Clinical trial NCT03157167
Conditions: Kaposi Sarcoma HIV Infections
Keywords: Kaposi Sarcoma, KS, HIV
Sponsor: Navidea Biopharmaceuticals
Start date: 2017-12-01; Completion date: 2020-03-30
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
To determine the safety of escalating IV doses of Tc 99m tilmanocept in HIV (human immunodeficiency virus) subjects with confirmed KS and to compare results obtained from subcutaneous and IV administrations of Tc 99m tilmanocept in the same subjects.

Detailed description:
This is a Manocept Platform prospective, single-center, open-label, non-randomized, dose escalation, comparative, safety study of intravenously and subcutaneously injected Tc 99m tilmanocept in the localization and detection of cutaneous and non-cutaneous KS tumor(s) in subjects with biopsy-confirmed KS. Three IV doses (µg/mCi) of tilmanocept will be evaluated in three cohort groups. One subcutaneous dose will be evaluated in cohort group 3.

This study is designed to evaluate the safety and tolerability of escalating doses of IV Tc 99m tilmanocept and to compare results obtained from IV and subcutaneous administrations of Tc 99m tilmanocept in the same subjects. Whole body planar as well as SPECT/CT imaging will be performed to provide greater resolution of areas of Tc 99m tilmanocept localization. A biopsy of a non-visceral KS lesion will be taken to correlate pathology with Tc 99m tilmanocept localization.

This study is designed to evaluate the use of Tc 99m tilmanocept as an imaging agent in HIV-positive subjects with known KS by evaluating localization in known and unknown cutaneous and non-cutaneous lesions.

Arms: arm 1: Four subjects will receive a single IV injection of 100 micrograms of Tc99m tilmanocept radiolabeled with 5 mCi. arm 2: Four subjects will receive a single IV injection of 100 micrograms of Tc99m tilmanocept radiolabeled with 10 mCi. arm 3: Up to six subjects will receive a single subcutaneous injection and a single IV injection of 200 micrograms of Tc99m tilmanocept radiolabeled with 5 mCi.
Interventions: intervention 1: Tc99m-tilmanocept
Intervention descriptions: intervention 1: Tilmanocept is a radiotracer that accumulates in macrophages by binding to a mannose binding receptor that resides on the surface.

Protocol documents:
ICF_002.pdf: 
NAV3-24 INFORMED CONSENT FORM 1/30/19 PAGE 1 OF 12                                                                              INITIAL HERE:____________
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
Study Title: An Evaluation of the Safety of Escalating Doses of Tc 99m Tilmanocept by 
Intravenous (IV) Injection and a Comparison to Subcutaneous (SC) Injection in Human 
Immunodeficiency Virus (HIV) Subjects Diagnosed with Kaposi Sarcoma (KS) – Protocol 
NAV3-24
This is a clinical trial, a type of research study.  Your study doctor(s), Dr. Kieron Leslie and 
study staff from the UCSF Department of Dermatology will explain the clinical trial to you.
Clinical trials include only people who choose to take part.  Please take your time to make your 
decision about participating.  You may discuss your decision with your family and friends and 
with your health care team.  If you have any questions, you may ask your study doctor.
You are being asked to take part in this study because you have been diagnosed with HIV and 
also have Kaposi Sarcoma (KS).
Why is this study being done?
The purpose of this research study is to learn if using a tracing agent called Tilmanocept can 
identify the Kaposi Sarcoma tumor cells in your body when it is administered into your 
bloodstream by IV injection or into your legs by subcutaneous injection (into the fat layer 
between the skin and the muscle).  This drug is experimental or investigational, which means 
that it is currently being tested in patients with Kaposi Sarcoma (KS). The study drug has been 
tested in approximately 15 clinical trials. The study drug is also called Lymphoseek® and is 
approved by the U.S. Food and Drug Administration (FDA) for use in mapping lymph nodes. 
The study drug is investigational (being used for research) in this study because it is being used 
for a different purpose and at a different amount. 
Tilmanocept has been tested previously in Kaposi Sarcoma patients, where an injection under the 
skin was able to identify KS cells in the body.  
Patients participating in this study will receive one of 3 potential doses of technetium Tc 99m 
tilmanocept. The purpose of this study is to find out which dose is the safest and works the best 
at finding KS lesions (abnormal tissue). There are three groups of participants in this study. All 
participants will receive the study drug by intravenous (IV) injection on a single occasion. The 
study drug will travel through your blood stream. Participants in Group 3 will also receive the 
study drug subcutaneously (into the fat layer between the skin and the muscle) on a single 
occasion approximately one week prior to the IV injection.  
Tilmanocept has attached to it a radioactive substance called technetium 99m.  Technetium can 
be detected by a gamma camera (scan). The Tilmanocept, which binds to your Kaposi Sarcoma 
tumor cells, can be seen in images (pictures) taken using a SPECT scanner. The SPECT scanner 
detects the radiation given off by the decay of the Tilmanocept and produces images of where 
Tilmanocept was located in your body.
IRB NUMBER: 17-23045
IRB APPROVAL DATE: 10/10/2019
IRB EXPIRATION DATE: 10/09/2020


NAV3-24 INFORMED CONSENT FORM 1/30/19 PAGE 2 OF 12                                                                              INITIAL HERE:____________
How many people will take part in this study?
Up to 14 people will take part in this single center study at UCSF.
Voluntary Participation:
Your decision to participate in this study is entirely voluntary. It is your choice to participate or 
not. If you choose not to consent, there will be no penalty or loss of benefits to you, and all of the 
medical care you would normally receive will continue and nothing will change. 
You can change your mind later and stop your participation in the study, even if you agreed 
earlier. Your decision to withdraw from this study will not cause any penalty or loss of benefits 
to you, nor will it affect the medical care that you would receive. If you decide to withdraw from 
participation, no additional follow up will be required for the study. 
What will happen if I take part in this research study? You will need to have the 
following exams, tests or procedures to find out if you can be in the main part of the study. Some 
of these exams, tests or procedures are part of regular cancer care and may be done even if you 
do not join the study. If you have had some of them recently, they may not need to be repeated. 
This will be up to your study doctor.
This is a non-randomized dose escalation safety study. All patients will receive one of 3 potential 
IV doses on a single occasion. Doses will begin starting with the lowest dose and moving to the 
highest dose. The dose you will receive will be determined by the time at which you are enrolled 
into the study. Patients in Group 3 will additionally receive one dose subcutaneously (into the fat 
layer between the skin and the muscle) on a single occasion approximately one week prior to the 
IV dose. 
Study screening procedures will be done at San Francisco General Hospital, 1001 Potrero 
Avenue, Bldg 90, Ward 92, San Francisco, CA 94143
Visit 1: Screening

The screening visit will take approximately 1-2 hours and may occur over more 
than one day. The information gathered during this visit will help your doctor 
confirm you are an appropriate candidate for the study.

You will be asked questions about your medical and surgical history, medications 
and demographic information (such as age, gender, and race).

You will have a physical examination (routine examination of your body 
including assessing your height and weight).

Vital signs, which include assessing your body temperature, blood pressure, heart 
rate, and breathing rate, will be recorded.

You will have an ECG (electrocardiogram), which records the electrical activity 
of your heart.

Your blood will be taken (about 2 teaspoons) for routine testing.

Your urine will be collected for routine urinalysis. 
IRB NUMBER: 17-23045
IRB APPROVAL DATE: 10/10/2019
IRB EXPIRATION DATE: 10/09/2020


NAV3-24 INFORMED CONSENT FORM 1/30/19 PAGE 3 OF 12                                                                              INITIAL HERE:____________

You will be assessed for any areas of swelling. 

You will have an evaluation of your KS. Photographs of any visible KS lesions 
(abnormal tissue) will be taken. 

If you are able to get pregnant, your blood will be taken for a serum pregnancy 
test before the study drug injection. If you are pregnant, you will not be able to 
participate.
If the screening exams, tests and procedures show that you can be in the main part of the study, 
and you choose to take part, then you will also need the following tests and procedures done that 
are either being tested in this study or being done to see how the study is affecting your body.
Day 1 (Visit 2): IV Injection of Study Drug, Imaging, and Biopsy for Groups 1 and 2
You will arrive at China Basin for the SPECT Imaging. Study procedures will be done at UCSF 
China Basin Imaging Center at 185 Berry St. Suite 180 and 190, Lobby 6, San Francisco, CA 
94107.
Before Injection 

If you are able to get pregnant, you must have a negative urine pregnancy test within 48 
hours before the tilmanocept injection. If you are pregnant, you will not be able to 
participate.

Your vital signs will be repeated.

You will be asked about any changes in your health and medications since your last visit.
Injection of Tc 99m tilmanocept 

You will receive the injection of the study drug through an IV placed in your arm. The 
amount of the study drug injection is small, less than a teaspoon.
After injection of the study drug at about 30 minutes:

Your vital signs will be repeated.

You will have an ECG.
SPECT Scanning:

You will be imaged at one time point on Day 1 beginning at 60-75 minutes after 
injection. Your body will be positioned in the large donut-shaped SPECT/CT scanner 
while you rest lying flat on the scanner bed. The scanning session could take up to 1 
hour. The SPECT part of the scanner detects the radiation in the study drug to create a 
picture of the study drug in your body. The CT part of the scanner uses a small amount of 
radiation to create a clearer picture of the tumor cells in your body. It is important that 
during all scans, you keep your body as still as possible. During the scan it will be 
important that you try to rest quietly with your eyes closed, keeping your head and the 
rest of your body as still as possible.
IRB NUMBER: 17-23045
IRB APPROVAL DATE: 10/10/2019
IRB EXPIRATION DATE: 10/09/2020


NAV3-24 INFORMED CONSENT FORM 1/30/19 PAGE 4 OF 12                                                                              INITIAL HERE:____________
After study drug injection and scanning is complete:

You will be assessed for any adverse events.

Your blood will be taken (about 2 teaspoons) for safety testing.

Blood drawing: blood samples will be drawn by inserting a needle into a 
vein in your arm.  A total of about 4 teaspoons will be drawn for the whole 
study.

Your urine will be collected for routine urinalysis. 
Following injection and imaging procedures, you will travel to San Francisco General Hospital, 
1001 Potrero Avenue, Bldg 90, Ward 92, San Francisco, CA 94143.

A skin biopsy will be taken. 

A skin biopsy of up to 6 millimeters in size, about the width of a pencil 
eraser, will be collected from a Kaposi’s sarcoma tumor to analyze the 
tumor cells. The skin around the tumor will be cleaned with iodine 
solution or other topical antiseptic agent and then an anesthetic will be 
injected at the site where the biopsy will be taken.

This skin will be sent to the lab for testing after injection with Tc 99m 
tilmanocept. The area from which the biopsy has been removed will then 
be closed with a suture(s).
Day 1 (Visit 2): Subcutaneous Injection of Study Drug and Imaging for Group 3
You will arrive at China Basin for the SPECT Imaging. Study procedures will be done at UCSF 
China Basin Imaging Center at 185 Berry St. Suite 180 and 190, Lobby 6, San Francisco, CA 
94107.
Before Injection 

If you are able to get pregnant, you must have a negative urine pregnancy test within 48 
hours before the tilmanocept injection. If you are pregnant, you will not be able to 
participate.

Your vital signs will be repeated.

You will be asked about any changes in your health and medications since your last visit.
Injection of Tc 99m tilmanocept 

You will receive the injection of the study drug in each your left and right leg. The 
amount of the study drug injection is small, less than a teaspoon.
After injection of the study drug at about 30 minutes:

Your vital signs will be repeated.

You will have an ECG.
IRB NUMBER: 17-23045
IRB APPROVAL DATE: 10/10/2019
IRB EXPIRATION DATE: 10/09/2020


NAV3-24 INFORMED CONSENT FORM 1/30/19 PAGE 5 OF 12                                                                              INITIAL HERE:____________
SPECT Scanning:

You will be imaged at two time points on Day 1 beginning at 60-75 minutes and 4-6 
hours after injection. Your body will be positioned in the large donut-shaped SPECT/CT 
scanner while you rest lying flat on the scanner bed. Each scanning session could take up 
to 1 hour. The SPECT part of the scanner detects the radiation in the study drug to create 
a picture of the study drug in your body. The CT part of the scanner uses a small amount 
of radiation to create a clearer picture of the tumor cells in your body. It is important that 
during all scans, you keep your body as still as possible. During the scan it will be 
important that you try to rest quietly with your eyes closed, keeping your head and the 
rest of your body as still as possible.
After study drug injection and scanning is complete:

You will be assessed for any adverse events.

Your blood will be taken (about 2 teaspoons) for safety testing.

Blood drawing: blood samples will be drawn by inserting a needle into a 
vein in your arm.  A total of about 6 teaspoons will be drawn for the whole 
study.

Your urine will be collected for routine urinalysis. 
Day 7 ± 3 (Visit 3): IV Injection of Study Drug, Imaging, and Biopsy for Group 3 
You will arrive at China Basin for the SPECT Imaging. Study procedures will be done at UCSF 
China Basin Imaging Center at 185 Berry St. Suite 180 and 190, Lobby 6, San Francisco, CA 
94107.
Before Injection 

If you are able to get pregnant, you must have a negative urine pregnancy test within 48 
hours before the tilmanocept injection. If you are pregnant, you will not be able to 
participate.

Your vital signs will be repeated.

You will be asked about any changes in your health and medications since your last visit.
Injection of Tc 99m tilmanocept 

You will receive the injection of the study drug through an IV placed in your arm. The 
amount of the study drug injection is small, less than a teaspoon.
After injection of the study drug at about 30 minutes:

Your vital signs will be repeated.

You will have an ECG.
SPECT Scanning:
IRB NUMBER: 17-23045
IRB APPROVAL DATE: 10/10/2019
IRB EXPIRATION DATE: 10/09/2020


NAV3-24 INFORMED CONSENT FORM 1/30/19 PAGE 6 OF 12                                                                              INITIAL HERE:____________

You will be imaged at one time point on Day 7 ± 3 beginning at 60-75 minutes after 
injection. Your body will be positioned in the large donut-shaped SPECT/CT scanner 
while you rest lying flat on the scanner bed. The scanning session could take up to 1 
hour. The SPECT part of the scanner detects the radiation in the study drug to create a 
picture of the study drug in your body. The CT part of the scanner uses a small amount of 
radiation to create a clearer picture of the tumor cells in your body. It is important that 
during all scans, you keep your body as still as possible. During the scan it will be 
important that you try to rest quietly with your eyes closed, keeping your head and the 
rest of your body as still as possible.
After study drug injection and scanning is complete:

You will be assessed for any adverse events.

Your blood will be taken (about 2 teaspoons) for safety testing.

Blood drawing: blood samples will be drawn by inserting a needle into a 
vein in your arm.  A total of about 6 teaspoons will be drawn for the whole 
study.

Your urine will be collected for routine urinalysis. 
Following injection and imaging procedures, you will travel to San Francisco General Hospital, 
1001 Potrero Avenue, Bldg 90, Ward 92, San Francisco, CA 94143.

A skin biopsy will be taken. 

A skin biopsy of up to 6 millimeters in size will be collected from a 
Kaposi’s sarcoma tumor to analyze the tumor cells. The skin around the 
tumor will be cleaned with iodine solution or other topical antiseptic agent 
and then an anesthetic will be injected at the site where the biopsy will be 
taken.

This skin will be sent to the lab for testing after injection with Tc 99m 
tilmanocept. The area from which the biopsy has been removed will then 
be closed with a suture(s).
Safety Telephone Follow-Up (7±3 days after IV injection for all Groups)

You will be asked about changes in your health and medication.

You will be asked about any adverse events.
How long will I be in the study?
IRB NUMBER: 17-23045
IRB APPROVAL DATE: 10/10/2019
IRB EXPIRATION DATE: 10/09/2020


NAV3-24 INFORMED CONSENT FORM 1/30/19 PAGE 7 OF 12                                                                              INITIAL HERE:____________
The screening period begins after you have signed this consent form. A follow-up telephone call 
will occur 7 ± 3 days after you have received IV injection of the study drug. Total participation 
may last up to 18 hours over the course of up to 50 days. 
Can I stop being in the study?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop your participation safely. 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
Tilmanocept can be evaluated by your doctor. Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped.
What side effects or risks can I expect from being in the study?
While the possibility of adverse (bad) reactions happening during this study is very low, it is 
possible that you may experience adverse or allergic reactions or discomfort. Every person 
taking part in the study will be watched carefully for any side effects or allergic reactions. 
Doctors don’t know all of the side effects that might happen. It is important that you talk to your 
study doctor about any changes in health that you experience while taking part in this study. All 
side effects or changes in your normal health should be reported, even those changes you might 
not consider to be important.
In other clinical trials with the study drug, no patients experienced serious adverse reactions and 
the most common adverse reactions were injection site irritation and/or pain (<1%).  The study 
drug has been available commercially for other medical uses since May 2013, and since that time 
over 250,000 patients have received this drug.  The most commonly reported adverse reactions 
have been lack of effect (<0.067%), injection site pain (<0.02%) and rash (<0.02%).

Blood drawing risks:  Drawing blood may cause temporary discomfort from the needle 
stick, bruising, infection, and fainting. 

IV insertion:  IV insertion may cause slight pain or discomfort. You may experience 
tenderness, warmth, or redness along the vein or at the injection site. Inflammation of the 
vein is common and may occur after the insertion of the IV catheter (tube). Bruising may 
occur from an unsuccessful IV insertion or during removal of an IV. In some rare cases, an 
infection can occur at the IV site.

Subcutaneous injection: Group 3 participants will additionally receive the study drug as an 
injection into each leg. Injection may cause slight pain or discomfort. You may experience 
tenderness, warmth, or redness at the injection site. In some rare cases, an infection can occur 
at the injection site.
IRB NUMBER: 17-23045
IRB APPROVAL DATE: 10/10/2019
IRB EXPIRATION DATE: 10/09/2020


NAV3-24 INFORMED CONSENT FORM 1/30/19 PAGE 8 OF 12                                                                              INITIAL HERE:____________

Radiation risks:
This research study involves exposure to radiation from Tilmanocept injections and the 
SPECT/CT scans. This radiation exposure is not necessary for your medical care and is for 
research purposes only. The additional amount of radiation that you will receive as a result of 
participating in this study will be a maximum of approximately 8 mSv, or three times the 
yearly natural background of radiation in the US, which is 3 mSv (a mSv, or milliSievert, is a 
measurement of radiation).  This amount of radiation may involve a low, lifetime risk of 
cancer. If you are pregnant or breast feeding, you SHOULD NOT participate in this study.  If 
you have any questions regarding the use of radiation or the risks involved, please consult the 
physician conducting the study.

SPECT/CT scan risks: SPECT/CT scans involve the risks of radiation (see above).  
Having a CT scan may mean some added discomfort for you.  In particular, you may be 
bothered by feelings of claustrophobia when placed inside the CT scanner, or by lying in one 
position for a long time.  You may feel warm and flushed. Incidental findings may arise as a 
result of having a CT scan as a part of this study. Any incidental findings will be reviewed 
with you and your study doctor, and your study doctor will determine appropriate follow-up 
procedures.

Biopsy risks: The biopsy may be slightly painful and there is a small risk of infection at the 
biopsy site. If you have any sensitivity to iodine or lidocaine, please notify the study staff as 
both will be used during the procedure.

Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a 
baby while on this study.  It is important to understand that you need to use birth control 
while on this study.  Check with your study doctor about what kind of birth control methods 
to use and how long to use them.  Some methods might not be approved for use in this study.  
For Men and Women:
Whether you are a man or a woman, there may be risks to your unborn children. If you take 
part in this study, you must use an effective birth control method as discussed with your 
study doctor.
Examples of birth control methods include:
•
 Oral birth control pills
•
 Birth control patch
•
 Implanted (injectable contraceptive hormones or mechanical products such as 
intrauterine device)
•
 Barrier methods (diaphragm or condoms)
•
 Tubal ligation or vasectomy
•
 Abstinence (no sexual intercourse)
You should discuss the method of birth control that is best for you to use during the study.
Please place your initials in the appropriate box below:
IRB NUMBER: 17-23045
IRB APPROVAL DATE: 10/10/2019
IRB EXPIRATION DATE: 10/09/2020


NAV3-24 INFORMED CONSENT FORM 1/30/19 PAGE 9 OF 12                                                                              INITIAL HERE:____________
I am surgically sterile (hysterectomy, tubal ligation or vasectomy) or have gone
through menopause.
I understand and agree to use contraception during treatment and for the time 
recommended by my doctor after the treatment is over.

Allergic Reaction Risks
Sometimes people have allergic reactions to drugs. If you have a very bad allergic reaction, you 
could die. Some things that happen during an allergic reaction that could be a sign or symptom of 
a life-threatening allergic reaction (anaphylaxis) are:

Rash or hives

Having a hard time breathing

Wheezing when you breathe

Inability to breathe without assistance

Sudden change in blood pressure (making you feel dizzy or lightheaded)

Swelling around the mouth, throat or eyes

Fast pulse

Sweating

A feeling of dread
You should get medical help and contact the study doctor or staff if you have any of these or any 
other side effects during the study.

Unknown Risks: The experimental treatments may have side effects that no one knows 
about yet.  The researchers will let you know if they learn anything that might make you 
change your mind about participating in the study.

For more information about risks and side effects, ask your study doctor.
Are there benefits to taking part in the study?
You will not receive any medical benefit as a result of being in this study, but the information 
obtained in this study may benefit future cancer patients. We do know that the information from 
this study will help doctors learn more about Tilmanocept as a tracing agent for cancer.  
What other choices do I have if I do not take part in this study?
Your other choices may include:

Getting treatment or care for your cancer without being in a study. 

Taking part in another study.

Getting no treatment.
Please talk to your doctor about your choices before deciding if you will take part in this study.
How will information about me be kept confidential?
IRB NUMBER: 17-23045
IRB APPROVAL DATE: 10/10/2019
IRB EXPIRATION DATE: 10/09/2020


NAV3-24 INFORMED CONSENT FORM 1/30/19 PAGE 10 OF 12                                                                              INITIAL HERE:____________
Participation in research involves some loss of privacy.  We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total privacy.  Some 
information from your medical records will be collected and used for this study.  If you do not 
have a UCSF medical record, one will be created for you.  Your signed consent form and some 
of your research tests will be added to your UCSF medical record.  Therefore, people involved 
with your future care and insurance may become aware of your participation and of any 
information added to your medical record as a result of your participation.  Study tests that are 
performed by research labs and information gathered directly from you by the researchers will be 
part of your research records but will not be added to your medical record.  Your personal 
information may be given out if required by law.  If information from this study is published or 
presented at scientific meetings, your name and other personal information will not be used.
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include:

Navidea Biopharmaceuticals, Inc.

Representatives of Navidea Biopharmaceuticals, Inc.

The University of California 

The National Cancer Institute (NCI) and other government agencies, e.g., the Food and 
Drug Administration (FDA), involved in keeping research safe for people. 
Are there any costs to me for taking part in this study?
No.  The sponsor has agreed to pay for all procedures associated with this research study; you or 
your insurer will not be billed.
Will I be paid for taking part in this study?
You will be paid for the time that is required to complete the study visits. You will receive 
the following amounts for each completed visit:
Visit 1: $ 75.00
Visit 2: $ 250.00
Visit 3 (Group 3 only): $ 250.00
Safety Telephone Follow-Up: $ 25.00
If you feel that the payment listed may interfere with your making a good decision about whether 
or not you should volunteer to be in this study, you should not agree to participate. You will be 
paid at the end of your participation for each completed visit.
You may be required to report the payment received for this study to the Internal Revenue 
Service as taxable income. You have to provide your social security number because the IRS 
may be told how much you were paid to take part in this study.
IRB NUMBER: 17-23045
IRB APPROVAL DATE: 10/10/2019
IRB EXPIRATION DATE: 10/09/2020


NAV3-24 INFORMED CONSENT FORM 1/30/19 PAGE 11 OF 12                                                                              INITIAL HERE:____________
If you withdraw from the study, you will receive a prorated amount for each scheduled visit 
made to the clinic. A check will be mailed to you about 6-8 weeks after your participation in the 
study has ended.  
What happens if I am injured because I took part in this study?
It is important that you tell your study doctor, Dr. Kieron Leslie, if you feel that you have been 
injured because of taking part in this study. You can tell the doctor in person or call her at (415) 
206-8680.
Treatment and Compensation for Injury:  If you are injured as a result of being in this 
study, the University of California will provide necessary medical treatment.  The costs 
of the treatment may be billed to you or your insurer just like any other medical costs, or 
covered by the University of California or the study sponsor, Navidea, depending on a 
number of factors.  The University and the study sponsor do not normally provide any 
other form of compensation for injury.  For further information about this, you may call 
the office of the Committee on Human Research at 415- 476-1814. 
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution. 
What if new information becomes available?
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.
Are there reasons we might take you out of the study?
Even if you want to stay in the study, there may be reasons we need to take you out of it. You 
may be taken out of this study if:

We find out it is not safe for you to stay in the study. For example, your health 
may worsen or we may find out that the study drug might harm you.

