) within 30 minutes prior to administration of Tc 99m tilmanocept 
• Vital signs after at least 1 minute in a resting position (body temperature, heart rate, 
blood pressure, and respiratory rate) within 30 minutes prior to administration of Tc 
99m tilmanocept 
 
Tc 99m Tilmanocept Administration 
 
IV administration of Tc 99m tilmanocept will be at study time 00:00. The preferred site of IV 
placement will be between the elbow and the wrist. The filled syringes will be connected to 
the catheter for a slow push injection. At the completion of the injections, a 10-mL sterile 
normal saline flush will be administered. The IV administration will be performed in the 
nuclear medicine department by an onsite Certified Nuclear Medicine Technologist or Nuclear 
Medicine Physician. Subjects will be continuously monitored for adverse events. 
0-30 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• ECG (completed before vital signs) 
• Vital signs after at least 1 minute in a resting position (body temperature, heart rate, 
blood pressure, and respiratory rate) 
 
60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• Image acquisition (in the following order); 
1. Planar scan of the whole body followed by up to a 15-minute pause (includes 
patient preparation for the subsequent acquisition); 
2. Planar scan of the bilateral hands and wrists followed by immediate preparation (up 
to 10 minutes) for the subsequent scan; 
3. Consecutive planar scan of the whole body followed by up to  a 15-minute pause 
(includes patient preparation for the subsequent acquisition); 


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4. Consecutive planar scan of the bilateral hands and wrists followed by a pause until 
the 180 ± 15-minute imaging timepoint. 
 
180 ± 15 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• Image acquisition (in the following order): 
1. 
Planar scan of the whole body followed by up to a 15-minute pause (includes 
patient preparation for the subsequent acquisition); 
2. 
Planar scan of the bilateral hands and wrists followed by immediate preparation 
(up to 10 minutes) for the subsequent scan; 
3. 
Consecutive planar scan of the whole body followed by up to a 15-minute pause 
(includes patient preparation for the subsequent acquisition); 
4. 
Consecutive planar scan of the bilateral hands and wrists  
• Clinical labs (after imaging) 
• Urinalysis (after imaging) 
 
Visit 3 (Day 5 ± 3; Follow-up Telephone Safety Assessment) 
• Review of concomitant medications 
• Assessment of adverse events 
 
7.1.2 
Arm 2 (RA Subjects on Stable Therapy) 
Visit 1 (Screening; Day -30 to Day -1) 
• Preliminary review of inclusion and exclusion criteria 
• Obtain signed informed consent for study participation 
• Allocation of unique subject number; this number will be used to document the subject 
data in the case report forms (CRFs) and enrollment log 
• Demography – date of birth, gender, race 
• Medical surgical history – all relevant prior medical and surgical conditions will be 
recorded in the CRF. Documented medical conditions will also note the month and year 
of onset if the condition is still active. 
• Concomitant medications (within 30 days before injection). 
• Vital signs (body temperature, heart rate, blood pressure, and respiratory rate after at 
least 1 minute in a resting position) 
• Physical examination will include an assessment of height, weight, and an examination 
of general appearance, skin, eyes, ears, nose, throat, head and neck (including thyroid), 
lungs, heart, abdomen, lymph nodes, musculoskeletal, and nervous system. Any 
clinically relevant finding is to be documented as a baseline finding. Physical exams 
that are conducted as standard of care prior to signing informed consent may be used if 
they are performed within 30 days of injection. 
• Clinical laboratory tests – study subjects will have blood obtained for hematology, 
chemistry, and an RA panel (see Table 11)  


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• Urine collection for routine analysis 
• Urine pregnancy test for women of child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who 
are not of childbearing potential will not require a pregnancy test. 
• RA Evaluations: Swollen and tender joints will be identified and documented during 
physical examination as established by the 2010 ACR/EULAR and DAS28. A review 
of the subject’s RA history including previous treatments, date of symptom onset, and 
date of diagnosis will also be performed.  
 
Visit 2 (Day 0; Tc 99m Tilmanocept Administration and Imaging) 
All subjects will be assessed for adverse events in an ongoing manner from the day of injection 
through the end of participation.  
Pre-Tc 99m Tilmanocept Administration 
 
The following procedures will be completed for all subjects on the day of injection prior to the 
administration of Tc 99m tilmanocept: 
• A urine pregnancy test for women of child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 
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 
• ECG within 30 minutes prior to administration of Tc 99m tilmanocept 
• Post-ECG vital signs after at least 1 minute in a resting position (body temperature, 
heart rate, blood pressure, and respiratory rate) within 30 minutes prior to 
administration of Tc 99m tilmanocept 
 
Tc 99m Tilmanocept Administration 
 
IV administration of Tc 99m tilmanocept will be at study time 00:00. The preferred site of IV 
placement will be between the elbow and the wrist. The filled syringes will be connected to 
the catheter for a slow push injection. At the completion of the injections, a 10-mL sterile 
normal saline flush will be administered. The IV administration will be performed in the 
nuclear medicine department by an onsite Certified Nuclear Medicine Technologist or Nuclear 
Medicine Physician. Subjects will be continuously monitored for adverse events. 
0 to 30 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• ECG (completed before vital signs) 
• Vital signs after at least 1 minute in a resting position (body temperature, heart rate, 
blood pressure, and respiratory rate) 


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60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• Image acquisition (in the following order): 
1. Planar scan of the whole body followed by up to a 15-minute pause (includes 
patient preparation for the subsequent acquisition); 
2. Planar scan of the bilateral hands and wrists followed by immediate preparation (up 
to 10 minutes) for the subsequent scan; 
3. Consecutive planar scan of the whole body followed by up to a 15-minute pause 
(includes patient preparation for the subsequent acquisition); 
4. Consecutive planar scan of the bilateral hands and wrists followed by a pause until 
the 180 ± 15-minute imaging timepoint. 
 
180 ± 15 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• Image acquisition 
1. 
Planar scan of the whole body followed by up to a 15-minute pause (includes 
patient preparation for the subsequent acquisition); 
2. 
Planar scan of the bilateral hands and wrists followed by immediate preparation 
(up to 10 minutes) for the subsequent scan; 
3. 
Consecutive planar scan of the whole body followed by up to a 15-minute pause 
(includes patient preparation for the subsequent acquisition); 
4. 
Consecutive planar scan of the bilateral hands and wrists. 
• Clinical labs (after imaging) 
• Urinalysis (after imaging) 
 
Visit 3 (Day 5 ± 3; Follow-up Telephone Safety Assessment) 
• Review of concomitant medications 
• Assessment of adverse events 
 
Visit 4 (Day 8 ± 1; Tc 99m Tilmanocept Administration and Imaging) 
Pre-Tc 99m Tilmanocept Administration 
The following procedures will be completed for all subjects on the day of injection prior to the 
administration of Tc 99m tilmanocept: 
• A urine pregnancy test for women of child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who 
are not of childbearing potential will not require a pregnancy test. 
• Assessment of adverse events 
• Concomitant medication review 
• ECG within 30 minutes prior to administration of Tc 99m tilmanocept 


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• Post-ECG vital signs after at least 1 minute in a resting position (body temperature, 
heart rate, blood pressure, and respiratory rate) within 30 minutes prior to 
administration of Tc 99m tilmanocept 
 
Tc 99m Tilmanocept Administration 
IV administration of Tc 99m tilmanocept will be at study time 00:00. The preferred site of IV 
placement will be between the elbow and the wrist. The filled syringes will be connected to 
the catheter for a slow push injection. At the completion of the injections, a 10-mL sterile 
normal saline flush will be administered. The IV administration will be performed in the 
nuclear medicine department by an onsite Certified Nuclear Medicine Technologist or Nuclear 
Medicine Physician. Subjects will be continuously monitored for adverse events. 
0 to 30 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• ECG (completed before vital signs) 
• Vital signs after at least 1 minute in a resting position (body temperature, heart rate, 
blood pressure, and respiratory rate) 
 
60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration: 
• AE assessment 
• Image acquisition (in the following order): 
1. Planar scan of the whole body followed by up to a 15--minute pause (includes 
patient preparation for the subsequent acquisition) 
2. Planar scan of the bilateral hands and wrists followed by a pause until the 180 ± 
15-minute imaging timepoint 
 
180 ± 15 Minutes Post-Tc 99m Tilmanocept Administration 
• AE assessment 
• Image acquisition 
1. Planar scan of the whole body followed by up to a 15-minute pause (includes 
patient preparation for the subsequent acquisition); 
2. Planar scan of the bilateral hands and wrists followed by immediate preparation 
(up to 15 minutes) for the subsequent SPECT/CT scan 
3. SPECT/CT scan of the bilateral hands and wrists. 
• Clinical labs (after imaging) 
• Urinalysis (after imaging) 
 
Visit 5 (Visit 4 + 1-3 days; Follow-up Telephone Safety Assessment) 
• Review of concomitant medications 
• AE assessment 
 


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7.1.3 
Arm 3 (RA Patients Initiating Change in Anti-TNFα bDMARD Therapy)* 
Visit 1 (Screening; Day -30 to Day -1) 
• Preliminary review of inclusion and exclusion criteria 
• Obtain signed informed consent for study participation 
• Allocation of unique subject number; this number will be used to document the subject 
data in the case report forms (CRFs) and enrollment log 
• Demography – date of birth, gender, race 
• Medical surgical history – all relevant prior medical and surgical conditions will be 
recorded in the CRF. Documented medical conditions will also note the month and year 
of onset if the condition is still active. 
• Concomitant medications (within 30 days before injection). 
• Vital signs (body temperature, heart rate, blood pressure, and respiratory rate after at 
least 1 minute in a resting position) 
• Physical examination will include an assessment of height, weight, and an examination 
of general appearance, skin, eyes, ears, nose, throat, head and neck (including thyroid), 
lungs, heart, abdomen, lymph nodes, musculoskeletal, and nervous system. Any 
clinically relevant finding is to be documented as a baseline finding. Physical exams 
that are conducted as standard of care prior to signing informed consent may be used if 
they are performed within 30 days of injection. 
• Clinical laboratory tests – study subjects will have blood obtained for hematology, 
chemistry, and an RA panel (Table 11)  
• Urine collection for routine analysis 
• Urine pregnancy test for women of child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who 
are not of childbearing potential will not require a pregnancy test. 
• RA Evaluations: Swollen and tender joints will be identified and documented during 
physical examination as established by the 2010 ACR/EULAR and DAS28. A 
HAQ-DI© 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.  
• WPI Assessment 


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Visit 2 (Day 0;Drug Administration/Imaging) 
Pre-Tc 99m Tilmanocept Administration 
The following procedures will be completed for all subjects on the day of injection prior to 
the administration of Tc 99m tilmanocept: 
• A urine pregnancy test for women of child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who 
are not of childbearing potential will not require a pregnancy test. 
• Assessment of adverse events 
• Concomitant medication review 
• ECG within 30 minutes prior to administration of Tc 99m tilmanocept 
• Post-ECG vital signs after at least 1 minute in a resting position (body temperature, 
heart rate, blood pressure, and respiratory rate) within 30 minutes prior to 
administration of Tc 99m tilmanocept 
 
Tc 99m Tilmanocept Administration 
 
IV administration of Tc 99m tilmanocept will be at study time 00:00. The preferred site of IV 
placement will be between the elbow and the wrist. The filled syringes will be connected to 
the catheter for a slow push injection. At the completion of the injections, a 10-mL sterile 
normal saline flush will be administered. The IV administration will be performed in the 
nuclear medicine department by an onsite Certified Nuclear Medicine Technologist or Nuclear 
Medicine Physician. Subjects will be continuously monitored for adverse events. 
0 to 30 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• ECG (completed before vital signs) 
• Vital signs after at least 1 minute in a resting position (body temperature, heart rate, 
blood pressure, and respiratory rate) 
 
60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration  
• AE assessment 
• Image acquisition (in the following order): 
1. Planar scan of whole body 
2. Planar scan of bilateral hands and wrists 
• Clinical labs (after imaging) 
• Urinalysis (after 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 


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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 
 
Visit 3 (Day 5 ± 3; Follow-up Telephone Safety Assessment) 
• Review of concomitant medications 
• AE assessment 
 
Visit 4 (Week 5 ± 1; Tc 99m Tilmanocept Administration, Imaging, and Clinical 
Assessments)  
Pre-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 
 
Pre-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 child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who 
are not of childbearing potential will not require a pregnancy test. 
• Assessment of adverse events 
• Concomitant medication review 
• ECG within 30 minutes prior to administration of Tc 99m tilmanocept 
• Post-ECG vital signs after at least 1 minute in a resting position (body temperature, 
heart rate, blood pressure, and respiratory rate) within 30 minutes prior to 
administration of Tc 99m tilmanocept 
 
Tc 99m Tilmanocept Administration 
 
IV administration of Tc 99m tilmanocept will be at study time 00:00. The preferred site of IV 
placement will be between the elbow and the wrist. The filled syringes will be connected to 
the catheter for a slow push injection. At the completion of the injections, a 10-mL sterile 
normal saline flush will be administered. The IV administration will be performed in the 


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nuclear medicine department by an onsite Certified Nuclear Medicine Technologist or Nuclear 
Medicine Physician. Subjects will be continuously monitored for adverse events. 
0 to 30 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of AEs 
• ECG (completed before vital signs) 
• Post-ECG vital signs after at least 1 minute in a resting position (body temperature, 
heart rate, blood pressure, and respiratory rate) 
 
60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration  
• AE assessment 
• Image acquisition (in the following order): 
• Planar scan of whole body 
• Planar scan of bilateral hands and wrists 
• Clinical Labs (after imaging) 
• RA labs (after imaging) 
• Urinalysis (after imaging) 
 
Visit 5 (5 ± 3 Days After Visit 4; Follow-up Telephone Safety Assessment) 
• Review of concomitant medications 
• AE assessment 
 
Visit 6 (Week 12 ± 1; Tc 99m Tilmanocept Administration, Imaging, and Clinical 
Assessments)* 
Pre-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  
• HAQ-DI© 
• WPI 
 
Pre-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 child-bearing potential. Females of child bearing 
potential are defined as women who 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. 


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• Assessment of AEs 
• Concomitant medication review 
• ECG within 30 minutes prior to administration of Tc 99m tilmanocept 
• Post-ECG vital signs after at least 1 minute in a resting position (body temperature, 
heart rate, blood pressure, and respiratory rate) within 30 minutes prior to 
administration of Tc 99m tilmanocept 
 
Tc 99m Tilmanocept Administration 
 
IV administration of Tc 99m tilmanocept will be at study time 00:00. The preferred site of IV 
placement will be between the elbow and the wrist. The filled syringes will be connected to 
the catheter for a slow push injection. At the completion of the injections, a 10-mL sterile 
normal saline flush will be administered. The IV administration will be performed in the 
nuclear medicine department by an onsite Certified Nuclear Medicine Technologist or Nuclear 
Medicine Physician. Subjects will be continuously monitored for adverse events. 
0-30 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of adverse events 
• ECG (completed before vital signs) 
• Post-ECG vital signs after at least 1 minute in a resting position (body temperature, 
heart rate, blood pressure, and respiratory rate) 
 
60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration  
• AE assessment 
• Image acquisition (n the following order): 
1. Planar scan of whole body 
2. Planar scan of bilateral hands and wrists 
• Clinical labs (after imaging) 
• RA labs (after imaging) 
• Urinalysis (after imaging) 
 
Visit 7 (5 ± 3 Days After Visit 6; Follow-up Telephone Safety Assessment) 
• Review of concomitant medications 
• AE assessment 
 
Visit 8 (Week 24 ± 1; Post-Tc 99m Tilmanocept Administration, Imaging, Clinical 
Assessments) 
Pre-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: 


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• CDAI 
• DAS28  
• HAQ-DI© 
• WPI 
 
Pre-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 child-bearing potential. Females of child bearing 
potential are defined as women that are not surgically sterile (hysterectomy or bilateral 
oophorectomy) nor postmenopausal for at least 1 year prior to screening. Women who 
are not of childbearing potential will not require a pregnancy test. 
• Assessment of adverse events 
• Concomitant medication review 
• ECG within 30 minutes prior to administration of Tc 99m tilmanocept 
• Post-ECG vital signs after at least 1 minute in a resting position (body temperature, 
heart rate, blood pressure, and respiratory rate) within 30 minutes prior to 
administration of Tc 99m tilmanocept 
 
Tc 99m Tilmanocept Administration 
 
IV administration of Tc 99m tilmanocept will be at study time 00:00. The preferred site of IV 
placement will be between the elbow and the wrist. The filled syringes will be connected to 
the catheter for a slow push injection. At the completion of the injections, a 10-mL sterile 
normal saline flush will be administered. The IV administration will be performed in the 
nuclear medicine department by an onsite Certified Nuclear Medicine Technologist or Nuclear 
Medicine Physician. Subjects will be continuously monitored for adverse events. 
0-30 Minutes Post-Tc 99m Tilmanocept Administration 
• Assessment of AEs 
• ECG (completed before vital signs) 
• Post-ECG vital signs after at least 1 minute in a resting position (body temperature, 
heart rate, blood pressure, and respiratory rate) 
 
60 ± 15 Minutes Post-Tc 99m Tilmanocept Administration  
• AE assessment 
• Image acquisition (in the following order): 
1. Planar scan of whole body 
2. Planar scan of bilateral hands and wrists 
• Clinical labs (after imaging) 


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• RA labs (after imaging) 
• Urinalysis (after imaging) 
 
Visit 9 (5 ± 3 Days After Visit 7; Follow-up Telephone Safety Assessment) 
• Review of concomitant medications 
• AE assessment 
 
*If a subject in Arm 3 requires early exit from the study between Week 16 and Week 
24, an attempt should be made to complete a final imaging visit and all clinical 
assessments. If possible, this should include all Visit 8 (Week 24 ± 1; Post-Tc 99m 
Tilmanocept Administration, Imaging, Clinical Assessments) procedures. 
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. 
 