Your healthcare is not being managed properly or you are not coming for study 
visits as scheduled

The study doctor feels it is not in your best interest to continue

If the sponsor or study doctor decides that the study or your participation should 
be stopped for any reason
IRB NUMBER: 17-23045
IRB APPROVAL DATE: 10/10/2019
IRB EXPIRATION DATE: 10/09/2020


NAV3-24 INFORMED CONSENT FORM 1/30/19 PAGE 12 OF 12                                                                              INITIAL HERE:____________
Who can answer my questions about the study?
You can talk to your study doctor about any questions, concerns, or complaints you have about 
this study.  Contact your study doctor(s) Dr. Kieron Leslie at (415) 206-8680.
If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have about 
the study, please call the Office of the Committee on Human Research at 415-476-1814. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time.
CONSENT
You have been given copies of this consent form and the Experimental Subject's Bill of Rights to
keep.
You will be asked to sign a separate form authorizing access, use, creation, or disclosure of
health information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to
participate or to withdraw at any point in this study without penalty or loss of benefits to which
you are otherwise entitled.
If you wish to participate in this study, you should sign below.
Date
Participant's Signature for Consent
Date
Person Obtaining Consent
Date
Witness – Only required if the participant is a non-English speaker
IRB NUMBER: 17-23045
IRB APPROVAL DATE: 10/10/2019
IRB EXPIRATION DATE: 10/09/2020

Prot_000.pdf: 
 Clinical Trial Protocol: NAV3-24 
Study Title: 
An Evaluation of the Safety of Escalating Doses of Tc 99m 
Tilmanocept by Intravenous (IV) Injection and a Comparison to 
Subcutaneous (SC) Injection in Human Immunodeficiency Virus 
(HIV) Subjects Diagnosed with Kaposi Sarcoma (KS)  
Study Number: 
NAV3-24 
Study Phase: 
1 
Product Name: 
technetium Tc 99m tilmanocept 
IND Number: 
132943 
Investigator(s): 
Toby A. Maurer, MD 
Box SFGH 
1001 Potrero Ave, SFGH 90, 92 
University of California, San 
Francisco 
San Francisco, CA 94143 
Spencer Behr, MD 
Box 0628 
505 Parnassus Ave, Long, 332A 
University of California, San 
Francisco 
San Francisco, CA 94143 
 
Sponsor: 
Navidea Biopharmaceuticals, Inc. 
4995 Bradenton Ave., Suite 240 
Dublin, OH 43017 
 
Sponsor Contact: 
Bonnie Abbruzzese, MS, CCRA 
Senior Director, Clinical Research 
614-946-8077 
 
Medical Monitor: 
Michael Blue, MD 
Senior Medical Director 
614-571-4313 
 
Date 
Original Protocol: 
29 August 2016 
Amendment #1 
26 June 2017 
Amendment #2 
01 May 2018 
Amendment #3 
30 January 2019 
 
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 
 


Technetium Tc99m tilmanocept 
 
Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-24 
 
30 January 2019 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................13 
TRIAL ADMINISTRATIVE STRUCTURE ..........................................................................16 
1 
INTRODUCTION ...........................................................................................................17 
1.1 
Background ............................................................................................................17 
1.2 
Preliminary Data ....................................................................................................18 
1.2.1 
Prior Experience of Tilmanocept Injection in KS Patients ..........................20 
1.3 
Previous Experience with Tc 99m Tilmanocept ....................................................21 
1.3.1 
Nonclinical Evaluations – IV and Intraperitoneal Administration ..............21 
1.3.2 
Clinical Pharmacokinetics and Pharmacodynamics in Lymphatic 
Mapping Clinical Trials (Subcutaneous, Peritumoral and Intradermal 
administration) .............................................................................................25 
1.3.3 
Clinical Efficacy in Lymphatic Mapping/Sentinel Node Mapping 
Clinical Trials...............................................................................................26 
1.3.4 
Clinical Safety using Intradermal, Subcutaneous, Peritumoral, and 
Intravenous Injections ..................................................................................26 
2 
TRIAL OBJECTIVES .....................................................................................................27 
2.1 
Primary Objective(s) ..............................................................................................27 
2.2 
Secondary Objective(s) ..........................................................................................27 
2.3 
Exploratory Objective(s) ........................................................................................27 
3 
OVERVIEW OF METHODOLOGY AND DESIGN .....................................................28 
3.1 
Overall Trial Design ..............................................................................................28 
3.2 
Justification for Study Design and Population.......................................................28 
3.3 
Protocol Adherence ................................................................................................28 
3.4 
Trial Duration.........................................................................................................28 
4 
STUDY POPULATION ..................................................................................................29 
4.1 
Inclusion Criteria ...................................................................................................29 
4.2 
Exclusion Criteria ..................................................................................................29 
4.3 
Kaposi Sarcoma Classification ..............................................................................29 
4.4 
Recruitment ............................................................................................................30 
4.5 
Withdrawal .............................................................................................................30 
4.6 
Enrollment and Screen Failures .............................................................................30 
5 
INVESTIGATIONAL PRODUCT ..................................................................................32 
5.1 
Identification of Investigational Product ...............................................................32 
5.2 
Investigational Product Dosage and Administration .............................................32 
5.3 
Treatment Assignment ...........................................................................................32 
5.4 
Packaging and Labeling .........................................................................................33 


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Clinical Trial Protocol: NAV3-24 
 
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5.5 
Investigational Product Accountability ..................................................................33 
6 
THERAPIES OTHER THAN INVESTIGATIONAL PRODUCT .................................34 
6.1 
Prior and Concomitant Therapy .............................................................................34 
6.2 
Post-Study Therapy ................................................................................................34 
7 
STUDY PROCEDURES .................................................................................................35 
7.1 
Screening Visit (within 30 days of Day 1 injection) ..............................................35 
7.2 
Day 1 (IV Injection) ...............................................................................................36 
7.2.1 
Before Injection ...........................................................................................36 
7.2.2 
IV Administrstion of Tc 99m tilmanocept ...................................................36 
7.2.3 
Post-Injection ...............................................................................................36 
7.3 
Follow-Up Telephone Call (7±3 days after Tc 99m tilmanocept injection) ..........37 
7.4 
Day 1 (SC Injection) ..............................................................................................37 
7.4.1 
Before Injection ...........................................................................................37 
7.4.2 
SC Administrstion of Tc 99m tilmanocept ..................................................37 
7.4.3 
Post-Injection ...............................................................................................37 
7.5 
Day 7 ± 3 (IV Injection) .........................................................................................38 
7.5.1 
Before Injection ...........................................................................................38 
7.5.2 
IV Administrstion of Tc 99m tilmanocept ...................................................38 
7.5.3 
Post-Injection ...............................................................................................38 
7.6 
Follow-Up Telephone Call (7±3 days after IV Tc 99m tilmanocept injection) ....39 
7.7 
Imaging and Acqusition of Imaging Data ..............................................................39 
7.8 
Image Acqusition ...................................................................................................39 
7.9 
Evaluation of Planar and SPECT Images ..............................................................39 
7.10 
End of Study ..........................................................................................................39 
8 
PROCEDURES AND VARIABLES ..............................................................................40 
8.1 
Population Characteristics .....................................................................................40 
8.1.1 
Demographic and Other Baseline Characteristics .......................................40 
8.1.2 
Medical and Surgical History ......................................................................40 
8.1.3 
Prior and Concomitant Medication ..............................................................40 
8.2 
Tc 99m Tilmanocept Preparation and Administration...........................................40 
8.3 
SPECT/SPECT-CT Image Acquisition .................................................................40 
8.4 
Post-Injection and Imaging Biopsy Acquisition ....................................................41 
8.5 
Pharmacokinetics ...................................................................................................42 
8.6 
Safety .....................................................................................................................42 
8.6.1 
Adverse Events ............................................................................................42 
8.6.1.1 
Definition of Adverse Event ..............................................................42 
8.6.1.2 
Categories for Adverse Event Assessment ........................................42 
8.6.1.3 
Assessments and Documentation of Adverse Events ........................44 


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Clinical Trial Protocol: NAV3-24 
 
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8.6.1.4 
Expected Adverse Events ..................................................................45 
8.6.1.5 
Serious Adverse Events .....................................................................45 
8.6.2 
Further Safety Assessments .........................................................................47 
8.6.2.1 
Physical Exam ....................................................................................47 
8.6.2.2 
Electrocardiogram ..............................................................................47 
8.6.2.3 
Vital Signs ..........................................................................................47 
8.6.2.4 
Clinical Laboratory Parameters for Screening and Safety .................48 
9 
STATISTICAL METHODS ............................................................................................50 
9.1 
Randomization Methods ........................................................................................50 
9.2 
Safety Variables .....................................................................................................50 
9.3 
Efficacy Variables ..................................................................................................50 
9.4 
Sample Size Justification .......................................................................................51 
9.5 
Statistical Analyses ................................................................................................51 
9.5.1 
Analysis Populations ....................................................................................51 
9.5.2 
Analysis of Baseline and Demographic Characteristics ..............................51 
9.5.3 
Analysis of Efficacy Variables ....................................................................51 
9.5.4 
Analysis of Safety Variables ........................................................................52 
9.5.5 
Handling Missing Values .............................................................................53 
9.5.6 
Interim Analysis ...........................................................................................53 
10 DATA HANDLING AND QUALITY ASSURANCE ...................................................54 
10.1 
Data Recording ......................................................................................................54 
10.1.1 
eCRF Design ................................................................................................54 
10.2 
Monitoring .............................................................................................................54 
10.3 
Data Processing ......................................................................................................54 
10.4 
Auditing .................................................................................................................54 
10.5 
Archiving ...............................................................................................................55 
10.6 
Premature Termination of the Trial .......................................................................55 
10.6.1 
Trial as a Whole ...........................................................................................55 
10.6.2 
Center ...........................................................................................................56 
10.6.3 
Study Participant ..........................................................................................56 
11 ETHICAL AND LEGAL ASPECTS...............................................................................57 
11.1 
Ethical and Legal Conduct of the Study ................................................................57 
11.2 
Subject Information and Consent...........................................................................57 
11.3 
Financing/Financial Disclosure .............................................................................58 
11.4 
Publication Policy ..................................................................................................58 
11.5 
Subject Injury .........................................................................................................58 
12 REFERENCE LIST .........................................................................................................59 
 


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Clinical Trial Protocol: NAV3-24 
 
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LIST OF IN-TEXT TABLES 
Table 1.  
Dosing Cohorts ............................................................................................32 
Table 2. 
Clinical Laboratory Parameters ...................................................................48 
Table 3.  
Approximate Amount of Blood Withdrawn ................................................49 
 
LIST OF IN-TEXT FIGURES 
Figure 1.  
Macrophage CD206 Expression Permits Targeting of a Broad Range of 
Immuno-Inflammatory Disorders ................................................................19 
Figure 2.  
Kaposi Sarcoma Tumor and Macrophages Express CD206 ........................19 
Figure 3.  
Ex Vivo Tilmanocept Localization in Tumor Tissue from a KS Patient .....20 
Figure 4.  
Localization of Tc 99m Tilmanocept in KS Lesions ...................................21 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events – Cohorts 1 and 2 ...............................................62 
Appendix 2 
Schedule of Events – Cohort 3...........................................................63 
Appendix 3 
Dose Escalation Diagram ...................................................................64 
Appendix 4 
Edema Scale .......................................................................................65 
Appendix 5 
KS Lesion Assessment/ Photography Protocol..................................66 
Appendix 6 
Sponsor Signatures.............................................................................71 
Appendix 7 
Investigators’ Signature .....................................................................72 
 
 
 


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Clinical Trial Protocol: NAV3-24 
 
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SYNOPSIS 
Study Title 
An Evaluation of the Safety of Escalating Doses of Tc 99m Tilmanocept 
by Intravenous (IV) Injection and a Comparison to Subcutaneous 
(SC) Injection in Human Immunodeficiency Virus (HIV) Subjects 
Diagnosed with Kaposi Sarcoma (KS) 
Study Phase 
Phase 1 
Study Drug 
Technetium Tc 99m tilmanocept injection  
Dose(s) and Route of 
Administration 
Route of Administration: Administrations of  Tc 99m tilmanocept will 
occur through an intravenous (IV) and subcutaneous (SC) route of 
injection.  
For the IV doses, a single syringe will be used and injected as a slow 
push into the peripheral venous catheter. The preferred site of catheter 
placement will be the left or right antecubital vein. At the completion of 
the injection, a 10 cc sterile normal saline flush will be administered. 
For SC doses, two syringes will be used and injected bilaterally as a slow 
push into the ankle(s) or the dorsal surface of the foot (feet).  
 
Doses: Cohort 1 subjects will receive an IV administration of 100 µg/ 5 
mCi Tc 99m tilmanocept. Cohort 2 subjects will receive an IV 
administration of 100 µg/ 10 mCi Tc 99m tilmanocept. Cohort 3 subjects 
will receive a SC and an IV administration of 200 µg/ 5 mCi Tc 99m 
tilmanocept approximately one week apart.  
Study Objectives 
Primary Objective(s): 
To determine the safety of escalating doses of Tc 99m tilmanocept in 
HIV subjects with biopsy-confirmed KS. 
 
Secondary Objective(s): 
 
• 
Concordance between clinical assessment/diagnosis and the 
localization of Tc 99m tilmanocept by planar and/or SPECT 
(single photon emission computed tomography)/CT (X-ray 
computed tomography) imaging in cutaneous and non-cutaneous 
sites of KS. 
• 
Qualify and quantify Tc 99m tilmanocept localization intensity on 
imaging with CD206 locale and quantity by histology and 
immunohistochemistry (IHC) in biopsied KS lesions to determine 
optimal IV dose.  
• 
Concordance of localization of Tc 99m tilmanocept via IV and SC 
routes of administration by planar and/or SPECT/CT imaging in 
cutaneous and non-cutaneous sites of KS. 
 
Exploratory Objective(s): 


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Clinical Trial Protocol: NAV3-24 
 
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• 
Quantify HHV8 in biopsied KS lesions by real-time polymerase 
chain reaction (qPCR) 
 
Safety: 
General safety will be evaluated by examining the incidence of adverse 
events (AEs) and changes over time in laboratory tests, vital signs, 
ECGs (electrocardiogram) and physical examination findings.  
Inclusion Criteria 
1. The subject has provided written informed consent with HIPAA 
(health insurance portability and accountability act) authorization 
before the initiation of any study-related procedures. 
2. The subject is at least 18 years of age at the time of consent. 
3. The subject is HIV positive. 
4. The subject has a biopsy-confirmed diagnosis of KS and is classified 
into one of the categories below: 
a. Confirmed cutaneous KS/oral lesions without 
edema 
b. Confirmed cutaneous KS/oral lesions with edema 
c. Confirmed cutaneous KS/oral lesions with or 
without edema and suspected non-cutaneous KS 
due to clinical symptomology or confirmed non-
cutaneous KS lesion(s). 
 
Exclusion Criteria 
1. The subject is pregnant or lactating. 
2. The subject has received chemotherapy or radiation therapy to 
KS sites within six weeks of enrollment. 
3. The subject has known sensitivity to dextran. 
4. The subject has received an investigational product within 30 
days prior to the Tc 99m tilmanocept administration on Day 1. 
5. The subject has received any radiopharmaceutical within 7 
days prior to the administration of Tc 99m tilmanocept on Day 
1.  
6. Any condition that, in the clinical judgment of the treating 
physician, is likely to prevent the subject from complying with 
any aspect of the protocol or that may put the subject at 
unacceptable risk. 
 
Investigational Product 
technetium Tc 99m tilmanocept  
Study design 
Prospective, single center, open-label, non-randomized, dose escalation, 
comparative, safety study of Tc 99m tilmanocept in the localization and 
detection of cutaneous and non-cutaneous lesions in HIV subjects with 
KS by planar and optional SPECT/CT imaging. Cohort 1 subjects will 
receive an IV administration of 100 µg/ 5 mCi Tc 99m tilmanocept. 
Cohort 2 subjects will receive an IV administration of 100 µg/ 10 mCi 
Tc 99m tilmanocept. Cohort 3 subjects will receive a SC and an IV 


Technetium Tc99m tilmanocept 
 
Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-24 
 
30 January 2019 
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administration of 200 µg/ 5 mCi Tc 99m tilmanocept approximately one 
week apart. At least one subject enrolled into each cohort must meet 
inclusion criteria 4c, as defined above (suspected non-cutaneous or 
confirmed non-cutaneous KS). For determination of the primary 
endpoint, a review meeting for safety will be held after the completion 
of each cohort prior to opening the next dose cohort. Cohorts will be 
dosed per the following table: 
 
Tc 99m 
tilmanocept 
Dose 
Route of 
Administration 
Number of 
Subjects 
Cohort 1 
100 µg/ 5 mCi 
IV 
n = 4 
Cohort 2 
100 µg/ 10 mCi 
IV 
n = 4 
Cohort 3 
200 µg/ 5 mCi 
IV and SC 
n = up to 6 
 
Following IV administration, all subjects will have a whole body planar 
scan with optional SPECT/CT region of interest scanning beginning at 
60-75 minutes post-injection. Subjects in Cohort 3 will additionally 
have a whole body planar scan with optional SPECT/CT region of 
interest scanning beginning at 60-75 minutes and 4-6 hours following 
SC injection. 
Methodology 
 The study includes: screening, enrollment, pre- and post-injection 
assesments, injection, imaging, and follow-up. 
 
Cohorts 1 and 2: 
 
Visit 1, Screening (Day -29 to Day 0): 
The screening visit will include an assessment of eligibility, informed 
consent, collection of medical history including medications, vital 
signs, ECG, physical exam including height and weight, assessment of 
KS lesions, photographs of all visible cutaneous KS lesions, 
assessment of edema/lymphedema, clinical labs, urinalysis, and serum 
pregnancy test for subjects of child bearing potential. 
 
Visit 2 (Day 1):  
Pre-Tc 99m Tilmanocept Injection 
• 
Before Injection  
o Urine pregnancy test will be performed for subjects 
of child bearing potential within 48 hours of injection 
o Concomitant medication review 
o Vital signs—within 30 minutes prior to injection 
 
Tc 99m Tilmanocept IV Injection: Subjects will receive their open 
label serial IV dose assignment in accordance with Table 1. Adverse 
event monitoring will continue through completion of the trial. 


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Clinical Trial Protocol: NAV3-24 
 
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Post-Tc 99m Tilmanocept Injection: 
• 
Within 30 Minutes Post-Injection 
o ECG 
o Vital Signs 
o Assessment of Adverse Events 
• 
60-75 Minutes Post -Injection 
o Assessment of Adverse Events 
o Whole body planar imaging followed by optional 
SPECT/CT scan of region(s) of interest 
• 
At Completion of Imaging: 
o Safety Labs 
o Biopsy of designated non-visceral KS lesion  
 
7 ± 3 (4-10) Days Post Injection Telephone Follow-up: 
• 
Assessment of Adverse Events 
• 
Concomitant medication review 
 
Cohort 3: 
 
Visit 1, Screening (Day -29 to Day 0): 
The screening visit will include an assessment of eligibility, informed 
consent, collection of medical history including medications, vital 
signs, ECG, physical exam including height and weight, assessment of 
KS lesions, photographs of all visible cutaneous KS lesions, 
assessment of edema/lymphedema, clinical labs, urinalysis, and serum 
pregnancy test for subjects of child bearing potential. 
 
Visit 2 (Day 1):  
Pre-Tc 99m Tilmanocept Injection 
• 
Before Injection  
o Urine pregnancy test will be performed for subjects 
of child bearing potential within 48 hours of injection 
o Concomitant medication review 
o Vital signs—within 30 minutes prior to injection 
 
Tc 99m Tilmanocept SC Injection: Subjects will receive their open 
label SC dose in accordance with Table 1. Adverse event monitoring 
will continue through completion of the trial. 
 
Post-Tc 99m Tilmanocept Injection: 


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Clinical Trial Protocol: NAV3-24 
 
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• Within 30 Minutes Post-Injection 
o ECG 
o Vital Signs 
o Assessment of Adverse Events 
• 
60-75 Minutes Post -Injection 
o Assessment of Adverse Events 
o Whole body planar imaging followed by optional 
SPECT/CT scan of region(s) of interest 
• 
4 – 6 Hours Post -Injection 
o Assessment of Adverse Events 
o Whole body planar imaging followed by optional 
SPECT/CT scan of region(s) of interest 
• 
At Completion of Imaging: 
o Safety Labs 
 
Visit 3 (Day 7 ± 3):  
Pre-Tc 99m Tilmanocept Injection 
• 
Before Injection  
o Follow-up assessment from SC injection including 
changes in concomitant medication and adverse 
events  
o Urine pregnancy test will be performed for subjects 
of child bearing potential within 48 hours of injection 
o Concomitant medication review 
o Vital signs—within 30 minutes prior to injection 
 
Tc 99m Tilmanocept IV Injection: Subjects will receive their open 
label serial IV dose assignment in accordance with Table 1. Adverse 
event monitoring will continue through completion of the trial. 
 
Post-Tc 99m Tilmanocept Injection: 
• 
Within 30 Minutes Post-Injection 
o ECG 
o Vital Signs 
o Assessment of Adverse Events 
• 
60-75 Minutes Post -Injection 
o Assessment of Adverse Events 
o Whole body planar imaging followed by optional 
SPECT/CT scan of region(s) of interest 
• 
At Completion of Imaging: 


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Clinical Trial Protocol: NAV3-24 
 
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o Safety Labs 
o Biopsy of designated non-visceral KS lesion 
 
7 ± 3 Days Post-IV Injection Telephone Follow-up: 
• 
Assessment of Adverse Events 
• 
Concomitant medication review 
 
For determination of the secondary endpoints, the Tc 99m tilmanocept 
whole body planar and SPECT/CT images will be visually assessed for 
localization by a Nuclear Medicine Physician.  
Planned Study Dates 
Start of study recruitment 
January 2018 
End of Recruitment: June 2019 
End of Study/ September 2019 
Planned number of study 
centers 
One (1) in the United States 
Number of subjects 
Total: Up to 14 evaluable subjects may be enrolled, injected, and 
imaged. KS symptoms will be divided into three categories: a) 
confirmed cutaneous/oral lesions without edema, b) confirmed 
cutaneous/oral lesions with edema, or c) confirmed cutaneous/oral 
lesions with or without edema and suspected non-cutaneous KS due to 
clinical symptomology or confirmed non-cutaneous lesions.  After the  
subjects are dosed and imaged in each cohort, safety and imaging data 
will be reviewed by the Co-PIs and Navidea for assessment of safety 
and preliminary localization.  
Primary Endpoint 
Proportion of subjects experiencing noxious pharmacologic 
activity/Adverse Drug Reaction (ADR). 
Secondary Endpoints 
The secondary endpoints for this study are:  
• Per subject localization rate of Tc 99m tilmanocept in at least 
one KS suspected or confirmed lesion by planar and/or 
SPECT/CT imaging  
• Per lesion/region concordance of Tc 99m localization with 
anatomical areas of active KS defined by confirmed diagnosis 
or clinical symptomology.  
• Localization intensity for each biopsied and clinically defined 
lesion as determined by quantitative SPECT gamma counts  
• Per biopsied lesion proportion of CD206-expressing cells and 
total CD206 as determined by histology and relative IHC 
fluorescence  
• Per lesion/region concordance of IV vs SC Tc 99m 
localization with anatomical areas of active KS defined by 
confirmed diagnosis or clinical symptomology. 
• Per subject localization rate of Tc 99m tilmanocept in areas 
other than KS by planar and/or SPECT/CT imaging  


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• Per area localization rate of Tc 99m tilmanocept in the most 
frequently identified areas other than KS by planar and/or 
SPECT/CT imaging 
Exploratory Endpoint 
Per biopsied lesion quantity of HHV8 as determined by qPCR 
Data Analysis 
The following analysis population will be defined for the study: 
• Intent-to-Diagnose (ITD) Population - Subjects who are 
enrolled in the study, injected with Tc 99m tilmanocept, and 
are imaged will be included in the ITD analysis population. 
• Safety Population – All patients who are enrolled in the study 
and injected with Tc 99m tilmanocept will be included in the 
safety population. 
 
All safety data analyses will be conducted on the safety population.  All 
efficacy data analyses will be conducted on the ITD population. 
The distribution of each baseline and demographic variable of interest 
will be summarized by dose cohort. Continuous variables will be 
summarized via mean, median, standard deviation, and range. 
Categorical variables will be summarized via counts and percentages. 
For the primary safety endpoint, the number and percentage of subjects 
with ADRs will be tabulated by dose group and overall. 
The number and percentage of subjects with at least one biopsy-
confirmed or clinically suspected KS lesion that has localized with Tc 
99m tilmanocept by planar and/or SPECT/CT imaging will be 
computed.  A 95% exact confidence interval on the per subject 
localization rate will be computed.  This analysis will be performed by 
dose and overall.     
Per region lesion localization of Tc 99m tilmanocept by planar and/or 
SPECT/CT imaging will be computed across all biopsy-confirmed or 
clinically suspected KS lesions of all subjects.  A 95% exact confidence 
interval on per region lesion localization will be calculated.  This 
analysis will be performed by dose and overall. Additional analyses of 
efficacy will be performed as decribed in Section 9.5.  
Other efficacy analyses not addressed in this protocol will be described 
in the Statistical Analysis Plan (SAP) for the study. 
 