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8 
PROCEDURES AND VARIABLES 
8.1 
Population Characteristics 
8.1.1 
Demographics and Other Baseline Characteristics 
One-hundred and five (105) evaluable subjects will be enrolled across all 3 study arms. Arms 
1 and 2 will each contain 38 male or female subjects, and Arm 3 will contain 29 subjects. 
Subjects in Arm 1 will be male or female HCs who are clinically free of any inflammatory 
and/or joint disease. Subjects in Arm 2 will be male or female individuals with clinically 
diagnosed active RA who are on stable anti-inflammatory and/or anti-rheumatic therapy. 
Subjects in Arm 3 will be male or female individuals who are candidates for initiation of, or 
change to, a new anti-TNFα bDMARD treatment.  
8.1.2 
Medical, Rheumatological, and Surgical History 
Relevant medical, rheumatological, and surgical histories will be obtained on all study 
subjects.  As part of the medical history, the date of the last spontaneous menstruation will be 
recorded if childbearing potential is not excluded by surgical sterilization. Rheumatological 
history will include date of RA diagnosis as well as the timing, dose, administration frequency, 
and administration route (when available) of all RA-specific drugs taken in the last 6 months. 
8.1.3 
Prior and Concomitant Medication 
All prior non-RA medications used up to 30 days before the first screening examination 
through the follow-up safety visit will be documented. In addition to the summarization of 
prior RA-specific treatments (Section 8.1.2), recent or concomitant treatments taken for RA in 
the last 6 months must be collected in accordance with the following time windows listed in 
Table 7. 
Table 7  
Documentation Window for Recent or Concomitant RA-specific 
Treatments 
Drug Class 
Documentation Window 
Traditional DMARDs 
On therapy ≥ 90 days and at a stable dose ≥ 30 days prior to 
the first imaging visit (Day 0) 
bDMARDs 
>180 days prior to the first imaging visit (Day 0) 
JAK inhibitors 
> 180 days prior to the first imaging visit (Day 0) 
NSAIDs/Corticosteroids 
≥ 28 days prior to the first imaging visit (Day 0) 
  
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 between the elbow and the wrist. The filled syringe will be connected to the catheter for a 


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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 5 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 
Subjects assigned to Arms 2 and 3 will be evaluated for the DAS28 (Prevoo 1995) at screening. 
Additional time intervals for DAS28 assessment will vary by study arm (Table 8). DAS28 is 
calculated from 4 components: TJC, 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 6 for details. 
Table 8  
Timing of DAS28 Evaluations by Study Arm 
Arm  
Visit (Day) 
1 
Not performed 
2 
Visit 1 (Day -30 to -1) 
3 
Visit 1 (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) 
Visit 8 (24 ± 1 Weeks post-initiation of new anti-TNFα bDMARD) 
 
8.3.3 
CDAI 
Subjects in Arm 3 will be evaluated for disease activity using the Clinical Disease Activity 
Index (CDAI) (Aletaha 2009). CDAI will be collected a total of 4 times per subject (Table 9). 
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 


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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 7 for details. 
Table 9  
Timing of CDAI Evaluations by Study Arm 
Arm  
Visit (Day) 
1 
Not performed 
2 
Not performed 
3 
Visit 1 (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) 
Visit 8 (24 ± 1 Weeks post-initiation of new anti-TNFα bDMARD) 
 
8.3.4 
ACR Response Criteria 
Subjects in Arm 3 will be evaluated using the ACR Response Criteria (Ward 2014). 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). Response is reported as percent (%) improvement from baseline to a 
later timepoint. In this case, a total of 3 timepoints will be evaluated per subject (Table 10).  
Percent improvement is defined as a combination of reductions in swollen or 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 or 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 or 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 or swollen joint counts as well as 20% improvement in at least 3 of the 
other 5 criteria. See Appendix 7 for details. 
Table 10  
Timing of ACR Response Evaluations by Study Arm 
Arm  
Visit (Day) 
1 
Not performed 
2 
Not performed 
3 
Visit 4 (5 ± 1 Weeks post-initiation of new anti-TNFα bDMARD) 
Visit 6 (12 ± 1 Weeks post-initiation of new anti-TNFα bDMARD) 
Visit 8 (24 ± 1 Weeks post-initiation of new anti-TNFα bDMARD) 
 


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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 score (Section 8.3.1), DAS28 score (Section 
8.3.2), CDAI score (Section 8.3.3), and ACR Response (Section 8.3.4). 
8.3.5.2 
Global Assessment of Disease Activity 
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 (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 (Section 8.3.4). 
8.3.5.3 
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 (Section 8.3.4). 
8.3.5.4 
Patient Assessment of Physical Function (HAQ-DI©) 
Patient assessment of physical function will be evaluated using the HAQ Disability Index 
(HAQ-DI©) questionnaire. 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 9 for more 
information. 
8.3.5.5 
Acute-phase Reactant 
ESR will be obtained in the RA-specific laboratory panel (see Table 12). 


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8.3.5.6 
Widespread Pain Index 
Assessment of widespread pain will be evaluated using the widespread pain index (WPI). 
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 1 to 19). This assessment will be used 
as an additional pain assessment tool to evaluate central pain.  
8.4 
Imaging 
8.4.1 
Image Acquisition 
8.4.1.1 
Planar Scintigraphy 
Planar image acquisition occurs in all subjects. The frequency of planar imaging is contingent 
upon study arm assignment (Table 11). 
Whole Body and Anterior and Posterior Spot View of the Hands and Wrists will also be 
obtained based on study arm assignment. 
Table 11  
Planar Image Acquisition by Study Arm 
Arm Whole Body a 
Bilateral Hands and Wrists b 
Total 
1 
Visit 2 
60 ± 15 min. p.i.  
60 ± 15 min. p.i. (consecutive) 
180 ± 15 min. p.i.  
180 ± 15 min. p.i. (consecutive) 
Visit 2 
60 ± 15 min. p.i.  
60 ± 15 min. p.i. (consecutive) 
180 ± 15 min. p.i.  
180 ± 15 min. p.i. (consecutive) 
8 
2 
Visit 2 
60 ± 15 min. p.i.  
60 ± 15 min. p.i. (consecutive) 
180 ± 15 min. p.i.  
180 ± 15 min. p.i. (consecutive) 
 
Visit 4 
60 ± 15 min. p.i.  
180 ± 15 min. p.i.  
 
Visit 2 
60 ± 15 min. p.i.  
60 ± 15 min. p.i. (consecutive) 
180 ± 15 min. p.i.  
180 ± 15 min. p.i. (consecutive) 
 
Visit 4 
60 ± 15 min. p.i.  
180 ± 15 min. p.i.  
12 


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Table 11  
Planar Image Acquisition by Study Arm 
Arm Whole Body a 
Bilateral Hands and Wrists b 
Total 
3 
Visit 2 
60 ± 15 min. p.i.  
 
Visit 4 
60 ± 15 min. p.i.  
 
Visit 6 
60 ± 15 min. p.i.  
 
Visit 8 
60 ± 15 min. p.i.  
Visit 2 
60 ± 15 min. p.i.  
 
Visit 4 
60 ± 15 min. p.i.  
 
Visit 6 
60 ± 15 min. p.i.  
 
Visit 8 
60 ± 15 min. p.i.  
8 
p.i.  = post injection 
a Whole body scan always precedes planar scans of bilateral hands/wrists. 
b This scan always follows whole body planar scans. 
 
8.4.1.2 
SPECT/CT 
SPECT/CT images are acquired in Arm 2 on Visit 4 (Day 8 ± 1) after the completion of all 
planar imaging at the 180 ± 15-minute imaging timepoint. SPECT/CT is performed on the 
bilateral hands and wrists only. Refer to the Image Acquisition Guidelines for all required 
imaging technical specifications and acquisitions. 
8.4.1.3 
Tilmanocept Uptake Value (TUV) 
TUV is a quantitative imaging metric used to characterize the amount of CD206 activity on 
planar imaging. Results from a prior Phase 1 and 2 study 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 whole body planar images and static images of 
the bilateral hands and wrists to derive relevant count statistics, which are input parameters for 
joint-specific (TUVjoint) and global (TUVglobal) TUVs. TUV metrics are further described in the 
NAV3-31 Statistical Analysis Plan. 


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8.5 
Adverse Events 
8.5.1 
Definition of Adverse Event 
The definitions below follow International Conference on Harmonization (ICH) – Good 
Clinical Practice (GCP) (see also ICH Guideline for Clinical Safety Data Management:  
Definitions and Standards for Expedited Reporting). 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product.  
Any clinically significant change in a condition (worsening) from screening that results in a 
change in subject management will be considered an AE and will be recorded on the AE page 
of the CRF. 
By definition for this study, all untoward medical occurrences beginning on the Visit 2 (Day 0) 
until the final visit (variable per arm) are to be reported as AEs.  AEs continuing after study 
completion will be followed to normalization or stabilization. Additionally, untoward medical 
events occurring prior to the day of Tc 99m tilmanocept administration will be collected and 
added to the subject’s medical history unless they are related to a study procedure, in which 
case the event will be recorded as an AE. SAEs will be reported from the time of consent 
through the end of participation. 
8.5.2 
Categories for Adverse Event Assessment 
The severity of an AE is classified according to the following categories, taking into account 
the possible range of the intensity of the event: 
• Mild  
The adverse event is transient and easily tolerated by the subject. 
• Moderate   The adverse event causes the subject discomfort and interrupts the 
subject’s usual activities 
• Severe  
The adverse event causes considerable interference with the subject’s 
usual activities and may be incapacitating or life-threatening. 
 
Specific drug treatment 
Any specific drug treatment will be documented.  
Causal relationship to investigational product 
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of investigational product:  


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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 0) will be recorded in the subject’s medical history unless 
related to study procedure, in which case the event will be recorded as an AE. Untoward 
medical events beginning on Visit 2 (Day 0) until the final visit (variable per arm) will be 
reported as adverse events.     


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Any AE (observed, volunteered, or elicited) should be recorded in detail in the source 
documentation. 
The following information is required: 
• The date and time of onset of any AE. 
• The duration (the entire duration of an event or symptom, calculated from date of onset 
to date of end, if not recorded directly). 
• The seriousness of the AE will be assessed by the investigator.  If the investigator 
deems that an AE qualifies as an SAE, a special form provided by the sponsor should 
be completed and the event must be immediately reported to the sponsor.  A definition 
of serious adverse events is provided in Section 8.5.5. 
• The maximum intensity (mild, moderate, or severe). 
• Whether drug treatment was administered for the event, any specific drug treatment 
must be documented. 
• The relationship of the AE to the investigational product and to study conduct (for 
definitions, see above). 
• The outcome of the AE (resolved, resolved with sequelae, not resolved, unknown, 
death). 
 
AEs will be coded according to an internationally recognized dictionary (Medical Dictionary 
for Regulatory Activities [MedDRA]). 
8.5.4 
Expected Adverse Events 
Investigational Product-Related Risks 
In all completed studies of Lymphoseek (Tc 99m tilmanocept), involving 553 subjects, only 3 
events (breast pain and injection site pain reported by subjects with breast cancer and injection 
site irritation reported by a subject with head and neck squamous cell cancer) were deemed 
definitely related to the administration of Lymphoseek by the investigator. The most common 
adverse reactions (incident < 1%) have been lack of effect (< 0.067%), injection site pain (< 
0.02%) and rash (< 0.02%). Adverse events from the radioactive dose are not expected, since 
the applied radiation doses are far below doses that can cause acute effects in human tissues.  
In addition to the Lymphoseek pre-approval clinical studies, post-marketing surveillance 
shows that Lymphoseek has been administered to more than 250,000 patients with not a single 
drug-related SAE. Routes of administration included: subcutaneous, intradermal, and 
peritumoral.  
The intended route of administration in this study is intravenous. There have been 
approximately 60 IV administrations of Tc 99m tilmanocept and no SAEs or ADRs have been 
reported to date.  
Risks of Imaging Procedures 


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Radiation dose considerations from Tc 99m Tilmanocept planar and SPEC/CT scans – Patients 
enrolled in this trial will have whole body and hand/wrist planar gamma camera scans 
following Tc 99m Tilmanocept injection, with subjects enrolled in Arm 2 also receiving one 
hand/wrist SPECT/CT scan.   
The average effective radiation dose per 10 mCi Tc 99m Tilmanocept injection is calculated 
to be 2.7 mSv (equivalent to about ten months of natural background radiation received in the 
US). Subjects enrolled in Arm 1 will receive one injection, equal to 2.7 mSv total; subjects 
enrolled in Arm 2 will receive a maximum of two injections plus one SPECT/CT scan- with 
an estimated effective dose of 1 mSv for the CT portion- amounting to 6.4 mSv total; subjects 
enrolled in Arm 3 will receive a maximum of four injections, equal to 10.8 mSv total. The 
maximum possible dose of ~10.8 mSv for any enrolled subject (no one will cross over into 
more than one study arm) is considered to be a moderate risk level corresponding to the benefit 
to the patient (category III based on the International Commission on Radiological Protection 
62 (ICRP62)) and is balanced against the possible substantial societal benefit that can be gained 
from the trial (European Commission Radiation Protection 99, 1998 and ICRP 62, 1992). For 
further reference, the effective dose from a standard CT abdomen and pelvis, with and without 
contrast, is up to 20 mSv.  
Precautionary Measures 
Special precautionary measures are not considered necessary for this study.  In case of 
emergency, standard emergency procedures will be employed. 
Unexpected Adverse Events 
An unexpected adverse event is defined as an adverse reaction that in nature and severity is 
not consistent with the applicable product information (e.g., Investigator’s Brochure).  Any 
adverse experience that is not listed in the current Investigator’s Brochure or which is, with 
regard to the specificity or severity, not consistent with the risk information shall be regarded 
as unexpected.  
Examples would be (a) acute renal failure listed in the Investigator’s Brochure with a 
subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant 
hepatitis.  “Unexpected” as used in this definition refers to an adverse drug experience that has 
not been previously observed and included in the Investigator’s Brochure, rather than from the 
perspective of such experience not being anticipated from the pharmacological properties of 
the investigational product. 
8.5.5 
Serious Adverse Events 
Definition of Serious Adverse Events 
The following SAE definition is based on ICH guidelines and the final rule issued by the Food 
and Drug Administration (FDA) and effective 06 Apr 1998.   


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


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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: 
• General Appearance 
• Skin/dermatological 
• Eyes, ears, nose, throat 
• Head and neck (including thyroid) 
• Lungs 
• Heart 
• Abdomen (liver, kidney, spleen, gastrointestinal) 
• Lymph nodes 
• Musculoskeletal 
• Nervous system 
 
8.7 
Vital Signs 
Vital signs comprise the measurement of body temperature, heart rate, respiration, systolic and 
diastolic blood pressure. All measurements will be taken after the subject has been in a resting 
position for at least 1 minute. Vital signs will be measured at screening, within 30 minutes 
before investigational product injection, and within 30 minutes post injection. Any clinically 
significant change from screening (worsening) that results in a change in subject management 
will be considered an AE and will be recorded on the AE page of the CRF. 
8.8 
Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) will be obtained up to 30 minutes before 
investigational product administration and within 30 minutes after investigational product 
administration. The ECG will be measured with the subject in a resting position for at least 1 
minute. Continuous ECG monitoring is not required.  At a minimum, the heart rate, QRS, PR 
and QT intervals will be collected.  QTc will be calculated using the Fridericia formulas. 


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On-site investigator’s responsibilities 
The immediate cardiac safety of the subject will be ensured by the on-site qualified physician.  
Any 12-lead ECG intervals, waveform abnormalities, and rhythm changes that are clinically 
significant in that they result in a change in subject management will be considered an AE.  In 
the case of an SAE, once SAE notification is decided upon, investigators are required to follow 
the procedure described for SAE notification and document abnormal ECG findings (intervals 
and waveforms).  Any interval data or abnormal waveform finding that resulted in an AE (i.e., 
change of patient management) must be followed to normalization or stabilization. Each 12-
lead ECG tracing must be signed and dated and stored in the subject’s source documentation.   
8.9 
Clinical Laboratory Parameters 
Table 12  
Clinical Laboratory Parameters 
Hematology 
Hemoglobin (Hgb), hematocrit (HCT), platelets, neutrophils, 
basophils, lymphocytes, monocytes, red blood cells (RBC), white 
blood cells (WBC) 
Serum chemistry  
Aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase, total bilirubin, creatinine, chloride, 
potassium, sodium, total protein, albumin, carbon dioxide 
(CO2)/bicarbonate, blood urea nitrogen (BUN), glucose  
Urinalysis 
pH, specific gravity 
Rheumatoid Panel 
Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), 
rheumatoid factor (RF); anti-citrullinated peptide antibody 
(ACPA) 
 
All laboratory reports must be promptly reviewed for clinical significance by the investigator, 
and upon review, initialed and dated by the investigator. 
Good clinical practice would suggest that a copy of the laboratory results also be provided to 
the subject’s referring physician. 
Only abnormal laboratory values will be collected in the electronic database. Any change in a 
laboratory value, which results in a change in subject management (additional controls or 
treatment required), will be reported as a clinically significant change. Clinically significant 
changes in laboratory parameters, 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 13. 


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Table 13  
Approximate Amount of Blood Drawn per Subject by Study Arm 
Arm 
Timepoint 
Test (Sample Volume) 
Total Blood Drawn at 
Timepoint 
1 
Visit 1 (Day -30 to -1) 
Chemistry (5 mL) 
Hematology (4 mL) 
RA panel (4 mL) 
13 mL (2.6 teaspoons) 
Visit 2 (Day 0) 
Chemistry (5 mL) 
Hematology (4 mL) 
9 mL (1.8 teaspoons) 
Total (Arm 1) 
22 mL (4.5 teaspoons) 
2 
Visit 1 (Day -30 to -1) 
Chemistry (5 mL) 
Hematology (4 mL) 
RA Panel (4 mL) 
13 mL (2.6 teaspoons) 
Visit 2 (Day 0) 
Chemistry (5 mL) 
Hematology (4 mL) 
9 mL (1.8 teaspoons) 
Visit 4 (Day 8 ± 1) 
Chemistry (5 mL) 
Hematology (4 mL) 
9 mL (1.8 teaspoons) 
Total (Arm 2) 
31 mL (6.3 teaspoons) 
3 
Visit 1 (Day -30 to -1) 
Chemistry (5 mL) 
Hematology (4 mL) 
RA panel (4 mL) 
13 mL (2.6 teaspoons) 
Visit 2 (Day 0) 
Chemistry (5 mL) 
Hematology (4 mL) 
9 mL (1.8 teaspoons) 
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 
Chemistry (5 mL) 
Hematology (4 mL) 
RA panel (4 mL) 
13 mL (2.6 teaspoons) 
Visit 8 (24 ± 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) 
Total (Arm 3) 
61 mL (12.4 teaspoons) 
 


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9 
STATISTICAL METHODS 
This is a prospective, open-label, multicenter study of the patterns of variation in planar 
imaging using IV injected Tc 99m tilmanocept for the quantitative detection of disease activity 
in the skeletal joints of HC subjects and subjects with active RA. In addition to quantitative 
assessments, this study will also include qualitative (i.e., visual) evaluations of SPECT/CT in 
detecting localization within synovial spaces of the bilateral hands and wrists.   
The study is stratified into 3 groups. Arm 1 consists of HC subjects. Arm 2 consists of RA 
patients on stable therapy. Arm 3 consists of RA patients who are candidates for initiation of, 
or change to, a new anti-TNFα bDMARD treatment. 
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) 
• ECG parameters 
• Vital signs 
 
9.3 
Efficacy Variables 
The efficacy variables for this study are defined below: 
• Quantitative determination of TUVjoint and TUVglobal  
• Qualitative (i.e., visual) evaluation of SPECT/CT in detecting localization within 
synovial spaces of the bilateral hands and wrists 
• Subject RA status as summarized in the CDAI and ACR Response Criteria overall 
score and their constituent sub-scores 
 
It is presumed that the presence of radiotracer uptake for a joint indicates the presence of 
activated macrophages. The use of the term “localization” is synonymous with radiotracer 
uptake. 
The efficacy endpoints for this study, by arm, are as follows: 
Primary Endpoint(s) 
ARMS 1-2 
• The camera-specific precision of TUVjoint and TUVglobal in subjects with active RAand 
HCs, which is defined as the Root Mean Square Difference (RMSD) between the 
consecutive 15-minute planar images. 


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• The stability of the mean/variance relationship, which is assessed by comparing the 
Coefficient of Variation (CV) of TUVjoint and TUVglobal in subjects with active RA and 
HCs. 
 
ARM 2  
• The longitudinal (8-day) precision of TUVjoint and TUVglobal in subjects with active 
RA, which is defined as the RMSD of images at the same time point.   
 
ARM 3  
• The correlation of ΔTUVglobal[5w] 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). The correlation of ΔTUVglobal[5w] and 
response to new anti-TNFα bDMARD therapy from baseline to 12 ± 1 weeks and 24 
± 1 weeks defined by ACR Response Criteria (ACR12w and ACR24w, respectively). 
 
Secondary Endpoint(s) 
ARMS 1-2 
• The temporal stability of the 150 mcg tilmanocept mass dose/10 mCi radiolabeling 
dose. 
 
ARM 1  
• The normal ranges of TUVjoint in HC subjects, which is defined as the 5 and 95 
percentiles of:  
- 
TUVjoint of bilateral joints (i.e., bilateral wrists, MCPs, PIPs, knees, elbows, 
shoulders) 
 
ARM 2 
• The qualitative evaluations of SPECT/CT in detecting localization within synovial 
spaces of the bilateral hands and wrists. 
 
ARM 3 
• The correlation of the TUVglobal[0week] 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) and by ACR Response Criteria 
(ACR12w and ACR24w, respectively). 
• The correlation of ΔTUVglobal[12w] and ΔTUVglobal[24w] 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) and by ACR Response 
Criteria (ACR12w and ACR24w, respectively).   
• The correlation of ΔTUVglobal[5w] and constituent parameters of ΔCDAI12/24w and 
ACR12/24w including: 
1. Tender Joint Count (TJC) 
2. Swollen Joint Count (SJC) 


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3. Patient assessment of global disease activity 
4. Rheumatologist assessment of global disease activity 
5. Patient assessment of pain 
6. Patient assessment of physical function 
7. Acute-phase reactant value 
 
9.4 
Sample Size Justification 
The study will enroll up to 105 evaluable subjects in Arms 1, 2, 3 allocated below, imaged at 
up to 10 study centers. Arm 1 will have N = 38 evaluable subjects, Arm 2 will have N = 38 
evaluable subjects, and Arm 3 will have N = evaluable 29 subjects. A subject is considered 
evaluable if he/she meets the criteria for the analysis population and has the data necessary for 
computing the primary endpoint. 
The sample size for Arm 1 was determined to assess temporal stability of the 150 mcg 
tilmanocept mass dose/10 mCi radiolabeling dose. The sample size for Arm 2 was determined 
to power the hypothesis test at 0.80. The sample size for Arm 3 was determined to provide a 
lower 97.5% confidence limit for the rank correlation of at most 0.15 when rho = 0.70, using 
Fisher’s Z-transformation methods. 
9.5 
Statistical Analyses 
9.5.1 
Analysis Populations 
The following populations are defined for this study: 
Intent-to-Diagnose (ITD) Population – the ITD population includes all subjects who have 
been enrolled in the study, injected with Tc 99m tilmanocept, and received all imaging and 
evaluations necessary for the primary endpoint(s) appropriate to their respective arm. 
Per-Protocol (PP) Population – the PP population consists of all ITD subjects without major 
protocol violations. 
Safety Population – The safety population includes all subjects who have been enrolled in the 
study and injected with at least 1 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 (gender, race and ethnicity) will be summarized via counts and 
percentages. 


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9.5.3 
Analysis of Efficacy Variables 
All efficacy analyses will be conducted on both the ITD and PP populations. The ITD 
population will be the primary analysis set. 
9.5.3.1 
Primary Endpoints Arms 1- 2 
Precision endpoints will be assessed estimating the mean, standard deviation, n, minimum, 
median, and maximum of the signed differences, calculated as change from the initial 
measurement. The RMSD will be calculated and a 95% confidence interval on its value will 
be provided.  
Stability of the mean/variance relationship will be assessed by the coefficient of variation of 
the differences for active RA subjects and HC subjects at 60 minutes and 180 minutes. 95% 
confidence intervals for the difference in CVs following the methods of (Forkman 2009) and 
from the bootstrap sampling distribution of the difference of the CVs will be provided based 
on N = 5000 bootstrap samples. 
9.5.3.2 
Secondary Endpoints Arms 1- 2 
The normal ranges of TUVjoint will be estimated from data collected from HC subjects (Arm 1 
only) at 60 minutes and 180 minutes post-injection. The mean, standard deviation, n (number 
of joints), and quantile regression estimates of the 5 and 95 percentiles will be provided for 
shoulder, elbow, wrist, MCP, PIP, and knee. 
9.5.3.3 
Primary endpoint Arm 3 
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 ΔACR12w 
and ΔACR24w (overall scores only) will be computed and a 95% confidence interval for its 
value will be computed using Fisher’s Z-transformation. 
9.5.3.4 
Secondary endpoint Arm 3 
The Kendall rank correlations between ΔTUVglobal[5w] with the subscores of ΔACR12w and 
ΔACR24w (including tender joint count, swollen joint count, 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) will be computed 
and a 95% confidence interval for its value will be computed using Fisher’s Z-transformation. 
The Kendall rank correlations between TUVglobal[0w], ΔTUVglobal[12w], ΔTUVglobal[24w] with the 
ΔCDAI12w, ΔCDAI24w, ΔACR12w, ΔACR24w will be computed and a 95% confidence interval 
for their values will be computed using Fisher’s Z-transformation. 
Additional efficacy analyses may be described in the Statistical Analysis Plan (SAP) for the 
study. 


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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) for each Arm and overall at each time point. 
Other safety analyses may be described in the SAP for the study. 
9.5.5 
Handling of Missing Values 
The analysis of the efficacy variables will be carried out on the observed data, i.e. a complete 
case analysis.  
9.5.6 
Interim Analyses 
After the injection, imaging, and quantitation of a total of 4 subjects in Arms 1 and 2 combined, 
an interim analysis (interim analysis 1) will be held for the review of quantitative TUV results 
and assessment of imaging parameters and logistics. A second interim analysis will be held 
after a total of 30 subjects (≥ 15 RA) in Arms 1 and 2 are injected, imaged, and quantified for 
the review of intra-and inter-subject TUV variation to contribute to the power analysis of a 
future Phase 3 study and/or to terminate the study on grounds of data sufficiency. 
After 15 subjects in Arm 3 have completed Visit 4, an interim analysis (interim analysis 3) will 
be performed to estimate the distribution of treatment effects on TUV and to optimize the TUV 
metric based on the interim data from all three Arms.   


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


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In addition, inspections by health authority representatives and IRB(s) are possible at any time.  
The investigator is to notify the sponsor of any such inspection immediately. 
10.5 Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.  Patient (hospital) files will be archived 
according to local regulations and in accordance with the maximum period of time permitted 
by the hospital, institution, or private practice.  Where the archiving procedures do not meet 
the minimum timelines required by the sponsor, alternative arrangements must be made to 
ensure the availability of the source documents for the required period. 
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g., relocation or transfer of ownership). 
The investigator site file is not to be destroyed without the sponsor’s approval. 
The investigator’s contract will contain all regulations relevant for the study center. 
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. 
 
10.6.3 Study as a Whole 
The sponsor retains the right to prematurely terminate the study as a whole at any time.   


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


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


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


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Appendix 1 
Schedule of Events (Arms 1-2) 
Evaluation 
Visit 1 
Screening 
(Day -30 
to -1) 
Visit 2 
(Day 0) 
Visit 3 
Telephone 
(Day 5 ± 3) 
Visit 4 
(Day 8 ± 1) 
 
Visit 5 
Telephone 
(Visit 4 + 1-3 
days) 
- 00:30 
to 
- 00:01 
00:00 
Injection 
 
00:01 
to 
00:30 
60 
± 
15 min 
180 
± 
15 min 
After 
Imaging 
- 00:30 
to 
- 00:01 
00:00 
Injection 
 
00:01 
to 
00:30 
60 
± 
15 min 
180 
± 
15 min 
After 
Imaging 
Informed consent 
1, 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Entry criteria 
1, 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, RA history, 
demography 
1, 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
1, 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory evaluation: 
chemistry, hematology, 
urinalysis 
1, 2 
 
 
 
 
 
1, 2 
 
 
 
 
 
 
2 
 
RA panel 
1, 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
1, 2 
1, 2 
 
 
 
 
 
 
2 
 
 
 
 
 
 
2010 ACR/EULAR 
1, 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DAS28 
 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
1, 2 
 
1, 2 
 
 
 
 
2 
 
2 
 
 
 
 
Vital signs (obtained post-
ECG at Visits 2 and 4) 
1,2 
1, 2 
 
1, 2 
 
 
 
 
2 
 
2 
 
 
 
 
Tc 99m tilmanocept 
administration 
 
 
1, 2 
 
 
 
 
 
 
2 
 
 
 
 
 
Whole body planar scan 
 
 
 
 
1, 2 
1, 2 
 
 
 
 
 
2 
2 
 
 
Planar scan of bilateral 
hands/wrists 
 
 
 
 
1, 2 
1, 2 
 
 
 
 
 
2 
2 
 
 
Consecutive whole body 
planar scan 
 
 
 
 
1, 2 
1, 2 
 
 
 
 
 
 
 
 
 
Consecutive planar scan of 
bilateral hands/wrists 
 
 
 
 
1, 2 
1, 2 
 
 
 
 
 
 
 
 
 
SPECT/CT of bilateral 
hands/wrists 
 
 
 
 
 
 
 
 
 
 
 
 
2 
 
 
Concomitant medications 
1, 2 
1, 2 
 
 
 
 
 
1, 2 
2 
 
 
 
 
 
2 
AE monitoring 
1, 2 
1, 2 
1, 2 
1, 2 
1, 2 
1, 2 
 
1, 2 
2 
2 
2 
2 
2 
 
2 
1   Arm 1 
2   Arm 2 
1,2 Arms 1 and 2 
 


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Appendix 2 
Workflow Diagram (Arms 1-2) 
 


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Appendix 3 
Schedule of Events (Arm 3) 
a Initiation of anti-TNFα bDMARD therapy change will occur following Day 0 procedures 
b DAS28, CDAI, HAQ-DI©, and WPI assessments are to be performed within seven days prior to injection  
 
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 
± 
15 min 
After 
Imaging a 
- 00:30 
to  
- 00:01 
00:00 
00:01 to 
00:30 
60 
± 
15 min 
After 
Imaging 
Informed consent  
x 
 
 
 
 
 
 
 
 
 
 
 
Entry criteria  
x 
 
 
 
 
 
 
 
 
 
 
 
Medical History, RA History, 
Demography  
x 
 
 
 
 
 
 
 
 
 
 
 
2010 ACR/EULAR  
x 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (obtained post-
ECG at Visits 2 and 4) 
x 
x 
 
x 
 
 
 
x 
 
x 
 
 
ECG 
 
x 
 
x 
 
 
 
x 
 
x 
 
 
Physical Examination  
x 
 
 
 
 
 
 
 
 
 
 
 
DAS28 
x 
 
 
 
 
 
 
xb 
 
 
 
 
CDAI 
x 
 
 
 
 
 
 
xb 
 
 
 
 
HAQ-DI© 
x 
 
 
 
 
 
 
xb 
 
 
 
 
WPI 
x 
 
 
 
 
 
 
xb 
 
 
 
 
Clinical laboratory evaluation: 
chemistry, hematology, UA 
x 
 
 
 
 
x 
 
 
 
 
 
x 
RA panel 
x 
 
 
 
 
 
 
 
 
 
 
x 
Urine pregnancy test  
x 
x 
 
 
 
 
 
x 
 
 
 
 
Tc 99m tilmanocept 
administration  
 
 
x 
 
 
 
 
 
x 
 
 
 
Planar Imaging: whole body 
followed by 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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a Initiation of anti-TNFα bDMARD therapy change will occur following Day 0 procedures 
b DAS28, CDAI, HAQ-DI©, and WPI assessments are to be performed within seven days prior to injection  
 
 
Evaluation  
Visit 5 
Telephone 
(5 ± 3 days 
after Visit 4) 
Visit 6  
(12 ± 1 Week Post-Treatment Change) 
Visit 7 
Telephone 
(5 ± 3 days 
after Visit 6) 
Visit 8 
(24 ± 1 Week Post Treatment Change) 
Visit 9 
Telephone 
(5 ± 3 days 
after Visit 8) 
- 00:30 
to  
- 00:01 
00:00 
00:01 
to 
00:30 
60 
± 
15 min 
After 
Imaging 
- 00:30 
to  
- 00:01 
00:00 
00:01 
to 
00:30 
60 
± 
15 min 
After 
Imaging 
Informed consent  
 
 
 
 
 
 
 
 
 
 
 
 
 
Entry criteria  
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, RA 
History, Demography  
 
 
 
 
 
 
 
 
 
 
 
 
 
2010 ACR/EULAR  
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (obtained 
post-ECG at Visits 6   
and 8) 
 
x 
 
x 
 
 
 
x 
 
x 
 
 
 
ECG 
 
x 
 
x 
 
 
 
x 
 
x 
 
 
 
Physical Examination  
 
 
 
 
 
 
 
 
 
 
 
 
 
DAS28 
 
xb 
 
 
 
 
 
xb 
 
 
 
 
 
CDAI 
 
xb 
 
 
 
 
 
xb 
 
 
 
 
 
HAQ-DI© 
 
xb 
 
 
 
 
 
xb 
 
 
 
 
 
WPI 
 
xb 
 
 
 
 
 
xb 
 
 
 
 
 
Clinical laboratory 
evaluation: chemistry, 
hematology, UA 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
RA panel 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
Urine pregnancy test  
 
x 
 
 
 
 
x 
 
 
 
 
 
Tc 99m tilmanocept 
administration  
 
 
x 
 
 
 
 
x 
 
 
 
 
Planar Imaging: whole 
body followed by 
bilateral hands and wrists  
 
 
 
 
x 
 
 
 
 
 
x 
 
 
Concomitant medications 
x 
x 
x 
x 
 
 
 
 
x 
AE monitoring  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


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Appendix 4 
Workflow Diagram (Arms 3) 
 


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


Technetium Tc 99m tilmanocept 
 
Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-31 
 
02 February 2021 
 
 
 
 
Confidential 
Page 95 of 103 
 
** In this category, at least 1 of the involved joints must be a small joint; the other joints can include any 
combination of large and additional small joints, as well as other joints not specifically listed elsewhere (e.g., 
temporomandibular, acromioclavicular, sternoclavicular, etc.).  
†† Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the laboratory 
and assay; low-positive refers to IU values that are higher than the ULN but ≤ 3times the ULN for the laboratory 
and assay; high-positive refers to IU values that are > 3 times the ULN for the laboratory and assay. Where 
rheumatoid factor (RF) information is only available as positive or negative, a positive result should be scored as 
low-positive for RF. ACPA = anti-citrullinated protein antibody. 
‡‡ Normal/abnormal is determined by local laboratory standards. CRP = C-reactive protein; ESR = erythrocyte 
sedimentation rate.  
§§ Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (e.g., pain, 
swelling, tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status. 
Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of 
Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 
2010;62(9):2569-2581. 