 
 


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Clinical Trial Protocol: NAV3-24 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADR 
Adverse drug reaction 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
BUN 
blood urea nitrogen 
CD206 
mannose binding receptors 
CNS 
central nervous system 
CRA 
clinical research associate 
CRC 
Colorectal cancer 
CRF 
case report form 
CRO 
contract research organization 
CT 
X-ray computed tomography 
CVD 
Cardiovascular disease 
DICOM 
Digital Imaging Communications in Medicine  
DTPA 
pentetic acid 
ECG 
electrocardiogram 
EU 
European Union 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FNR 
false negative rate 
FOV 
field of view  
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HCT 
hematocrit 
Hgb 
hemoglobin 
HHV8/KSHV 
Kaposi sarcoma herpes virus 
HIPAA 
Health Information Portability and Accountability Act 


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Clinical Trial Protocol: NAV3-24 
 
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HIV 
human immunodeficiency virus infection 
ICF 
informed consent form 
ICH 
International Conference on Harmonization  
ID 
intradermal 
%IDSN 
percentage of Injected Dose in the Sentinel Node 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
ILM 
intraoperative lymphatic mapping 
IND 
Investigational New Drug  
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISF 
investigator site file 
ITD 
intent to diagnose 
IV 
intravenous 
KS 
Kaposi Sarcoma 
LSN 
primary sentinel lymph node 
MBR 
mannose binding receptor  
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose  
NASH 
Nonalcoholic steatohepatitis 
NOAEL 
no-observed adverse-effect level 
PI 
principal investigator 
PK 
pharmacokinetics 
PT 
peritumoral 
QC 
quality control 
qPCR 
real-time polymerase chain reaction 
RA 
Rheumatoid arthrirtis 
RBC 
red blood cell 
SAE 
serious adverse event 


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SAP 
statistical analysis plan 
SC 
subcutaneous 
SCC 
squamous cell carcinoma 
SD 
study day 
SLNB 
sentinel lymph node biopsy  
SPECT 
single photon emission computed tomography 
SUSARs 
Suspected, Unexpected, Serious Adverse Reactions 
TAMs 
Tumor-associated macrophages 
TcSC 
Tc 99m sulfur colloid 
TEAE 
treatment emergent adverse event 
tilmanocept 
Technetium Tc 99 tilmanocept 
TMF 
trial master file 
US 
United States  
VBD 
vital blue dye 
 
 
 


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


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1 
INTRODUCTION 
1.1 
Background 
Tilmanocept (technetium Tc 99m tilmanocept) Injection was approved by the US (United States) Food 
and Drug Administration (FDA) for use in lymphatic mapping to assist in the localization of lymph 
nodes draining a primary tumor site in patients with solid tumors for which this procedure is a 
component of intraoperative management and for guiding sentinel lymph node biopsy (SLNB) in 
patients with clinically node negative squamous cell carcinoma (SCC) of the oral cavity, breast cancer, 
or melanoma. 
Tilmanocept Injection is approved in the European Union (EU) for use in imaging and intraoperative 
detection of sentinel lymph nodes draining a primary tumor in adult patients with breast cancer, 
melanoma, or localized squamous cell carcinoma of the oral cavity (SEE: www.Lymphoseek.com). 
Tilmanocept is a radiotracer that accumulates in lymphatic tissue by binding to a mannose binding 
receptor that resides on the surface of dendritic cells and macrophages within the first draining lymph 
nodes. Tilmanocept is a macromolecule consisting of multiple units of diethylenetriaminepentaacetic 
acid acid (DTPA) and mannose, each synthetically attached to a 10 kilodalton dextran backbone. The 
mannose acts as a substrate for the receptor, and the DTPA serves as a chelating agent for labeling with 
Tc-99m. Tilmanocept's small diameter permits rapid transit from the injection site (subcutaneous [SC] 
or intradermal [ID]) to the lymphatic channels and blood capillaries resulting in enhanced diffusion 
into lymph nodes.  
The pathogenesis of cancer is a complex multistep process involving the acquisition of genetic 
abnormalities by cancer cells and tumor progression associated with an ongoing inflammatory process. 
The inflammation is generally driven by tumor-associated macrophages (TAMs), and these cells have 
been proven in a variety of systems to provide a supportive environment for tumor progression. In 
addition, there is increasing evidence that tumor metastasis is associated with tumor cells that co-
express macrophage markers that allow more efficient metastasis. As metastasis is critical to the overall 
pathogenesis of cancer and survival in patients with cancer, both TAMs and tumor cells bearing 
macrophage markers would be important targets for quantitative imaging in the development of anti-
cancer therapeutics. In this context, AIDS(acquired immunodeficiency syndrome)-associated Kaposi 
sarcoma (KS) is a form of cancer in which inflammation plays a critical role in tumor development. 
Because tilmanocept binds to CD206 (mannose binding receptor), it could have a significant role in the 
development of a new wave of diagnostic and anti-tumor agents directed against TAMs and metastatic 
tumor cells by imaging their metastatic pattern and response to therapy.  
Macrophages are one of the most versatile cell types in the body, largely owing to their ability to 
fluctuate between activation states depending on their microenvironment. They function in both innate 
and adaptive immunity through the phagocytosis of foreign materials and pathogens, as well as by 
stimulating the activation of other immune cells. Macrophages make up a large portion of the 
inflammatory infiltrate for most cancer types, including KS, and may represent up to 80% of the total 
tumor mass. Monocyte recruitment is essential for tumor development as these cells are present during 
the early stages of tumor growth and promote progressive tumorigenesis. Blood monocytes are 
recruited from the vasculature into the tumor, in response to chemo-attractants released by tumor cells, 
where they differentiate into TAMs. TAMs are a heterogeneous mass of cells consisting of resident 
macrophages, early infiltrating perivascular macrophages, and monocytes/macrophages. Depending on 
the microenvironment, macrophages either become M1 (classically activated, MAC387-positive) in 
response to pro-inflammatory molecules and pathogens, or become M2 (alternatively activated, 


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CD163-positive). In KS, as well as many other cancer types, the primary infiltrating form of 
macrophage is the M2 subset (1-4).  
AIDS-related KS is an aggressive, multifocal, angioproliferative neoplasm associated with Kaposi 
sarcoma herpes virus (HHV8/KSHV) infection. It involves cutaneous and non-cutaneous tissues, with 
later forms of disease associated with widespread organ involvement. It is the most common cancer in 
patients infected with HIV. Effective antiviral therapy has produced a decline in the incidence of AIDS-
related KS, but HIV-infected individuals still have a 3,640-fold greater risk of developing KS than the 
uninfected population. In general, no imaging studies have been able to identify specific KS-involved 
tissues, apart from standard ultrasound and CT (computed tomography) imaging, in which therapy-
associated changes are implied to be associated with KS lesion shrinkage (1-4).  
KS lesions are comprised of KS spindle cells infected with HHV8/KSHV, as well as numerous 
macrophage antigen-expressing cells. Crucially, a large collection of both skin and visceral forms of 
KS were tested to determine whether the CD206 molecule would be present on both KS tumor cells 
and TAMs, allowing the potential for using Tc 99m tilmanocept as a tumor-specific imaging agent 
capable of identifying both tumor cells and TAMs in patients with KS.  
Historically, no imaging platform has been able to identify KS-specific lesions in patients with KS. 
This has caused problems for the delivery of clinical care, as physicians are unable to appropriately 
stage patients with KS, other than by tracking skin lesions. KS is known to involve lymph nodes and 
organs, but to date no approach has been able to confirm tumor involvement beyond skin. Our 
investigations have confirmed that the majority of both TAMs and KS cells express the macrophage 
marker CD206, the receptor for the tilmanocept imaging agent.  
The observation that tilmanocept binds specifically to CD206-positive macrophages has been extended 
to CD206-positive tissue from KS patients.  This performance makes tilmanocept an ideal agent for use 
in patients with KS to stage and quantitatively image tumor-specific response to therapy. By extension, 
other classes of tumors may be similar hybrid-like cells and may be imaged with tilmanocept and 
clinically addressed using macrophage-targeted therapy(5-15). 
1.2 
Preliminary Data 
As prelude to this clinical study, Navidea, in collaboration with Drs. Michael McGrath and Toby 
Maurer undertook an ex vivo assessment of the expression of macrophage markers in KS and the 
expression of CD206 and the determination of co-localization of these markers using a fluorescent 
congener of tilmanocept (Cy-3-tilmanocept; red fluorescence reporting). The results of this study are 
presented in Figure 1, Figure 2, and Figure 3(16). In summary, Cy3-tilmanocept binds to the KS lesions 
with high specificity and sensitivity and co-localizes with markers for HHV8, CD68, and CD163.  All 
of the evidence acquired in this assessment suggests that localization and imaging of not only primary 
KS lesions but disseminated KS disease will strongly localize Tc 99m tilmanocept.  In addition to the 
ex vivo study, Dr. Maurer completed a Phase 2 study, which confirmed that Tc 99m tilmanocept 
administered through a subcutaneous injection localized in KS lesions as well as lymph nodes. Thus, 
this receptor targeting approach to CD206 presents itself as a novel portal for imaging and staging KS.  
 


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Figure 1.  Macrophage CD206 Expression Permits Targeting of a Broad Range 
of Immuno-Inflammatory Disorders 
 
Figure 2.  Kaposi Sarcoma Tumor and Macrophages Express CD206 
 
 
Blue: Nuclear Stain 
Red: tumor cell HHV8 
Green: CD206 


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Figure 3.  Ex Vivo Tilmanocept Localization in Tumor Tissue from a KS Patient 
 
 
1.2.1 
Prior Experience of Tilmanocept Injection in KS Patients  
Imaging of KS with high specificity and sensitivity has been a remarkable challenge even with today’s 
high resolution technology and available imaging agents(17-29).  In addition to the ex vivo study, Dr. 
Maurer completed a phase II clinical pilot study in KS patients at the University of California San 
Francisco (UCSF Protocol 14-13522). Five subjects received a subcutaneous injection of 50 µg 
tilmanocept radiolabeled with 2.0 mCi Tc 99m. No subjects experienced any SAEs. Three AEs were 
reported in two subjects, including peripheral edema (probably not related to study drug or procedures) 
and fatigue and nausea (possibly related to study drug or procedures). No interaction of tilmanocept 
with HAART therapy or other drugs utilized in the treatement of HIV or HHV8 was observed.  
Tc 99m tilmanocept localized regionally in clinically confirmed KS lesions as well as lymph nodes, as 
shown in Figure 4. Thus, this receptor targeting approach to CD206 presents itself as a novel portal for 
imaging and staging KS. Based on this previous experience, it is anticipated that IV-administered Tc 
99m tilmanocept will be able to systemically localize both cutaneous and non-cutaneous (i.e. visceral 
or CNS) KS lesions.   


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Figure 4.  Localization of Tc 99m Tilmanocept in KS Lesions  
 
 
1.3 
Previous Experience with Tc 99m Tilmanocept 
A detailed evaluation of safety and efficacy data from nonclinical and clinical studies can be found in 
the accompanying Investigator’s Brochure supplied by Navidea Biopharmaceuticals, Inc. 
1.3.1 
Nonclinical Evaluations – IV and Intraperitoneal Administration 
Nonclinical studies with tilmanocept demonstrated that the drug selectively binds to its intended 
receptor (the MBR), is appropriately distributed for radio detection of lymphatic tissue, and is well 
tolerated by rats, rabbits, guinea pigs, and dogs. 
PK (pharmacokinetics) data obtained from SC repeated dose toxicity studies in rats and dogs 
demonstrated that absorption into the plasma was rapid in both species. Urinary excretion was a major 
pathway of elimination. A tissue distribution study demonstrated that tilmanocept exhibited rapid 
clearance from the injection site, rapid uptake by the local lymph node, and low uptake by the remaining 
lymph nodes. In addition, substantial accumulation was noted in the kidneys, bladder, and bladder 
contents by 3 hours post dose, providing additional evidence that urinary excretion occurs rapidly and 
is a major route of elimination. Tilmanocept was well tolerated at all doses tested in nonclinical safety 
pharmacology studies and in a number of 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) in the definitive repeated dose studies in rats and dogs was 42 μg/kg/day. 
Tilmanocept was not mutagenic or genotoxic in vitro (mouse lymphoma test, Ames test) or in vivo 
(mouse micronucleus test). No signs or symptoms of hypersensitivity were observed in an in vivo study 


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in male guinea pigs. Most of the nonclinical safety studies used SC drug administration, a proposed 
route for administration to humans. The human dose for clinical studies is 50 μg Tilmanocept per 
procedure, equivalent to 0.714 μg/kg if a conservative estimate of 70 kg is used for human body weight. 
The single dose administration in animals ranged from 14 to 280 μg/kg in animals, which is 
approximately 20 to 390 times the human μg/kg dose. Repeated doses in animals ranged from 10.5 to 
42 μg/kg/day in animals and are approximately 15 and 60 times the human μg/kg dose. These doses 
were all well tolerated in the nonclinical studies. 
Dosing in Dogs, Guinea Pigs and Mice: Intravenous (IV) dosing nonclinical studies represents 
cumulative dosing in male and female beagle dogs [eight dogs (4/sex; wt females= 7.6 kg;  wt males = 
10.5 kg ) given an IV injection of saline on Study Day (SD) 1 and 2 and DTPA-mannosyl-dextran at 
0.084 mg/kg on SD 4, 0.42 mg/kg on SD 6, and 0.84 mg/kg on SD 8 and 10] 1,560X the 50 µg and 
195X the 400 µg dose (female dogs) and 1706X the 50 µg dose and 213X the 400µg dose (male dogs).  
Based on the highest single dose administration (0.84 mg/kg) the dogs received 600X the 50 µg and 
75X the 400 µg dose (female dogs) and 657X the 50 µg and 82X the 400 µg dose (male dogs). [NOTE: 
In a separate dog study the dose was 0.56 mg/kg in 2 each male and female dogs of similar weight/sex), 
no effect was noted in that study, consistent with the higher dose dog study]. 
With regard to the sensitization test (IV administration in guinea pigs, wt = 0.415 kg) the maximum 
dose was the equivalent of 96X of the anticipated high dose tilmanocept. 
Lastly, although intraperitoneal administered in mice, based on the highest single dose administration 
(2000 mg/kg) the mice received 300,000 X the 50 µg and 37,500X the 400 µg dose (female mice, wt = 
22 gm) and 340,000X the 50 µg and 42,500X the 400 µg dose (male mice, wt = 29 gm). 
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 


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Type of Study / 
Description 
Test System 
Method of 
Administration 
Dosing 
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 
Ion Channel 
In vitro 
See Individual Tests Below 
K Ion Channel 
Ion Channel 
The cardiac potassium 
channel, hERG, is 
responsible for a rapid 
delayed rectifier current 
(IKr) in human ventricles. 
This channel has been 
selected for evaluation 
because inhibition of IKr 
is the most common cause 
of cardiac action potential 
prolongation by non-
cardiac drugs. In this 
assay, hERG potassium 
channels are expressed in 
a human embryonic 
kidney (HEK293) cell line 
that lacks endogenous 
IKr. 
0.025, 
0.05, 0.25, 
0.5 mg/mL 
Na Ion Channel 
Ion Channel 
Cloned hNav1.5 sodium 
channels (SCN5A gene 
expressed in CHO cells) 
0.025, 
0.05, 0.25, 
0.5 mg/mL 


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Type of Study / 
Description 
Test System 
Method of 
Administration 
Dosing 
Ca Ion Channel 
Ion Channel 
1. Cloned L-type calcium 
channels (hCav1.2, 
encoded by the human 
CACNA1C gene and 
coexpressed with the β2 
subunit, encoded by the 
human CACNB2 gene 
and the α2δ1 subunit 
encoded by the human 
CACNA2D1 gene in 
CHO cells), responsible 
for ICa,L, high threshold 
calcium current. 
2. Cloned hNav1.5 
sodium channels (SCN5A 
gene expressed in CHO 
cells). 
0.025-0.5 mg/mL 
 
 
Conclusions from these Tests: 
CNS: In conclusion, a single IV administration of tilmanocept was well tolerated in rats at levels of 
0.15, 0.75, and 1.50 mg/kg. Brief sedation shortly after dosing was observed at 0.75 and 1.50 mg/kg, 
which resolved by the time of the first functional observational battery assessments and was attributed 
to the mannosyl-dextran content of tilmanocept. There were no tilmanocept-related effects on 
functional observational battery parameters. 
Single Bolus Toxicity: Tilmanocept-related clinical pathology changes were limited to minimally 
greater, dose-related, aspartate aminotransferase values for 0.75 and 1.5 mg/kg males and females that 
were likely caused by muscle or erythrocyte release as changes did not occur in other hepatobiliary-
related clinical pathology parameters. This change had resolved at the end of the recovery phase. 
At the Day 2 necropsy, dark focus in the glandular stomach was considered to be a potential test article-
related gross pathology finding in males at ≥ 0.75 mg/kg. The gross finding of dark focus in the stomach 
correlated microscopically with focal erosion or minimal hemorrhage. Focal erosion in the stomach 
was test article related in males at ≥0.75 mg/kg, but was considered to be of little toxicological 
significance. No test article-related organ weight changes were noted.  At the end of the recovery phase 
(Day 15), there were no test article-related findings in gross pathology, organ weights, or 
histopathology. 
Respiratory: In conclusion, respiratory function was assessed in male Crl:CD(SD) rats given a single 
IV injection dose of vehicle control article or 0.150, 0.300, or 0.750 mg/kg of tilmanocept at a dose 
volume of 3 mL/kg.  Administration of tilmanocept had no effect on mortality, but it was associated 
with severe abnormal clinical observations of hypoactivity, ataxia, labored or irregular respiration, and 
pale skin of entire body for animals given 0.750 mg/kg.  Administration of >0.150 mg/kg tilmanocept 
had no direct effect on respiration rate, but it was associated with higher tidal volume (up to +26, +14, 
and +50% in animals given 0.150, 0.300, or 0.750 mg/kg, respectively) and higher minute volume (up 
to +18, +5, and +40% 0.5 through 1 hour post-dose in animals given 0.150, 0.300, or 0.750 mg/kg, 
respectively). 


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CYP:  This study was designed to independently evaluate the in vitro inhibitory effect of tilmanocept 
on major CYP enzymes in human liver microsomes. Specifically, the inhibition of CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 (utilizing two different substrates) by 
tilmanocept was assessed with the aim of ascertaining the potential of tilmanocept to inhibit the 
metabolism of concomitantly administered drugs. 
To evaluate tilmanocept as a direct, time-dependent and metabolism-dependent inhibitor of CYP 
activity, human liver microsomes from a pool of 200 human donor sources were incubated with marker 
substrates in the presence or absence of tilmanocept. To distinguish between time-dependent and 
metabolism-dependent inhibition, tilmanocept was preincubated with human liver microsomes for 30 
min without and with an NADPH-generating system, respectively, prior to the incubation with the 
marker substrate. Known direct and metabolism-dependent inhibitors of CYP enzymes were included 
as positive controls in all experiments. 
Under these experimental conditions, there was little or no evidence of direct, time- or metabolism-
dependent inhibition of any CYP enzyme by tilmanocept. 
ABC and SLC transporters: It was found that tilmanocept was not an inhibitor of  human transporters 
(namely P-gp, BRCP, OAT1B1, OATP1B3, OAT1, OAT3, and OCT2) under the conditions tested.  
Hemolysis: No hemolysis and no flocculation were observed following in vitro treatment of human 
whole blood with tilmanocept at final whole blood concentrations of 2.5, 25 or 250 μg/mL. 
Ion Channels (Na+, K+, Ca2+): Although there is a small dose-dependent effect that is fractional to 
the positive control, variability within concentration renders the median value observations not 
significantly different (Kruskal-Wallis). 
1.3.2 
Clinical Pharmacokinetics and Pharmacodynamics in Lymphatic Mapping 
Clinical Trials (Subcutaneous, Peritumoral and Intradermal administration) 
After a single peritumoral (PT), ID, or SC dose for solid tumor lymphatic mapping, Tc 99m tilmanocept 
demonstrated significantly faster injection site clearance than Tc 99m sulfur colloid (TcSC, filtered and 
unfiltered), the standard imaging agent and comparator used in the Phase 1 trials. 
The mean Tc 99m tilmanocept injection site clearance half-life was approximately 2 to 3 hours vs. 
approximately 15 to 27 hours for TcSC. Absolute uptake in the primary “sentinel” lymph node (LSN) 
was dose-related for Tilmanocept, although relative nodal uptake (%IDSN) overall was independent of 
dose and ranged from 0.05%IDSN to 1.81%IDSN, while the TcSC values ranged from 0.64%IDSN to 
3.66%IDSN; differences between Tc 99m tilmanocept and TcSC were not statistically significant. 
In the Phase 2 trial, Tc 99m tilmanocept was highly effective in identifying tumor-draining lymph nodes 
(i.e., overall, a “hot spot” from Tc 99m tilmanocept was identified in 93.0% of patients for whom 
preoperative lymphoscintigraphy was performed, and the per patient intraoperative localization rate 
was 96.2%). Diagnostic performance of in vivo Tc 99m tilmanocept findings relative to pathology 
assessment of tumor tissue indicated a high per tissue sensitivity estimate (overall, 92.0%). The overall 
false negative rate (FNR) for pathology was 8.0%, supporting the accuracy of Tc 99m tilmanocept in 
identifying lymph nodes with a high potential for containing tumor metastases in the lymphatics 
draining the tumor bed. The effect of time between Tc 99m tilmanocept injection and surgery on the 
localization rate was also evaluated, with surgeries done either on the same day as the Tc 99m 
tilmanocept injection or on the following day. In patients with melanoma, the time interval made no 
difference in the localization rate. In patients with breast cancer, the same day surgery group had a 


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95.5% (21 out of 22 patients) localization rate compared with 88.9% (8 of 9 patients) in the next-day 
surgery group, although the difference is not statistically  significant (p = 0.5032, Fisher’s exact test) 
and can be attributed to the small number of breast cancer patients in the next day surgery group, and 
not the time between injection and surgery. 
1.3.3 
Clinical Efficacy in Lymphatic Mapping/Sentinel Node Mapping Clinical 
Trials 
Clinical efficacy was evaluated in two pivotal Phase 3 clinical trials in patients with breast cancer and 
melanoma, comparing lymph node detection of Tc 99m tilmanocept and with the FDA-approved 
intraoperative Tc 99m tilmanocept mapping (ILM) agent and standard-of-care, vital blue dye (VBD). 
Tc 99m tilmanocept demonstrated a statistically significant concordance rate with VBD (meta-analysis 
concordance rate = 99.99%, p < 0.0001). 
The detection concordance between Tc 99m tilmanocept and VBD was similar among patients with 
melanoma and patients with breast cancer (meta-analysis concordance rate = 99.99% for both 
populations). Tc 99m tilmanocept also demonstrated a higher sensitivity for detecting tumor-positive 
(as confirmed by pathology) lymph nodes, corresponding to a decreased FNR when compared with 
VBD on a per node basis. The corresponding sensitivity rate in detection of lymph nodes most likely 
to be positive for tumor cells for Tc 99m tilmanocept was 99.99%, compared with 78.02% for VBD. 
The FNR for VBD (21.98%) was higher than the FNR for Tc 99m tilmanocept (0.01%). These findings 
suggest that, when VBD is used as the imaging agent, there is an increased risk of missing the detection 
of tumor-involved lymph nodes and incorrectly staging cancer patients. The Tc 99m tilmanocept-only 
findings (pathology-positive nodes that were hot/not blue) suggest that Tc 99m tilmanocept was 
markedly more effective in identifying lymph nodes that harbored disease than was VBD. Clinical 
safety has been evaluated in an integrated analysis of the pooled safety population (506 patients) from 
six completed trials and one ongoing clinical trial. No on-study deaths in Tc 99m tilmanocept -treated 
patients have occurred in this population. Twenty-seven serious adverse events (SAEs) have been 
reported for 26 patients across all Tilmanocept studies. None of the SAEs were attributed to the use of 
Tc 99m tilmanocept. No patients were withdrawn from any study due to an SAE or adverse event (AE). 
No clinically significant safety event associated with the use of Tc 99m tilmanocept has been reported 
in the clinical trials. 
1.3.4 
Clinical Safety using Intradermal, Subcutaneous, Peritumoral, and 
Intravenous Injections 
Non-IV Experience - Well over 250,000 patients in clinical trials and US commercial use for 
intraoperative lymphatic mapping (ILM) with sentinel lymph node biopsy (SLNB) have been exposed 
to tilmanocept, and there have been no safety signals, no deaths due to drug, and no SAEs due to 
tilmanocept. There are no known drug interactions leading to contraindications with the use of 
tilmanocept. Post-marketing reports have shown less than 0.12% of subjects experiencing AEs, with 
the most common one being lack of node localization. 
IV Experience - Navidea is currently conducting disease imaging studies in patients with rheumatoid 
arthritis (RA), nonalcoholic steatohepatitis (NASH), colorectal cancer (CRC) with metastases to the 
liver, and cardiovascular disease (CVD) utilizing Tc 99m tilmanocept administered IV. Dosages consist 
of 50, 100, 200 or 400 µg of tilmanocept labeled with 1, 2, 5, or 10 millicurie(s) (mCi) of 99mTc injected 
IV.  At the time of this writing, sixty (60) subjects have received IV administration of Tc 99m 
tilmanocept.  No subject has exhibited any adverse reaction to the drug that was related to the drug.   
 


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2 
TRIAL OBJECTIVES 
2.1 
Primary Objective(s)  
To determine the safety of escalating IV doses of Tc 99m tilmanocept in HIV subjects with biopsy-
confirmed KS. 
 
2.2 
Secondary Objective(s)  
• 
Concordance between clinical assessment/diagnosis and the localization of Tc 99m 
tilmanocept by planar and/or SPECT/CT imaging in cutaneous and non-cutaneous sites of 
KS. 
• 
Qualify and quantify Tc 99m tilmanocept localization intensity on imaging with CD206 
locale and quantity by histology and IHC in biopsied KS lesions to determine optimal IV 
dose.   
• 
Concordance of localization of Tc 99m tilmanocept via IV and SC routes of administration 
by planar and/or SPECT/CT imaging in cutaneous and non-cutaneous sites of KS. 
 
2.3 
Exploratory Objective(s) 
• 
Quantify HHV8 in biopsied KS lesions by qPCR 
 
 


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3 
OVERVIEW OF METHODOLOGY AND DESIGN 
3.1 
Overall Trial Design 
This is a prospective, single-center, open-label, non-randomized, dose escalation, comparative, safety 
study of IV and SC injected Tc 99m tilmanocept in the localization and detection of cutaneous and non-
cutaneous KS lesions in subjects with biopsy-confirmed KS. This study includes IV administration of  
3 doses Tc 99m tilmanocept: 100µg/ 5 mCi, 100 µg/ 10 mCi and 200µg/ 5 mCi. All subjects will receive 
IV administration at one of these three doses. Cohort 3 will serve as a comparator arm, and Cohort 3 
subjects will additionally receive a SC injection of Tc 99m tilmanocept at the Cohort 3 dose of 200µg/ 
5 mCi . Following IV injection of Tc 99m tilmanocept, all subjects will have whole body planar imaging 
with optional SPECT/CT imaging beginning 60-75 minutes post-IV injection.  Following SC injection 
of Tc 99m tilmanocept, Cohort 3 subjects will undergo whole body planar imaging with optional 
SPECT/CT imaging twice: first beginning  60-75 minutes after SC injection , and again 4-6 hours post-
SC injection. The Schedule of Events, Appendix 1, contains a list of all study procedures and time-
points. Study activities are described in detail in Section 7. 
3.2 
Justification for Study Design and Population 
This study is designed to evaluate the safety and tolerability of escalating doses of IV Tc 99m 
tilmanocept and to compare results obtained from IV and SC administrations of Tc 99m tilmanocept in 
the same subjects. Whole body planar imaging will be utilized, as well as optional SPECT/CT to 
provide greater resolution of areas of Tc 99m tilmanocept localization.   
This study is designed to evaluate the use of Tc 99m tilmanocept as an imaging agent in HIV-positive 
subjects with biopsy-confirmed KS by evaluating the localization in known and unknown cutaneous 
and non-cutaneous lesions.   
No prior clinical trials have been conducted to evaluate IV administration of Tc 99m tilmanocept 
performance in subjects with KS. One previous clinical trial was conducted to evaluate SC 
administration of Tc 99m tilmanocept performance in subjects with KS. The rationale for evaluating 
Tc 99m tilmanocept in this subject population is discussed in Section 1.1 and Section 1.2.  
3.3 
Protocol Adherence 
Strict adherence to all specifications outlined in this protocol is required for all aspects of the study 
conduct; the investigator may not modify or alter the procedures described in this protocol. If protocol 
modifications are necessary, all alterations that are not solely of an administrative nature require a 
formal protocol amendment for the involvement of the Institutional Review Board(s) (IRB(s)). 
If an investigator has deviated from the protocol in order to eliminate an immediate hazard to subjects 
or for other inevitable medical reasons, the investigator shall document all such deviations, including 
the reasons thereof, and submit the document to the sponsor and the head of the medical institution as 
applicable. 
3.4 
Trial Duration 
Subjects will be “on trial” for up to 50 days. 