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Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-31 
 
02 February 2021 
 
 
 
 
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Appendix 6 
DAS28 Scoring 
Courtesy of http://www.iche.edu/newsletter/DAS28.pdf 


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Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-31 
 
02 February 2021 
 
 
 
 
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Appendix 7 
CDAI Scoring 
 
 
Courtesy of https://www.rheumatology.org/Portals/0/Files/CDAI%20Form.pdf


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Clinical Trial Protocol: NAV3-31 
 
02 February 2021 
 
 
 
 
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Appendix 8 
ACR Response Criteria 
 
Courtesy of https://www.phusewiki.org/wiki/index.php?title=ACR_Response_Criteria


Technetium Tc 99m tilmanocept 
 
Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-31 
 
02 February 2021 
 
 
 
 
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Appendix 9 
HAQ-DI© Questionnaire 
 


Technetium Tc 99m tilmanocept 
 
Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-31 
 
02 February 2021 
 
 
 
 
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Technetium Tc 99m tilmanocept 
 
Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-31 
 
02 February 2021 
 
 
 
 
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Courtesy of https://integrationacademy.ahrq.gov/center/default/files/-DI_0.pdf 


Technetium Tc 99111 tilmanocept 
Clinical Trial Protocol: NA V3-3 I 
Sponsor Signatures 
Navidea Biopharmaceuticals, Inc. 
02 February 2021 
Appendix 10 
Study Title: 
Evaluation of the Precision and Sensitivity ofTilmanocept Uptake 
Value (TUV) on Tc 99m Tilmanocept Planar Imaging 
Study Number: 
Original Date: 
Amendment 1 Date: 
Amendment 2 Date: 
Amendment 3 Date 
Amendment 4 Date 
NAV3-31 
16 November 2018 
28 February 2019 
19 April 2019 
24 April 2019 
02 February 2021 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor. The f:llow.ing p:;:.npntributed to writing and/or approving this protocol: 
Signed: /,/~· 
Date: 
11 February2021 
William Regan 
Chief Compliance Officer 
Navidea Biopharmaceuticals, Inc. 
/1/1~~ .. 
A 
/ 
Signed:~ /J,,.~, .~ 
Michael Blue, MD, F ACEP 
Senior Medical Director 
Navidea Biopharmaceuticals, Inc. 
Signed: ~
~ 
Bonnie Abbruzzese,MS,,CCRA 
Senior Director, Clinical Research & Development 
Signed:Nav~ 
_ 
Mic~ 
h'-....------"" 
Chief Medical Officer 
Navidea Biopharmaceuticals, Inc. 
Confidential 
Page 102 of 103 
Date: 
l l t:=='~ zo z_. ( 
Date: 


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Clinical Trial Protocol: NAV3-31 
 
02 February 2021 
 
 
 
 
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Appendix 11 
Investigator’s Signature 
Study Title: 
Evaluation of the Precision and Sensitivity of Tilmanocept Uptake 
Value (TUV) on Tc 99m Tilmanocept Planar Imaging 
Study Number: 
NAV3-31 
Original Date: 
16 November 2018 
Amendment 1 Date: 
28 February 2019 
Amendment 2 Date: 
19 April 2019 
Amendment 3 Date: 
24 April 2019 
Amendment 4 Date: 
02 February 2021 
I have read the protocol described above. I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  
 
 
Signed: 
 
 
Date:  
 
 

SAP_001.pdf: 
Statistical Analysis Plan (SAP) 
Evaluation of the Precision and Sensitivity of 
Tilmanocept Uptake Value (TUV) on Tc 99m 
Tilmanocept Planar Imaging 
Study No: NAV3-31 
Version 1.1 
July 6, 2021 
Prepared for 
Navidea Biopharmaceuticals, Inc. 
4995 Bradenton Avenue, Suite 240 
Dublin, OH  43017 
Prepared by 
STATKING Clinical Services 
759 Wessel Drive 
Fairfield, OH  45014 
513-858-2989
www.statkingclinical.com STATKING Clinical Services
NCT03938636






Statistical Analysis Plan 
 
Study No. NAV3-31 
 
 
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Version 1.1                                                                                                             July 6, 2021                                  
Revision History 
 
Version 1.0 to 1.1: 
 
• Updated the TUV prediction algorithms 1 and 4 in Section 4.2.2 to include 
a 10% decrease as a predicted responder.  The prior SAP version defined 
a responder as one with a strictly greater than 10% decrease. 
• Added clarification in Section 4.2.2 that the TUV prediction algorithms are 
to be implemented after rounding the change in TUV calculations to the 
nearest integer percentage (i.e., nearest hundredths place for a 
proportion). 
 
 
 


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


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


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Table of Contents 
 
APPROVAL PAGE ............................................................................................ 1 
REVISION HISTORY ......................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................... 5 
INTRODUCTION ................................................................................................ 9 
1.0 SYNOPSIS OF STUDY DESIGN/PROCEDURES ....................................... 9 
1.1 Design and Treatment .......................................................................................................................10 
1.2 Study Procedures ...............................................................................................................................10 
1.3 Sample Size .........................................................................................................................................12 
2.0  DATA ANALYSIS CONSIDERATIONS .................................................... 13 
2.1 Types of Analyses ...............................................................................................................................13 
2.2 Analysis Populations ..........................................................................................................................13 
2.3 Missing Data Conventions .................................................................................................................13 
2.4 Interim Analyses ................................................................................................................................13 
2.5 Calculation of TUV ............................................................................................................................14 
2.6 Study Center Considerations in the Data Analysis .........................................................................16 
2.7 Documentation and Other Considerations ......................................................................................16 
3.0 ANALYSIS OF BASELINE PATIENT CHARACTERISTICS ..................... 17 
4.0 ANALYSIS OF EFFICACY ........................................................................ 17 
4.1 Description of Efficacy Variables .....................................................................................................17 
4.2 Analysis of Efficacy Variables ..........................................................................................................21 
5.0  ANALYSIS OF SAFETY ........................................................................... 27 
5.1 Description of Safety Variables ........................................................................................................27 


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5.2 Description of Safety Analysis ..........................................................................................................27 
6.0  OTHER RELEVANT DATA ANALYSES/SUMMARIES ........................... 29 
6.1 Patient Completion ............................................................................................................................29 
6.3 Study Drug Administration...............................................................................................................29 
6.4 RA Evaluation and Screening Physical Exam .................................................................................29 
6.5 Concomitant Medications..................................................................................................................29 
7.0  LIST OF ANALYSIS TABLES, FIGURES AND LISTINGS ...................... 31 
9.0  REFERENCES .......................................................................................... 35 
APPENDIX A – TABLES, FIGURES AND LISTING SPECIFICATIONS ........ 36 
APPENDIX B – TABLE SHELLS .................................................................... 38 
 
 
 


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INTRODUCTION 
 
Description 
 
This Statistical Analysis Plan (SAP) is consistent with Amendment 4 of the study 
protocol (dated 2 February 2021) and includes the latest details of efficacy and 
safety summaries to be included in the clinical study report (CSR). 
The preparation of this SAP was done in accordance with STATKING Clinical 
Services SOP SCI 02-54, Statistical Analysis Plans. 
 
1.0 Synopsis of Study Design/Procedures 
 
This study is a prospective, open-label, multicenter, evaluation of the reliability 
and sensitivity of Tilmanocept Uptake Value (TUV) assessments based on planar 
imaging localization of intravenously (IV) injected Tc 99m tilmanocept to skeletal 
joints in subjects with and without active rheumatoid arthritis (RA). 
The study has three arms. Arm 1 consists of Healthy Control (HC) subjects. Arm 
2 consists of RA patients on stable therapy. Arm 3 consists of RA patients who 
are candidates for initiation of, or change to a new anti-tumor necrosis factor  
(TNF) biological disease-modifying antirheumatic drug (bDMARD) treatment. 
The objectives of the study are: 
Primary Objectives: 
• To assess the longitudinal precision of TUVjoint and TUVglobal on planar 
imaging in subjects with clinically diagnosed active RA on stable anti-
rheumatic therapy. 
• To evaluate camera-specific precision of TUVjoint and TUVglobal on planar 
imaging in HCs and in subjects with clinically diagnosed active RA using 
centralized and standardized imaging parameters. 
• To assess the correlation of TUV and changes in TUV with changes in 
clinical assessments at multiple time points after initiation of a new anti-
anti-TNF bDMARD therapy. 
Secondary Objectives: 
• To assess the temporal post-injection stability of TUVjoint and TUVglobal at 
a dose of 150mcg tilmanocept radiolabeled with 10 mCi of Tc 99m. 
• To establish normal ranges for TUVjoint in HCs. 


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• To assess Tc 99m tilmanocept anatomic localization based on single 
photon 
emission 
computed 
tomography/ 
computed 
tomography 
(SPECT/CT) imaging of the synovial space in hands and wrists. 
Safety Objective: 
• To evaluate safety through the examination of adverse event (AE) 
incidence and changes over time in laboratory tests, vital signs, and 
physical examination findings.  
1.1 Design and Treatment 
 
Subjects will receive the administration of Tc 99m tilmanocept through an IV 
route of administration. All subjects will receive a 150 g mass dose of 
tilmanocept labeled with 10 mCi of Tc 99m in a 3 ml volume. Following injection 
a 10 ml sterile normal saline flush will be administered. The preferred site of IV 
placement will be between the elbow and wrist.  
Arm 1 HC subjects receive a single administration of 10 mCi of Tc 99m in a 150 
g mass dose of tilmanocept. Arm 2 RA subjects receive two (2) IV 
administrations of 10 mCi Tc 99m in a 150 g mass dose of tilmanocept. Arm 3 
RA subjects receive up to four (4) administrations of 10 mCi Tc 99m in a 150 g 
mass dose of tilmanocept. 
Table 1 Study arms 
Arm 
Subjects 
Evaluations 
1 
HC subjects clinically free of any 
inflammatory disease and/or joint pain. 
Image, Re-image 
2 
Subjects with clinically diagnosed RA who 
have been on stable anti-rheumatic 
therapy. 
Image, Re-image 
Test, Re-test 
3 
Subjects with clinically diagnosed RA who 
are candidates for initiation of, or change 
to, a new anti-TNF bDMARD treatment. 
Positive Predictive 
Value, Negative 
Predictive Value, 
Clinical Concordance 
 
1.2 Study Procedures 
 
Subjects will visit the study site for screening procedures up to 30 days (Day -30 
to Day -1) before enrollment into the study. Screening procedures 
(demographics, vital signs, medical history, blood and urine samples for clinical 


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labs, RA specific labs, urine pregnancy testing for subjects of childbearing 
potential, and physical exam) will be completed along with RA evaluations using 
the 2010 ACR/EULAR score. The DAS28 score instrument will be used in Arms 
2 and 3.   
Subjects arriving for Study Day 0 will be considered enrolled in the study. On Day 
0 subjects will receive Tc 99m injection and imaging procedures. Pre-injection 
procedures include the following: a urine pregnancy test will be administered to 
all subjects with childbearing potential. Up to 30 minutes prior to drug 
administration an ECG will be performed, followed by assessment of vital signs 
and AEs. After pre-injection procedures are completed subjects will receive a 
single IV dose with 150 g of tilmanocept radiolabeled with 10 mCi of Tc 99m. 
Within 30 minutes of injection, subjects will receive an ECG followed by vital sign 
and AE check.  Whole body planar imaging will be conducted on the subject at 
the time points specified for the arm into which he/she was enrolled (see Section 
1.0). For subjects in Arms 1 and 2, planar images of the whole body and bilateral 
hands and wrists will be taken at 60 (+ 15) minutes and at 180 (+ 15) minutes 
after injection. Blood will be drawn for clinical laboratory evaluations after all 
image acquisitions have been completed. 
On Study Day 5 (+ 3 days) a safety follow-up telephone call will include a review 
of concomitant medications and assessment of adverse events. Arm 1 HC 
subjects have completed the study at this point. 
On Study Day 8 (+ 1 day) RA subjects in Arm 2 will receive repeat Tc 99m 
tilmanocept imaging. Pre-injection procedures include the following: a urine 
pregnancy test will be administered to all subjects with childbearing potential. Up 
to 30 minutes prior to drug administration an ECG will be performed, followed by 
assessment of vital signs and AEs. After pre-injection procedures are completed 
subjects will receive a single IV dose with 150 g of tilmanocept radiolabeled with 
10 mCi of Tc 99m. Within 30 minutes of injection, subjects will receive an ECG 
followed by vital signs and AE assessment. Planar images of the whole body and 
bilateral hands and wrists will be taken at 60 (+ 15) minutes and 180 (+ 15) 
minutes after injection. Following the 180 minute planar imaging, subjects will 
have SPECT/CT images of the bilateral hands and wrists taken. Blood will be 
drawn for clinical laboratory evaluations after all image acquisitions have been 
completed. 
From 1 to 3 days of the second imaging day (i.e., Study Day 9 to 11 if imaging is 
done on Study Day 8), a safety follow-up telephone call will be made to review 
concomitant medications and AE check. Arm 2 RA subjects have completed the 
study at this point. 
For RA subjects in Arm 3, Study Day 0 is modified to include planar whole body 
and planar images of the hands and wrists once only at 60 minutes post-injection. 
All other procedures remain the same on Study Day 0. The new therapy (anti-


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TNF bDMARD) will be initiated following the Day 0 imaging. A safety follow-up 
telephone call will be conducted on Study Day 5 (± 3 days).  Follow-up images 
of the hands and wrists and whole body will be made at 5 weeks (+ 1 week) after 
initiation of the new anti-TNF bDMARD therapy using the same procedures as 
in Arm 2 Day 8, except that no images will be taken at 180 minutes in Arm 3 and 
the post imaging clinical laboratory assessments will include an RA panel. CDAI, 
DAS28, HAQ-DI, WPI, and an AE check will also occur at this visit. A safety 
follow-up telephone call will be conducted 1 to 3 days later. At weeks 12 (± 1 
week) and 24 (+ 1 week) after initiation of the new anti-TNF bDMARD therapy, 
Arm 3 subjects will have a return visit for imaging and assessment of their RA 
status. These visits will include clinical laboratory assessments and RA-specific 
labs (post imaging), tilmanocept injection and image acquisition 60 (+ 15) 
minutes following injection, CDAI, DAS28, HAQ-DI, WPI , and AE check at both 
of these time points. ACR Response Criteria will be assessed at weeks 5, 12 and 
24. After the week 24 visit, Arm 3 RA subjects have completed the study.  
 
The centralized core image laboratory contracted by Navidea Biophar-
maceuticals completed a quantitative read of the images to determine the 
amount of radiotracer uptake in the joints (TUVjoint) and in the brain (TUVbrain) for 
Interim Analysis 2. The core image laboratory will also evaluate localization of Tc 
99m tilmanocept in the 180 minute planar and SPECT/CT images of Arm 2 RA 
patients. Navidea internal work instructions and imaging charter will be followed 
for all other quantitative and qualitative reads for all other imaging data. 
1.3 Sample Size 
 
Up to 105 subjects from up to 10 study centers will be enrolled into Arms 1, 2, 
and 3 as allocated below, and imaged. Arm 1 will have N = 38 evaluable subjects, 
Arm 2 will have N = 38 evaluable subjects, and Arm 3 will have N = 29 evaluable 
subjects. A subject is considered evaluable if he/she meets the criteria for the 
analysis population and has the data necessary for computing the primary 
endpoint. 
 
The sample size for Arm 1 was determined to assess temporal stability of the 
150 g mass dose/10mCi radiolabeling dose. The sample size for Arm 2 was 
determined to power a hypothesis test at 0.80: 
 
𝐻0: π ≤0.80
𝑣𝑠
𝐻𝑎: π > 0.80,
 
 
where  represent the fraction of unsigned differences less than 7.5% The 
sample size for Arm 3 was determined to provide a lower 97.5% confidence limit 
for the rank correlation of at most 0.15 when  = 0.70, using Fisher’s Z-
transformation methods. 


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2.0  Data Analysis Considerations 
 
2.1 Types of Analyses 
 
Data analyses described in this SAP will consist of analyzing efficacy and safety 
data.  
 
2.2 Analysis Populations 
 
The following analysis populations will be used in the study: 
 
Safety Population – The safety population includes all patients that have been 
enrolled in the study and injected with at least one dose of Tc 99m tilmanocept. 
 
Intent-to-Diagnose (ITD) Population – The ITD population includes all patients 
that have been enrolled in the study, injected with Tc 99m tilmanocept, and 
received all imaging and evaluations necessary for the primary endpoint(s) 
appropriate to their respective arm. 
 
Per Protocol (PP) Population: The PP population will include all ITD subjects 
without major protocol violations. All protocol deviations will be classified as 
major or minor prior to database lock. 
 
All efficacy analyses will be carried out on the ITD and PP populations with the 
ITD population being the primary analysis set. All analyses of safety data and 
baseline subject characteristics will be carried out on the safety population. A 
data listing displaying the patients excluded from each population will be created, 
as shown in Appendix B.   
 
2.3 Missing Data Conventions 
 
No missing value imputation will be used in this analysis.  All analyses will be 
based on the observed data. 
 
2.4 Interim Analyses 
     
After the injection, imaging, and quantitation of a total of 4 subjects in Arms 1 and 
2 combined, an interim analysis (Interim Analysis 1) was held for the review of 
quantitative TUV results and assessment of imaging parameters and logistics. A 
second interim analysis was held after a total of 30 subjects (and at least 15 RA 
subjects) in Arms 1 and 2 were injected, imaged, and quantified for the review of 
inter- and intra-subject TUV variation to contribute to the power analysis of a 
future Phase 3 study and/or to terminate the study on grounds of data sufficiency. 
 


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After 15 subjects in Arm 3 completed Visit 4, an interim analysis (Interim Analysis 
3) was performed to estimate the distribution of treatment effects on TUV and to 
optimize the TUV metric based on the interim data from all three arms. 
 