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4 
STUDY POPULATION 
The evaluation of Tc 99m tilmanocept in KS will involve up to 14 enrolled, injected, and imaged 
subjects. 
4.1 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study. 
1. The subject has provided written informed consent with HIPAA authorization before the 
initiation of any study related procedures. 
2. The subject is at least 18 years of age at the time of consent. 
3. The subject is HIV positive. 
4. The subject has a biopsy-confirmed diagnosis of KS and is classified into one of the categories 
below: 
a. Confirmed cutaneous KS/oral lesions without edema 
b. Confirmed cutaneous KS/oral lesions with edema 
c. Confirmed cutaneous KS/oral lesions with or without edema and suspected non-cutaneous 
KS due to clinical symptomology or confirmed non-cutaneous KS lesion(s). 
 
4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. The subject is pregnant or lactating. 
2. The subject has received chemotherapy or radiation therapy to KS sites within six weeks of 
enrollment. 
3. The subject has known sensitivity to dextran. 
4. The subject has received an investigational product within 30 days prior to the Tc 99m 
tilmanocept administration on Day 1. 
5. The subject has received any radiopharmaceutical within 7 days prior to the administration of 
Tc 99m tilmanocept on Day 1. 
6. Any condition that, in the clinical judgment of the treating physician, is likely to prevent the 
subject from complying with any aspect of the protocol or that may put the subject at 
unacceptable risk. 
 
4.3 
Kaposi Sarcoma Classification 
All subjects will have a biopsy-confirmed diagnosis of  KS prior to screening.  Subjects will be 
classified into 1 of 3 categories: a) confirmed cutaneous/oral lesions without edema, b) confirmed 
cutaneous/oral lesions with edema, or c) confirmed cutaneous/oral lesions with or without edema and 
suspected non-cutaneous KS due to clinical symptomology or confirmed non-cutaneous lesions.   


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4.4 
Recruitment 
Up to fourteen (14) evaluable subjects will be recruited from medical practice in accordance with the 
inclusion and exclusion criteria listed above. Potentially suitable subjects will be asked by the treating 
specialist about their willingness to participate in this trial. An assessment of safety and preliminary 
localization results will occur at the completion of each cohort. Up to fourteen (14) subjects will be 
enrolled, injected, and imaged.  
4.5 
Withdrawal 
In accordance with the Declaration of Helsinki, each subject is free to withdraw from the trial at any 
time and without providing a reason. 
A subject who withdraws consent prior to arrival at the study site on Day 1 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.   
The investigator may withdraw a subject from the trial 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 
 
4.6 
Enrollment and Screen Failures 
Subjects who sign an informed consent form (ICF) but are ultimately not enrolled in the trial will be 
considered screen failures. Subjects will be assigned a subject identification number at the time the ICF 
is signed. A subject will be considered enrolled once injected with technetium Tc 99m on Day 1. 
Demographic data and the reason for the screen failure will be collected for all screen failure subjects.  
Enrollment will continue until a total of up to 14 subjects have completed planar imaging.   
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: Trial number 24  
Digits 3 to 4: Site number (e.g., “01”)  
Digits 5 to 7: Sequential subject number (e.g., “001”, “002”, “003”)  


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For example, the first subject consented at site 01 is subject number “24-01-001.”  
Subjects will maintain the same number given at screening for the entire trial. If a subject is a screen 
failure, the number will not be used for any other subject. 


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5 
INVESTIGATIONAL PRODUCT 
5.1 
Identification of Investigational Product 
Tc 99m tilmanocept is a radiopharmaceutical that accumulates in KS lesions and lymphatic tissue by 
binding to mannose binding receptors (CD206) that reside on the surfaces of dendritic cells and 
macrophages.  
5.2 
Investigational Product Dosage and Administration 
This study includes IV administration of  3 doses Tc 99m tilmanocept: 100µg/ 5 mCi, 100 µg/ 10 mCi, 
and 200 µg/ 5 mCi. All subjects will receive IV administration at one of these three doses. Cohort 3 
will serve as a comparator arm, and Cohort 3 subjects will additionally receive a SC injection of Tc 
99m tilmanocept at the Cohort 3 dose of 200 µg/ 5 mCi (see Table 1). At least one subject enrolled into 
each cohort must meet inclusion criteria 4c (suspected non-cutaneous or confirmed non-cutaneous KS), 
as described in Section 4.1. 
Table 1.  Dosing Cohorts 
 
Tc 99m 
tilmanocept 
Dose 
Route of 
Administration 
Number of 
Subjects 
Cohort 1 
100 µg/ 5 mCi 
IV 
n = 4 
Cohort 2 
100 µg/ 10 mCi 
IV 
n = 4 
Cohort 3 
200 µg/ 5 mCi 
IV and SC 
n = up to 6 
 
All subjects will receive Tc 99m tilmanocept through an IV route of administration. A single syringe 
will be used and injected as a slow push into the venous catheter. The preferred site of catheter 
placement will be the left or right antecubital vein. Injection volume will be 1.0 mL in sterile normal 
saline. At the completion of the injection, a 10 cc sterile normal saline flush will be administered. 
Cohort 3 subjects will also receive Tc 99m tilmanocept through a SC route of administration. Two 
syringes will be used and injected bilaterally as a slow push into the ankle(s) or the dorsal surface of 
the foot (feet). Total injection volume will be 1.0 mL (0.5 in each syringe) in sterile normal saline.  
Each syringe will contain half of the intended total dose of 200 µg/ 5 mCi (100 µg/ 2.5 mCi per syringe).  
 
5.3 
Treatment Assignment 
In this prospective, single center, open-label, non-randomized, dose-escalation, comparative, safety 
study, Cohort 1 subjects will receive an IV administration of 100 µg/ 5 mCi Tc 99m tilmanocept. Cohort 
2 subjects will receive an IV administration of 100 µg/ 10 mCi Tc 99m tilmanocept. Cohort 3 subjects 
will receive a SC and an IV administration of 200 µg/ 5 mCi Tc 99m tilmanocept approximately one 
week apart. Cohort 1 will be the starting dose group. Four subjects will be enrolled into Cohort 1.  
If one of the four Cohort 1 subjects experiences a noxious pharmacologic activity/an ADR, two more 
subjects will be treated at the same tilmanocept mass dose and same radiolabel level as the subject with 
the ADR. If 2 out of 4 or 3 out of 6 subjects experiences a noxious pharmacologic activity/an ADR in 


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Cohort 1, the maximum tolerated dose (MTD) cannot be determined. If no additional noxious 
pharmacologic activities/ADRs are observed in the expanded cohort, the dose escalation will continue 
with Cohort 2. If one additional noxious pharmacologic activity/ADR is observed, the current dose will 
be deemed the MTD. If more than one additional pharmacologic activity or ADR is observed in the 
expanded cohort, the previous dose will be deemed the MTD.  
If no noxious pharmacologic activities/ADRs are experienced in Cohort 1, Cohort 2 will be open for 
enrollment. 
Dose escalation will continue until the MTD is found or until Cohort 3 is reached with only one ADR 
or without any ADRs. The maximum tolerated dose is defined as the highest dose level at which no 
more than 33% of subjects experienced an ADR. Visual representation of the dose escalation scheme 
may be found in Appendix 2.  
NOTE: Adverse Drug Reaction 
An Adverse Drug Reaction (ADR) includes all noxious and unintended responses to a medicinal 
product related to any dose or dose regimen. The phrase “responses to a medicinal product” means 
that a casual relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e. the relationship cannot be ruled out. 
5.4 
Packaging and Labeling 
Tilmanocept cartons ready for radiolabeling will be shipped and stored at the region-specific Cardinal 
Health radiopharmacy.  Tilmanocept is provided in a vial. Vials are packaged as a kit. A carton contains 
five vials of tilmanocept. One kit, which is one tilmanocept vial, should be used for no more than one 
subject. The carton also contains five shield labels and 25 syringe labels. This package has been 
designed specifically for tilmanocept and protects the vials during shipment, handling, and storage.  
Navidea will provide a radiolabeling protocol and Quality Control worksheets. Cardinal Health will 
radiolabel tilmanocept with the protocol cohort specified tilmanocept dose and the cohort assigned 
millicurie dose Tc 99m in 1.0 mL and deliver one syringe for IV doses and two syringes (0.5 mL each) 
for SC doses to the clinical site that is/are ready for administration. 
5.5 
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 trial and in 
accordance with this study protocol.  For each subject, he/she will keep a record of the investigational 
product dispensed and all other accompanying forms to the investigational product.  These documents 
are to be filed in the ISF. 
Overall drug accountability and reconciliation will be completed by the sponsor or its representative.  
A list of investigational product vials and other materials that were returned, or destroyed, must be 
recorded and signed by the principal investigatior (PI) or an appropriately qualified designee as 
documented in the study site responsibility sheet.  Each time the investigational product is dispensed 
to a subject, the following information should be recorded on the Drug Accountability Log: subject 
number, radiolabel date, and the date delivered to nuclear medicine.  At the completion or termination 
of the trial, a final drug accountability review and reconciliation must be completed and any 
discrepencies must be investigated and their resolution documented.  All unused trial kits will be 
destroyed in accordance with institutional destruction procedures.  


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6 
THERAPIES OTHER THAN INVESTIGATIONAL PRODUCT 
6.1 
Prior and Concomitant Therapy 
All medications taken 30 days prior to Visit 2 (Day 1) Tc 99m tilmanocept injection through the  
Follow-Up Phone Call will be documented.  
6.2 
Post-Study Therapy  
There are no post-study therapy restrictions. 


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7 
STUDY PROCEDURES 
Cohorts 1, 2, and 3: 
7.1 
Screening Visit (within 30 days of Day 1 injection) 
• Obtain signed informed consent for study participation 
• Preliminary review of inclusion and exclusion criteria 
• Allocation of unique subject number; this number will be used to document the subject data in the 
case report forms (CRFs) and enrollment log 
• Interview including the following subject-specific characteristics: 
- 
Demographic data - 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 Day 1 injection). 
• Vital signs (body temperature, heart rate, blood pressure, and respiratory rate after at least 1 
minute in a resting position). 
• Electrocardiogram (ECG); subjects will either have a normal ECG or an abnormal ECG deemed 
not clinically significant by the PI.  
• Blood draw for routine hematology, chemistry, serum 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.  
• Urine collection for routine urinalysis. 
• Physical examinations will include assessment of height and 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. 
• Assessment of edema/lymphedema, utilizing a pitting edema scale as provided in Appendix 3, 
will be performed.  
• KS history and classification. 
• KS Lesion Assessment: 
• Cutaneous KS evaluation: All cutaneous lesions will be identified, documented, and 
photographed during the screening exam. Photographs will be collected per the photography 
protocol currently in use within the Department of Dermatology at UCSF, as provided in 
Appendix 4. 
• Non-cutaneous KS evaluation: Confirmed based on specific appropriate tests or suspected 
based on clinical symptomology. Non-cutaneous lesions will be identified and documented.  


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Changes in health occurring after consent and prior to the day of injection will be added to the 
subject’s medical history unless related to a study procedure. 
Cohorts 1 and 2: 
7.2 
Day 1 (IV Injection) 
7.2.1 
Before Injection 
• Assessment of adverse events 
• Concomitant medication review 
• A negative urine pregnancy test for women of child-bearing potential within 48 hours of 
injection.   
• Final check of inclusion/exclusion criteria 
• Vital signs (body temperature, heart rate, systolic and diastolic blood pressure, and respiratory 
rate within 30 minutes prior to investigational product injection, after at least 1 minute in a resting 
position) 
7.2.2 
IV Administrstion of Tc 99m tilmanocept 
IV administration of Tc 99m tilmanocept will be at study time 00:00. The preferred site of IV placement 
will be the left or right antecubital vein.   
Tc 99m tilmanocept shall be administered through the catheter as a slow IV push followed by a 10 cc 
sterile normal saline flush. The injection will be performed in the nuclear medicine department by an 
onsite Certified Nuclear Medicine Technologist or Nuclear Medicine Physician.  
7.2.3 
Post-Injection 
The following procedures will be completed at the specified timepoints: 
• 
0-30 Minutes Post-Injection 
o ECG (completed before vital signs) 
o Vital signs (body temperature, heart rate, systolic and diastolic blood pressure, and 
respiratory rate) will be collected  
o Assessment of adverse events 
• 
60-75 Minutes Post-Injection  
o Assessment of adverse events 
o Whole body planar imaging  
o Optional SPECT/CT region(s) of interest imaging 
• 
After the 60-75 Minute Imaging:  
 
Clinical labs and urinalysis will be performed. 
 
A KS tissue biopsy will be taken of an imaging-visualized non-visceral 
lesion 


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 
If no lesion is visualized on imaging, a lesion of at least 5-6 mm in a 
clinically accessible area will be biopsied as chosen by the 
Investigator(s) who will record selection and rationale 
 
A photograph of the biopsy site with a measurement scale must be 
taken and stored with the subject’s research chart 
 
7.3 
Follow-Up Telephone Call (7±3 days after Tc 99m tilmanocept 
injection) 
• Concomitant medication review  
• Assessment of adverse events 
Cohort 3: 
7.4 
Day 1 (SC Injection) 
7.4.1 
Before Injection 
• Assessment of adverse events 
• Concomitant medication review 
• A negative urine pregnancy test for women of child-bearing potential within 48 hours of 
injection.   
• Final check of inclusion/exclusion criteria 
• Vital signs (body temperature, heart rate, systolic and diastolic blood pressure, and respiratory 
rate within 30 minutes prior to investigational product injection, after at least 1 minute in a resting 
position) 
7.4.2 
SC Administrstion of Tc 99m tilmanocept 
SC administration of Tc 99m tilmanocept will be at study time 00:00. The preferred site of SC injection 
placement will be the ankle(s) or the dorsal surface of the foot (feet). 
The injection will be performed in the nuclear medicine department by an onsite Certified Nuclear 
Medicine Technologist or Nuclear Medicine Physician.  
7.4.3 
Post-Injection 
The following procedures will be completed at the specified timepoints: 
• 
0-30 Minutes Post-Injection 
o ECG (completed before vital signs) 
o Vital signs (body temperature, heart rate, systolic and diastolic blood pressure, and 
respiratory rate) will be collected  
o Assessment of adverse events 
• 
60-75 Minutes Post-Injection  


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o Assessment of adverse events 
o Whole body planar imaging  
o Optional SPECT/CT region(s) of interest imaging 
• 
4-6 Hours Post-Injection  
o Assessment of adverse events 
o Whole body planar imaging  
o Optional SPECT/CT region(s) of interest imaging 
• 
After the 4 – 6 Hour Imaging:  
 
Clinical labs and urinalysis will be performed. 
 
7.5 
Day 7 ± 3 (IV Injection) 
7.5.1 
Before Injection 
o Follow-up assessment from SC injection including changes in concomitant 
medication and adverse events  
• A negative urine pregnancy test for women of child-bearing potential within 48 hours of 
injection.   
• Final check of inclusion/exclusion criteria 
• Vital signs (body temperature, heart rate, systolic and diastolic blood pressure, and respiratory 
rate within 30 minutes prior to investigational product injection, after at least 1 minute in a resting 
position) 
7.5.2 
IV Administrstion of Tc 99m tilmanocept 
IV administration of Tc 99m tilmanocept will be at study time 00:00. The preferred site of IV placement 
will be the left or right antecubital vein.   
Tc 99m tilmanocept shall be administered through the catheter as a slow IV push followed by a 10 cc 
sterile normal saline flush. The injection will be performed in the nuclear medicine department by an 
onsite Certified Nuclear Medicine Technologist or Nuclear Medicine Physician.  
7.5.3 
Post-Injection 
The following procedures will be completed at the specified timepoints: 
• 
0-30 Minutes Post-Injection 
o ECG (completed before vital signs) 
o Vital signs (body temperature, heart rate, systolic and diastolic blood pressure, and 
respiratory rate) will be collected  
o Assessment of adverse events 
• 
60-75 Minutes Post-Injection  
o Assessment of adverse events 
o Whole body planar imaging  
o Optional SPECT/CT region(s) of interest imaging 


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• 
After the 60-75 Minute Imaging:  
 
Clinical labs and urinalysis will be performed. 
 
A KS tissue biopsy will be taken of an imaging-visualized non-visceral 
lesion 
 
If no lesion is visualized on imaging, a lesion of at least 5-6 mm in a 
clinically accessible area will be biopsied as chosen by the 
Investigator(s) who will record selection and rationale 
 
A photograph of the biopsy site with a measurement scale must be 
taken and stored with the subject’s research chart 
 
7.6 
Follow-Up Telephone Call (7±3 days after IV Tc 99m tilmanocept 
injection) 
• Concomitant medication review  
• Assessment of adverse events 
7.7 
Imaging and Acqusition of Imaging Data 
Imaging will be a whole body planar scan followed by optional SPECT/CT region(s) of interest scan 
beginning at 60-75 minutes post-IV injection (all Cohorts) and 60-75 minutes and 4-6 hours post-SC 
injection (Cohort 3 only).   
7.8 
Image Acqusition 
The same scanner should be used during the entire course of the study and any updates to hardware or 
software should be avoided.  If changes occur, they must be reported to the sponsor. Whole body planar 
with optional SPECT/CT images will be obtained from each subject at the 60-75 minute post-injection 
timepoint following IV injection (all Cohorts) and at the 60-75 minute and 4-6 hours post-injection 
timepoints following SC injection (Cohort 3 only).  
7.9 
Evaluation of Planar and SPECT Images 
Tc 99m tilmanocept localization in cutaneous and non-cutaneous lesions will be evaluated through  
image analysis by the onsite Nuclear Medicine physician. First, an assessment of the overall technical 
adequacy of the scan will be made. Following the technical assessment, an overall assessment of the 
scan will be made. For each subject, the de-identified planar images and SPECT/CT scans (in DICOM 
[digital imaging communications in medicine] format) will be forwarded to the sponsor. 
7.10 End of Study 
For the entire study, end of study is defined as the follow-up telephone call. 


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8 
PROCEDURES AND VARIABLES 
8.1 
Population Characteristics 
8.1.1 
Demographic and Other Baseline Characteristics 
Up to fourteen (14) HIV-positive female or male subjects ≥ 18 years that have been diagnosed with 
biopsy-confirmed KS will be enrolled, injected, and imaged.  There are no minimum or maximum 
numbers for gender in the cohorts.  
8.1.2 
Medical and Surgical History 
Relevant medical and surgical histories, specifically for HIV and KS, 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. 
8.1.3 
Prior and Concomitant Medication 
All prior medications used within the last 30 days before Visit 2 (Day 1) Tc 99m tilmanocept 
administration through the Follow-Up Call will be documented. 
8.2 
Tc 99m Tilmanocept Preparation and Administration 
Based on the dose cohort the subject is enrolled in, the dose of Tc 99m tilmanocept should be ordered 
from Cardinal Health once the subject has been scheduled for imaging. 
In Nuclear Medicine, prior to IV injection and imaging, an indwelling catheter will be placed for venous 
access. The preferred site of IV placement should be the left or right antecubital vein. Other IV access 
sites are acceptable if access is problematic. 
The filled syringe will be connected to the catheter for a slow push injection. Immediately after the 
completion of the injection, a 10 cc sterile normal saline flush will be administered. Injection of Tc 99m 
tilmanocept will be at study time 0:00. 
For SC injection, the preferred site of placement is the ankle(s) or the dorsal surface of the foot (feet). 
Approximately 0.5 mL of the 1.0 mL prepared injection shall be administered to each the left and right 
leg. Injection of Tc 99m tilmanocept will be at study time 0:00. 
8.3 
SPECT/SPECT-CT Image Acquisition  
The camera used to obtain the images should be a 2-headed SPECT or SPECT/CT camera equipped 
with a low-energy, high-resolution collimator with a 15% window (20% can be used if 15% setting not 
available) centered over a 140keV peak.   
The camera must have passed the daily SPECT QC (quality control) tests as per the manufacturer’s 
recommendation for that day’s scan schedule. 
Whenever possible, subject should be asked to void after injection and prior to the imaging session.  


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Subjects should be positioned supine with arms at their side. The subject’s head, legs, hands, and hips 
should be in the true anterior position. The subject should be instructed to remain as motionless as 
possible during the scan and asked to breathe as shallowly as comfortable when the camera is passing 
over the chest. To help minimize leg motion, a light tape around the ankles can be used to keep the legs 
together. A pillow under the knees is often very helpful for comfort. 
A whole body planar scan should be obtained at the following time points: 
• 60-75 minutes post-IV/SC administration 
• 4-6 hours post-SC injection 
 
Optional SPECT/CT region(s) of interest scan(s) can be obtained at the following time points: 
• 60-75 minutes post-IV/SC administration 
• 4-6 hours post-SC injection 
 
It is anticipated that the whole body planar scan would be acquired first for 25-30 minutes. Using  a 2-
headed camera (nominal 20” x 15” FOV [field of view]) a target of 5-7 million counts should be 
obtained for the summed view of both heads. For the higher activity injections, it may be possible to 
attain this target in a shorter time, allowing the subject more time off the bed between scans. 
Following the whole body scan, optional SPECT/CT region(s) of interest scan(s) can be obtained.  It is 
anticipated that a SPECT/CT scan would be acquired over 25-30minutes. The use of a calibration 
syringe for each SPECT scan is not necessary. It is very important that the subject remain motionless 
for the duration of the complete SPECT/CT scan. 
SPECT/CT slices will be reconstructed using the manufacturer’s recommended reconstruction 
algorithms including the recommended attenuation correction. 
It is strongly recommended that each site should perform all imaging acquisitions per their camera 
manufacturer and model parameters and in accordance with their institutional practices for both the 
whole body scan as well as the SPECT/CT imaging. 
De-identified DICOM copies of all acquired images will be transmitted to Navidea Biopharmaceuticals. 
The areas of localization will be identified, documented and captured in the eCRFs. 
8.4 
Post-Injection and Imaging Biopsy Acquisition  
The purpose of the KS lesion biopsy will be to determine the proportion of CD206-expressing cells and 
quantitiy of CD206 (IHC fluorescence) in KS tissues in parallel with an analysis of KS imaged with Tc 
99m tilmanocept. A non-visceral site of KS for biopsy post-imaging in each subject will be chosen by 
the Nuclear Medicine physician based on visualized localization and lesion size. If no lesion is 
determined to localize Tc 99m tilmanocept, a lesion of at least 5-6 mm in a clinically accessible area 
will be biopsied as chosen by the Investigator(s) who will record selection and rationale. 
All subjects will receive the biopsy on the day of IV Tc 99m tilmanocept administration at the 
completion of imaging.  


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A biopsy up to 6mm of the designated lesion will be taken, and a photograph of the biopsy site with a 
measurement scale will be taken and stored with the subject’s research chart. The tissue will be obtained 
at the completion of Tc 99m tilmanocept IV injection and imaging and delivered on ice to the 
Department of Pathology at Zuckerberg San Francisco General Hospital. The biopsy will be sectioned 
into a formalin-fixed paraffin-embedded (FFPE) segment and a fresh or frozen segment to be used for 
other analyses.  FFPE tissue sections will be quantified for CD206 and LANA through a standardized 
quantitative image analysis program. HHV8 will be quantified by qPCR. 
8.5 
Pharmacokinetics 
No pharmacokinetic investigation will be performed in this study.  
8.6 
Safety  
8.6.1 
Adverse Events 
8.6.1.1 
Definition of Adverse Event 
The definitions below follow International Conference on Harmonization (ICH) – Good Clinical 
Practice (GCP) (see also ICH Guideline for Clinical Safety Data Management:  Definitions and 
Standards for Expedited Reporting). 
Adverse Event (AE) 
An AE is defined as any untoward medical occurrence in a subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product.  
Any clinically significant change in a condition (worsening) from screening that results in a change in 
subject management will be considered an AE and will be recorded on the AE page of the CRF. 
By definition for this study, all untoward medical occurrences beginning on the day of Visit 2 Baseline 
(Day 1) through the Follow-up Phone Call 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. 
8.6.1.2 
Categories for Adverse Event Assessment 
All AEs will be assessed and documented by the investigator according to the categories detailed below. 
Seriousness 
For each AE, the seriousness must be determined according to the criteria given in Section 8.6.1.5. 


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Severity 
The severity of an AE is classified according to the following categories, taking into account the 
possible range of the intensity of the event: 
• Mild - 
The AE is transient and easily tolerated by the subject. 
• Moderate -  
The AE causes the subject discomfort and interrupts the subject’s usual 
activities. 
• Severe -  
The AE causes considerable interference with the subject’s usual activities and 
may be incapacitating or life-threatening. 
 
Specific drug treatment 
Any specific drug treatment will be documented.  
Causal relationship to investigational product 
The investigator will use the following definitions to assess the relationship of the adverse event to the 
use of investigational product:  
Definitely related: 
Event can be fully explained by administration of the investigational 
product. 
Probably related: 
Event is most likely to be explained by administration of the 
investigational product rather than the subject’s clinical state or other 
agents/therapies. 
Possibly related: 
Event may be explained by administration of the investigational product 
or by the subject’s clinical state or other agents/therapies. 
Probably not related: 
Event is most likely to be explained by the subject’s clinical state or other 
agents/therapies, rather than the investigational product. 
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 the 
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. 


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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. 
8.6.1.3 
Assessments and Documentation of Adverse Events 
Attention shall be paid to the occurrence of AEs for the duration of subject participation. Events 
occurring prior to Visit 2 (day of Tc 99m tilmanocept administration) will be recorded in the subject’s 
medical history unless determined to be related to the study procedure. Untoward medical events 
beginning on Visit 2 (day of Tc 99m tilmanocept administration) through the completion of the Follow-
up Phone Call will be reported as adverse events.  Thus, subjects should be closely observed by the 
investigator both during and after the evaluation.   
Any AE (observed, volunteered, or elicited) should be recorded in detail in the source documentation. 
The following information is required: 
• The date and time of onset of any AE. 
• The duration (the entire duration of an event or symptom, calculated from date of onset to 
date of end, if not recorded directly). 
• The seriousness of the AE will be assessed by the investigator.  If the investigator deems that 
an AE qualifies as an SAE, a special form provided by the sponsor should be completed and 
the event must be immediately reported to the sponsor.  A definition of SAEs is provided in 
Section 8.6.1.5.  
• 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]). 


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8.6.1.4 
Expected Adverse Events 
Investigational Product-Related Risks 
In all completed studies of Lymphoseek involving 553 subjects, only three 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%).  
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 include subcutaneous, intradermal, and peritumoral.  
In Tc 99m tilmanocept trials for indications beyond lymphatic mapping and SLNB, there have been 
approximately 20 SC and 60 IV administrations of Tc 99m tilmanocept, and no SAEs or ADRs have 
been reported to date.  
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. 
 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. 
8.6.1.5 
Serious Adverse Events 
Definition of Serious Adverse Events 
Definition 
The following SAE definition is based on ICH guidelines and the final rule issued by the Food and 
Drug Administration (FDA) and effective 06 Apr 1998.   
An SAE is classified as any untoward medical occurrence that at any dose: 
• results in death, or 


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• 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 one day (i.e., within 24 hours) of becoming aware of the 
SAE. Written notification of the SAE will be emailed to Navidea Biopharmaceuticals 
Pharmacovigilance at safety@navidea.com. For fatal or life-threatening adverse events where 
important or relevant information is missing, active follow-up is undertaken immediately. 
Pregnancy will have the same time reporting obligations to the sponsor as SAEs. Upon notification, 
Navidea will provide a form for collection of pregnancy information. 
All SAEs must also be recorded on the Adverse Event eCRFs. 
Notification of the IRB(s) 
The sponsor and/or the investigator will notify the IRB(s) about all relevant events (e.g., SAEs and 
Suspected, Unexpected, Serious Adverse Reactions [SUSARs]) according to all applicable regulations. 
Notification of the authorities 
The sponsor will process and report all relevant events (e.g., SAEs, SUSARs) to the authorities 
according to all applicable regulations. 
Sponsor’s notification of the investigators 
The sponsor will inform all investigators about reported relevant events (e.g., SAEs, SUSARs) 
according to all applicable regulations. 


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8.6.2 
Further Safety Assessments 
8.6.2.1 
Physical Exam  
A complete physical examination at screening will be conducted according to the Schedule of Study 
Events (see Appendix 1). Height and body weight will be collected. 
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 
 
8.6.2.2 
Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) will be obtained at screening and within 30 minutes after 
investigational product injection. The ECG will be measured with the subject in a resting position for 
at least 1 minute. No continuous ECG monitoring will be required.  At a minimum the heart rate, QRS, 
PR and QT intervals will be collected.  QTc will be calculated using the Fridericia formula. 
On-site investigator’s responsibilities 
The immediate cardiac safety of the subject will be ensured by the on-site qualified physician.  Any 12-
lead ECG intervals, waveform abnormalities, and rhythm changes that are clinically significant in that 
they result in a change in subject management will be considered an AE.  In the case of an SAE, once 
SAE notification is decided upon, investigators are required to follow the procedure described for SAE 
notification and document abnormal ECG findings (intervals and waveforms).  Any interval data or 
abnormal waveform finding that resulted in an AE (i.e., change of patient management) must be 
followed to normalization or stabilization.  
Each 12-lead ECG tracing must be signed and dated and stored in the subject’s source documentation.   
8.6.2.3 
Vital Signs 
Vital signs comprise the measurement of body temperature, heart rate, respiration, and systolic and 
diastolic blood pressure. All measurements will be taken after the subject has been in a resting position 
for at least 1 minute.  


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Vital signs will be measured at screening and 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. 
8.6.2.4 
Clinical Laboratory Parameters for Screening and Safety 
Clinical laboratory tests to be evaluated in this study include hematology, serum chemistry, and 
urinalysis.  Clinical laboratory tests will include the following as defined in Table 2. 
Table 2. Clinical Laboratory Parameters 
Hematology 
Leukocytes,  hemoglobin (Hgb), hematocrit (HCT),  neutrophils, 
eosinophils, basophils, lymphocytes, monocytes, red blood cells 
(RBC), platelets 
Serum chemistry  
 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase, total bilirubin, creatinine, chloride, potassium, 
sodium, total protein, albumin, globulin, carbon dioxide (CO2), blood 
urea nitrogen (BUN) 
Urinalysis 
pH, specific gravity 
 
The site laboratory will provide the necessary supplies to collect the blood and urine samples. 
All laboratory reports must be promptly reviewed for clinical significance by the investigator, and upon 
review, initialed and dated by the investigator. 
Good clinical practice would suggest that a copy of the laboratory results also be provided to the 
subject’s referring physician. 
Any change in a laboratory value, which results in a change in subject management (additional controls 
or treatment required), will be reported as a clinically significant change. Clinically significant changes 
in laboratory parameters, which are not the result of laboratory error, are to be recorded as AEs. 
Any clinically significant changes in laboratory values are to be followed up with repeated tests at 
appropriate intervals (as determined by the investigator) until the values return to baseline level or until 
the abnormality is explained by the investigator.  
The expected amount of blood to be withdrawn is shown in Table 3. 


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Table 3.  Approximate Amount of Blood Withdrawn 
Time point of examination 
Amount of blood taken 
Laboratory examination (Screening) 
10 mL 
Laboratory examination (Post-IV Imaging) 
10 mL 
Laboratory examination (Post-SC Imaging: 
Cohort 3 only) 
10 mL 
Total 
20 mL (Cohort 3: 30 mL) 
 


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9 
STATISTICAL METHODS 
The study is a prospective, open-label, single-center, dose escalation, comparative, safety study of 
injected Tc 99m tilmanocept in the detection of and assessment of localization to cutaneous KS or non-
cutaneous focus (visceral or other, e.g. CNS [central nervous system]) in HIV-positive subjects with 
active KS by planar and SPECT/CT imaging.  The dose escalation portion of the study is a 4+2 design 
with no dose de-escalation.  The statistical objective of the study is to determine the maximum tolerated 
dose (MTD) of Tc 99m tilmanocept and to compare the capabilities of Tc 99m tilmanocept to localize 
in cutaneous and non-cutaneous sites of KS. A study center is defined as a treatment administration site 
or cohort of treatment administration sites under the control and supervision of the same PI.   
9.1 
Randomization Methods 
The study is not randomized.   
9.2 
Safety Variables 
The primary variable for this study is the presence or absence of an ADR during the subject’s 
participation in the trial following Tc 99m tilmanocept injection.  The primary safety endpoint will be 
computed as the proportion of subjects with an ADR.  
9.3 
Efficacy Variables 
The efficacy variables for this study are as follows: 
• Nuclear medicine specialist determination of presence/absence of illumination (i.e., 
localization positive/negative, anatomic site) relative to background from SPECT imaging 
results for each subject;  
• Clinically identified presence/absence of KS (based on any previous diagnostic evaluations);   
• Quantitative SPECT gamma counts for each biopsied lesion. 
 
The efficacy endpoints for this study are as follows: 
• Per subject localization rate of Tc 99m tilmanocept in at least one KS suspected or confirmed 
lesion by planar and/or SPECT/CT imaging  
• Per lesion/region concordance of Tc 99m localization with anatomical areas of active KS 
defined by confirmed diagnosis or clinical symptomology 
 
• Localization intensity for each biopsied and clinically defined lesion as determined by 
quantitative SPECT gamma counts  
• Per biopsied lesion proportion of CD206-expressing cells and total CD206 as determined by 
histology and relative IHC fluorescence  
• Per lesion/region concordance of IV vs SC Tc 99m localization with anatomical areas of 
active KS defined by confirmed diagnosis or clinical symptomology. 
• Per subject localization rate of Tc 99m tilmanocept in areas other than KS by planar and/or  
SPECT/CT imaging  


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• Per area localization rate of Tc 99m tilmanocept in the most frequently identified areas other 
than KS by planar and/or SPECT/CT imaging  
 
A localized subject is one for whom Tc 99m by planar and/or SPECT/CT imaging results in the 
illumination of at least one site relative to background as determined by the nuclear medicine specialist.   
A localized KS lesion is a lesion that is both clinically identified or suspected KS and planar or 
SPECT/CT illuminated. 
Localization in areas other than KS will also be defined per subject and per area, where these areas are 
clinically negative KS locations based on clinical symptomology. 
9.4 
Sample Size Justification 
The dose escalation portion of this study is a design with no dose de-escalation. The sequential cohort 
enrollment characteristics of this design do not allow a fixed computation of sample size.  In a previous 
study with subjects receiving a 200 µg dose radiolabeled at 5 mCi (i.e., the maximum dose planned for 
this study), zero (0) subjects had an ADR.  Therefore, it is expected that no subjects will have an ADR 
in this study and that each cohort will enroll the planned sample size of subjects.  With 2 cohorts of 4 
subjects and one cohort of up to 6 subject, it is anticpated that the study will enroll up to n=14 subjects.    
 
 
9.5 
Statistical Analyses 
9.5.1 
Analysis Populations 
The following analysis populations will be defined for the study: 
• Intent-to-Diagnose (ITD) Population - Subjects who are enrolled in the study, injected with 
Tc 99m tilmanocept, and are imaged will be included in the ITD analysis population. 
• Safety Population – All subjects who are enrolled in the study and are injected with Tc 99m 
tilmanocept will be included in the safety population. 
 
All safety data analyses will be conducted on the safety population.  All efficacy data analyses will be 
conducted on the ITD population. 
9.5.2 
Analysis of Baseline and Demographic Characteristics 
The distribution of each baseline and demographic variable of interest will be summarized by dose 
cohort. Continuous variables will be summarized via mean, median, standard deviation, and range. 
Categorical variables will be summarized via counts and percentages. This analysis will be performed 
on the safety population.  
9.5.3 
Analysis of Efficacy Variables 
The number and percentage of subjects with at least one biopsy-confirmed or clinically suspected KS 
lesion that has localized with Tc 99m tilmanocept by planar and/or SPECT/CT imaging will be 


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computed.  A 95% exact confidence interval on the per subject localization rate will be computed.  This 
analysis will be performed by dose.     
Per region lesion localization of Tc 99m tilmanocept by planar and/or SPECT/CT imaging will be 
computed across all biopsy-confirmed or clinically suspected KS lesions of all subjects.  A 95% exact 
confidence interval on per region lesion localization will be calculated.  This analysis will be performed 
by dose. 
Localization intensities of biopsied lesions will be summarized by descriptive statistics (mean, median, 
standard deviation, minimum, maximum and range) for each dose.  
Per biopsied lesion proportion of CD206-expressing cells and quantity of CD206 as determined by 
histology and IHC fluorescence  will be summarized by descriptive statistics (mean, median, standard 
deviation, minimum, maximum and range) for each dose.   
Concordance between between IV and SC tilmanocept in biopsy-confirmed or clinically suspected KS 
lesion sites will assessed with a cross-tabulation including the joint probability distribution. The site 
will be the sampling unit for this analysis. An exact version of McNemar’s test will be performed, 
testing the null hypothesis 
𝐻𝐻0:π𝐼𝐼𝐼𝐼= π𝑆𝑆𝑆𝑆 
𝐻𝐻𝐴𝐴: π𝐼𝐼𝐼𝐼≠π𝑆𝑆𝑆𝑆 
whereπIV andπ𝑆𝑆𝑆𝑆 represent the probabilities of localization with IV (only) tilmanocept and localization 
with SC tilmanocept only respectively.  
In addition, descriptive statistics will be generated relative to the concordance and reverse concordance 
of  observed sites of discrete localization of Tc 99m tilmanocept following IV and SC administration.  
The number and percentage of subjects with at least one anatomical site other than KS that has been 
localized with Tc 99m tilmanocept by SPECT imaging will be computed.  A 95% exact confidence 
interval on the per subject localization rate will be computed.  This analysis will be performed by dose 
and overall. 
Locations showing localization of Tc 99m tilmanocept by planar and/or SPECT/CT imaging that are 
not locations of biopsy-confirmed or clinically suspected KS sites will be computed across all sites in 
all subjects.  A 95% exact confidence interval on per location localization will be calculated.  This 
analysis will be performed by dose and overall. 
Other efficacy analyses will be described in the Statistical Analysis Plan (SAP) for the study. 
9.5.4 
Analysis of Safety Variables 
The number and percentage of subjects with ADRs will be tabulated by dose group and overall. 
All AEs will be observed for each subject from the time of signing of informed consent until exit from 
the study.  A treatment emergent adverse event (TEAE) is defined as an adverse event whose start date 
is on or after the Tc 99m tilmanocept injection date and time.  If the injection date and time and/or the 
AE start date are missing, the AE will be considered treatment emergent.  


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Prior to analysis, all AEs will be coded using the MedDRA coding dictionary. Based on these coded 
terms, treatment emergent AEs will be summarized by dose group and overall as follows: 
• by system organ class and preferred terms 
• by system organ class and preferred terms and relation to study drug 
• by system organ class and preferred terms 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, median, 
standard deviation, minimum, maximum and range) by dose group and overall.  
Other safety analyses will be described in the SAP for the study. 
9.5.5 
Handling Missing Values 
The analysis of the primary efficacy variables will be carried out on the observed data, i.e., a complete 
case analysis.     
9.5.6 
Interim Analysis 
There are no interim analyses planned for this study. 


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10 DATA HANDLING AND QUALITY ASSURANCE 
10.1 Data Recording 
Data required according to this protocol are to be entered into the CRFs (provided by the sponsor) as 
soon as possible. 
10.1.1 
eCRF Design 
Electronic CRFs (eCRFs) will be used for collecting all data generated during the trial.  eCRF 
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 trial will be monitored regularly by a clinical research associate (CRA) from the sponsor or a 
contract research organization (CRO).  Monitoring procedures include one or more visits designed to 
clarify all prerequisites before the trial starts and will be governed by a trial-specific monitoring plan.  
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 data entries, their compliance 
with the protocol and with GCP, and will compare the eCRFs with the source data. 
All data recorded in the eCRF 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 and SAEs have been appropriately reported 
(including adherence to the time periods required for SAEs). 
10.3 Data Processing 
Trial data documentation will be maintained specifying all relevant aspects of data processing for the 
trial (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. 
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 trial site and the trial documents 
originating there.  The auditor(s) will usually be accompanied by a CRA or the trial team lead.  The 
investigator will be informed about the outcome of the audit. 
In addition, inspections by health authority representatives and IEC(s) [independent ethics 
committee]/IRB(s) are possible at any time.  The investigator is to notify the sponsor of any such 
inspection immediately. 


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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 ISF is not to be destroyed without the sponsor’s approval. 
The investigator’s contract will contain all regulations relevant for the trial center. 
10.6 Premature Termination of the Trial 
Termination by the Sponsor 
The Sponsor may terminate the trial 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 
Termination by the Investigator 
If the Investigator terminates the trial prematurely, the Investigator must do the following: 
• Return all unused investigational products and related trial materials to the Sponsor. 
• Provide the IRB and the sponsor with a written statement describing why the trial was terminated 
prematurely. Prompt compliance with this requirement is essential so that the sponsor may 
comply with its regulatory obligations. 
10.6.1 
Trial as a Whole 
The sponsor retains the right to prematurely terminate the trial as a whole at any time.   
At the discretion of the sponsor, the entire trial may be canceled for medical reasons.  In addition, the 
sponsor retains the right to end the trial at any time if the study cannot be carried out as agreed upon in 
the protocol.  


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In case of premature termination or suspension of the trial, the principal investigator/sponsor will 
promptly inform the investigator/institutions, regulatory authorities, and IRB of the termination or 
suspension and the reason for it. 
10.6.2 
Center 
At any time, the trial 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. 
 
10.6.3 
Study Participant 
Individual subjects may be withdrawn from the trial according to the criteria specified in Section 4.5. 
 


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11 ETHICAL AND LEGAL ASPECTS 
11.1 Ethical and Legal Conduct of the Study 
The planning and conduct of this clinical trial are subject to national laws. Only when all of the 
requirements of the appropriate regulatory authority have been fulfilled will the trial begin. The trial 
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 PI, the entire trial may 
be canceled for medical reasons. In addition, the sponsor retains the right to end the trial for medical-
scientific or GCP-relevant reasons. In the case of premature termination the investigators, IRB/IECs, 
and Regulatory Authorities will be informed by the Study Manager. As required by local law, current 
safety-relevant information will be provided to the IEC / IRB 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 trial 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 subject information and informed consent form is provided as a document separate to this 
protocol. 
Based on this consent form and, if required, the subject information sheet, the investigator will explain 
all relevant aspects of the trial to each subject, before his/her entry into the trial (i.e., before 
examinations and procedures associated with selection for the trial are performed).  
The investigator will also mention that written approval of the IRB/IEC has been obtained.  
Each subject will have ample time and opportunity to ask questions and will be informed about the 
right to withdraw from the trial 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 
informed consent form and has done so, may he/she enter the trial. Additionally, the investigator or 
his/her nominated designee will personally sign and date the form, too. The subject will receive a 
duplicate of the signed and dated form.  
The investigator will record in the source documentation the time and date of obtaining informed 
consent. 
In the event that informed consent is obtained on the date that screening trial procedures are performed, 
the trial record or subject's clinical record must clearly show that informed consent was obtained prior 
to these procedures.  
The informed consent form 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 informed consent form. The investigator will inform the subject of 
changes in a timely manner and will ask the subject to confirm his/her participation in the trial by 


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signing the revised informed consent form. Any revised written informed consent form and written 
information must receive the IRB/IEC's approval/favorable opinion in advance of use. 
11.3 Financing/Financial Disclosure 
Each investigator (including principal and/or any sub-investigators; as well as their spouses and 
dependent children) who is directly involved in the treatment or evaluation of research subjects has to 
provide a financial disclosure according to all applicable legal requirements. All relevant 
documentation will be filed in the TMF and/or ISF, 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 trial 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 trial 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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12 REFERENCE LIST 
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L, Silverman JF. Fine-needle aspiration cytology of disseminated Kaposi sarcoma 
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10.1159/000369855. Epub 2014 Dec 24. PubMed PMID: 25547261. 
 
2. Fukumoto H, Kanno T, Hasegawa H, Katano H. Pathology of Kaposi's 
Sarcoma-Associated Herpesvirus Infection. Front Microbiol. 2011 Aug 25;2:175. 
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Central PMCID: PMC3161246. 
 
3.  Qin Z, Kearney P, Plaisance K, Parsons CH. Pivotal advance: Kaposi's 
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4.  Salata C, Curtarello M, Calistri A, Sartori E, Sette P, de Bernard M, Parolin  
C, Palù G. vOX2 glycoprotein of human herpesvirus 8 modulates human primary 
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10.1002/jcp.21722. PubMed PMID: 19229882. 
 
5. Denis D, Seta V, Regnier-Rosencher E, Kramkimel N, Chanal J, Avril MF, Dupin 
N. A fifth subtype of Kaposi's sarcoma, classic Kaposi's sarcoma in men who have  
sex with men: a cohort study in Paris. J Eur Acad Dermatol Venereol. 2018 Jan 29. 
doi: 10.1111/jdv.14831. [Epub ahead of print] PubMed PMID: 29377280. 
 
6.  Ikeri NZ, Akinjo AO, Ajayi OO, Fehintola Banjo AA. Histological types of 
soft-tissue sarcomas at the lagos university teaching hospital. Niger Postgrad 
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29355158. 
 
7.  Mahale P, Engels EA, Coghill AE, Kahn AR, Shiels MS. Cancer risk in older 
people living with human immunodeficiency virus infection in the United States. 
Clin Infect Dis. 2018 Jan 8. doi: 10.1093/cid/ciy012. [Epub ahead of print] 
PubMed PMID: 29325033. 
 
8. Windon AL, Shroff SG. Iatrogenic Kaposi's Sarcoma in an HIV-Negative Young 
Male With Crohn's Disease and IgA Nephropathy: A Case Report and Brief Review of  
the Literature. Int J Surg Pathol. 2017 Nov 1:1066896917736610. doi: 
10.1177/1066896917736610. [Epub ahead of print] PubMed PMID: 29169276. 
 
9.  Lepe M, Hui Y, Pisharodi L, Canepa M. Primary diagnosis of angiosarcoma by 
fine needle aspiration: Lessons learned from 3 cases. Diagn Cytopathol. 2017 Oct  
31. doi: 10.1002/dc.23853. [Epub ahead of print] PubMed PMID: 29087044. 
 
10.   Kotzias G, Agunbiade M, Isaac L, Khaladj M. Human Immunodeficiency 
Virus-Negative-Associated Lymphangioma-like Kaposi's Sarcoma with Variable 
Clinical Presentations(A Case Report). J Am Podiatr Med Assoc. 2017 
Sep;107(5):461-466. doi: 10.7547/15-079. PubMed PMID: 29077499. 
 


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11.  Bansal R, Tomaino C, Baum J. Gastric Kaposi's Sarcoma. Am J Med Sci. 2017 
Jul;354(1):70. doi: 10.1016/j.amjms.2016.12.016. Epub 2016 Dec 23. PubMed PMID: 
28755741. 
 
12.  Kumar V, Soni P, Garg M, Abduraimova M, Harris J. Kaposi Sarcoma Mimicking 
Acute Flare of Ulcerative Colitis. J Investig Med High Impact Case Rep. 2017 Jun  
12;5(2):2324709617713510. doi: 10.1177/2324709617713510. eCollection 2017 
Apr-Jun. PubMed PMID: 28638838; PubMed Central PMCID: PMC5470652. 
 
13.  Tancredi MV, Pinto VM, Silva MHD, Pimentel SR, Silva TSBD, Ito SMA, Golub JE,  
Toscano ALCC. Prevalence of Kaposi's sarcoma in patients with AIDS and associated 
factors, São Paulo-SP, Brazil, 2003-2010. Epidemiol Serv Saude. 2017 
Apr-Jun;26(2):379-387. doi: 10.5123/S1679-49742017000200015. Portuguese, English. 
PubMed PMID: 28492779. 
 
14.  Kennedy-LeJeune E, Cataldo VD. Kaposi's Sarcoma of the Oral Cavity. N Engl J  
Med. 2017 Mar 30;376(13):1268. doi: 10.1056/NEJMicm1611553. PubMed PMID: 
28355516. 
 
15. F Cope, W Metz, M Pykett, M Blue, B Potter, D Colborn, B Abbruzzese, J Shuping,  C 
Reininger, A Azad, M Rajaram, L Schlesinger, W Jarjour, M McGrath, L Huysentruyt, R Zhang, P 
Bracci.  Innovations in receptor-targeted precision imaging:  Diagnosis up close & personal.  Nature; 
Oct 24, 2013, s98-102.  Nature/Nature Outlook; Nov 7, 2013 
16. Cope FO, Abbruzzese B, Sanders J, Metz W, Sturms K, Ralph D, Blue M, et al. The inextricable 
axis of targeted diagnostic imaging & therapy: An immunological natural history approach. Nucl Med 
Biol. 2016 Mar; 43(3):215-25. 
17. Bansal R, Tomaino C, Baum J. Gastric Kaposi's Sarcoma. Am J Med Sci. 2017 Jul;354(1):70. 
doi: 10.1016/j.amjms.2016.12.016. Epub 2016 Dec 23. PubMed PMID: 28755741. 
18. Alwassia A, Alshathri Z, Khosla R, Spagnolo SV. Pulmonary Kaposi sarcoma presenting as 
complete lung consolidation. BMJ Case Rep. 2017 Mar 22;2017. pii: bcr2016219048. doi: 
10.1136/bcr-2016-219048. PubMed PMID: 28331023. 
19. Chen F, Gulati M, Tchelepi H. Hepatic Kaposi Sarcoma Revisited: An Important but Less 
Commonly Seen Neoplasm in Patients With Acquired Immunodeficiency-29 Syndrome. Ultrasound 
Q. 2017 Mar;33(1):109-111. doi: 10.1097/RUQ.0000000000000267. PubMed PMID: 27984514. 
20. Petribu NC, Cisneiros MS, Carvalho GB, Baptista Lde M. Pulmonary Kaposi's sarcoma in a 
female patient: Case report. Rev Assoc Med Bras (1992). 2016 Sep-Oct;62(5):395-8. doi: 
10.1590/1806-9282.62.05.395. PubMed PMID: 27656847. 
21. Goyal P, Alomari AI, Kozakewich HP, Trenor CC 3rd, Perez-Atayde AR, Fishman SJ, Greene 
AK, Shaikh R, Chaudry G. Imaging features of kaposiform lymphangiomatosis. Pediatr Radiol. 2016 
Aug;46(9):1282-90. doi: 10.1007/s00247-016-3611-1. Epub 2016 Apr 6. PubMed PMID: 27053281. 
22. Gottlieb M. Pulmonary Kaposi Sarcoma. CJEM. 2016 Sep;18(5):399-400. doi: 
10.1017/cem.2015.72. Epub 2015 Jul 16. PubMed PMID: 26791020. 
23. Carrascosa R, Alfageme F, Roustán G, Suarez MD. Skin Ultrasound in Kaposi 


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Sarcoma. Actas Dermosifiliogr. 2016 May;107(4):e19-22. doi: 
10.1016/j.ad.2015.05.019. Epub 2015 Dec 17. English, Spanish. PubMed PMID: 
26706712. 
 
24. Halankar J, Martinovic E, Hamilton P. Kaposi's Sarcoma Presenting as Acute 
Small Bowel Obstruction Diagnosed on Multidetector Computed Tomography with 
Histopathological Correlation. Case Rep Radiol. 2015;2015:581470. doi: 
10.1155/2015/581470. Epub 2015 Mar 17. PubMed PMID: 25866694; PubMed Central 
PMCID: PMC4381971. 
 