Interim analysis plans (IAPs) were written and approved for the second interim 
analysis of Arms 1 and 2 and for the third interim analysis of all three study arms. 
 
2.5 Calculation of TUV 
 
All calculations are done on a reader-specific basis. That is, there is no statistical 
aggregation of the reader results. 
 
Calculating Joint TUV  
For an individual joint, TUVjoint is defined as the average pixel intensity of the 
joint divided by the average pixel intensity of the hand, right or left and anterior 
or posterior, (includes the region from one wrist region of interest (ROI) 
diameter above the wrist ROI down to the fingertips). 
 
Calculating Global TUV 
For each independent blind reader, determine the average TUVjoint and 95% 
prediction interval of both the anterior and posterior views of the wrists, MCPs, 
and PIPs in healthy individuals (NAV3-31 Arm 1). For all following calculations, 
reader specific average TUVjoint and 95% prediction intervals will be used.  
 
For each RA subject do the following. 
Step 1: Calculate TUVjoint for each of the 22 DAS 28 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
. 


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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 (TUVglobal[b]): 
ΔTUVglobal[5w] = 100 ⋅
TUVglobal[5w] −TUVglobal[b]
TUVglobal[b]
. 
Arms 1 and 2: 
 
Precision endpoints for both arms will be assessed estimating the mean, 
standard deviation, n, minimum, median, and maximum of the signed differences 
(change from baseline) of TUV for each evaluated DAS28 joint. The RMSD will 
be calculated using the following equation: 
 
𝑅𝑀𝑆𝐷= √
1
𝑛−1 ∑(𝑦𝑘−𝑤𝑘)2
𝑛
𝑘=1
 
 
where yk and wk are the measurements at the two timepoints (for example, the 
two scans at 60 minutes, the two scans at 180 minutes, or the first 60-minute 
scan and the first 180-minute scan) and k represents the subject number. A 95% 
confidence interval for the RMSD based on Normal theory will be provided, as 
will a 95% bootstrap confidence interval based on N = 5000 bootstrap samples. 
Box-and-whisker plots of TUV will be provided by arm at each timepoint for each 
joint, pooling small joints (MCPs and PIPs) and all joints bilaterally. Joints will not 
be pooled by type or bilaterally in IA 3. 
 
TUV will be summarized with descriptive statistics as the signed difference. If 
T1 represents the observed TUV at the first time point and T2 the observed TUV 
at the second time point, then 
 
∆𝑇𝑈𝑉= 𝑇2 −𝑇1. 
 


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Arm 1 Only: 
 
The distribution of TUVjoint in healthy controls will be summarized by time point 
for global TUV and each evaluated DAS28 joint with the number of joints, mean, 
standard deviation, 80th and 90th percentiles, the median, and 95% prediction 
limits for a future observation of that type at that time point. Joints will not be 
pooled. Box-and-whisker plots of the data will be presented by joint and time 
point. A scatter plot matrix for the three readers will be provided on a joint-specific 
basis showing the relationship between the reader TUV for the A and B scans. 
 
Arm 2 Only: 
 
The longitudinal precision of TUVjoint will be analyzed for each evaluated DAS28 
joint. The signed differences will be analyzed with descriptive statistics and the 
RMSD will be calculated as defined for Arms 1 and 2 above. A 95% confidence 
interval for the RMSD based on Normal theory will be provided, as will a 95% 
bootstrap confidence interval based on N = 5000 bootstrap samples. Joints will 
not be pooled by type or bilaterally. A scatter plot matrix for the three readers will 
be provided on a joint-specific basis showing the relationship between the reader 
TUV for the A and B scans. 
 
Arm 3 Only: 
 
The Kendall rank correlation between ΔTUVglobal[5w] with ΔCDAI12w 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 each of the ACR Response Criteria 
components at 12 weeks (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, and acute-phase reactant value) will be computed and a 95% 
confidence interval for its value will be computed using Fisher’s Z-transformation. 
 
2.6 Study Center Considerations in the Data Analysis 
 
A study center is defined as a treatment administration site or group of treatment 
administration sites under the control and supervision of the same Principal 
Investigator (PI). There will be no selective pooling of study centers. 
 
2.7 Documentation and Other Considerations 
 
The data analyses described in this SAP will be conducted using SAS© Software, 
version 9.4 or later.   
 


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3.0 Analysis of Baseline Patient Characteristics 
 
Baseline and demographic characteristics of the safety population will be 
summarized by subject arm and overall.  Continuous variables (age, height, 
weight, and time from diagnosis of RA) will be summarized via mean, standard 
deviation, minimum, maximum, and number of non-missing responses. 
Categorical variables (gender, race, and ethnicity) will be summarized via counts 
and percentages.   
 
A detailed listing of baseline data for each patient in the safety population will 
also be provided, as shown in Appendix B. 
 
4.0 Analysis of Efficacy 
 
4.1 Description of Efficacy Variables 
     
The efficacy variables for this study are as follows: 
• Quantitative determination of TUVjoint and TUVglobal at Day 0, Day 8, Week 
5, Week 12, and Week 24 as appropriate to the subject’s study arm. 
• Qualitative determination of tilmanocept localization in planar images and 
SPECT/CT images of the bilateral hands and wrists. 
• Subject RA status evaluations in Arm 3 as summarized in the CDAI overall 
score and its subscores. 
• Subject RA status evaluation in Arm 3 as summarized by the ACR 
Response Criteria. 
• Change in TUV. 
The presence of radiotracer uptake for a joint indicates the presumed presence 
of activated macrophages.  The use of the term “localization” in this SAP is 
synonymous with the presence of radiotracer uptake.   
TUV is defined as: 
TUVjoint = 𝑋̅𝑗𝑜𝑖𝑛𝑡
𝑋̅RR
; 
  
where 
 
• 𝑋̅joint is the average voxel intensity of a particular joint of a subject at the 
anterior or posterior views at 1 or 3-hours post-injection; 


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• 𝑋̅RR is the average voxel intensity of the reference region (RR) of a subject 
at the anterior or posterior views at 1 or 3-hours post-injection.  
 
4.1.1 Primary efficacy variables 
The primary efficacy variables for this study are: 
• Quantitative measurement of TUVjoint (all arms) and TUVglobal (Arms 2 and 
3 only) 
• CDAI scores at baseline, 12 (+ 1) weeks and 24 (+ 1) weeks (Arm 3 only) 
• DAS28 scores at baseline, 12 (+ 1) weeks and 24 (+ 1) weeks (Arm 3 
only) 
• ACR Response Criteria at 12 (+ 1) weeks and 24 (+ 1) weeks (Arm 3 only). 
The primary efficacy variables of this study in Arms 1 and 2 are: 
• The camera-specific precision of TUVjoint and TUVglobal in subjects with 
active RA and healthy controls, which is defined as the Root Mean Square 
Difference (RMSD) between the consecutive 15-minute planar images. 
• The stability of the mean/variance relationship, which is assessed by 
comparing the Coefficient of Variation (CV) of TUVjoint and TUVglobal in 
subjects with active RA and healthy controls. 
An added primary variable in Arm 2 only is: 
• The longitudinal (8-day) precision of TUVjoint and TUVglobal in subjects with 
active RA, which is defined as the RMSD of the TUV between the baseline 
and 8 day image at the same time point. 
The primary endpoints in Arm 3 are: 
• The Kendall rank correlation of TUVglobal[5w] with the response to new 
anti-TNF bDMARD therapy defined as CDAI12w and CDAI24w (overall 
scores only) in study arm 3. 
• The Kendall rank correlation of TUVglobal[5w] with the response to new 
anti-TNF bDMARD therapy defined as the changes from baseline in 
DAS28 and in each of the ACR Response Criteria components at 12 (+ 1) 
weeks and at 24 (+ 1) weeks in study arm 3. 


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4.1.2 Secondary efficacy variables 
• Qualitative evaluations of SPECT/CT image detecting localization of Tc 
99m tilmanocept in the synovial spaces of the bilateral hands and wrists. 
(Arm 2 only). 
• CDAI score at baseline (CDAI0w), 12 (CDAI12w) and 24 weeks (CDAI24w) 
(Arm 3 only). 
• ACR Response Criteria at 12 and 24 weeks (Arm 3 only). 
• 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 
o TJC 
o SJC 
o Patient Global Assessment 
o Physician Global Assessment. 
 
The secondary efficacy endpoints for this study are: 
ARMS 1-2  
• The temporal stability of TUVjoint and TUVglobal using a 150 mcg 
tilmanocept mass dose/10 mCi radiolabeling dose, which is defined as the 
squared difference between the 1-hour and 3-hour planar images. (This 
endpoint was analyzed to the sponsor’s satisfaction in IA-3.) 
 
ARM 1  
• The normal upper limit of TUVjoint in HC subjects, which is defined the 
upper limit of a 95% prediction interval at 60 ±15 minutes:  
- 
TUVjoint of evaluated joints (i.e., wrists, MCPs, PIPs, knees, elbows, 
shoulders in Arms 1 and 2, and wrists, MCPs, and PIPs in Arm 3). 
 
ARM 2  
• The qualitative evaluations of SPECT/CT in detecting localization within 
synovial spaces of the bilateral hands and wrists.  
 


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ARM 3  
• TUVglobal[0w]  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) and by the changes from 
baseline in each of the ACR Response Criteria components at 12 (+ 1) 
weeks and at 24 (+ 1) weeks. 
 
• TUVglobal[5w] and response to new anti-TNFα bDMARD therapy defined 
by the CFB of CDAI to 12 ± 1 weeks and 24 ± 1 weeks (CDAI12w and 
CDAI24w, respectively). 
 
• TUVglobal[12w]  and TUVglobal[24w].  
 
• Concordance of improvement classification using TUVglobal[5w] and 
TUVglobal[5w] with anti-citrullinated protein/peptide antibody (ACPA) 
bucketing improvement classification using clinical criteria, including ACR 
Response Criteria, CDAI, DAS28, and HAQ-DI. See section 4.2.2 below 
for the definitions of improvement on these clinical criteria. 
 
• Concordance of improvement classification using TUVglobal[12w] and 
TUVglobal[12w] with ACPA bucketing improvement classification using 
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 (CDAI12w and CDAI24w, 
respectively). 
 
• The correlation of TUVglobal[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:  
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.  
 


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4.2 Analysis of Efficacy Variables 
 
4.2.1 Primary Efficacy Variables 
Primary Endpoints for Arms 1 and 2 
All TUV data will be analyzed with summary statistics (mean, standard deviation, 
n, minimum, median, maximum) by study arm and joint. 
 
Precision endpoints will be assessed estimating the mean, standard deviation, 
n, minimum, median, and maximum of the signed differences (CFB). The RMSD 
will be calculated 
 
𝑅𝑀𝑆𝐷= 
1
𝑛−1 ∑(𝑦𝑘−𝑤𝑘)2
𝑛
𝑘=1
 
 
where yk and wk are the measurements at the two timepoints and k represents 
the subject number. A 95% confidence interval for the RMSD based on Normal 
theory will provided, as will a 95% bootstrap confidence interval based on N = 
5000 bootstrap samples. Timepoints analyzed in this way will include the 60 
minute A and B scans, the 180 minute A and B scans, and the difference between 
the 60 and 180 minute A scans. These will be done for all joints assessed and 
for TUVglobal. (These analyses were completed to the sponsor’s satisfaction in IA-
3.) 
 
Primary Endpoint for Arm 2 Only 
The longitudinal (8-day) variation of TUV will be analyzed for each DAS28 joint 
and globally. The signed differences will be analyzed with descriptive statistics 
and the RMSD will be calculated as defined for Arm 2 above. A 95% confidence 
interval for the RMSD based on Normal theory will provided, as will a 95% 
bootstrap confidence interval based on N = 5000 bootstrap samples will be 
computed, and 95% confidence limits for its value will be provided. This will be 
done for TUVjoint for all evaluated joints and TUVglobal in the 60 minute images 
using the “A” image at baseline. The fraction of unsigned TUVglobal values less 
than 7.5% will be summarized in a frequency table and an exact binomial test of 
the hypotheses described in Section 1.3 will be included for each timepoint. 
 
Primary Endpoints for Arm 3 Only 
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. 
 


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4.2.2 Secondary Efficacy Variables 
Secondary Endpoints for Arm 1 only 
The normal ranges of TUVjoint will be estimated from data collected from healthy 
subjects (study arm 1) at 60 minutes post-injection. The mean, standard 
deviation, n (number of joints), and quantile regression estimates of the 5 and 95 
percentiles will be provided for shoulder, elbow, wrist, MCP, PIP, and knee. All 
joints will be summarized individually. 
 
Secondary Endpoints for Arms 1 and 2 
The temporal quantitative stability of the images will be assessed by computing 
the fraction of observations for which |TUVglobal| < 0.075 for the difference 
between the 60 and 180 minute images. The hypotheses  
 
𝐻0: π ≤0.80
𝑣𝑠
𝐻𝑎: π > 0.80,
 
 
where  represent the fraction of unsigned differences less than 7.5% will be 
tested with an exact test and a Clopper-Pearson (exact) 95% confidence interval 
for p will be provided. The RMSD will be analyzed by joint, providing 95% 
confidence intervals for the RMSD using both Normal theory methods and a 
bootstrap estimate with 5000 bootstrap replications. 
 
The 80th and 90th percentiles of the distribution of unsigned differences will be 
estimated using quantal regression methods. (These analyses were completed 
to the sponsor’s satisfaction in IA-3.) 
  
Secondary Endpoint for Arm 2 only 
Qualitative evaluations of SPECT/CT imaging in localizing tilmanocept uptake 
will be estimated from the active RA subjects (Arm 2 only) on the joints of the 
hands and wrists. A frequency table of counts and percent of subjects will be 
provided. 
 
Secondary Endpoints for Arm 3 only 
All RA quantitative assessment variables (CDAI, ACR Response Criteria 
component scores, DAS28 score, and HAQ-DI) will be summarized by arm, 
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 subject at that time point. 
That is, a subject who satisfies ACR50 also satisfies ACR20 but will not appear 
in the frequency count for ACR20. 
 


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The Kendall rank correlation between TUVglobal at 5 weeks, TUVglobal at 12 and 
24 weeks with the component parameters of CDAI12w and CDAI24w will be 
computed and 95% confidence intervals for the values provided using Fisher’s 
Z-transformation.  This analysis will be repeated for the correlation between 
TUVglobal at 12 and 24 weeks with change in DAS28 and with ACR Response 
Criteria components at 12 weeks and 24 weeks (Note: the Kendall rank 
correlation analysis with DAS28 and ACR Response Criteria components at 5 
weeks is a primary endpoint, as described above in Section 4.2.1).  The marginal 
distributions of the variables will be characterized with the mean, standard 
deviation, and the number of data pairs. 
 
Concordance of improvement classification for: 1) TUVglobal[5w] bucketing; 2) 
TUVglobal[5w]; 3) TUVglobal[5w] bucketing with ACPA bucketing; 4) TUVglobal[12w] 
bucketing; 5) TUVglobal[12w]; 6) TUVglobal[12w] bucketing with ACPA bucketing; 
and 7) ACPA bucketing alone with clinical criteria (ACR Response, CDAI, 
DAS28, and HAQ-DI) will be analyzed as follows.  
 
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 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 
or swollen joint counts as well as 20% improvement in at least 3 of the 
other 5 criteria.  
• ACR50: An ACR50 indicates that 50% improvement is observed in tender 
or 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 
or swollen joint counts as well as 70% improvement in at least 3 of the 
other 5 criteria.  
 
Each subject 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 subject is a yes for 
ACR70 at a given time point, then the subject is also a yes for ACR50 and ACR20 
for that same time point. 
 
A subject 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 subject is not improved. 


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• If the baseline value is between 10 and 22 (inclusive) a decrease of more 
than 6 will classified as improved. Otherwise, the subject is not improved. 
• If the baseline value is less than 10, a decrease of more than 1 will be 
classified as improved. Otherwise the subject is not improved. 
 
A subject 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 subject is not improved on the HAQ-DI. 
 
The TUVglobal[5w] values will be used to predict improvement at 12 and 24 weeks 
according to algorithms 1-3. The TUVglobal[12w] values will be used to predict 
improvement at 24 weeks according to algorithms 4-6. A seventh algorithm 
based on ACPA bucketing alone with also be applied to predict improvement at 
12 and 24 weeks. Algorithms 1-6 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). 
 
1. TUVglobal[5w] bucketing 
 
In the below, TUVglobal represents the global TUV at the current time point 
and TUVglobal[Day 0] represents the global TUV at baseline: 
• If TUVglobal[Day 0] is < 5 then the prediction is N (No improvement) 
• Else if  
ΔTUVglobal[5w] =
TUVglobal[5w] −TUVglobal[Day0]
TUVglobal[Day0]
≤−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[5w]  
 
The TUVglobal prediction of improvement will also be computed according 
to the following algorithm: 
 
• If TUVglobal goes down by greater than or equal to 10%, then predict 
response  
• If TUVglobal does not go down by 10% or more, then predict no response  
 
3. TUVglobal[5w] bucketing with ACPA bucketing 
 


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The TUVglobal prediction of improvement will also be evaluated by combination 
of the above two algorithms such that: 
 
For patients with TUVglobal of below 5.0 at baseline: 
• ACPA Levels before initiation (at baseline) of the new anti-TNF 
therapy: 
o ACPA levels ≤85 predicts treatment failure (non-response) 
o ACPA level >85 predicts treatment success (significant clinical 
improvement) 
 
For patients with TUVglobal at or above 5.0 at baseline: 
• If TUVglobal goes down by greater than or equal to 10%, then predict 
response (no need to refer to ACPA) 
• If TUVglobal does not go down by 10% or more, then refer to baseline 
ACPA for prediction: 
o ACPA levels ≤85 predicts treatment failure (non-response) 
o ACPA level >85 predicts treatment success (significant clinical 
improvement) 
 
4. TUVglobal[12w] bucketing 
 
In the below, TUVglobal represents the global TUV at the current time point 
and TUVglobal[Day 0] represents the global TUV at baseline: 
• If TUVglobal[Day 0] is < 5 then the prediction is N (No improvement) 
• Else if  
ΔTUVglobal[12w] =
TUVglobal[12w] −TUVglobal[Day0]
TUVglobal[Day0]
≤−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. 
 