25. Verma R, Toma AA, Boetticher NC, Strickler JG Jr. Education and imaging. 
Gastrointestinal: Gastric involvement in disseminated lymphadenopathic Kaposi 
sarcoma. J Gastroenterol Hepatol. 2015 Apr;30(4):654. doi: 10.1111/jgh.12881. 
PubMed PMID: 25776961. 
 
26. Reuter S, Vrachimis A, Huss S, Wardelmann E, Weckesser M, Pavenstädt H. A 
challenging case of rapid progressive Kaposi sarcoma after renal transplantation: 
diagnostics by FDG PET/CT. Medicine (Baltimore). 2014 Sep;93(11):e67. doi: 
10.1097/MD.0000000000000067. PubMed PMID: 25192485; PubMed Central PMCID: 
PMC4616271. 
 
27. Nozaki T, Matsusako M, Mimura H, Osuga K, Matsui M, Eto H, Ohtake N, Manabe 
A, Kusakawa I, Tsutsumi Y, Nosaka S, Kamo M, Saida Y. Imaging of vascular tumors  
with an emphasis on ISSVA classification. Jpn J Radiol. 2013 Dec;31(12):775-85. 
doi: 10.1007/s11604-013-0249-x. Epub 2013 Oct 18. PubMed PMID: 24135879. 
 
28. Ozdemir E, Poyraz NY, Keskin M, Kandemir Z, Turkolmez S. (18)F-FDG PET/CT 
findings in a case with HIV (-) Kaposi sarcoma. Rev Esp Med Nucl Imagen Mol. 2014 
May-Jun;33(3):175-7. doi: 10.1016/j.remn.2013.08.003. Epub 2013 Oct 10. PubMed 
PMID: 24119549. 
 
29. Sathekge M, Maes A, Van de Wiele C. FDG-PET imaging in HIV infection and 
tuberculosis. Semin Nucl Med. 2013 Sep;43(5):349-66. doi: 
10.1053/j.semnuclmed.2013.04.008. Review. PubMed PMID: 23905617. 
 
 


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Appendix 1 
Schedule of Events – Cohorts 1 and 2 
Evaluation 
VISIT 1 
Screening Days 
 -29 to 0 
VISIT 2 
Pre- and Post-IV Injection 
Day 1 
Follow-up Phone Call 
(Day 7±3) 
 
 
0:00 
60-75 
Minutes 
 
Informed Consent 
x 
 
 
 
Entry Criteria  
x 
 
 
 
Medical History 
x 
 
 
 
Vital Sign Assessment 
x 
xbe 
 
 
ECG 
x 
xe 
 
 
Physical Examination  
xc 
 
 
 
Assessment of Edema/Lymphedema 
x 
 
 
 
Photography of all KS Cutaneous Lesions 
x 
 
 
 
Review of Medications 
x 
x 
 
x 
Clinical Laboratory Evaluation: Chemistry, Hematology, UA 
x 
 
xd 
 
Serum Pregnancy Test 
x 
xa 
 
 
Tilmanocept Administration 
 
x 
 
 
Whole Body Planar and Whole Body SPECT/CT Imaging 
 
 
x 
 
Biopsy of Non-Visceral Lesion 
 
 
xd 
 
Adverse Event Monitoring 
x 
x 
x 
x 
a. Urine pregnancy test must be completed and determined to be negative in women of childbearing potential within 48 hours of injection. 
b. Time point 0:00 is before Tilmanocept administration (a 30 minute pre- and post injection window is permitted for vital signs). 
c. Physical examinations done within 30 days of injection may be used even if conducted prior to obtaining informed consent if they are 
ordered and conducted at the direction of the Investigator as part of his/her standard of care. 
d.  Labs and biopsy will be completed at the conclusion of the 60-75 minute post-injection scan. 
e.  ECG and vital signs must be within 30 minutes post-injection.   


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Appendix 2 
Schedule of Events – Cohort 3 
Evaluation 
VISIT 1 
Screening 
Days 
 -29 to 0 
VISIT 2 
Pre- and Post-SC Injection 
Day 1 
VISIT 3 
Pre- and Post-IV 
Injection 
Day 7 ± 3 
7 ± 3 Day 
Post-IV 
Follow-up 
Phone Call 
 
 
0:00 
60-75 Minutes 
4-6 Hours 0:00 
60-75 Minutes 
 
Informed Consent 
x 
 
 
 
 
 
 
Entry Criteria  
x 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
Vital Sign Assessment 
x 
xbe 
 
 
xbe 
 
 
ECG 
x 
xe 
 
 
xe 
 
 
Physical Examination  
xc 
 
 
 
 
 
 
Assessment of Edema/Lymphedema 
x 
 
 
 
 
 
 
Photography of all KS Cutaneous Lesions 
x 
 
 
 
 
 
 
Review of Medications 
x 
x 
 
 
x 
 
x 
Clinical Laboratory Evaluation 
x 
 
 
xd 
 
xd 
 
Serum Pregnancy Test 
x 
xa 
 
 
xa 
 
 
Tilmanocept Administration 
 
x 
 
 
x 
 
 
Whole Body Planar and Optional SPECT/CT Imaging 
 
 
x 
x 
 
x 
 
Biopsy of Non-Visceral Lesion 
 
 
 
 
 
xd 
 
Adverse Event Monitoring 
x 
x 
x 
x 
x 
x 
x 
a. 
Urine pregnancy test must be completed and determined to be negative in women of childbearing potential within 48 hours of injection. 
b. 
Time point 0:00 is Tilmanocept administration (a 30 minute pre- and post-injection window is permitted for vital signs). 
c. 
Physical examinations done within 30 days of injection may be used even if conducted prior to obtaining informed consent if they are ordered and conducted at the direction 
of the Investigator as part of his/her standard of care. 
d.  Labs and biopsy will be completed at the conclusion of the 60-75 minute post-injection scan. 
e.  
ECG and vital signs must be within 30 minutes post-injection.   


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Appendix 3 
Dose Escalation Diagram  
 
 


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Appendix 4 
Edema Scale 
Grade 
Description 
Physical Characteristics 
0 
None 
N/A 
1+ 
Trace 
Slight pitting, no visible change in the shape of the 
extremity; depth of indentation 0-¼” (<6mm) 
2+ 
Mild 
No marked change in the shape of the extremity; depth of 
indentation ¼-½” (6-12mm); disappears in 10 to 15 
seconds 
3+ 
Moderate 
Noticeably deep pitting, swollen extremity; depth of 
pitting ½ -1” (1-2.5 cm); duration 1 to 2 minutes 
4+ 
Severe 
Very swollen, distorted extremity; depth of pitting >1” 
(>2.5cm); duration 2 to 5 minutes 
 
 


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Appendix 5 
KS Lesion Assessment/ Photography Protocol 
INTERNATIONAL 
COLLABORATIVE 
Participant ID Number 
Interviewer 
Initials  
Date of Visit 
Visit 
Number 
 
 
/
/
 
 
 
  Day         Month             Year 
 
 
 
Reviewer 
Initials 
Date of Review 
Interim 
Visit 
Number 
 
 
 
 
 
/
/
 
 
 
 
  Day         Month             Year 
 
KS LESION ASSESSMENT 
 
A “KS-suspicious” lesion is defined as a lesion that is either known to be KS (by virtue of biopsy) or clinically 
suspected to be KS.  In the questions below, when asked about KS-suspicious lesions, consider only those which are 
hyperpigmented with the usual characteristics of KS, regardless if they are flat or raised.  Do not count lesions which 
have subcutaneous swelling alone, without hyperpigmentation, as KS-suspicious. 
A. Overall Cutaneous   Do not count oral cavity lesions. 
1. 
 Overall inventory: How many KS-suspicious lesions are present? 
 
1-49 
 ≥ 50 
2. 
 Indicate if KS-suspicious lesions are absent or present in each of these sites. 
 
Site # 
Absent 
Present 
Site # 
Absent 
Present 
Site # 
Absent 
Present 
12 – Head 
 
 
17 – Right arm 
 
 
22 – Left hand 
 
 
13 – Neck  
 
 
18 – Left arm 
 
 
23 – Right foot 
 
 
14 – Chest 
 
 
19 – Right leg 
 
 
24 – Left foot 
 
 
15 – Abdomen 
 
 
20 – Left leg 
 
 
25 – Genital 
 
 
16 – Back 
 
 
21 – Right hand 
 
 
26 – Gluteal 
 
 
Lesion Counts 
Include only KS-suspicious lesions (do not include lesions with subcutaneous swelling alone).  
If ≥ 50 lesions overall, select three sites that are most representative of the total body in terms of lesion 
characteristics and which have a combined lesion count of at least 50.  If three such areas cannot be found which 
total at least 50 lesions, choose 3 areas with the largest combined count. Indicate the sites using the corresponding 
codes above. Do not use the mouth.  If lesions are only present in the mouth, go to question 4.  
If < 50 lesions overall, enter code 11 (“total body”) as the representative area.  
Definition of a flat lesion: Area of skin that is hyperpigmented but not raised (i.e., the borders are not palpable; e.g., 
macule or patch are examples of flat lesions).  
Definition of a raised lesion: any lesion that protrudes from skin surface and is palpable (e.g., plaque, nodule, or 
tumor)  
3. 
 
Representative site 
(Site Code) 
Number of FLAT lesions 
(macule/patch) 
Number of RAISED lesions 
(plaque/nodule/tumor) 
 
 
 
I. 
 
 
 
 


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II. 
 
 
 
 
 
III. 
 
 
 
 
Questions 4-6 relate to lesions anywhere on the body:  
4. 
  
Identity the KS-suspicious lesion with the 
largest diameter in its footprint on the skin.  
This can be a flat or raised lesion.  
Record, in mm, this diameter as well as the 
diameter that is perpendicular to the largest 
diameter (as in the image shown). 
x
mm  
 
5. 
 
How many KS-suspicious lesions are present which meet 
the definition a tumor?  A tumor is substantially raised above 
the surface of the skin, the height is nearly the same or 
greater than the footprint on the skin, and at least one 
diameter on the footprint of the skin is at least 20 mm (2 cm).  
 
 
 tumors 
 
6. 
 
What is the vertical height (in mm, as in 
image shown) of the tallest KS-
suspicious lesion? 
mm 
 
B. Feet
7. 
 Are there KS-suspicious lesions present on either 
foot (below a horizontal transection at the ankle)? 
  Yes 
 
No  Skip to 9 
8. 
 How many flat or raised lesions are on each foot? 
 
Right 
Left 
 
Flat 
 
 
Raised (plaque/ 
nodular/tumor) 
 
 
C. Oral Cavity 
9. 
  Are there any KS-suspicious lesions in the oral cavity? 
  Yes 
 No  Skip to 11 
10. 
 Evaluation of oral cavity by site.  
 
 
KS Lesions 
Mark all that apply 
Oral Site 
Absent 
Present 
Raised 
Flat 
Gingiva/gums 
 
 
 
 
Hard palate 
 
 
 
 
Soft palate 
 
 
 
 
Buccal mucosa 
 
 
 
 
Tongue 
 
 
 
 
Floor of mouth 
 
 
 
 
Tonsils 
 
 
 
 
Uvula 
 
 
 
 


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Posterior pharynx 
 
 
 
 
D. Edema 
11. 
 Is there any edema present? 
 Yes 
  No  Skip to 14 
12. 
 Evaluation of edema by site.   
 
 
Edema 
Edema Site 
Absent 
Present 
Face (Including Periorbital) 
 
 
Genital 
 
 
Right arm 
 
 
Left arm 
 
 
Right hand 
 
 
Left hand 
 
 
Right leg 
 
 
Left leg 
 
 
Right foot 
 
 
Left foot 
 
 
13. 
 Measurement of extremity circumferences (in cm). 
 
 
Right (cm) 
Left (cm) 
Foot: At one-half the length of the foot. 
.
 
.
 
Lower leg: One-third of the way from 
ankle to mid-knee joint (closer to ankle). 
.
 
.
 
Thigh: Half-way between mid-knee joint 
and iliac crest.   
.
 
.
 
E. Ulceration and Superinfection Oral cavity lesions may be considered. 
14. 
 Is there evidence of ulceration on any KS-suspicious lesions?  
 Yes 
 No  Skip to 15 
 
Choose the two lesions with greatest surface area of ulceration.  
For each area of ulceration, use Area Site Codes and then provide a brief description of the specific location.  
Extent of ulceration: Do not measure entire lesion; only measure ulcerated area. 
 For the diameters, use the 2 perpendicular diameters at 90 degrees to each other  
that cover the area with greatest involvement of ulceration. 
 
 
 
Site Code 
Specify Location (e.g., below right eye; medial aspect of knee) 
Diameters of ulceration, in mm 
a. 
 
 
 
____________________________________________________________ 
x
 mm 
b. 
 
 
 
x
 mm 


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____________________________________________________________ 
 
15. 
 Is there evidence of superinfection on any KS-suspicious lesions? 
  Yes 
 No  Skip to 16 
 
Superinfections is defined as having evidence of infection. Signs may include pus, crust, or odor. 
Choose the two areas with greatest surface area of involvement.  For each area of superinfection, use Area Site Codes and 
then provide a brief description of the specific location.  
Extent of superinfection: Do not measure entire lesion; only measure superinfected area. As above, for diameters, use the 
2 perpendicular diameters at 90 degrees to each other that cover the area with greatest involvement of superinfection.  
 
 
 
Site Code 
Specify Location (e.g., below right eye; medial aspect of knee) 
Diameters of superinfection, in mm 
a. 
 
 
______________________________________________ 
x
 mm 
b. 
 
 
______________________________________________ 
x
 mm 
16. 
 Following the given photographic cues, take 9 photos of the participant from the angles specified.  
 
 
Take a photo of 
patient’s ID 
number.  
Photo # 
 
 
Take a photo 
of face with 
black cloth 
over eyes. 
 
Photo # 
 
 
Take a photo of 
the bottom of 
the right foot.  
 
Photo # 
 
 
Take a photo 
of the bottom 
of the left 
foot. 
 
 
Photo # 
 
 
Take a photo of 
the inside of the 
right lower leg. 
 
Photo # 
 
 
Take a photo 
of the inside 
of the left 
lower leg. 
 
 
Photo # 
 
 
Take a photo of 
the front of both 
legs together. 
 
Photo # 
 
 
Take a photo 
of the groin, 
taking care to 
include 
inguinal 
lymph nodes. 
Minimal 
underwear 
can be worn. 
 
Photo # 
 


Technetium Tc99m tilmanocept 
 
Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-24 
 
30 January 2019 
 
Confidential 
Page 70 of 72 
 
 
Take a photo of 
the chest and 
arms, with the 
palms of the 
hands facing 
forward. 
 
Photo # 
 
 
Take a photo 
of the back 
and arms, 
including 
backs of the 
hands. 
 
Photo # 
 
 




Technetium Tc99m tilmanocept 
 
Navidea Biopharmaceuticals, Inc. 
Clinical Trial Protocol: NAV3-24 
 
30 January 2019 
 
Confidential 
Page 72 of 72 
 
Appendix 7 
Investigators’ Signature 
Study Title: 
An Evaluation of the Safety of Escalating Doses of Tc 99m 
Tilmanocept by Intravenous (IV) Injection and a Comparison to 
Subcutaneous (SC) Injection in Human Immunodeficiency Virus 
(HIV)  Subjects Diagnosed with Kaposi Sarcoma (KS) 
Study Number: 
NAV3-24 
Original Protocol Date: 
29 August 2016 
Amendment 1 Date: 
26 June 2017 
Amendment 2 Date: 
01 May 2018 
Amendment 3 Date: 
30 January 2019 
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: 
 
 
Toby Maurer, MD 
Professor of Clinical Dermatology 
Box SFGH 
1001 Potrero Ave., SFGH 90,92 
University of California, San Francisco 
San Francisco, CA 94143 
 
 
 
Signed: 
 
 
Date: 
 
 
Spencer Behr, MD 
Assistant Professor of Clinical Radiology 
Box 0628 
505 Parnassus Ave, Long, 332A 
Universtiy of California, San Francisco, CA 94143 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (SAP) 
 
 
Study No. NAV3-24 
 
 
An Evaluation of the Safety of Escalating Doses of Tc 
99m Tilmanocept by Intravenous (IV) Injection and a 
Comparison to Subcutaneous (SC) Injection in Human 
Immunodeficiency Virus (HIV) Subjects Diagnosed with 
Kaposi Sarcoma (KS) 
 
Version 1.0 
 
 
 
July 23, 2020 
 
 
Prepared for 
Navidea Biopharmaceuticals 
4995 Bradenton Avenue, Suite 240 
Dublin, Ohio 43017 
 
 
 
Prepared by 
STATKING Clinical Services 
759 Wessel Drive 
Fairfield, OH  45014 
513-858-2989 
www.statkingclinical.com 
 
 


Statistical Analysis Plan 
NAV3-24 
Approval Page 
By entering into this Statistical Analysis Plan (SAP), the parties 
acknowledge and agree that this SAP shall be incorporated into and 
subject to the terms of the Master Services Agreement (MSA). Any 
changes requested by Client to this SAP shall be subject to Section I.C of 
the MSA requiring a mutually agreed upon "Change Order" prior to any 
modification of the procedures set forth herein. 
I agree to the format and content of this document. 
Approved by: 
Michael Rosol, PhD 
Chief Medical Officer 
Navidea Biopharmaceuticals 
4995 Bradenton Avenue, Suite 240 
Dublin, Ohio 43017 
mrosol@navidea.com 
Approved by: 
~
· 
~ 
~,i,&_A_/lOAQ__ 
29 J'°t.)L 2020 
Bonnie Abbruz~ 
Date 
Senior Director, Clinical Research and Development 
Navidea Biopharmaceuticals 
4995 Bradenton Avenue, Suite 240 
Dublin, Ohio 43017 
babbruzzese@navidea.com 
Authored by: 
Ian Lees, MS 
Statistician 
STATKING Clinical Services 
759 Wessel Drive 
Fairfield, OH 45014 
513-858-2989 ext. 327 
ian@statkingclinical.com 
STATKING Clinical Services 
Version 1.0 
Page 2 of74 
0·1 1-z °' ) 
2 0 2 0 
Date 
1 
Navldea Blopharmaceutlcals 
July 23, 2020 


Statistical Analysis Plan 
Lori Christman, PhD 
"' 
Statistician 
STATKING Clinical Services 
759 Wessel Drive 
Fairfield, OH 45014 
513-858-2989 ext. 317 
lori@statkinqclinical.com 
Clare Geij7e'r, RN 
Project Manager 
STATKING Clinical Services 
759 Wessel Drive 
Fairfield, OH 45014 
513-858-2989 ext. 304 
clare@statkinqclinical.com 
STATKING Clinical Services 
Version 1.0 
Date 
Page 3 of74 
NAV3-24 
Navidea Biopharmaceuticals 
July 23, 2020 


Statistical Analysis Plan 
 
NAV3-24 
 
 
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Revision History 
 
N/A 
 
 


Statistical Analysis Plan 
 
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Version 1.0                                                                                                              July 23, 2020 
 
Table of Contents 
1.0  SYNOPSIS OF STUDY DESIGN PROCEDURES ...................................... 7 
1.1 Design and Treatment .......................................................................................................... 7 
1.1.1 Localization Definitions .................................................................................................... 8 
1.2 Study Procedures ................................................................................................................. 8 
1.2.1 Cohorts 1 and 2 ................................................................................................................. 8 
1.2.2 Cohort 3 ............................................................................................................................ 10 
1.3 Sample Size ........................................................................................................................ 11 
2.0  DATA ANALYSIS CONSIDERATIONS .................................................... 12 
2.1 Types of Analyses .............................................................................................................. 12 
2.2 Analysis Populations ......................................................................................................... 12 
2.2.1 Subgroup Definitions ...................................................................................................... 12 
2.3 Missing Data Conventions ................................................................................................ 12 
2.4 Interim Analyses ................................................................................................................. 12 
2.5 Study Center Considerations in the Data Analysis ........................................................ 13 
2.6 Documentation and Other Considerations ...................................................................... 13 
3.0 ANALYSIS OF BASELINE PATIENT CHARACTERISTICS ..................... 13 
4.0 ANALYSIS OF EFFICACY ........................................................................ 13 
4.1 Description of Efficacy Variables ..................................................................................... 13 
4.2 Analysis of Efficacy Variables .......................................................................................... 14 
5.0 ANALYSIS OF SAFETY ............................................................................ 16 
6.0 OTHER RELEVANT DATA ANALYSES AND SUMMARIES ................... 18 
6.1 Subject Completion ............................................................................................................ 18 
6.2 Study Drug Administration................................................................................................ 18 


Statistical Analysis Plan 
 
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6.3 Subject Imaging .................................................................................................................. 18 
7.0  LIST OF ANALYSIS TABLES, FIGURES AND LISTINGS ...................... 19 
8.0  REFERENCES .......................................................................................... 21 
APPENDIX A – TABLES, FIGURES AND LISTING SPECIFICATIONS ........ 22 
APPENDIX B – TABLE SHELLS .................................................................... 24 
 
 
 


Statistical Analysis Plan 
 
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1.0  Synopsis of Study Design Procedures 
 
This study will enroll up to fourteen (14) HIV (human immunodeficiency virus) -
positive female or male subjects at least 18 years of age who have biopsy-
confirmed Kaposi Sarcoma (KS).  
 
The primary objective of this study is: 
 
• To determine the safety of escalating doses of Tc 99m tilmanocept in HIV 
subjects with biopsy-confirmed KS 
 
The secondary objectives of this study are: 
 
• Concordance between clinical assessment/diagnosis and the localization 
of Tc 99m tilmanocept by planar and/or SPECT (single photon emission 
computed tomography) / CT (X-ray computed tomography) imaging in 
cutaneous and non-cutaneous sites of KS. 
• 
Qualify and quantify Tc 99m tilmanocept localization intensity on imaging 
with CD206 locale and quantity by histology and immunohistochemistry 
(IHC) in biopsied KS lesions to determine optimal IV dose. 
• 
Concordance of localization of Tc 99m tilmanocept via IV and SC routes 
of administration by planar and/or SPECT/CT imaging in cutaneous and 
non-cutaneous sites of KS. 
 
The exploratory objective of this study is: 
 
• Quantify HHV8 in biopsied KS lesions by real-time polymerase chain 
reaction (qPCR) 
 
General safety will be evaluated by examining the incidence of adverse events 
(AEs) and changes over time in laboratory tests, vital signs, ECGs 
(electrocardiogram) and physical examination findings. 
 
1.1 Design and Treatment 
 
This study is a prospective, open-label, single center study of Tc 99m tilmanocept 
in the localization of KS lesions. Subjects will receive an injection of tilmanocept 
at one of two mass doses radiolabeled with Tc 99m at one of two radiolabel 
doses according to the following table: 
 


Statistical Analysis Plan 
 
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Table 1: Description of Cohorts 
Cohort Number 
Dose 
Sample Size 
1 
100µg/5mCi (IV) 
4 
2 
100µg/10mCi (IV) 
4 
3 
200µg/5mCi SC, 
and 200µg/5mCi IV 
one week later. 
up to 6 
 
The 100 or 200 µg mass doses will require 1 vial of tilmanocept radiolabeled with 
the assigned mCi dose delivered in one syringe for IV injections and two syringes 
for SC injections. Subjects in Cohorts 1 and 2 will have whole body planar 
imaging beginning 60-75 minutes post-injection followed by optional SPECT/CT 
of regions of interest. Subjects in Cohort 3 will have a whole-body planar scan 
with optional SPECT/CT of region of interest scanning beginning at 60- 75 
minutes following both the IV and SC injections and 4- 6 hours following SC 
injection. 
 
1.1.1 Localization Definitions 
 
A localized subject is one for whom Tc 99m tilmanocept by planar and/or 
SPECT/CT imaging results in the illumination of at least one site relative to 
background as determined by the nuclear medicine specialist. 
 
A localized KS lesion is a lesion that is both clinically identified or suspected KS 
(via biopsy-confirmed diagnosis or clinical symptomology) and is illuminated by 
planar and/or SPECT/CT imaging. 
 
Localization in areas other than KS will also be defined per subject and per area, 
where these areas are clinically negative KS locations based on clinical 
symptomology. 
 
1.2 Study Procedures 
 
The study includes procedures at screening (within 30 days of injection), pre-
injection, injection, and post-injection. The post-injection time points include 
measurements at 30 minutes, 60 - 75 minutes, 4 - 6 hours, and 4 - 10 days post-
injection. The following describes the procedures to be conducted on each study 
day at each time point.   
 
1.2.1 Cohorts 1 and 2 
 
Screening Visit (Visit 1, Day -29 to Day 0): The screening visit will include 
informed consent, review of study eligibility, allocation of unique subject number, 
demographic data, medical and surgical history, vital signs (henceforth, vital 


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signs refers to body temperature, heart rate, systolic and diastolic blood pressure 
and respiration rate), physical exam including height and body weight, 
assessment of edema/lymphedema, ECG, blood draw for clinical lab results, 
cutaneous and non-cutaneous KS evaluation, photographs of all visible 
cutaneous KS lesions, KS history and classification, urine sample collection for 
routine urinalysis, urine pregnancy test for women of child-bearing potential, and 
review of medications.  
 
Pre-tilmanocept Injection (Visit 2, Day 1):  
• Concomitant medication review  
• A negative urine pregnancy test for women of child-bearing potential 
• Vital signs (within 30 minutes preceding injection) 
 
Tilmanocept Injection (Day 1): Based on Cohort assignment, subjects will 
receive their study drug dose by IV route of administration.  
 
Post-tilmanocept Injection (Day 1):  
• Within 30 minutes post-injection 
o ECG (completed before vital signs) 
o Vital signs 
o Adverse event assessment 
• 60- 75 minutes post-injection:   
o Adverse event assessment 
o Whole body planar imaging  
o SPECT/CT imaging of region(s) of interest (optional) 
o After the imaging is complete 
 Blood sample for hematology and serum chemistry 
 Urine sample for routine urinalysis 
 Biopsy of designated non-visceral KS lesion  
 Photograph of biopsy lesion with a measurement scale. This 
image is to be stored within the subject’s research file. 
 
Follow-Up Telephone Call (7+3 days post-tilmanocept injection): 
• Concomitant medication review  
• Adverse event assessment 
 
Each subject’s participation in the study is complete after the follow-up telephone 
call.  
 
For determination of secondary endpoints, the Tc 99m tilmanocept whole body 
planar and SPECT/CT images will be visually assessed for localization by a 
Nuclear Medicine Physician. 
 


Statistical Analysis Plan 
 
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1.2.2 Cohort 3 
 
Screening Visit (Visit 1, Day -29 to Day 0): The screening visit will include 
informed consent, review of study eligibility, allocation of unique subject number, 
demographic data, medical and surgical history, vital signs, physical exam 
including height and body weight, assessment of edema/lymphedema, ECG, 
blood draw for clinical lab results, cutaneous and non-cutaneous KS evaluation, 
photographs of all visible cutaneous KS lesions, KS history and classification, 
urine sample collection for routine urinalysis, urine pregnancy test for women of 
child-bearing potential, and review of medications.  
 
Pre-tilmanocept Injection (Visit 2, Day 1):  
• Concomitant medication review  
• A negative urine pregnancy test for women of child-bearing potential 
• Vital signs (within 30 minutes preceding injection) 
 
Tilmanocept Injection (Day 1): Subjects will receive their SC study drug dose 
of 5 mCi Tc 99m/200 µg tilmanocept.  
 
Post-tilmanocept Injection (Day 1):  
• Within 30 minutes post-injection 
o ECG (completed before vital signs) 
o Vital signs 
o Adverse event assessment 
• 60- 75 minutes post-injection:   
o Adverse event assessment 
o Whole body planar imaging  
o SPECT/CT imaging of region(s) of interest (optional) 
• 4- 6 hours post-injection:   
o Adverse event assessment 
o Whole body planar imaging  
o SPECT/CT imaging of region(s) of interest (optional) 
o After the imaging is complete 
 Blood sample for hematology and serum chemistry 
 Urine sample for routine urinalysis 
 
Pre-tilmanocept Injection (Visit 3, Day 7±3):  
• Concomitant medication review  
• A negative urine pregnancy test for women of child-bearing potential 
• Vital signs (within 30 minutes preceding injection) 
 
Tilmanocept Injection (Day 7±3): Subjects will receive their IV study drug dose 
of 5 mCi Tc 99m/200 µg tilmanocept.  
 


Statistical Analysis Plan 
 
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Post-tilmanocept Injection (Day 7±3):  
• Within 30 minutes post-injection 
o ECG (completed before vital signs) 
o Vital signs 
o Adverse event assessment 
• 60- 75 minutes post-injection:   
o Adverse event assessment 
o Whole body planar imaging  
o SPECT/CT imaging of region(s) of interest (optional) 
o After the imaging is complete 
 Blood sample for hematology and serum chemistry 
 Urine sample for routine urinalysis 
 Biopsy of designated non-visceral KS lesion  
 Photograph of biopsy lesion with a measurement scale. This 
image is to be stored within the subject’s research file. 
 
Follow-Up Telephone Call (7+3 days post-IV tilmanocept injection): 
• Concomitant medication review  
• Adverse event assessment 
 
Each subject’s participation in the study is complete after the follow-up telephone 
call. 
 
For determination of secondary endpoints, the Tc 99m tilmanocept whole body 
planar and SPECT/CT images will be visually assessed for localization by a 
Nuclear Medicine Physician. 
 
1.3 Sample Size 
 
The dose escalation portion of this study is a design with no dose de-
escalation. The sequential cohort enrollment characteristics of this design do 
not allow a fixed computation of sample size. In a previous study with subjects 
receiving a 400 μg dose radiolabeled at 10 mCi (i.e., twice the maximum dose 
planned for this study), zero (0) subjects had an Adverse Drug Reaction (ADR). 
Therefore, it is expected that no subjects will have an ADR in this study and 
that each cohort will enroll the minimum planned sample size of subjects. With 
2 cohorts of 4 subjects and one cohort of up to 6 subjects, it is anticipated that 
the study will enroll no more than n=14 subjects. 
 
 


Statistical Analysis Plan 
 
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2.0  Data Analysis Considerations 
 
2.1 Types of Analyses 
 
All results will be based on descriptive statistics. Unless otherwise stated, 
continuous variables will be summarized via sample size, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be 
summarized via frequency counts and percentages.    
 
2.2 Analysis Populations 
 
The following analysis populations will be defined:  
Safety: The safety population will include all enrolled subjects who are injected 
with Tc 99m tilmanocept. 
Intent-to-Diagnose (ITD): The ITD population will include all subjects who sign 
informed consent, who are injected with Tc 99m tilmanocept, and who are 
imaged. 
The analysis of all efficacy endpoints will be conducted on the ITD population. 
The analysis of all safety and baseline subject characteristics will be conducted 
on the safety population.  
2.2.1 Subgroup Definitions 
 
Analyses may be performed by dose group (Cohort 1, 100µg/5mCi; Cohort 2, 
100µg/10mCi; Cohort 3, 200µg/5mCi) and by route of administration (Cohort 3 
SC and IV).  
 
2.3 Missing Data Conventions 
 
The analysis of the primary efficacy variables will be carried out on the observed 
data, i.e., a complete case analysis.   
    
2.4 Interim Analyses 
     
No interim analyses are planned for this study. 
  


Statistical Analysis Plan 
 
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2.5 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). 
 
Because this is a single-center study, there will be no selective pooling of study 
centers in the analysis. 
 
2.6 Documentation and Other Considerations 
 
The data analyses will be conducted using SAS Software, version 9.4 or later. 
 
3.0 Analysis of Baseline Patient Characteristics 
 
Baseline and demographic characteristics will be summarized by dose group for 
all subjects in the safety population. Continuous variables will be displayed via 
summary statistics (mean, median, sample size, standard deviation, minimum, 
and maximum). Categorical variables will be summarized via counts and 
percentages. 
    
A detailed listing of demographic data for each subject will also be provided as 
shown in Appendix B. 
 
4.0 Analysis of Efficacy 
 
4.1 Description of Efficacy Variables 
       
Secondary objectives of the study are to determine the concordance between 
clinical assessment/diagnosis and the localization of Tc 99m tilmanocept by 
planar and/or SPECT/CT imaging in cutaneous and non-cutaneous sites of KS; 
to qualify and quantify Tc 99m tilmanocept localization intensity on imaging with 
CD 206 locale and quantity by histology and IHC in biopsied KS lesions to 
determine the optimal IV dose; and concordance of localization of Tc 99m 
tilmanocept via IV and SC routes of administration by planar and/or SPECT/CT 
imaging in cutaneous and non-cutaneous sites of KS. The relevant endpoints 
are the following: 
 
• Per subject localization rate of Tc 99m tilmanocept in at least one KS 
suspected or confirmed lesion by planar and/or SPECT/CT imaging  
• Per lesion/region concordance of Tc 99m localization with anatomical 
areas of active KS defined by confirmed diagnosis or clinical 
symptomology 
 


Statistical Analysis Plan 
 
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• Localization intensity for each biopsied and clinically defined lesion 
localized on imaging following IV injection as determined by quantitative 
SPECT gamma counts  
• Per biopsied lesion proportion of CD206-expressing cells and proportion 
of HHV8-expressing cells as determined by histology and relative IHC 
fluorescence  
• Per lesion/region concordance of IV vs SC Tc 99m localization with 
anatomical areas of active KS defined by confirmed diagnosis or clinical 
symptomology. 
• Per subject localization rate of Tc 99m tilmanocept in areas other than 
KS by planar and/or SPECT/CT imaging  
• Per area localization rate of Tc 99m tilmanocept in the most frequently 
identified areas other than KS by planar and/or SPECT/CT imaging  
 
 
An exploratory objective of the study is to use quantitative Polymerase Chain 
Reaction (qPCR) methods to measure the amount of Human Herpes Virus 8 
(HHV8) present in the biopsy tissue. 
 
The relevant variables are the following: 
 
• Nuclear medicine specialist determination of presence/absence of 
illumination (i.e., localization positive or negative per anatomic site) 
relative to background from planar and/or SPECT/CT imaging results for 
each subject; 
• Clinically identified presence or absence of KS based on any previous 
diagnostic evaluation; 
• Proportion of CD206-expressing cells (IHC fluorescence);  
• Quantitative SPECT gamma counts for each biopsied lesion localized on 
imaging following IV injection; and, 
• HHV8 concentrations as determined by qPCR for each biopsied lesion. 
 
The calculations and analyses pertaining to each of the variables are shown in 
Sections 4.2. 
 
4.2 Analysis of Efficacy Variables 
 
Localization in KS Sites 
The number and percentage of subjects with at least one biopsy-confirmed or 
clinically suspected KS lesion that has localized with Tc 99m tilmanocept by 
planar and/or SPECT/CT imaging will be computed. A 95% exact confidence 
interval on the per-subject localization rate will be computed. This analysis will 
be performed by dose group and route of administration. 


Statistical Analysis Plan 
 
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Per-lesion/region localization of Tc 99m tilmanocept by planar and/or SPECT/CT 
imaging will be computed across all biopsy-confirmed or clinically suspected KS 
lesions of all subjects. A 95% exact confidence interval on the per-lesion/region 
localization will be calculated. This analysis will be performed by dose group and 
route of administration. 
 
An analysis table will also be provided to display the counts of KS lesions 
localized by imaging that were not previously identified clinically. 
 
Concordance between IV and SC tilmanocept in biopsy-confirmed or clinically-
suspected KS lesion sites will be assessed with a cross-tabulation of the IV and 
SC findings, including the joint probability distribution. The sampling unit for this 
analysis will be the site. An exact conditional version of McNemar’s test will be 
performed to test the hypotheses 
 
𝐻𝐻0: 𝜋𝜋𝐼𝐼𝐼𝐼= 𝜋𝜋𝑆𝑆𝑆𝑆
𝐻𝐻𝐴𝐴: π𝐼𝐼𝐼𝐼≠π𝑆𝑆𝑆𝑆, 
 
where πIV and π𝑆𝑆𝑆𝑆 represent the probabilities of localization with IV (only) 
tilmanocept and SC (only) tilmanocept, respectively. In addition, the number and 
proportion of subjects with concordance and reverse concordance of observed 
sites of discrete localization of Tc 99m tilmanocept following IV and SC 
localization will be summarized. 
 
Localization Intensity by Planar and/or SPECT/CT Imaging 
Tc 99m tilmanocept average pixel intensity and percent above background will 
be summarized with descriptive statistics (mean, standard deviation, minimum, 
median, maximum, and range) for each biopsied lesion localized on imaging 
following IV injection of Tc 99m tilmanocept by dose group. Summary statistics 
will be presented separately by imaging type (planar, SPECT/CT).  
 
Proportion of CD206-expressing Cells  
Per biopsied-lesion proportion of CD206-expressing cells as determined by 
histology and IHC fluorescence will be summarized by descriptive statistics 
(mean, standard deviation, minimum, median, maximum, and range) by dose 
group.  
  
Localization in Non-KS Sites 
The number and percentage of subjects with at least one anatomical site other 
than KS that has been localized with Tc 99m tilmanocept by planar and/or 
SPECT/CT imaging will be computed. A 95% exact confidence interval on the 
per subject localization rate will be computed. This analysis will be performed by 
dose group and route of administration. 
 


Statistical Analysis Plan 
 
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Locations showing localization of Tc 99m tilmanocept by planar and/or 
SPECT/CT imaging will be computed across all sites other than biopsy-
confirmed or clinically suspected KS sites of all subjects. A 95% exact confidence 
interval on per location localization will be calculated. (i.e. the rate of localization 
of each site with respect to the number of subjects). This analysis will be 
performed by dose group and route of administration. 
 
5.0 Analysis of Safety 
 
Adverse Drug Reactions (ADRs) are defined as all noxious and unintended 
responses to a medicinal product related to any dose or dose regimen. The 
phrase ‘responses to a medicinal product’ means that a causal relationship 
between a medicinal product and an adverse event. The primary safety variable 
is the proportion of patients experiencing at least one ADR. The number and 
percentage of subjects with ADRs will be tabulated by dose group and overall. 
Other safety endpoints are noted below. 
 
Analysis of Safety Endpoints 
Attention shall be paid to the occurrence of adverse events (AEs) from the time 
of signing informed consent until exit from the study. Events occurring prior to Tc 
99m tilmanocept administration will be recorded in the subject’s medical history 
unless determined to be related to the study procedure. A treatment emergent 
adverse event (TEAE) is defined as an adverse event whose start date is on or 
after the first study drug administration date. If the study drug administration date 
and/or the AE start date are missing, the AE will be considered treatment 
emergent. 
 
Prior to analysis, all AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). The MedDRA version used will be stated in the 
final validated tables. Based on these coded terms, AEs and TEAEs will be 
summarized by dose group and overall as follows:  
 
• by system organ class and preferred terms; 
• by system organ class and preferred terms and relation to study drug; and, 
• by system organ class and preferred terms and severity. 
 
 
In addition to the above endpoints, the following describes the analyses of the 
other safety data being collected for the study. 
 
Vital Signs  
Vital signs will include heart rate, blood pressure, respiration rate, and body 
temperature. Vital signs will be taken during screening, prior to study drug 
administration on Day 1 (and Day 7 [± 3] for Cohort 3), and within 30 minutes 
following study drug administration. For each vital sign, summary statistics 


Statistical Analysis Plan 
 
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(mean, standard deviation, minimum, median, maximum, range, n) on the raw 
values as well as their changes from pre-injection on Day 1 (and Day 7 [± 3] for 
Cohort 3) will be presented by dose group and overall.  Time points included in 
this analysis are Day 1 (and Day 7 [± 3] for Cohort 3) within 30 minutes pre-
injection and within 30 minutes post-Injection. If repeat vital signs are taken at a 
given time point, then the last measurement will be used for the analysis tables. 
A 
shift 
table 
will 
be 
created 
showing 
shifts 
Abnormal/Abnormal, 
Abnormal/Normal, Normal/Abnormal, Normal/Normal from pre-injection to post-
injection of Tc 99m tilmanocept. This analysis will be performed by dose group 
and overall. 
 
All vital signs will be listed, including those not presented in the analysis tables.    
 
Physical Exams 
A complete physical exam will be performed during screening.  A data listing of 
the physical exam results will be created as shown in Appendix B. 
 
Concomitant Medications 
All concomitant medications will be coded with WHO Drug Dictionary (Uppsala 
Monitoring Centre) version March 2017 or later. A data listing will be constructed 
with Preferred Term, Verbatim Term, ATC Level 1 Code, and ATC Level 4 Code.  
A summary table will be provided to show the counts and percentages of subjects 
taken medications by ATC Level 4 Code and Preferred Term by dose group and 
overall. 
 
Clinical Laboratory Parameters 
Changes in hematology, clinical serum chemistry and urinalysis between 
screening (i.e., baseline) and the post-injection time point will be calculated, and 
descriptive statistics will be calculated on the raw and change from baseline 
values by dose group and overall. A copy of the normal laboratory values for all 
laboratories utilized for this study will be submitted to the Sponsor (or designee) 
prior to initiation of the study. A shift table will be created showing shifts 
Abnormal/Abnormal, Abnormal/Normal, Normal/Abnormal, Normal/Normal from 
screening baseline to post-injection of Tc 99m tilmanocept. This analysis will be 
performed by dose group and overall. 
 
ECG 
ECG recordings will be obtained during screening (i.e., baseline) and within 30 
minutes following study drug administration. ECG parameters (heart rate, PR 
interval, QRS interval, QT interval, and QTcF interval) will be summarized as raw 
values and change-from-baseline (CFB). A shift table will be created showing 
shifts Abnormal/Abnormal, Abnormal/Normal, Normal/Abnormal, Normal/Normal 
from screening baseline to post-injection of Tc 99m tilmanocept. Both the 
quantitative and shift table analyses will be performed by dose group and overall. 
 


Statistical Analysis Plan 
 
NAV3-24 
 
 
Page 18 of 74 
STATKING Clinical Services                                                       Navidea Biopharmaceuticals 
Version 1.0                                                                                                              July 23, 2020 
 
6.0 Other Relevant Data Analyses and Summaries 
 
6.1 Subject Completion 
 
A table will be constructed with counts of screen failures and enrolled subjects.  
Of those enrolled, counts and percentages of the number of subjects 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 dose group and overall.  
A data listing of all subject completion and withdrawal data will also be 
constructed. 
6.2 Study Drug Administration 
 
The mass dose and radioactivity of Tc 99m tilmanocept injected will be 
summarized by dose group and overall.   
 
6.3 Subject Imaging 
 
Each subject will undergo whole body planar imaging. SPECT/CT imaging of 
region(s) of interest is optional for each subject. Results of all imaging procedures 
will be listed. 
 
 


Statistical Analysis Plan 
 
NAV3-24 
 
 
Page 19 of 74 
STATKING Clinical Services                                                       Navidea Biopharmaceuticals 
Version 1.0                                                                                                              July 23, 2020 
 
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 Cohort 
X 
X 
2 
Demographics and Baseline Data Summary Statistics 
by Cohort – Continuous Variables (Safety Population) 
X 
X 
3 
Demographics and Baseline Data Summary Statistics 
by Cohort – Categorical Variables (Safety Population) 
X 
X 
4 
Summary of Study Drug Administration by Cohort 
(Safety Population) 
X 
X 
5 
Subject-Level Localization of KS Lesions – Nuclear 
Medicine Findings (ITD Population) 
X 
X 
6 
Lesion-Level Localization of KS Lesions – Nuclear 
Medicine Findings (ITD Population) 
X 
X 
7 
Additional KS Lesions Identified from Imaging That 
Were Not Seen Clinically – Nuclear Medicine Findings 
(ITD Population) 
X 
X 
8 
Lesion-Level Non-Localization of KS Lesions – Nuclear 
Medicine Findings (ITD Population) 
X 
X 
9 
Number and Percentage of Concordant and Reverse 
Concordant Lesions (ITD Population) 
X 
X 
10 
Summary of Imaging-Localized Biopsied Lesion 
Localization Intensity by Cohort – Imaging = Planar (ITD 
Population) 
X 
X 
11 
Summary of Imaging-Localized Biopsied Lesion 
Localization Intensity by Cohort – Imaging = SPECT/CT 
(ITD Population) 
X 
X 
12 
Summary of Per Biopsied Lesion Proportion of CD206-
Expressing Cells and Proportion of HHV8-Expressing 
Cells by IHC (ITD Population) 
X 
X 
13 
Summary of Per Biopsied Lesion HHV8 Quantitation by 
qPCR (ITD Population) 
X 
X 
14 
Subject-Level Localization in Areas Other Than KS Sites 
– Nuclear Medicine Findings (ITD Population) 
X 
X 
15 
Site-Level Localization in Areas Other Than KS Sites – 
Nuclear Medicine Findings (ITD Population) 
X 
X 
16 
Number and Percent of Subjects with Adverse Events 
(Safety Population) 
X 
X 
17 
Summary of Adverse Events (Safety Population) 
X 
X 
18 
Number and Percent of Subjects with Treatment 
Emergent Adverse Events (Safety Population) 
X 
X 
19 
Summary of Treatment Emergent Adverse Events 
(Safety Population) 
X 
X 
20 
Number and Percent of Subjects with Adverse Drug 
Reactions (Safety Population) 
X 
X 
21 
Number and Percent of Subjects with Serious Adverse 
Events (Safety Population) 
X 
X 
22 
Vital Sign Parameters Summary Statistics (Safety 
Population) 
X 
X 


Statistical Analysis Plan 
 
NAV3-24 
 
 
Page 20 of 74 
STATKING Clinical Services                                                       Navidea Biopharmaceuticals 
Version 1.0                                                                                                              July 23, 2020 
 
 
Table 
No. 
 
 
Table Title 
Included 
in Final 
Tables 
 
Shown in 
Appendix B 
 
 
 
 
23 
Vital Sign Shift Table (Safety Population) 
X 
X 
24 
Clinical Laboratory Parameters Summary Statistics 
(Safety Population) 
X 
X 
25 
Clinical Laboratory Parameters Shift Table (Safety 
Population) 
X 
X 
26 
Electrocardiogram Parameters Summary Statistics 
(Safety Population) 
X 
X 
27 
Electrocardiogram Shift Table (Safety Population) 
X 
X 
28 
Number and Percent of Subjects Taking Concomitant 
Medications (Safety Population) 
X 
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 
Medical History Data Listing 
X 
X 
DL7 
Prior and Concomitant Medications Data Listing 
X 
X 
DL8 
Adverse Events Data Listing 
X 
X 
DL9 
Subject Laboratory Profiles - Hematology Data Listing 
X 
X 
DL10 
Subject Laboratory Profiles – Serum Chemistry Data 
Listing 
X 
X 
DL11 
Subject Laboratory Profiles – Urinalysis Data Listing 
X 
X 
DL12 
Electrocardiogram Data Listing 
X 
X 
DL13 
Physical Exam Data Listing 
X 
X 
DL14 
Vital Signs Data Listing 
X 
X 
DL15 
Study Drug Administration Data Listing  
X 
X 
DL16 
Post-Injection Imaging Data Listing 
X 
X 
DL17 
Quantitative Imaging Results Data Listing 
X 
X 
DL18 
Qualitative Imaging Results Data Listing 
X 
X 
DL19 
Lesion Biopsy Results Data Listing 
X 
X 
DL20 
Clinical KS Lesion Assessment Listing 
X 
X 
DL21 
Telephone Follow Up Contact Data Listing 
X 
X 


Statistical Analysis Plan 
 
NAV3-24 
 
 
Page 21 of 74 
STATKING Clinical Services                                                       Navidea Biopharmaceuticals 
Version 1.0                                                                                                              July 23, 2020 
 
8.0  References 
 
NA 


Statistical Analysis Plan 
 
NAV3-24 
 
 
Page 22 of 74 
STATKING Clinical Services                                                       Navidea Biopharmaceuticals 
Version 1.0                                                                                                              July 23, 2020 
 
Appendix A – Tables, Figures and Listing Specifications 
 
Orientation 
 
Tables, figures, and listings will be displayed in landscape.  
 
Margins  
 
Margins will be 1 inch on all sides.  Table, figure, and listing boundaries will not 
extend into the margins. 
 
Font 
 
Courier New, 8 point. 
 
Headers 
 
The table number will be on the second line of the title area.  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, one line 
above the name of the table. 
 
Footers 
 
- The first line will be a solid line. 
- Next will be any footnotes regarding information displayed in the table. 
- Below these footnotes will be displayed “STATKING Clinical Services (Date)” 
on the far left. 
- The last line will display the name of the SAS program that generated the 
table and (if applicable) the source data reference. 
 
Table Disclaimer 
 
The format of the mock tables shown in the appendix of this Statistical Analysis 
Plan (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 
 
NAV3-24 
 
 
Page 23 of 74 
STATKING Clinical Services                                                       Navidea Biopharmaceuticals 
Version 1.0                                                                                                              July 23, 2020 
 
 
Missing Values 
 
All missing values will be displayed on the output tables/listings as blanks. 
 
Computation Values for Study Dates 
 
The date format to be used is dd-mmm-yyyy.  Missing parts of dates are not 
shown (e.g., for a missing day value, the value displayed is in mmm-yyyy 
format).  When date computations are necessary, the following table indicates 
the substitutions used in order to make those computations. 
 