5. TUVglobal[12w]  
 
The TUVglobal prediction of improvement will also be computed according 
to the following algorithm: 
 
• If TUVglobal goes down by greater than or equal to 10%, then predict 
response  
• If TUVglobal does not go down by 10% or more, then predict no response 
 


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6. TUVglobal[12w] bucketing with ACPA bucketing 
 
The TUVglobal prediction of improvement will also be evaluated by combination 
of the above two algorithms such that: 
 
For patients with TUVglobal of below 5.0 at baseline: 
• ACPA Levels before initiation (at baseline) of the new anti-TNF 
therapy: 
o ACPA levels ≤85 predicts treatment failure (non-response) 
o ACPA level >85 predicts treatment success (significant clinical 
improvement) 
 
For patients with TUVglobal at or above 5.0 at baseline: 
• If TUVglobal goes down by greater than or equal to 10%, then predict 
response (no need to refer to ACPA) 
• If TUVglobal does not go down by 10% or more, then refer to baseline 
ACPA for prediction: 
o ACPA levels ≤85 predicts treatment failure (non-response) 
o ACPA level >85 predicts treatment success (significant clinical 
improvement) 
 
7. ACPA bucketing alone  
 
The following will be used to predict improvement solely on the basis of 
ACPA: 
 
• ACPA baseline level ≤85 predicts treatment failure (non-response) 
• ACPA baseline level >85 predicts treatment success (significant 
clinical improvement) 
 
For each of the RA improvement criteria, a cross-classification table will be 
provided. The Uncertainty coefficient for the clinical criterion given the 
TUVglobal[5w] of TUVglobal[12w] classification and its standard error will be 
calculated. The positive predictive value (PPV), negative predictive value (NPV), 
and overall accuracy (OA) will be calculated and 95% exact (Clopper-Pearson) 
confidence intervals will be provided.  
 
PPV and NPV will be calculated as follows, where TUVglobal[XXw] is either 
TUVglobal[5w] or TUVglobal[12w], as appropriate: 
 


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
Clinical Criterion Classification 
 
TUVglobal[XXw] and/or 
ACPA Classification 
Improved 
Not Improved 
Total 
Improved 
A 
B 
A+B 
Not Improved 
C 
D 
C+D 
Total 
A+C 
B+D 
A+B+C+D 
 
PPV = A/(A+B) 
NPV = D/(C+D) 
OA = (A+D)/(A+B+C+D). 
 
A separate table will be provided to summarize the baseline ACPA levels on a 
continuous scale and the number and percentage of subjects in each ACPA 
category (≤70, >70). 
 
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. 
 
5.0  Analysis of Safety  
 
5.1 Description of Safety Variables  
 
The safety analysis variables are defined as follows: 
 
• Adverse Events (AEs) 
• Clinical Laboratory Tests (hematology, serum chemistry, urinalysis, RA 
panel) 
• ECG Parameters 
• Vital Signs 
 
 
5.2 Description of Safety Analysis 
 
The following describes the safety analyses to be performed for the study. All 
safety analyses will be performed on the safety population. Follow up timing will 
vary by arm as noted above. 
 
Adverse Events  
Adverse events will be observed for each subject from signing of informed 
consent until termination from the study. AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA®). A treatment-emergent AE 
(TEAE) is defined as an AE whose start date is on or after the initial procedure 
date. Based on the coded terms, frequencies of each TEAE will be summarized 


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


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rate, systolic blood pressure, diastolic blood pressure, heart rate and 
temperature), summary statistics (mean, standard deviation, minimum, 
maximum, n) on the raw as well as their changes from baseline will be presented 
by timepoint, by dose, and overall. The baseline value for each of the post-
injection vital sign parameters will be the corresponding pre-injection time point.  
If there are multiple vital signs taken at any time point, then the latest set of vital 
signs will be used for the analysis. All vital sign data will be listed.   
 
6.0  Other Relevant Data Analyses/Summaries 
 
6.1 Patient Completion  
 
A table will be constructed with counts of screen failures and enrolled subjects.  
Of those enrolled, counts and percentages of patients withdrawing from the study 
before study completion and the number completing the study  will be displayed.  
For those subjects that withdraw before completion of the study, counts and 
percentages of the reasons for withdrawal will be tabulated. The table will include 
summary counts and percentages by study arm and overall. A data listing of all 
subject completion and withdrawal data will also be constructed. 
 
6.2 Physical Exam  
 
Physical exams will be performed at screening. All physical exam data will be 
listed. 
 
6.3 Study Drug Administration 
 
The volume, the calculated mass dose, and radioactivity of Tc 99m Tilmanocept 
injected will be summarized by arm and overall. All study drug administration 
data will be listed. 
 
6.4 RA Evaluation and Screening Physical Exam 
 
Each RA subject will undergo a DAS28 evaluation during screening. Arm 3 
subjects will also undergo a DAS28 evaluation 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 within the 6 months prior to Day 0 injection. In addition to the 
summarization of prior RA-specific treatments, recent or concomitant treatments 


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STATKING Clinical Services                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1                                                                                                             July 6, 2021                                  
taken for RA in the last 6 months must be collected in accordance with the 
following time windows: 
• Traditional DMARDs: On therapy at least 90 days and at a stable dose at 
least 30 days prior to the first imaging visit (Day 0) 
• bDMARDs: More than 180 days prior to the first imaging visit (Day 0) 
• JAK inhibitors: More than 180 days prior to the first imaging visit (Day 0) 
• NSAIDs/Corticosteroids: At least 28 days prior to the first imaging visit 
(Day 0) 
 
 
 
 


Statistical Analysis Plan 
 
Study No. NAV3-31 
 
 
Page 31 of 103 
STATKING Clinical Services                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1                                                                                                             July 6, 2021                                  
 
7.0  List of Analysis Tables, Figures and Listings 
 
 
Table 
No. 
 
 
Table Title 
Included 
in Final 
Tables 
Shown in 
Appendix 
B 
 
 
 
 
1 
Subject Disposition by Study Arm 
X 
X 
2 
Demographics and Baseline Data Summary Statistics by Arm  
- Continuous Variables (Safety Population) 
X 
X 
3 
Demographics and Baseline Data Summary Statistics by Arm 
– Categorical Variables (Safety Population) 
X 
X 
4 
Summary of Study Drug Administration by Arm (Safety 
Population) 
X 
X 
5 
Summary of TUV by Arm, Study Day, and DAS28 Joint (ITD 
population) 
X 
X 
6 
Summary of TUV by Arm, Study Day, and DAS28 Joint (PP 
Population) 
X 
 
7 
Summary for Eight-Day Longitudinal Stability of TUV (Arm 2 
Only) (ITD Population) 
X 
X 
8 
Summary for Eight-Day Longitudinal Stability of TUV (Arm 2 
Only) (PP Population) 
X 
 
9 
Analysis of Eight-Day Longitudinal Stability of TUVglobal (ITD 
population) 
X 
X 
10 
Analysis of Eight-Day Longitudinal Stability of TUVglobal (PP 
population) 
X 
X 
11 
Summary for Day 0 vs Day 8 RA Images (ITD Population) 
X 
X 
12 
Summary for Day 0 vs Day 8 RA Images (PP Population) 
X 
 
13 
Assessment of Mean/Variance Relationship by Time Point 
(ITD Population) 
X 
X 
14 
Assessment of Mean/Variance Relationship by Time Point (PP 
Population) 
X 
 
15 
Normal Range of TUV in Healthy Control Subjects (ITD 
Population) 
X 
X 
16 
Normal Range of TUV in Healthy Control Subjects (PP 
Population) 
X 
 
17 
RA Status Summaries (ITD Population) 
X 
X 
18 
RA Status Summaries (PP Population) 
X 
 
19 
Kendall Rank Correlation of TUV, CDAI, ACR Response 
Criteria Components, and DAS28 with TUV at 5 weeks in 
Arm 3 (ITD Population) 
X 
X 
20 
Kendall Rank Correlation of TUV, CDAI, ACR Response 
Criteria Components, and DAS28 with TUV at 5 weeks in 
Arm 3 (PP Population) 
X 
 
21 
Kendall Rank Correlation of TUV, CDAI, ACR Response 
Criteria Components, and DAS28 with TUV at 12 weeks in 
Arm 3 (ITD Population) 
X 
X 
22 
Kendall Rank Correlation of TUV, CDAI, ACR Response 
Criteria Components, and DAS28 with TUV at 12 weeks in 
Arm 3 (PP Population) 
X 
 


Statistical Analysis Plan 
 
Study No. NAV3-31 
 
 
Page 32 of 103 
STATKING Clinical Services                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1                                                                                                             July 6, 2021                                  
 
Table 
No. 
 
 
Table Title 
Included 
in Final 
Tables 
Shown in 
Appendix 
B 
23 
Kendall Rank Correlation of CDAI, ACR Response Criteria 
Components, and DAS28 with TUV at 24 weeks in Arm 3 
(ITD Population) 
X 
X 
24 
Kendall Rank Correlation of CDAI, ACR Response Criteria 
Components, and DAS28 with TUV at 24 weeks in Arm 3 
(PP Population) 
X 
 
25 
Frequency Counts of Localization in SPECT/CT Imaging in 
RA-2 Subjects (ITD Population) 
X 
X 
26 
Frequency Counts of Localization in SPECT/CT Imaging in 
RA-2 Subjects (PP Population) 
X 
 
27 
Number and Percentage of Subjects with TEAEs (Safety 
Population) 
X 
X 
28 
Summary of TEAEs (Safety Population) 
X 
X 
29 
Number and Percentage of Subjects with TESAEs (Safety 
Population) 
X 
X 
30 
Number and Percentage of Subjects With TEAEs by Severity 
Grade (Safety Population) 
X 
X 
31 
Number and Percentage of Subjects With TEAEs by Level of 
Relationship to Tc 99m Tilmanocept  (Safety Population) 
X 
 
32 
Number and Percentage of Subjects With TEAEs by Level of 
Relationship to Procedure (Safety Population) 
X 
X 
33 
Serum Chemistry Clinical Laboratory Parameters Summary 
Statistics by Arm (Safety Population) 
X 
X 
34 
Hematology Clinical Laboratory Parameters Summary 
Statistics by Arm (Safety Population) 
X 
 
35 
Urinalysis Clinical Laboratory Parameters Summary Statistics 
by Arm (Safety Population) 
X 
 
36 
Serum Chemistry Clinical Laboratory Parameters Shift Table 
by Arm (Safety Population) 
X 
X 
37 
Hematology Clinical Laboratory Parameters Shift Table by 
Arm (Safety Population) 
X 
 
38 
Urinalysis Clinical Laboratory Parameters Shift Table by Arm 
(Safety Population) 
X 
 
39 
ECG Parameters Summary Statistics by Arm (Safety 
Population) 
X 
X 
40 
ECG Shift Table by Arm (Safety Population) 
X 
X 
41 
Vital Signs Summary Statistics by Arm (Safety Population) 
X 
X 
42 
ACR Response Classification by Time Point (ITD Population) 
X 
X 
43 
ACR Response Classification by Time Point (PP Population) 
X 
 
44 
Concordance of TUVglobal[5w] Bucketing and Week 12 Clinical 
Improvement Criteria (ITD Population) 
X 
X 
45 
Concordance of TUVglobal[5w] Bucketing and Week 12 Clinical 
Improvement Criteria (PP Population) 
X 
 
46 
Concordance of TUVglobal[5w] Bucketing and Week 24 Clinical 
Improvement Criteria (ITD Population) 
X 
 
47 
Concordance of TUVglobal[5w] Bucketing and Week 24 Clinical 
Improvement Criteria (PP Population) 
X 
 
48 
Concordance of TUVglobal[5w] and Week 12 Clinical 
Improvement Criteria (ITD Population) 
X 
 


Statistical Analysis Plan 
 
Study No. NAV3-31 
 
 
Page 33 of 103 
STATKING Clinical Services                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1                                                                                                             July 6, 2021                                  
 
Table 
No. 
 
 
Table Title 
Included 
in Final 
Tables 
Shown in 
Appendix 
B 
49 
Concordance of TUVglobal[5w] and Week 12 Clinical 
Improvement Criteria (PP Population) 
X 
 
50 
Concordance of TUVglobal[5w] and Week 24 Clinical 
Improvement Criteria (ITD Population) 
X 
 
51 
Concordance of TUVglobal[5w] and Week 24 Clinical 
Improvement Criteria (PP Population) 
X 
 
52 
Concordance of TUVglobal[5w] Bucketing with ACPA Bucketing 
and Week 12 Clinical Improvement Criteria (ITD Population) 
X 
 
53 
Concordance of TUVglobal[5w] Bucketing with ACPA Bucketing 
and Week 12 Clinical Improvement Criteria (PP Population) 
X 
 
54 
Concordance of TUVglobal[5w] Bucketing with ACPA Bucketing 
and Week 24 Clinical Improvement Criteria (ITD Population) 
X 
 
55 
Concordance of TUVglobal[5w] Bucketing with ACPA Bucketing 
and Week 24 Clinical Improvement Criteria (PP Population) 
X 
 
56 
Concordance of TUVglobal[12w] Bucketing and Week 24 Clinical 
Improvement Criteria (ITD Population) 
X 
 
57 
Concordance of TUVglobal[12w] Bucketing and Week 24 Clinical 
Improvement Criteria (PP Population) 
X 
 
58 
Concordance of TUVglobal[12w] and Week 24 Clinical 
Improvement Criteria (ITD Population) 
X 
 
59 
Concordance of TUVglobal[12w] and Week 24 Clinical 
Improvement Criteria (PP Population) 
X 
 
60 
Concordance of TUVglobal[12w] Bucketing with ACPA Bucketing 
and Week 24 Clinical Improvement Criteria (ITD Population) 
X 
 
61 
Concordance of TUVglobal[12w] Bucketing with ACPA Bucketing 
and Week 24 Clinical Improvement Criteria (PP Population) 
X 
 
62 
Concordance of ACPA Bucketing Alone and Week 12 Clinical 
Improvement Criteria (ITD Population) 
X 
 
63 
Concordance of ACPA Bucketing Alone and Week 12 Clinical 
Improvement Criteria (PP Population) 
X 
 
64 
Concordance of ACPA Bucketing Alone and Week 24 Clinical 
Improvement Criteria (ITD Population) 
X 
 
65 
Concordance of ACPA Bucketing Alone and Week 24 Clinical 
Improvement Criteria (PP Population) 
X 
 
66 
ACPA Summary Statistics in Arm 3 (ITD Population) 
X 
X 
67 
ACPA Summary Statistics in Arm 3 (PP Population) 
X 
 
 
 
Figure 
No. 
 
 
Figure Title 
Included 
in Final 
Figures 
 
Shown in 
Appendix 
B 
 
 
 
 
Fig1 
Plot of TUVglobal by Imaging Time Point and ACR-20 for 
Arm 3 (ITD Population) 
X 
X 
Fig2 
Plot of TUVglobal by Imaging Time Point and ACR-50 for 
Arm 3 (ITD Population) 
X 
 
Fig3 
Plot of TUVglobal by Imaging Time Point and ACR-70 for 
Arm 3 (ITD Population) 
X 
 


Statistical Analysis Plan 
 
Study No. NAV3-31 
 
 
Page 34 of 103 
STATKING Clinical Services                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1                                                                                                             July 6, 2021                                  
 
Figure 
No. 
 
 
Figure Title 
Included 
in Final 
Figures 
 
Shown in 
Appendix 
B 
Fig4 
Plot of TUVglobal by Imaging Time Point and CDAI for Arm 3 
(ITD Population) 
X 
 
Fig5 
Plot of TUVglobal by Imaging Time Point and DAS28 for Arm 
3 (ITD Population) 
X 
 
 
 
 
Listing 
No. 
 
 
Data Listing Title 
Included 
in Final 
Listings 
 
Shown in 
Appendix 
B 
 
 
 
 
DL1 
Subject Disposition Data Listing 
X 
X 
DL2 
Inclusion/Exclusion Data Listing 
X 
X 
DL3 
Protocol Deviations Data Listing 
X 
X 
DL4 
Demographics Data Listing   
X 
X 
DL5 
Subjects Excluded from ITD Population Data Listing 
X 
X 
DL6 
Subjects Excluded from PP Population Data Listing 
X 
X 
DL7 
Subjects Excluded from Safety Population Data Listing 
X 
X 
DL8 
Medical History Data Listing 
X 
X 
DL9 
Prior and Concomitant Medications Data Listing 
X 
X 
DL10 
Prior and Concomitant RA Medications Data Listing 
X 
X 
DL11 
Adverse Events Data Listing 
X 
X 
DL12 
Subject Laboratory Profiles – Hematology Data Listing 
X 
X 
DL13 
Subject Laboratory Profiles – Serum Chemistry Data Listing 
X 
 
DL14 
Subject Laboratory Profiles – Urinalysis Data Listing 
X 
 
DL15 
Subject Laboratory Profiles – Rheumatology Panel Data 
Listing 
X 
 
DL16 
Physical Exam Data Listing 
X 
X 
DL17 
ACR/EULAR 2010 Classification Data Listing 
X 
X 
DL18 
ACR Data Listing 
X 
X 
DL19 
CDAI, DAS28, HAQ-DI, and WPI Scores Data Listing 
X 
X 
DL20 
DAS-28 by Joint Data Listing 
X 
X 
DL21 
DAS-28 by Subject 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 
ACR Response Criteria Data Listing 
X 
X 
 


Statistical Analysis Plan 
 
Study No. NAV3-31 
 
 
Page 35 of 103 
STATKING Clinical Services                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1                                                                                                             July 6, 2021                                  
9.0  References 
 
Food & Drug Administration Center for Drug Evaluation and Research and 
Center for Biologics Evaluation and Research (September 1998). Guidance for 
Industry: ICH E9 Statistical Principles for Clinical Trials. 
 
Forkman, J. (2009) Estimator and Tests for Common Coefficients of Variation in 
Normal Distributions. Communications in Statistics: Theory and Methods. 38:2, 
pp233- 251. 
 


Statistical Analysis Plan 
 
Study No. NAV3-31 
 
 
Page 36 of 103 
STATKING Clinical Services                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1                                                                                                             July 6, 2021                                  
Appendix A – Tables, Figures and Listing Specifications 
 
Orientation 
 
Tables and figures will be displayed in landscape.  
 
Margins  
 
Margins will be 1 inch on all sides.  Table and listing boundaries will not extend 
into the margins. 
 
Font 
 
Courier New, 8 point. 
 
Headers 
 
The table number will be on the first line of the title.  The title area will contain 
the Sponsor name, the study number, and the name of the table.  The title area 
will contain the page number (Page x of y) on the far right, 1 line above the 
name of the table. 
 
Footers 
 
- The first line will be a solid line. 
- Next will be any footnotes regarding information displayed in the table. 
- Below these footnotes will be displayed “STATKING Clinical Services (DD-
MMM-YYYY)” on the far left. 
- The last line will display the name of the SAS program that generated the 
table and (if applicable) the source data reference. 
 
Table Disclaimer 
 
The format of the mock tables shown in the appendix of this SAP will be the 
format of the deliverable tables to the extent that Word document constructed 
tables can match production tables produced by SAS.  This formatting includes 
the content and format of the header and footer areas of the tables.  The 
Sponsor agrees to the format of the tables as shown in the appendix. 
 
Further programming charges will be applicable for changes in the format of 
tables (including title statements, notes, data dependent footnotes, etc.) made 
after the approval of the SAP. 
 
 
 


Statistical Analysis Plan 
 
Study No. NAV3-31 
 
 
Page 37 of 103 
STATKING Clinical Services                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1                                                                                                             July 6, 2021                                  
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 (ie, for a missing day value, the value displayed is in yyyy-mm format).   
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 38 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
Appendix B – Table Shells  
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 39 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
 
Page x of y 
 
Table 1. Subject Disposition by Study Arm  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
 
 
 
 
 
  
 
 
 
Arma 
 
 
 
HC 
(N = xx) 
RA-2 
(N = xx) 
RA-3 
(N = xx) 
Overall 
(N = xx) 
Screen Failures 
 
 
 
 
xx 
 
 
 
 
 
 
Enrolled 
 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Completed 
 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
 
 
 
 
 
Withdrawn  
 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
 
 
 
 
 
Withdrawal Reason 
Adverse Event 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Protocol Violation 
 
 
 
 
 
Lost to Follow Up 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Withdrawal of Consent 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Sponsor Discretion 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Investigator Discretion xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Death 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Other 
xx (xxx%) xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen), RA-3 = rheumatoid arthritis (candidate for changed 
treatment). 
The denominator for all percentages in the table is the number of enrolled subjects in the respective arm and overall. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 40 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
 
Page x of y 
 
Table 2. Demographics and Baseline Data Summary Statistics by Arm – Continuous Variables 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
             
 
Variable 
 
Arma 
 
Mean 
 
Std Dev 
 
n 
 
Min 
 
Max 
 
Median 
 
 
 
 
 
 
 
 
Age (years) 
HC 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-3 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
Height (inches) 
HC  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-3 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
Weight (pounds) 
HC  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-3 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
Time from Diagnosis of RA (months)b 
RA-2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-3 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen), RA-3 = rheumatoid arthritis (candidate for changed 
treatment). 
b 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. NAV3-31 
 
Page 41 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 3. Demographics and Baseline Data Summary Statistics by Arm – Categorical Variables 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Arma 
 
Variable 
 
Category 
HC 
 (N=xxx) 
RA-2 
 (N=xxx) 
RA-3 
(N=xxx) 
 
 
 
 
 
Gender 
Male 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Female 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
Race 
American Indian or Alaska Native 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Asian 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Black or African American 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Native Hawaiian or Other Pacific Islander 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
White 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Other 
 
 
 
 
 
 
 
 
Ethnicity 
Hispanic or Latino 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
Not Hispanic or Latino 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen), RA-3 = rheumatoid arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 42 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
 
Page x of y 
 
Table 4. Summary of Study Drug Administration by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
Arma 
Mean 
Std Dev 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
Tc 99m Dose (mCi) 
HC 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
RA-2 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
RA-3 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
Mass Dose (µg) 
HC 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
RA-2 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
RA-3 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
Total Volume of Tc 99m Tilmanocept Injected (mL) 
HC 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
RA-2 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
RA-3 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 43 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 5. Summary of TUV by Arm, Study Day and DAS28 Joint 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
 
 
Arma 
 
DAS28 Joint 
Study Day 
View 
Number 
of 
Subjects 
Mean 
Std Dev 
n 
Min 
Max 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxxxxxxxxxxx  
xxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
xxxxxxxxxxxxxxxx 
xxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
xxxx 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
xxxxxxxxx 
xx 
xxxx.x 
xxxx.x 
xxx 
xxxx.x 
xxxx.x 
xxxx.x 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen), RA-3 = rheumatoid arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
All evaluated DAS28 joints for all groups (HC, RA-2, RA-3), all imaging days (for RA-2 and RA-3 only).  Table format is repeated for the 
PP population.   
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 44 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 7. Summary for Eight-Day Longitudinal Stability of TUV (Arm 2 Only) 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
Part 1 of 4 
 
Global TUV or 
DAS28 Joint TUV 
View 
Reader 
Number 
of 
Subjects 
Mean 
Difference 
Std Dev 
Coefficient 
of 
Variation 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx  
xx.xx 
xx.xx 
xx.xxx  
xx.xxx  
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
All evaluated DAS28 joints will be included in this table.  Table format is repeated for the PP population.   
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 45 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 7. Summary for Eight-Day Longitudinal Stability of TUV (Arm 2 Only) 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
Part 2 of 4 
 
Global TUV or 
DAS28 Joint TUV 
View 
Reader 
Number 
of 
Subjects 
Mean 
Absolute 
Difference 
80th Percentile 
of Absolute 
Differences 
90th Percentile 
of Absolute 
Differences 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
All evaluated DAS28 joints will be included in this table.  Table format is repeated for the PP population.   
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 46 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 7. Summary for Eight-Day Longitudinal Stability of TUV (Arm 2 Only) 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
Part 3 of 4 
 
Global TUV or 
DAS28 Joint TUV 
View 
Reader 
Percent 
|TUV| < 
7.5% 
95% Exact 
Confidence Limits 
 
 
 
 
 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
All evaluated DAS28 joints will be included in this table.  Table format is repeated for the PP population.   
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 47 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 7. Summary for Eight-Day Longitudinal Stability of TUV (Arm 2 Only) 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
Part 4 of 4 
 
Global TUV or  
DAS28 Joint TUV 
View 
Reader 
RMSD 
95% Confidence 
Limits 
95% Bootstrap 
Confidence Limits 
 
 
 
 
 
 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
All evaluated DAS28 joints will be included in this table.  Table format is repeated for the PP population.   
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 48 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 9. Analysis of Eight-Day Longitudinal Stability of TUVglobal 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
 
 
Reader 
|TUVglobal| < 7.5% 
Frequency 
Fraction 
95% Exact 
Confidence Limits 
P-value1 
 
 
 
 
 
 
xxx 
True 
xx  
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
 
False 
xx  
x.xxx 
 
 
 
 
 
 
 
 
xxx 
True 
xx  
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
 
False 
xx  
x.xxx 
 
 
 
 
 
 
 
 
xxx 
True 
xx  
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
 
False 
xx  
x.xxx 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
1 Exact binomial test of the hypotheses H0:  < 0.80 vs H1:  > 0.80. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for the PP population.   
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 49 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 11. Summary of Day 0 vs Day 8 RA Images  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
Part 1 of 2 
 
Global TUV or  
DAS28 Joint TUV 
View 
Reader 
Number of 
Joints 
Mean 
Difference 
Standard 
Deviation 
of 
Difference 
Minimum 
Difference 
Median 
Difference 
 
 
Maximum 
Difference 
 
 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
If there are no major protocol deviations, then analysis tables for the ITD and PP populations will contain identical results. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
All evaluated DAS28 joints will be included in this table.  Table format is repeated for the PP population.   
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 50 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 11. Summary of Day 0 vs Day 8 RA Images  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
Part 2 of 2 
 
DAS28 Joint 
Reader 
View 
|TUVglobal| 
< 7.5% 
95% Confidence 
Limits 
 
80 %tile 
90 %tile 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
xxxxxxxxxxxxxxxx 
xx 
xx 
xx.xxx  
(xx.xxx, xx.xxx) 
xx.xxx  
xx.xxx  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
If there are no major protocol deviations, then analysis tables for the ITD and PP populations will contain identical results. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
All evaluated DAS28 joints will be included in this table.  Table format is repeated for the PP population.   
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 51 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 13. Assessment of Mean/Variance Relationship by Time Point 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
Part 1 of 2 
 
Global TUV or  
DAS28 Joint TUV 
View 
Reader 
 
 
Arma 
Number 
of 
Joints 
Mean  
Std Dev  
Minimum  
Maximum  
Median  
 
 
 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxxx 
xx 
xx 
HC 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
RA-2 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
HC 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
RA-2 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
HC 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
RA-2 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
xx 
xx 
HC 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
RA-2 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
HC 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
RA-2 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
HC 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
RA-2 
xx 
xx.xxx  
xx.xxx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen).  
If there are no major protocol deviations, then analysis tables for the ITD and PP populations will contain identical results. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
All evaluated DAS28 joints will be included in this table.  Table format is repeated for the PP population, .   
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 52 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 13. Assessment of Mean/Variance Relationship by Time Point 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
Part 2 of 2 
 
Global TUV or  
DAS28 Joint TUV 
View 
Reader 
 
 
 
Arma 
Coefficient 
of 
Variation 
95% Confidence 
Limits 
 
Bootstrap 
Confidence 
Interval 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxxx 
xx 
xx 
HC 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
 
 
 
RA-2 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
 
 
xx 
HC 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
 
 
 
RA-2 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
 
 
xx 
HC 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
 
 
 
RA-2 
xx.xxx  
(xx.xxx, xx.xxx) 
(xx.xxx, xx.xxx) 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen).  
If there are no major protocol deviations, then analysis tables for the ITD and PP populations will contain identical results. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
All evaluated DAS28 joints will be included in this table.  Table format is repeated for the PP population.   
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 53 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
Page x of y 
 
Table 15. Normal Range of TUV in Healthy Control Subjects 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
Joint 
View 
Reader 
Number of 
Joints 
 
Mean 
Standard 
Deviation 
Estimated 
 5 %tile 
Estimated 
 95 %tile 
 
 
 
 
 
 
 
 
xxxxxxxxxxxxx 
xx 
xx 
xxx 
xxx.xx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
xxx 
xxx.xx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
xxx 
xxx.xx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
xx 
xxx 
xxx.xx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
xxx 
xxx.xx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
xxx 
xxx.xx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
If there are no major protocol deviations, then analysis tables for the ITD and PP populations will contain identical results. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
DAS28 joints will not be pooled in this table.  Table format is repeated for the PP population.   
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 54 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
Page x of y 
 
Table 17. RA Status Summaries 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
Arma 
RA Status 
Measure 
 
Study 
Visit 
 
Data 
Type 
Mean 
Standard 
Deviation 
 
 
n 
Min 
Max 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
xxxx 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a RA-2 = rheumatoid arthritis (stable treatment regimen), RA-3 = rheumatoid arthritis (candidate for changed treatment). 
If there are no major protocol deviations, then analysis tables for the ITD and PP populations will contain identical results. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for the PP population. RAW and CFB lines will exist only for ARM RA-3. 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 55 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 19. Kendall Rank Correlation of TUV, CDAI, ACR Response Criteria Components, and DAS28 with 
TUV at 5 Weeks in Arm 3 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
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. 
If there are no major protocol deviations, then analysis tables for the ITD and PP populations will contain identical results. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Table format is repeated for each reader. Entire table (all parts) is repeated for the PP population. 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 56 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 21. Kendall Rank Correlation of TUV, CDAI, ACR Response Criteria Components, and DAS28 with 
TUV at 12 Weeks in Arm 3 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
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. 
If there are no major protocol deviations, then analysis tables for the ITD and PP populations will contain identical results. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Table format is repeated for each reader. Entire table (all parts) is repeated for the PP population. 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 57 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 23. Kendall Rank Correlation of CDAI, ACR Response Criteria Components, and DAS28 with TUV at 
24 Weeks in Arm 3 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
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. 
If there are no major protocol deviations, then analysis tables for the ITD and PP populations will contain identical results. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Table format is repeated for each reader. Entire table (all parts) is repeated for the PP population. 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 58 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 25. Frequency Counts of Localization in SPECT/CT Imaging in RA-2 Subjects 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
 
Localized on SPECT/CT 
 
Reader 
 
No 
 
Yes 
 
Total 
 
 
 
 
xx 
xxx 
xxx 
xxx 
 
xx.x% 
xx.x% 
 
 
 
 
 
xx 
xxx 
xxx 
xxx 
 
xx.x% 
xx.x% 
 
 
 
 
 
xx 
xxx 
xxx 
xxx 
 
xx.x% 
xx.x% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for the PP population. 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 59 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
Page x of y 
 
Table 27. Number and Percentage of Subjects with TEAEs 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
Armb 
 
Adverse Event Categorya: 
HC 
RA-2 
RA-3 
Overall 
 
 
 
 
 
Total Number of TEAEs 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Subjects with at Least One TEAE 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
  System Organ Class 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
  System Organ Class 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a Adverse events coded with MedDRA Coding Dictionary Version XXX. 
b HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 60 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 28. Summary of TEAEs  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
Armb 
 
 
HC 
RA-2 
RA-3 
Overall 
 
 
 
 
 
Subjects With at Least One TEAE 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Maximum TEAE Severity Grade 
 
 
 
 
    Mild 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Moderate 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Severe 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
Highest Relationship of TEAE to Tc 99m tilmanocept 
 
 
 
 
    Definitely Not [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Probably Not [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Possibly [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Probably [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Definitely [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
Highest Relationship of TEAE to Study Procedure 
 
 
 
 
    Definitely Not [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Probably Not [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Possibly [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Probably [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Definitely [n(%)] 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
Subjects with at Least One TESAE 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
____________________________________________________________________________________________________________________________________ 
a Adverse events coded with MedDRA Coding Dictionary Version XXX. 
b HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 61 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 29. Number and Percentage of Subjects with TESAEs  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
Armb 
 
 
Adverse Event Categorya: 
HC 
RA-2 
RA-3 
Overall 
 
 
 
 
 
Total Number of TESAEs 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Subjects with at Least One TESAE 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
  System Organ Class 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
  System Organ Class 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a Adverse events coded with MedDRA Coding Dictionary Version XXX. 
b HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 62 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 30. Number and Percentage of Subjects With TEAEs by Severity Grade 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
Part 1 of 4 – HCa 
 
 
 
 
 
 
Severity Grade 
Adverse Event Categoryb: 
Mild 
Moderate 
Severe 
 
 
 
 
Total Number of TEAEs 
xxx 
xxx 
xxx 
 
 
 
 
Subjects with at Least One TEAE 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
  System Organ Class 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
  System Organ Class 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
b Adverse events coded with MedDRA Coding Dictionary Version XXX. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
Table format repeats for RA-2 and RA-3 (Parts 2 and 3) and overall (Part 4). 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 63 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 31. Number and Percentage of Subjects With TEAEs by Level of Relationship  
to Tc 99m Tilmanocept  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
Part 1 of 4 – HCa 
 
 
 
 
 
 
Level of Relationship 
Adverse Event Categoryb: 
Definitely 
Not 
Probably 
Not 
Possibly 
Related 
Probably 
Related 
Definitely 
Related 
 
 
 
 
 
 
Total Number of TEAEs 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Subjects with at Least One TEAE 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
  System Organ Class 1 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
  System Organ Class 2 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 1 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
    Preferred Term 2 
xxx (xxx%) xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
b Adverse events coded with MedDRA Coding Dictionary Version XXX. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
Table format repeats for RA-2 and RA-3 (Parts 2 and 3) and overall (Part 4). Full Table (all parts) repeats for Table 32. 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 64 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 33.  Serum Chemistry Clinical Laboratory Parameters Summary Statistics by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
                                  
 
Parameter(units) 
Arma 
Visit  
Data Typeb 
Mean 
Std 
Dev 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx(xxx) 
HC 
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 
 
RA-2 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 
RAW 
 
 
 
 
 
 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 8 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-3 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx(xxx) 
HC 
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 
 
RA-2 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 
RAW 
 
 
 
 
 
 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 8 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-3 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
xxxxxxxxxx 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
b RAW = data recorded in database; CFB = change from baseline= (parameter value at the current time point)-(Baseline parameter value).  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
Table format repeats for tables 34 and 35. 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 65 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
Page x of y 
 
Table 36. Serum Chemistry Clinical Laboratory Parameters Shift Table by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 1 of 7: Arm 1 HCa – Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for Tables 37 (Hematology) and 38 (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. NAV3-31 
 
Page 66 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 36. Serum Chemistry Clinical Laboratory Parameters Shift Table by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 2 of 7: Arm 2 RA-2a – Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for Tables 37 (Hematology) and 38 (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. NAV3-31 
 