Scenario 
Value Used for Computations 
Start date – Missing month and day values  
January 1 of the indicated year 
Start date – Missing day values  
The first day of the indicated month 
Stop date – Missing month and day values  
December 31 of the indicated year 
Stop date – Missing day values  
The last day of the indicated month 
 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 24 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
Appendix B – Table Shells  
 
 
 
 
 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 25 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
 
Page x of y 
 
Table 1. Subject Disposition by Cohort  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
 
 
 
 
 
  
            
 
 
 
 
 
 
 
Cohort 1 
Cohort 2 
Cohort 3 
 
Overall 
Screen Failures 
 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Enrolled 
 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Completed 
 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
 
 
 
 
 
Withdrawn  
 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
 
 
 
 
 
Reason for Withdrawal 
Adverse Event 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Lost To Follow-Up 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Death 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Physician Decision 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Protocol Deviation 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Study Terminated by 
Sponsor 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Withdrawal by Subject 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
Other 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
xx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
The denominator for all percentages in the table is the number of enrolled subjects in the respective cohort and overall. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 26 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
 
 
Page x of y 
 
Table 2. Demographics and Baseline Data Summary Statistics by Cohort – Continuous Variables 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
             
 
Variable 
Group 
 
Mean 
 
Std Dev 
 
n 
 
Min 
 
Max 
 
Median 
 
 
 
 
 
 
 
 
Age (years) 
Cohort 1 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Cohort 2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Cohort 3 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Overall 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
Height (in) 
Cohort 1 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Cohort 2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Cohort 3 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Overall 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
Weight (lb) 
Cohort 1 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Cohort 2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Cohort 3 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Overall 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
Number of KS lesionsa 
Cohort 1 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Cohort 2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Cohort 3 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Overall 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
______________________________________________________________________________________________________________________________________ 
a Number of KS lesions identified in screening, including cutaneous and non-cutaneous lesions. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 27 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 3. Demographics and Baseline Data Summary Statistics by Cohort – Categorical Variables 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
                   
 
Demographics 
Variable 
 
 
Category 
Cohort 1 
(N=xxx) 
Cohort 2 
(N=xxx) 
Cohort 3 
(N=xxx) 
 
Overall 
(N=xxx) 
 
 
 
 
 
 
Gender 
Male 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
 
Female 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
 
 
 
 
 
 
Race 
American Indian or Alaska 
Native 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
 
Asian 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
 
Black or African American 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
 
Native Hawaiian or Other 
Pacific Islander 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
 
White 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
 
Other 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
 
 
 
 
 
 
Ethnicity 
Hispanic or Latino 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
 
Not Hispanic or Latino 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
xxx 
(xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 28 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 4. Summary of Study Drug Administration by Cohort 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
           
 
Group 
Mean 
Std Dev 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
Tc 99m Dose (mCi) 
Cohort 1 IV 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
Cohort 2 IV 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
Cohort 3 IV 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
Cohort 3 SC 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mass Dose (µg) 
Cohort 1 IV 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
Cohort 2 IV 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
Cohort 3 IV 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
Cohort 3 SC 
xxxx 
xxxx 
xx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC.  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 29 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 5. Subject-Level Localization of KS Lesions–Nuclear Medicine Findings 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
                   
Group 
Number 
of Subjects 
Number 
(Proportion) 
Localized 
95% Exact One-
Sided Binomial 
CI for 
Proportion 
 
 
 
 
Cohort 1 IV 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
Cohort 2 IV 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
Cohort 3 IV 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
Cohort 3 SC 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
 
 
 
 
All Cohorts 
Combined 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC.  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 30 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 6. Lesion-Level Localization of KS Lesions–Nuclear Medicine Findings 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
                   
Group 
Number of 
Clinically 
Identified 
Lesionsa 
Number 
(Proportion) 
Localized by 
Imaging 
95% Exact One-
Sided Binomial 
CI for 
Proportion 
 
 
 
 
Cohort 1 IV 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
Cohort 2 IV 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
Cohort 3 IV 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
Cohort 3 SC 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
 
 
 
 
All Cohorts 
Combined 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Number of cutaneous and non-cutaneous lesions identified in screening.  
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC.  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 31 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 7. Additional KS Lesions Identified from Imaging That Were Not Seen Clinically – Nuclear 
Medicine Findings 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
                   
Group 
Number of 
Identified 
Lesions 
Number (Proportion) of 
Subjects with at Least 
1 Identified Lesion 
 
 
 
Cohort 1 IV 
xx 
xxx (xxx) 
 
 
 
Cohort 2 IV 
xx 
xxx (xxx) 
 
 
 
Cohort 3 IV 
xx 
xxx (xxx) 
 
 
 
Cohort 3 SC 
xx 
xxx (xxx) 
 
 
 
 
 
 
All Cohorts 
Combined 
xx 
xxx (xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC.  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 32 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 8. Lesion-level Non-Localization of KS Lesions – Nuclear Medicine Findings 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
                   
Group 
Number of 
Clinically 
Identified 
Lesionsa 
Number 
(Proportion) Not 
Localized by 
Imaging 
95% Exact One-
Sided Binomial 
CI for 
Proportion 
 
 
 
 
Cohort 1 IV 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
Cohort 2 IV 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
Cohort 3 IV 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
Cohort 3 SC 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
 
 
 
 
All Cohorts 
Combined 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Number of cutaneous and non-cutaneous lesions identified in screening. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 33 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 9. Number and Percentage of Concordant and Reverse Concordant Lesions 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
                   
 
SC Result 
 
 
 
 
IV Result 
Localized 
Not Localized 
Total 
Concordance 
Reverse 
Concordance 
p-Value 
(McNemar’s Test) 
 
 
 
 
 
 
 
Localized 
xx(xxx%) 
xx(xxx%) 
xx(xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx 
 
 
 
 
 
 
 
Not Localized 
xx(xxx%) 
xx(xxx%) 
xx(xxx%) 
 
 
 
 
 
 
 
 
 
 
Total 
xx(xxx%) 
xx(xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 34 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 10. Summary of Imaging-Localized Biopsied Lesion Localization Intensity by Cohort –  
Imaging = Planar 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
 
 
                   
Group 
 
 
Variablea 
Mean 
Std 
Dev 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 IV 
 
Avg Pixel Intensity 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Percent Above Background 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Cohort 3 IV 
 
Avg Pixel Intensity 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Percent Above Background 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All Cohorts Combined 
 
Avg Pixel Intensity 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Percent Above Background 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a All summary statistics are performed on the subject level.   
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC.  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 35 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 11. Summary of Imaging-Localized Biopsied Lesion Localization Intensity by Cohort –  
Imaging = SPECT/CT 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
 
 
                   
Group 
 
 
Variablea 
Mean 
Std 
Dev 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 IV 
 
Avg Pixel Intensity 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Percent Above Background 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Cohort 3 IV 
 
Avg Pixel Intensity 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Percent Above Background 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All Cohorts Combined 
 
Avg Pixel Intensity 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Percent Above Background 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a All summary statistics are performed on the subject level.   
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC.  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 
 
 
 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 36 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 12. Summary of Per Biopsied Lesion Proportion of CD206-Expressing Cells and Proportion of 
HHV8-Expressing Cells by IHC 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
                   
Group 
 
Variable 
Mean 
Std 
Dev 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
Proportion of CD206-Expressing Cells 
xx 
xx 
xx 
xx 
xx 
xx 
 
Proportion of HHV8-Expressing Cells 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Cohort 3 
Proportion of CD206-Expressing Cells 
xx 
xx 
xx 
xx 
xx 
xx 
 
Proportion of HHV8-Expressing Cells 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
All Cohorts 
Combined 
Proportion of CD206-Expressing Cells 
xx 
xx 
xx 
xx 
xx 
xx 
 
Proportion of HHV8-Expressing Cells 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
_____________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC.  
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 37 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 13. Summary of Per Biopsied Lesion HHV8 Quantitation by qPCR 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
                   
Group 
 
Variable (Unit) 
Mean 
Std 
Dev 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
Cohort 2 
HHV8 (RFU)  
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Cohort 3 
HHV8 (RFU) 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 38 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
 
Page x of y 
 
Table 14. Subject-Level Localization in Areas Other Than KS Sites – Nuclear Medicine Findings 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
                   
Group 
Number of 
Subjects  
Number  
(Proportion) 
Localized 
95% Exact One-
Sided Binomial 
CI for 
Proportion 
 
 
 
 
Cohort 1 IV 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
Cohort 2 IV 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
Cohort 3 IV 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
Cohort 3 SC 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
All Cohorts Combined 
xx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 39 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
 
Page x of y 
 
Table 15. Site-Level Localization in Areas Other Than KS Sites – Nuclear Medicine Findings 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
                   
Group 
 
 
 
Anatomical Site 
Number  
(Proportion) of 
Subjects with Site 
Localized 
95% Exact One-
Sided Binomial 
CI for 
Proportion 
 
 
 
 
Cohort 1 IV 
xxxxxxxxxxxxxxxx 
xxx (xxx) 
(xxx, xxx) 
 
xxxxxxxxxxxxxxxx 
 
 
Cohort 2 IV 
xxxxxxxxxxxxxxxx 
xxx (xxx) 
(xxx, xxx) 
 
xxxxxxxxxxxxxxxx 
 
 
Cohort 3 IV 
xxxxxxxxxxxxxxxx 
xxx (xxx) 
(xxx, xxx) 
 
xxxxxxxxxxxxxxxx 
 
 
Cohort 3 SC 
xxxxxxxxxxxxxxxx 
xxx (xxx) 
(xxx, xxx) 
 
xxxxxxxxxxxxxxxx 
 
 
All Cohorts Combined 
xxxxxxxxxxxxxxxx 
xxx (xxx) 
(xxx, xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 40 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
 
Page x of y 
 
Table 16. Number and Percent of Subjects with Adverse Events  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
Adverse Event Categorya: 
Cohort 1 
(N=xxx) 
Cohort 2 
(N=xxx) 
Cohort 3 
(N=xxx) 
Overall 
(N=xxx) 
 
 
 
 
 
Total Number of Adverse Events 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Subjects with at Least One Adverse Event 
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. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 41 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 17. Summary of Adverse Events  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxxx) 
 
 
 
 
Cohort 1 
(N=xxx) 
Cohort 2 
(N=xxx) 
Cohort 3 
(N=xxx) 
Overall 
(N=xxx) 
 
 
 
 
 
Subjects with at Least One 
Adverse Event 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
Maximum AE 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 AE 
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 AE 
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 
Serious Adverse Event 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 42 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 18. Number and Percent of Subjects with Treatment Emergent Adverse Events  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
Adverse Event Categorya: 
Cohort 1 
(N=xxx) 
Cohort 2 
(N=xxx) 
Cohort 3 
(N=xxx) 
Overall 
(N=xxx) 
 
 
 
 
 
Total Number of Treatment Emergent Adverse 
Events (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. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 43 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 19. Summary of Treatment Emergent Adverse Events  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxxx) 
 
 
 
 
Cohort 1 
(N=xxx) 
Cohort 2 
(N=xxx) 
Cohort 3 
(N=xxx) 
Overall 
(N=xxx) 
 
 
 
 
 
Subjects with at Least One 
Treatment Emergent Adverse 
Event (TEAE) 
xxx (xxx%) 
xxx (xxx%) 
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 
Serious TEAE Adverse Event 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 44 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 20. Number and Percent of Subjects with Adverse Drug Reactions  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
Adverse Event Categorya: 
Cohort 1 
(N=xxx) 
Cohort 2 
(N=xxx) 
Cohort 3 
(N=xxx) 
Overall 
(N=xxx) 
 
 
 
 
 
Total Number of Adverse Drug Reactionsb 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Subjects with at Least One Adverse Drug Reaction 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 Adverse drug reactions are defined as all noxious and unintended responses to a medicinal product related to any dose or dose 
regimen. The phrase ’responses to a medicinal product’ means that a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility, i.e. the relationship cannot be ruled out. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 45 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 21. Number and Percent of Subjects with Serious Adverse Events  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
Adverse Event Categorya: 
Cohort 1 
(N=xxx) 
Cohort 2 
(N=xxx) 
Cohort 3 
(N=xxx) 
Overall 
(N=xxx) 
 
 
 
 
 
Total Number of Serious Adverse 
Events 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Subjects with at Least One 
Serious Adverse Event 
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. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 46 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 22.  Vital Sign Parameters Summary Statistics  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
Group 
Vital Sign  
Parameter (units) 
Visit  
Data Typea 
Mean 
Std 
Dev 
n 
Min 
Max 
Median 
Cohort 1 IV 
xxxxxxxxxx (xxx) 
Pre-Injection (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
30 min Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Cohort 2 IV 
xxxxxxxxxx (xxx) 
Pre-Injection (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
30 min Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Cohort 3 IV 
xxxxxxxxxx (xxx) 
Pre-Injection (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
30 min Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Cohort 3 SC 
xxxxxxxxxx (xxx) 
Pre-Injection (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
30 min Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All IV Cohorts 
xxxxxxxxxx (xxx) 
Pre-Injection (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
30 min Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
______________________________________________________________________________________________________________________________________  
a RAW = data recorded in database; CFB = change from baseline  
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 47 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 23.  Vital Sign Shift Table 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
Group 
Vital Sign  
Parameter (units) 
Baseline 
Normal/Post 
Normal 
Baseline 
Abnormal/Post 
Normal 
Baseline 
Normal/Post 
Abnormal 
Baseline 
Abnormal/Post 
Abnormal 
 
 
 
 
 
 
Cohort 1 IV 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Cohort 2 IV 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Cohort 3 IV 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Cohort 3 SC 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
All IV Cohorts 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
______________________________________________________________________________________________________________________________________  
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 48 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 24.  Clinical Laboratory Parameters Summary Statistics 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
                                  
Group 
Laboratory Panel/ 
Parameter (units) 
Visit  
Data Typea 
Mean 
Std 
Dev 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
 
 
Cohort 1 IV 
xxxxxxxxxxxxx/ 
xxxxxxxxxx (xxx) 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Cohort 2 IV 
xxxxxxxxxxxxx/ 
xxxxxxxxxx (xxx) 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Cohort 3 IV 
xxxxxxxxxxxxx/ 
xxxxxxxxxx (xxx) 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Cohort 3 SC 
xxxxxxxxxxxxx/ 
xxxxxxxxxx (xxx) 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
All IV Cohorts 
xxxxxxxxxxxxx/ 
xxxxxxxxxx (xxx) 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
______________________________________________________________________________________________________________________________________ 
a RAW = data recorded in database; CFB = change from baseline  
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 49 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 25.  Clinical Laboratory Parameters Shift Table 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
Group 
Laboratory Panel/Parameter (units) 
Baseline 
Normal/Post 
Normal 
Baseline 
Abnormal/Post 
Normal 
Baseline 
Normal/Post 
Abnormal 
Baseline 
Abnormal/Post 
Abnormal 
 
 
 
 
 
 
Cohort 1 IV 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Cohort 2 IV 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Cohort 3 IV 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Cohort 3 SC 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
All IV Cohorts 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
xxxxxxxxxxxxx/xxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
______________________________________________________________________________________________________________________________________  
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 50 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
 
Page x of y 
 
Table 26.  Electrocardiogram Parameters Summary Statistics 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
                                  
Group 
Parameter (units) 
Visit  
Data Typea 
Mean 
Std 
Dev 
n 
Min 
Max 
Median 
 
 
 
 
 
 
 
 
 
 
Cohort 1 IV 
xxxxxxxxxxxxx (xxx) 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
30 min Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Cohort 2 IV 
xxxxxxxxxxxxx (xxx) 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
30 min Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Cohort 3 IV 
xxxxxxxxxxxxx (xxx) 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
30 min Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Cohort 3 SC 
xxxxxxxxxxxxx (xxx) 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
30 min Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
All IV Cohorts 
xxxxxxxxxxxxx (xxx) 
Screening (Baseline) 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
30 min Post-Injection 
RAW 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
CFB 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
______________________________________________________________________________________________________________________________________ 
a RAW = data recorded in database; CFB = change from baseline  
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas  
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 51 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
Page x of y 
 
 
Table 27. Electrocardiogram Shift Table 
 
 
Navidea Biopharmaceuticals – Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
Group 
Baseline Normal/Post 
Normal 
Baseline Abnormal/Post 
Normal 
Baseline Normal/Post 
Abnormal 
Baseline Abnormal/Post 
Abnormal 
 
 
 
 
 
Cohort 1 IV 
xxx 
xxx 
xxx 
xxx 
Cohort 2 IV 
xxx 
xxx 
xxx 
xxx 
Cohort 3 IV 
xxx 
xxx 
xxx 
xxx 
Cohort 3 SC 
xxx 
xxx 
xxx 
xxx 
All IV Cohorts 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________________________________________________________________________________________________  
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (month day, year) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 52 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Table 28. Number and Percent of Subjects Taking Concomitant Medications  
 
 
Navidea Biopharmaceuticals – Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
Medicationa: 
Cohort 1 
(N=xxx) 
Cohort 2 
(N=xxx) 
Cohort 3 
(N=xxx) 
Overall 
(N=xxx) 
 
 
 
 
 
Total Number of Medications 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Patients Taking at Least One Medication 
xxx (xxx%) xxx (xxx%) xxx (xxx%) xxx (xxx%) 
 
 
 
 
 
ATC Level 4 Term 1 
xxx (xxx%) xxx (xxx%) xxx (xxx%) xxx (xxx%) 
    ATC Preferred Term 1 
xxx (xxx%) xxx (xxx%) xxx (xxx%) xxx (xxx%) 
    ATC Preferred Term 2 
xxx (xxx%) xxx (xxx%) xxx (xxx%) xxx (xxx%) 
 
 
 
 
 
ATC Level 4 Term 2 
xxx (xxx%) xxx (xxx%) xxx (xxx%) xxx (xxx%) 
    ATC Preferred Term 1 
xxx (xxx%) xxx (xxx%) xxx (xxx%) xxx (xxx%) 
    ATC Preferred Term 2 
xxx (xxx%) xxx (xxx%) xxx (xxx%) xxx (xxx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a Medications coded with WHO Coding Dictionary xxxxxxxx. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (month day, year) 
Source Program: xxxxxxx.sas 
 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 53 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 1. Subject Disposition Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
Cohort 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 54 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 2. Inclusion/Exclusion Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Cohort 
 
 
Subject 
No. 
 
Did Subject 
Meet All 
Eligibility 
Criteria? 
Criterion  
 
 
Criterion 
Category 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 55 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 3. Protocol Deviations Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Cohort 
 
 
Subject 
No. 
 
 
 
Subject 
Visit 
 
Date of Deviation 
Deviation Description  
 
 
Deviation  
Category 
 
 
 
 
 
 
xxxxxx xxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxxxx xxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxxxx xxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
xxxxxx xxxx 
xxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 56 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 4. Demographics Data Listing  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
                        
 
                                                                                                                             
 
 
 
Cohort 
 
 
Subject 
No. 
 
Informed 
Consent 
Date/Time 
 
Date 
of 
Birth 
 
 
Age 
(yrs) 
 
 
 
Gender 
 
 
 
Race 
 
 
 
Ethnicity 
 
Screening 
Height 
(in)  
 
Screening 
Weight 
(lb) 
KS 
Lesions 
at 
Screening 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxx 
xxxxxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxx 
xxxxxx 
xxxxxx 
xxx 
xxxxxx xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________  
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 57 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 5. Subjects Excluded from ITD Population Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
All Enrolled Subjects (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
                                                                                                                                       
 
 
 
Cohort 
 
 
Subject No. 
 
 
Reason for Exclusion 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________  
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 58 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
 
Page x of y 
 
Data Listing 6. Medical History Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
Cohort 
 
 
Subject No. 
 
 
 
 
MedDRA System Organ Classa/ 
MedDRA Preferred Term/ 
CRF Verbatim Term 
Start Date  
 
 
 
 
 
 
Ongoing? 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxx 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Medical history terms coded with MedDRA Coding Dictionary Version xxx. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 59 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 7. Prior and Concomitant Medications Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
Cohort 
 
 
Subject No. 
 
 
WHO Drug Preferred Terma/ 
Verbatim Drug Name/ 
Indication/ 
ATC Level 1 Code/ 
ATC Level 4 Code 
 
 
 
 
 
Start 
Date 
 
 
 
 
 
 
Stop 
Date 
 
 
 
 
 
 
Route 
 
 
 
 
 
 
Ongoing? 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx  
xxxxx 
xxxxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxx  
xxxxx 
xxxxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
______________________________________________________________________________________________________________________________________ 
a Concomitant medications coded with WHO Coding Dictionary xxxxxxxxx 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 60 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 8. Adverse Events Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
 
Cohort 
 
 
Subject 
No. 
AE Start 
Date and 
Time/ 
End Date 
and Time 
Start Date 
and Time of 
most recent 
tilmanocept 
Injection 
MedDRA System 
Organ Classa/ 
MedDRA Preferred 
Term/ 
CRF Verbatim Term 
Treatment 
Emergent? 
Adverse 
Drug 
Reaction 
(Y/N) 
Severity  
Relation to: 
Tc-99m 
tilmanocept/ 
Procedure 
Serious 
Outcome 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxxx 
xxxxxxx 
xxxxxxx/ 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxx 
xxx 
xxxxxxxx 
xxxxxxxx/ 
xxxxxxxx 
 
xxx 
 
xxxxxxx
x 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxxxxx 
xxxxxxx 
xxxxxxx/ 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
xxx 
xxx 
xxxxxxxx 
xxxxxxxx/ 
xxxxxxxx 
 
xxx 
 
xxxxxxx
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a Adverse events coded with MedDRA Coding Dictionary Version xxx. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 61 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 9. Subject Laboratory Profiles - Hematology Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Normal Range 
 
 
 
Cohort 
 
 
Subject 
No. 
 
 
 
Visit 
Sample Date/ 
Time 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 62 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 10. Subject Laboratory Profiles – Serum Chemistry Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Normal Range 
 
 
 
Cohort 
 
 
Subject 
No. 
 
 
 
Visit 
Sample Date/ 
Time 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 63 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 11. Subject Laboratory Profiles – Urinalysis Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Normal Range 
 
 
 
Cohort 
 
 
Subject 
No. 
 
 
 
Visit 
Sample Date/ 
Time 
 
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 
 
 
 
 
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 
 
 
 
 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
xxxxxxxxxxxxx (xxx) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 64 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 12. Electrocardiogram Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
Cohort 
Subject 
No. 
Visit 
Date 
Time  
Heart  
Rate 
(bpm) 
PR 
Interval 
(msec) 
QRS 
Duration 
(msec) 
QT 
Interval 
(msec) 
QTcF 
Interval 
(msec) 
ECG Assessment/ If 
Abnormal, Specify 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxxxx/ 
xxxxxxxxxxxxxxxxxxx 
 
 
xxxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxxxx/ 
xxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 65 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 13. Physical Exam Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
  
 
 
Cohort 
 
 
Subject 
No. 
 
 
 
 
 
Visit 
 
 
 
 
 
Date 
 
 
 
 
 
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 
 
 
 
 
Heart 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Lungs 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Abdomen 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Lymph Nodes 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
Musculoskeletal 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
CNS/Neurological 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
    
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 66 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 14. Vital Signs Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
   
 
 
 
 
Temperature (ºF) 
Systolic Blood 
Pressure (mmHg) 
Diastolic Blood 
Pressure (mmHg) 
Heart Rate 
(bpm) 
Respirations 
per Minute 
Cohort 
Subject 
No. 
Visit/ 
Date 
Time  
Value 
Normal 
(Y/N) 
Value 
Normal 
(Y/N) 
Value 
Normal 
(Y/N) 
Value 
Normal 
(Y/N) 
Value 
Normal 
(Y/N) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx/ 
xxxxxx 
 
xxxxx 
xxx 
x 
xxx 
x 
xxx 
x 
xxx 
x 
xxx 
x 
 
 
 
xxxxx 
xxx 
x 
xxx 
x 
xxx 
x 
xxx 
x 
xxx 
x 
 
 
 
xxxxx 
xxx 
x 
xxx 
x 
xxx 
x 
xxx 
x 
xxx 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx/ 
xxxxxx 
xxxxx 
xxx 
x 
xxx 
x 
xxx 
x 
xxx 
x 
xxx 
x 
 
 
 
xxxxx 
xxx 
x 
xxx 
x 
xxx 
x 
xxx 
x 
xxx 
x 
 
 
 
xxxxx 
xxx 
x 
xxx 
x 
xxx 
x 
xxx 
x 
xxx 
x 
    
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 67 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 15. Study Drug Administration Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
 
 
                         
 
 
Cohort 
 
 
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) 
 
 
 
Lot  
Number 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxx/ 
xxxx 
xxxxxxxx 
xxx/ 
xxxx 
xxx/ 
xxxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxx/ 
xxxx 
xxxxxxxx 
xxx/ 
xxxx 
xxx/ 
xxxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________________________________________________________
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 68 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 16. Post-Injection Imaging Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
Cohort 
Subject 
No. 
 
Date of 
Imaging   
 
Start 
Time of 
Planar 
Imaging 
 
 
SPECT/CT 
Imaging Start 
Time 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxx 
xx:xx 
xx:xx 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxx 
xx:xx 
xx:xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 69 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
                                                  
 
 
Page x of y 
 
Data Listing 17. Quantitative Imaging Results Data Listing  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
 
 
Cohort 
 
Subject 
No. 
Identified 
Clinically or 
with Imaging? 
 
Lesiona 
Average 
Pixel 
Intensity 
Average 
Background 
Intensity 
Percent Above 
Background 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
xxxx 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxxxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a Lesions previously identified clinically and biopsied. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 70 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
  Page x of y 
Data Listing 18. Qualitative Imaging Results Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
 
 
Cohort 
 
Subject 
No. 
Identified 
Clinically or 
with Imaging? 
 
Lesiona 
Reader  
Visualization 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxxxxx 
xxx 
xxxxxx 
xxxx 
xxxxxxx 
xxxxxxxxxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a Lesions previously identified clinically and those additional lesions identified on imaging. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 71 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 19. Lesion Biopsy Results Data Listing  
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
 
 
 
 
 
 
 
 
 
Cohort 
 
 
Subject 
No. 
Biopsy 
Date/Time 
 
Location of 
Lesiona 
Measurement 
of Biopsy 
(mm) 
HHV8  
RFU 
Proportion 
of CD206-
expressing 
Cells 
Proportion of 
HHV8-
expressing 
Cells 
 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxxx / 
xx:xx 
xxxxxxxxxx 
xxx 
xxxxx 
xxxx 
xxxx 
xxxxxx 
xxxx 
xxxxxxxxxxx / 
xx:xx 
xxxxxxxxxx 
xxx 
xxxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a Lesions previously identified clinically and biopsied. 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 72 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 20. Clinical KS Lesion Assessment Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
Part 1 of 2 
 
 
 
 
 
 
 
 
                         
 
 
Cohorta 
 
 
Subject 
No. 
Assessment 
Date 
KS 
Diagnosis 
Date 
Biopsy 
Confirmation 
Date 
KS 
Classificationb 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxxxxxxxx 
xxxx 
xxxx 
x 
xxxxxx 
xxxx 
xxxxxxxxxx 
xxxx 
xxxx 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
a Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
b 1 = Confirmed cutaneous or oral lesions without edema, 2 = Confirmed cutaneous or oral lesions with edema, 3 = Confirmed cutaneous or 
oral lesions with or without edema and suspected or confirmed non-cutaneous lesions. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 73 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
Page x of y 
Data Listing 20. Clinical KS Lesion Assessment Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
ITD Population (N=xxx) 
Part 2 of 2 
 
 
 
 
 
 
 
 
                         
Suspected 
Non-
Cutaneous 
KS/Location 
Symptomology 
Confirmed 
Non-
Cutaneous 
KS/Location 
Symptomology 
Number 
of 
Overall 
Lesions 
Lesion 
Number 
Lesion 
Type/Location 
Edema Present?/ 
Edema Scale 
 
 
 
 
 
 
xxxx 
x 
xxx 
xx 
xxxx/xxxxx 
xxx/x 
 
 
 
xx 
xxxx/xxxxx 
xxx/x 
 
 
 
xx 
xxxx/xxxxx 
xxx/x 
xxxx 
x 
xxx 
xx 
xxx/xxxx 
xxx/x 
 
 
 
xx 
xxxx/xxxxx 
xxx/x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas 
 
 


Statistical Analysis Plan 
                                                                                                                                           NAV3-24 
 
Page 74 of 74 
STATKING Clinical Services                                                                                                                                        Navidea Biopharmaceuticals 
Version 1.0 
                                                                                                                                                                                         July 23, 2020 
 
 
Page x of y 
 
Data Listing 21. Telephone Follow Up Contact Data Listing 
 
 
Navidea Biopharmaceuticals - Study No. NAV3-24 
 
 
Safety Population (N=xxx) 
 
 
 
 
 
 
 
 
                         
 
 
Cohort 
 
 
Subject 
No. 
 
 
Was Telephone 
Contact 
Performed? 
 
 
 
Date of Contact 
Time of 
Contact 
Any AEs Since 
Previous Visit? 
Changes in Medications 
Since Previous Visit? 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
xxxxxx 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________________________________________________________________________________________________________ 
Cohort 1 = 100µg/5mCi IV; Cohort 2 = 100µg/10mCi IV; Cohort 3 = 200µg/5mCi IV and SC. 
STATKING Clinical Services (DD-MMM-YYYY) 
Source Program: xxxxxxx.sas