Page 67 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 36. Clinical Laboratory Parameters Shift Table by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 3 of 7: Arm 2 RA-2a – Day 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen), RA-3 = rheumatoid arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for Tables 37 (Hematology) and 38 (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. NAV3-31 
 
Page 68 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 36. Serum Chemistry Clinical Laboratory Parameters Shift Table by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 4 of 7: Arm 3 RA-3a – Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen), RA-3 = rheumatoid arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
Table format is repeated for Tables 37 (Hematology) and 38 (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. NAV3-31 
 
Page 69 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 36. Serum Chemistry Clinical Laboratory Parameters Shift Table by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 5 of 7: Arm RA-3a – Week 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen), RA-3 = rheumatoid arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for Tables 37 (Hematology) and 38 (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. NAV3-31 
 
Page 70 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 36. Serum Chemistry Clinical Laboratory Parameters Shift Table by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 6 of 7: Arm 3 RA-3a – Week 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen), RA-3 = rheumatoid arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
Table format is repeated for Tables 37 (Hematology) and 38 (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. NAV3-31 
 
Page 71 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 36. Serum Chemistry Clinical Laboratory Parameters Shift Table by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
Part 7 of 7: Arm 3 RA-3a – Week 24 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen), RA-3 = rheumatoid arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format is repeated for Tables 37 (Hematology) and 38 (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. NAV3-31 
 
Page 72 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 39.  ECG Parameters Summary Statistics by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
                                  
ECG 
Parameter(units) 
Arma 
Visit 
Data 
Typeb 
Mean 
Std Dev 
n 
Min 
Max 
Median 
xxxxxxxxx (xxx) 
HC 
Day 0 Pre-Injection (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-2 
Day 0 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-2 
Day 8 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 8 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-3 
Day 0 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-3 
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 
 
RA-3 
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 
 
RA-3 
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 HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen), RA-3 = rheumatoid arthritis (candidate for changed 
treatment). 
b RAW = data recorded in database; CFB = change from baseline= (parameter value at the current time point)-(Baseline parameter value).   
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas  
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 73 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 40. ECG Shift Table by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
 
 
 
Baseline Result/ 
Post-Injection Result 
Arm 
Visit 
 
Abnormal/ 
Abnormal 
Abnormal/ 
Normal 
Normal/ 
Abnormal 
Normal/ 
Normal 
 
 
 
 
 
 
xxxx 
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%) 
 
 
 
 
 
 
xxxx 
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%) 
 
 
 
 
 
 
xxxx 
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. NAV3-31 
 
Page 74 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
 
Page x of y 
 
Table 41.  Vital Signs Summary Statistics by Arm 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
                                 
Vital Sign 
Parameter (units) 
Arma 
Visit 
Data 
Typeb 
Mean 
Std Dev 
n 
Min 
Max 
Median 
xxxxxxxxx (xxx) 
HC 
Day 0 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-2 
Day 0 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-2 
Day 8 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 8 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-3 
Day 0 Pre-Injection(Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Day 0 Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
RA-3 
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 
 
RA-3 
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 
 
RA-3 
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 HC = healthy control, RA-2 = rheumatoid arthritis (stable treatment regimen), RA-3 = rheumatoid arthritis (candidate for changed 
treatment). 
b RAW = data recorded in database; CFB = change from baseline= (parameter value at the current time point)-(Baseline parameter value). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 75 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 42. ACR Response Classification by Time Point 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
Arm 3 – RA-3a Subjects Only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table Format Repeats for PP Population. 
 
 
Assessment 
Time Point 
ACR-0 
ACR-20 
ACR-50 
ACR-70 
 
 
 
 
 
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. NAV3-31 
 
Page 76 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
Page x of y 
 
Table 44. Concordance of TUVglobal[5w] Bucketing and Week 12 Clinical Improvement Criteria 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
Arm 3 – RA-3a Subjects Only 
 
Part 1 of 6: ACR-20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
b Values in parentheses are standard errors for the uncertainty coefficients, and p-values for positive predictive value and negative 
predictive value testing Ho:  = 0.6.  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
This part repeats for Part 2 (ACR-50), Part 3 (ACR-70), Part 4 (CDAI), Part 5 (DAS28), and Part 6 (HAQ-DI) 
Full table format repeats for PP population (table 45) and for tables 46 - 65. 
 
Clinical Assessment 
 
 
 
TUVglobal[5w] 
Classification 
Improved 
Not 
Improved 
Total 
Measure 
Valueb 
 
 
 
 
 
 
Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
Uncertainty Coefficient (C|R)  
xxxx (xxxxx) 
 
 
 
 
 
 
Not Improved 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
Uncertainty Coefficient (Symmetric) 
xxxx (xxxxx) 
 
 
 
 
 
 
Total 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
Positive Predictive Value  
xxxx 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
 
 
 
 
Negative Predictive Value 
xxxx 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 
 
 
 
 
 
 
 
 
 
 
Overall Accuracy 
xxxx 
 
 
 
 
Confidence Limits 
(xxxx, xxxx) 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 77 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Table 66.  ACPA Summary Statistics in Arm 3 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
                                  
Visit  
 
Variable or Categorya 
Statistic 
ITD Population  
(N=xxx) 
 
 
 
 
Screening (Baseline) 
Quantitative ACPA Level 
Mean (Std Dev) 
xxx (xxxx) 
 
n 
xxx 
 
 
Median 
xxx 
 
 
(Min, Max) 
(xxx, xxx) 
 
 
 
 
 
ACPA Level ≤ 70   
n (%) 
xxx (xxx%) 
 
 
 
 
 
ACPA Level > 70   
n (%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a Categories correspond to the ACPA bucketing levels used in the prediction of improvement algorithms.  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Table format repeats for PP population  
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 78 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Figure 1.  Plot of ΔTUVglobal by Imaging Time Point and ACR-20 for Arm 3 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
                                  
 
 
 
______________________________________________________________________________________________________________________________________  
Responder status based on ACR-20 at each week. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
Figure format repeats for Figures 2-5.  Footnote text will be updated in each figure to correspond to the  
clinical assessment noted in the title (ACR-50, ACR-70, CDAI, or DAS28).  


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 79 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
Page x of y 
 
Data Listing 1. Subject Disposition Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
Arma 
 
Subject 
No. 
 
 
Disposition Status 
 
Date of 
Completion or 
Withdrawal 
 
 
Withdrawal Reason 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 80 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
Page x of y 
 
Data Listing 2. Inclusion/Exclusion Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Arma 
 
 
Subject 
No. 
 
Did Subject 
Meet All 
Eligibility 
Criteria? 
Criterion Category 
 
 
Criterion 
Was a 
Waiver 
Granted? 
Is Subject a 
Screen 
Failure? 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
xxxxxx 
xxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
xxxxxx 
xxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
xxxxxx 
xxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 81 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
 
Page x of y 
 
Data Listing 3. Protocol Deviations Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Arma 
 
 
Subject 
No. 
Date of 
Deviation 
Deviation Description  
 
 
Deviation Category 
(Major/Minor) 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 82 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
 
Page x of y 
 
Data Listing 4. Demographics Data Listing  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
                        
 
                                                                                                                             
 
 
 
 Arma 
 
 
Subject 
No. 
 
Informed 
Consent 
Date/Time 
Time from 
Diagnosis 
of RA 
(months)b 
 
Date 
of 
Birth 
Height 
(inches) 
Weight 
(pounds) 
 
 
Age 
(years) 
 
 
 
Gender 
 
 
 
Race 
 
 
 
Ethnicity 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxx 
xxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxx 
xxxxxx 
xxx 
xxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
b 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. NAV3-31 
 
Page 83 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
 
Page x of y 
 
Data Listing 5. Subjects Excluded from ITD Population Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
All Enrolled Subjects (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Arma 
 
 
Subject No. 
 
 
Reason for Exclusion 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 84 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Data Listing 6. Subjects Excluded from PP Population Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
All Enrolled Subjects (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Arma 
 
 
Subject No. 
 
 
Reason for Exclusion 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 85 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Data Listing 7. Subjects Excluded from Safety Population Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
All Enrolled Subjects (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Arma 
 
 
Subject No. 
 
 
Reason for Exclusion 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 86 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Data Listing 8. Medical History Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
Arma 
Subject 
No. 
MedDRA System Organ Classb/ 
MedDRA Preferred Term/ 
CRF Verbatim Term 
Start Date  
Resolution/Stop 
Date 
Ongoing? 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
b Medical history terms coded with MedDRA Coding Dictionary Version xxx. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 87 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Data Listing 9. Prior and Concomitant Medications Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
Arma 
Subject 
No. 
Drug Preferred Termb/ 
Verbatim/ 
ATC Level 1 Text/ 
ATC Level 4 Text 
Indication Frequency 
Start 
Date 
Stop 
Date 
Route Ongoing? 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_______________________________________________________________________________________________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
b Medications coded with WHO Coding Dictionary xxxxxxxxx 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 88 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Data Listing 10. Prior and Concomitant RA Medications Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
Arma 
 
 
Subject 
No. 
 
 
Drug Preferred Termb/ 
Verbatim/ 
ATC Level 1 Text/ 
ATC Level 4 Text 
Indication Frequency 
 
 
 
 
 
Start 
Date 
 
 
 
 
 
 
Stop 
Date 
 
 
 
 
 
 
Route 
 
 
 
 
 
 
Ongoing? 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx  xxxxx 
xxxxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
b Medications coded with WHO Coding Dictionary xxxxxxxxx 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 89 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
Page x of y 
 
Data Listing 11. Adverse Events Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
Arma 
 
 
Subject 
No. 
Start 
Date and 
Time/ 
End Date 
and Time 
Start Date 
and Time of 
Nearest 
Previous 
tilmanocept 
Injection 
Treatment 
Emergent? 
MedDRA System Organ 
Classb/ 
MedDRA Preferred 
Term/ 
CRF Verbatim Term 
Severity  
Relation to 
Tc-99m 
tilmanocept/ 
Procedure 
Serious? 
Outcome 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxxx 
xxxxxxx 
xxxxxxx/ 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxx 
xxxxxxxx/ 
xxxxxxxx 
 
xxx 
 
xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxxx 
xxxxxxx 
xxxxxxx/ 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxx 
xxxxxxxx/ 
xxxxxxxx 
 
xxx 
 
xxxxxxxx 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
b Adverse events coded with MedDRA Coding Dictionary Version xxx. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 90 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
Page x of y 
 
Data Listing 12. Subject Laboratory Profiles - Hematology Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Normal Range 
 
 
Arma 
Subject 
No. 
 
Visit 
Sample Date 
and Time 
Lab Parameter (Units) 
 
Result 
 
Lab Low 
 
Lab High 
Clin. Sig? 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxx 
xxxxxxxx / xx:xx 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
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. NAV3-31 
 
Page 91 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Data Listing 16. Physical Exam Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
Arma 
 
 
Subject 
No. 
 
 
 
 
 
Visit 
 
 
 
 
Date 
Conducted 
 
 
 
 
 
Body System 
 
 
 
 
 
Result 
 
 
 
 
 
Abnormality 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxx 
General Appearance 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Skin 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Eyes, Ears, Nose, Throat 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Head and Neck 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Lungs 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Heart 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Abdomen 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Lymph Nodes 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Musculoskeletal 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Nervous System 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Other: XXXXXX 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
    
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 92 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Data Listing 17. ACR/EULAR 2010 Classification Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
ACR/EULAR 2010 
 
 
Arma 
 
 
Subject 
No. 
 
 
 
 
Visit 
 
 
 
 
Date 
Joint 
Involvement 
Serology 
Acute-
Phase 
Reactants 
Duration 
of 
Symptoms 
Total Score 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
xxxxxx 
xxxx 
xxxxxxx 
 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 93 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
Page x of y 
 
Data Listing 18. ACR Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACR Components 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arma 
 
 
Subject 
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 
ACR-
20 
ACR-
50 
ACR-
70 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxxxxx 
xxxx 
xxxxxxx xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 94 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Data Listing 19. CDAI, DAS28, HAQ-DI, and WPI Scores Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
 
 
CDAI Component 
 
 
 
 
 
 
 
 
Arma 
 
 
Subject 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x 
xx.x 
x 
xx.x 
xx.x 
xxxxxx 
xxxx 
xxxxxxx xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x 
xx.x 
x 
xx.x 
xx.x 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 95 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
 
Page x of y 
 
Data Listing 20. DAS28 by Joint Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
 
 
 
DAS28 Joint Classification 
 
 
Arma 
 
 
Subject 
No. 
 
Visit 
 
 
Date 
Joint 
Result  
(Right Body) 
Result  
(Left Body) 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxx 
xxxxxxxxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxx 
xxx 
xxx 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxx 
xxxxxxxxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxx 
xxx 
xxx 
 
 
 
    
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 96 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
Page x of y 
 
Data Listing 21. DAS28 by Subject Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
 
 
DAS28 
 
 
Arma 
 
 
Subject 
No. 
 
Visit 
 
 
Date 
Tender 
Joint 
Count 
Swollen 
Joint 
Count 
Patient 
VAS 
Global 
(mm) 
Erythrocyte 
Sedimentation 
Rate (ESR; 
mm/hr) 
DAS28 
Score 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 97 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
 
Page x of y 
 
Data Listing 22. Vital Signs Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
Arma 
 
 
Subject 
No. 
 
 
 
 
Visit 
 
 
 
 
Date 
 
 
 
 
Time  
 
 
 
Temp. 
(°F) 
 
Systolic 
Blood 
Pressure 
(mmHg) 
Diastolic 
Blood 
Pressure 
(mmHg) 
Heart 
Rate 
(bpm) 
 
 
 
Respirations 
per Minute 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
 
xxxxxxx 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
 
xxxxxxx 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
    
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 98 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Data Listing 23. ECG Parameters Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
     
Arma 
 
Subject 
No. 
 
 
 
Visit 
 
 
 
Date 
 
 
 
Time 
Heart Rate 
(bpm)  
 
 
PR Interval 
(msec) 
QRS 
Interval 
(msec) 
QT Interval 
(msec)  
 
QTcF 
Interval 
(msec) 
 
 
Overall 
Interpretation 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxx 
xxxxx 
xxxxxx 
xxxxxx 
xxxxxxxx 
xxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
       
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 99 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
 
Page x of y 
 
Data Listing 24. Study Drug Administration Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
 
Arma 
 
 
Subject 
No. 
Date/ 
Time of 
Injection  
 
 
 
Anatomic 
Location 
of 
Injection 
 
Pre-Injection 
Radioactivity 
(mCi)/Time of 
Measurement 
 
Post-
Injection 
Radioactivity 
(mCi)/Time of 
Measurement 
 
Calculated 
Amount of 
Administered 
Radioactivity 
(mCi) 
Calculated 
Mass Dose 
(µg) 
Volume 
Injected  
(mL) 
 
 
 
Lot  
Number 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxx/ 
xxxx 
xxxxxxxx 
xxx/ 
xxxx 
xxx/ 
xxxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxx/ 
xxxx 
xxxxxxxx 
xxx/ 
xxxx 
xxx/ 
xxxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx/ 
xxxx 
xxxxxxxx 
xxx/ 
xxxx 
xxx/ 
xxxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 100 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
    
 
Page x of y 
 
Data Listing 25. Post-Injection Imaging Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
 
Arma 
 
Subject 
No. 
 
Visit 
Date of 
Imaging  
Start Time 
of Imaging 
SPECT/CT Image 
Finding 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxx 
xxxxxx 
xx:xx 
xxx 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxx 
xxxxxx 
xx:xx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
b SPECT/CT imaging performed only in study arm RA-2. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
                                                  
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 101 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
 
Page x of y 
 
Data Listing 26. SPECT/CT Reader Results Data Listing – Hands and Wrists 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
Arma 
Subject 
No. 
Post-Injection 
Imaging Time Point 
Joint 
SPECT/CT 
Image Finding 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxxxxxxx 
xxxx 
 
 
 
xxxxxxxxxxxx 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxxxxxxx 
xxxx 
 
 
 
xxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 102 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Data Listing 27. TUV Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
 
 
TUV Classification of Improvement 
 
 
 
 
 
Arma 
Subject No. 
 
Algorithms 
Predicting 
Improvementb 
Algorithms 
Predicting No 
Improvementb 
Reader 
No. 
 
Visit 
Date/Time 
Region of 
Interestc 
TUV 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
x, x, x  
x, x, x, x 
xxx 
xxxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
 
 
 
 
xxx 
xxxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
 
 
 
 
xxx 
xxxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
 
 
 
 
xxx 
xxxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
 
 
 
 
xxx 
xxxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
x 
x, x, x, x, x, x 
xxx 
xxxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
b 1 = Change in Global TUV(5w) Bucketing, 2 = Change in Global TUV(5w), 3 = Change in Global TUV(5w) Bucketing with ACPA Bucketing, 4 = 
Change in Global TUV(12w) Bucketing, 5 = Change in Global TUV(12w), 6 = Change in Global TUV(12w) Bucketing with ACPA Bucketing, 7 = 
ACPA Bucketing Alone.  
c Region of Interest is joint for all arms, and joint or Global for the RA-2 and RA-3 arms. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
 
 
                            Study No. NAV3-31 
 
Page 103 of 103 
STATKING Clinical Services                                                                                                                              Navidea Biopharmaceuticals, Inc. 
Version 1.1 
                                                                                                                                                                           July 6, 2021 
 
 
Page x of y 
 
Data Listing 28. ACR Response Criteria Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-31 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
Arma 
Subject 
No. 
 
Visit 
ACR Response 
Assessmentb 
Number of 
Tender 
Joints 
Number of 
Swollen 
Joints 
Patient 
Global 
Assessment 
Physician 
Global 
Assessment 
HAQ Total 
VAS Pain 
Score 
ESR 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a HC = Healthy Control, RA-2 = Rheumatoid Arthritis (stable treatment regimen), RA-3 = Rheumatoid Arthritis (candidate for changed 
treatment). 
b Response assessment will be blank for baseline measurements. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas